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[ { "id": "PMID-12692549__text", "type": "abstract", "text": [ "IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. \nThe transcription factors interferon regulatory factor 3 (IRF3) and NF-kappaB are required for the expression of many genes involved in the innate immune response. Viral infection, or the binding of double-stranded RNA to Toll-like receptor 3, results in the coordinate activation of IRF3 and NF-kappaB. Activation of IRF3 requires signal-dependent phosphorylation, but little is known about the signaling pathway or kinases involved. Here we report that the noncanonical IkappaB kinase homologs, IkappaB kinase-epsilon (IKKepsilon) and TANK-binding kinase-1 (TBK1), which were previously implicated in NF-kappaB activation, are also essential components of the IRF3 signaling pathway. Thus, IKKepsilon and TBK1 have a pivotal role in coordinating the activation of IRF3 and NF-kappaB in the innate immune response.\n" ], "offsets": [ [ 0, 893 ] ] } ]

[ { "id": "PMID-12692549_T1", "type": "Gene_or_gene_product", "text": [ "IKKepsilon" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "PMID-12692549_T2", "type": "Gene_or_gene_product", "text": [ "TBK1" ], "offsets": [ [ 15, 19 ] ], "normalized": [] }, { "id": "PMID-12692549_T3", "type": "Gene_or_gene_product", "text": [ "IRF3" ], "offsets": [ [ 52, 56 ] ], "normalized": [] }, { "id": "PMID-12692549_T4", "type": "Gene_or_gene_product", "text": [ "interferon regulatory factor 3" ], "offsets": [ [ 103, 133 ] ], "normalized": [] }, { "id": "PMID-12692549_T5", "type": "Gene_or_gene_product", "text": [ "IRF3" ], "offsets": [ [ 135, 139 ] ], "normalized": [] }, { "id": "PMID-12692549_T6", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 145, 154 ] ], "normalized": [] }, { "id": "PMID-12692549_T7", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor 3" ], "offsets": [ [ 299, 319 ] ], "normalized": [] }, { "id": "PMID-12692549_T8", "type": "Gene_or_gene_product", "text": [ "IRF3" ], "offsets": [ [ 361, 365 ] ], "normalized": [] }, { "id": "PMID-12692549_T9", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 370, 379 ] ], "normalized": [] }, { "id": "PMID-12692549_T10", "type": "Gene_or_gene_product", "text": [ "IRF3" ], "offsets": [ [ 395, 399 ] ], "normalized": [] }, { "id": "PMID-12692549_T11", "type": "Gene_or_gene_product", "text": [ "IkappaB kinase" ], "offsets": [ [ 549, 563 ] ], "normalized": [] }, { "id": "PMID-12692549_T12", "type": "Gene_or_gene_product", "text": [ "IkappaB kinase-epsilon" ], "offsets": [ [ 574, 596 ] ], "normalized": [] }, { "id": "PMID-12692549_T13", "type": "Gene_or_gene_product", "text": [ "IKKepsilon" ], "offsets": [ [ 598, 608 ] ], "normalized": [] }, { "id": "PMID-12692549_T14", "type": "Gene_or_gene_product", "text": [ "TANK-binding kinase-1" ], "offsets": [ [ 614, 635 ] ], "normalized": [] }, { "id": "PMID-12692549_T15", "type": "Gene_or_gene_product", "text": [ "TBK1" ], "offsets": [ [ 637, 641 ] ], "normalized": [] }, { "id": "PMID-12692549_T16", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 680, 689 ] ], "normalized": [] }, { "id": "PMID-12692549_T17", "type": "Gene_or_gene_product", "text": [ "IRF3" ], "offsets": [ [ 739, 743 ] ], "normalized": [] }, { "id": "PMID-12692549_T18", "type": "Gene_or_gene_product", "text": [ "IKKepsilon" ], "offsets": [ [ 769, 779 ] ], "normalized": [] }, { "id": "PMID-12692549_T19", "type": "Gene_or_gene_product", "text": [ "TBK1" ], "offsets": [ [ 784, 788 ] ], "normalized": [] }, { "id": "PMID-12692549_T20", "type": "Gene_or_gene_product", "text": [ "IRF3" ], "offsets": [ [ 843, 847 ] ], "normalized": [] }, { "id": "PMID-12692549_T21", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 852, 861 ] ], "normalized": [] } ]

[ { "id": "PMID-12692549_E1", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 24, 33 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E3" }, { "role": "Cause", "ref_id": "PMID-12692549_T2" } ] }, { "id": "PMID-12692549_E2", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 24, 33 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E3" }, { "role": "Cause", "ref_id": "PMID-12692549_T1" } ] }, { "id": "PMID-12692549_E3", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 57, 74 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-12692549_T3" } ] }, { "id": "PMID-12692549_E4", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 265, 272 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_T7" } ] }, { "id": "PMID-12692549_E5", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 321, 328 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12692549_E4" }, { "role": "Theme", "ref_id": "PMID-12692549_E7" } ] }, { "id": "PMID-12692549_E6", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 321, 328 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12692549_E4" }, { "role": "Theme", "ref_id": "PMID-12692549_E8" } ] }, { "id": "PMID-12692549_E7", "type": "Regulation", "trigger": { "text": [ "coordinate" ], "offsets": [ [ 336, 346 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E9" } ] }, { "id": "PMID-12692549_E8", "type": "Regulation", "trigger": { "text": [ "coordinate" ], "offsets": [ [ 336, 346 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E10" } ] }, { "id": "PMID-12692549_E9", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 347, 357 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_T8" } ] }, { "id": "PMID-12692549_E10", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 347, 357 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_T9" } ] }, { "id": "PMID-12692549_E11", "type": "Activation", "trigger": { "text": [ "Activation" ], "offsets": [ [ 381, 391 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_T10" } ] }, { "id": "PMID-12692549_E12", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 400, 408 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E11" }, { "role": "Cause", "ref_id": "PMID-12692549_E14" } ] }, { "id": "PMID-12692549_E13", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 416, 425 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E14" } ] }, { "id": "PMID-12692549_E14", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 426, 441 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_T10" } ] }, { "id": "PMID-12692549_E15", "type": "Positive_regulation", "trigger": { "text": [ "implicated" ], "offsets": [ [ 666, 676 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E17" }, { "role": "Cause", "ref_id": "PMID-12692549_T12" } ] }, { "id": "PMID-12692549_E16", "type": "Positive_regulation", "trigger": { "text": [ "implicated" ], "offsets": [ [ 666, 676 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E17" }, { "role": "Cause", "ref_id": "PMID-12692549_T14" } ] }, { "id": "PMID-12692549_E17", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 690, 700 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_T16" } ] }, { "id": "PMID-12692549_E18", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 711, 720 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E20" }, { "role": "Cause", "ref_id": "PMID-12692549_T12" } ] }, { "id": "PMID-12692549_E19", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 711, 720 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E20" }, { "role": "Cause", "ref_id": "PMID-12692549_T14" } ] }, { "id": "PMID-12692549_E20", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 744, 761 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-12692549_T17" } ] }, { "id": "PMID-12692549_E21", "type": "Positive_regulation", "trigger": { "text": [ "have a pivotal role" ], "offsets": [ [ 789, 808 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12692549_T19" }, { "role": "Theme", "ref_id": "PMID-12692549_E25" } ] }, { "id": "PMID-12692549_E22", "type": "Positive_regulation", "trigger": { "text": [ "have a pivotal role" ], "offsets": [ [ 789, 808 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12692549_T18" }, { "role": "Theme", "ref_id": "PMID-12692549_E25" } ] }, { "id": "PMID-12692549_E23", "type": "Positive_regulation", "trigger": { "text": [ "have a pivotal role" ], "offsets": [ [ 789, 808 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12692549_T18" }, { "role": "Theme", "ref_id": "PMID-12692549_E26" } ] }, { "id": "PMID-12692549_E24", "type": "Positive_regulation", "trigger": { "text": [ "have a pivotal role" ], "offsets": [ [ 789, 808 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12692549_T19" }, { "role": "Theme", "ref_id": "PMID-12692549_E26" } ] }, { "id": "PMID-12692549_E25", "type": "Regulation", "trigger": { "text": [ "coordinating" ], "offsets": [ [ 812, 824 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E27" } ] }, { "id": "PMID-12692549_E26", "type": "Regulation", "trigger": { "text": [ "coordinating" ], "offsets": [ [ 812, 824 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_E28" } ] }, { "id": "PMID-12692549_E27", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 829, 839 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_T20" } ] }, { "id": "PMID-12692549_E28", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 829, 839 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12692549_T21" } ] } ]

[ { "id": "PMID-12692549_1", "entity_ids": [ "PMID-12692549_T4", "PMID-12692549_T5" ] }, { "id": "PMID-12692549_2", "entity_ids": [ "PMID-12692549_T12", "PMID-12692549_T13" ] }, { "id": "PMID-12692549_3", "entity_ids": [ "PMID-12692549_T14", "PMID-12692549_T15" ] } ]

[]

[ { "id": "PMID-12705896__text", "type": "abstract", "text": [ "Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system? \nOne of the many functions of liver peroxisomes is the beta-oxidation of long-chain fatty acids. It is essential for the continuation of peroxisomal beta-oxidation that a redox shuttle system exist across the peroxisomal membrane to reoxidize NADH. We propose that this redox shuttle system consists of a substrate cycle between lactate and pyruvate. Here we present evidence that purified peroxisomal membranes contain both monocarboxylate transporter 1 (MCT 1) and MCT 2 and that along with peroxisomal lactate dehydrogenase (pLDH) form a Peroxisomal Lactate Shuttle. Peroxisomal beta-oxidation was greatly stimulated by the addition of pyruvate and this increase was partially inhibited by the addition of the MCT blocker alpha-cyano-4-hydroxycinnamate (CINN). We also found that peroxisomes generated lactate in the presence of pyruvate. Together these data provide compelling that the Peroxisome Lactate Shuttle helps maintain organelle redox and the proper functioning of peroxisomal beta-oxidation.\n" ], "offsets": [ [ 0, 1094 ] ] } ]

[ { "id": "PMID-12705896_T1", "type": "Cellular_component", "text": [ "Peroxisomal membrane" ], "offsets": [ [ 0, 20 ] ], "normalized": [] }, { "id": "PMID-12705896_T2", "type": "Simple_chemical", "text": [ "monocarboxylate" ], "offsets": [ [ 21, 36 ] ], "normalized": [] }, { "id": "PMID-12705896_T3", "type": "Cellular_component", "text": [ "peroxisomes" ], "offsets": [ [ 124, 135 ] ], "normalized": [] }, { "id": "PMID-12705896_T4", "type": "Simple_chemical", "text": [ "long-chain fatty acids" ], "offsets": [ [ 161, 183 ] ], "normalized": [] }, { "id": "PMID-12705896_T5", "type": "Cellular_component", "text": [ "peroxisomal" ], "offsets": [ [ 225, 236 ] ], "normalized": [] }, { "id": "PMID-12705896_T6", "type": "Cellular_component", "text": [ "peroxisomal membrane" ], "offsets": [ [ 297, 317 ] ], "normalized": [] }, { "id": "PMID-12705896_T7", "type": "Simple_chemical", "text": [ "NADH" ], "offsets": [ [ 331, 335 ] ], "normalized": [] }, { "id": "PMID-12705896_T8", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 417, 424 ] ], "normalized": [] }, { "id": "PMID-12705896_T9", "type": "Simple_chemical", "text": [ "pyruvate" ], "offsets": [ [ 429, 437 ] ], "normalized": [] }, { "id": "PMID-12705896_T10", "type": "Cellular_component", "text": [ "peroxisomal membranes" ], "offsets": [ [ 478, 499 ] ], "normalized": [] }, { "id": "PMID-12705896_T11", "type": "Gene_or_gene_product", "text": [ "monocarboxylate transporter 1" ], "offsets": [ [ 513, 542 ] ], "normalized": [] }, { "id": "PMID-12705896_T12", "type": "Gene_or_gene_product", "text": [ "MCT 1" ], "offsets": [ [ 544, 549 ] ], "normalized": [] }, { "id": "PMID-12705896_T13", "type": "Gene_or_gene_product", "text": [ "MCT 2" ], "offsets": [ [ 555, 560 ] ], "normalized": [] }, { "id": "PMID-12705896_T14", "type": "Cellular_component", "text": [ "peroxisomal" ], "offsets": [ [ 581, 592 ] ], "normalized": [] }, { "id": "PMID-12705896_T15", "type": "Gene_or_gene_product", "text": [ "lactate dehydrogenase" ], "offsets": [ [ 593, 614 ] ], "normalized": [] }, { "id": "PMID-12705896_T16", "type": "Gene_or_gene_product", "text": [ "pLDH" ], "offsets": [ [ 616, 620 ] ], "normalized": [] }, { "id": "PMID-12705896_T17", "type": "Cellular_component", "text": [ "Peroxisomal" ], "offsets": [ [ 629, 640 ] ], "normalized": [] }, { "id": "PMID-12705896_T18", "type": "Cellular_component", "text": [ "Peroxisomal" ], "offsets": [ [ 658, 669 ] ], "normalized": [] }, { "id": "PMID-12705896_T19", "type": "Simple_chemical", "text": [ "pyruvate" ], "offsets": [ [ 727, 735 ] ], "normalized": [] }, { "id": "PMID-12705896_T20", "type": "Simple_chemical", "text": [ "alpha-cyano-4-hydroxycinnamate" ], "offsets": [ [ 813, 843 ] ], "normalized": [] }, { "id": "PMID-12705896_T21", "type": "Simple_chemical", "text": [ "CINN" ], "offsets": [ [ 845, 849 ] ], "normalized": [] }, { "id": "PMID-12705896_T22", "type": "Cellular_component", "text": [ "peroxisomes" ], "offsets": [ [ 871, 882 ] ], "normalized": [] }, { "id": "PMID-12705896_T23", "type": "Simple_chemical", "text": [ "lactate" ], "offsets": [ [ 893, 900 ] ], "normalized": [] }, { "id": "PMID-12705896_T24", "type": "Simple_chemical", "text": [ "pyruvate" ], "offsets": [ [ 920, 928 ] ], "normalized": [] }, { "id": "PMID-12705896_T25", "type": "Cellular_component", "text": [ "peroxisomal" ], "offsets": [ [ 1066, 1077 ] ], "normalized": [] } ]

[ { "id": "PMID-12705896_E1", "type": "Transport", "trigger": { "text": [ "transporters" ], "offsets": [ [ 37, 49 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12705896_T2" }, { "role": "FromLoc", "ref_id": "PMID-12705896_T1" }, { "role": "ToLoc", "ref_id": "PMID-12705896_T1" } ] }, { "id": "PMID-12705896_E2", "type": "Pathway", "trigger": { "text": [ "cycle" ], "offsets": [ [ 403, 408 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-12705896_T8" }, { "role": "Participant", "ref_id": "PMID-12705896_T9" } ] }, { "id": "PMID-12705896_E3", "type": "Conversion", "trigger": { "text": [ "generated" ], "offsets": [ [ 883, 892 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-12705896_T23" } ] }, { "id": "PMID-12705896_E4", "type": "Positive_regulation", "trigger": { "text": [ "generated" ], "offsets": [ [ 883, 892 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12705896_E3" }, { "role": "Cause", "ref_id": "PMID-12705896_T22" } ] } ]

[ { "id": "PMID-12705896_1", "entity_ids": [ "PMID-12705896_T11", "PMID-12705896_T12" ] }, { "id": "PMID-12705896_2", "entity_ids": [ "PMID-12705896_T15", "PMID-12705896_T16" ] }, { "id": "PMID-12705896_3", "entity_ids": [ "PMID-12705896_T20", "PMID-12705896_T21" ] } ]

[]

[ { "id": "PMID-12743037__text", "type": "abstract", "text": [ "Osmostress-induced transcription by Hot1 depends on a Hog1-mediated recruitment of the RNA Pol II. \nIn budding yeast, the mitogen-activated protein kinase (MAPK) Hog1 coordinates the transcriptional program required for cell survival upon osmostress. The Hot1 transcription factor acts downstream of the MAPK and regulates a subset of Hog1-responsive genes. In response to high osmolarity, Hot1 targets Hog1 to specific osmostress-responsive promoters. Here, we show that assembly of the general transcription machinery at Hot1-dependent promoters depends on the presence of Hot1 and active Hog1 MAPK. Unexpectedly, recruitment of RNA polymerase (Pol) II complex to target promoters does not depend on the phosphorylation of the Hot1 activator by the MAPK. Hog1 interacts with the RNA Pol II and with general components of the transcription machinery. More over, when tethered to a promoter as a LexA fusion protein, Hog1 activates transcription in a stress- regulated manner. Thus, anchoring of active Hog1 to promoters by the Hot1 activator is essential for recruitment and activation of RNA Pol II. The mammalian p38 also interacts with the RNA Pol II, which might suggest a conserved mechanism for regulation of gene expression by SAPKs among eukaryotic cells.\n" ], "offsets": [ [ 0, 1265 ] ] } ]

[ { "id": "PMID-12743037_T1", "type": "Gene_or_gene_product", "text": [ "Hot1" ], "offsets": [ [ 36, 40 ] ], "normalized": [] }, { "id": "PMID-12743037_T2", "type": "Gene_or_gene_product", "text": [ "Hog1" ], "offsets": [ [ 54, 58 ] ], "normalized": [] }, { "id": "PMID-12743037_T3", "type": "Complex", "text": [ "RNA Pol II" ], "offsets": [ [ 87, 97 ] ], "normalized": [] }, { "id": "PMID-12743037_T4", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein kinase" ], "offsets": [ [ 122, 154 ] ], "normalized": [] }, { "id": "PMID-12743037_T5", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 156, 160 ] ], "normalized": [] }, { "id": "PMID-12743037_T6", "type": "Gene_or_gene_product", "text": [ "Hog1" ], "offsets": [ [ 162, 166 ] ], "normalized": [] }, { "id": "PMID-12743037_T7", "type": "Gene_or_gene_product", "text": [ "Hot1" ], "offsets": [ [ 255, 259 ] ], "normalized": [] }, { "id": "PMID-12743037_T8", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 304, 308 ] ], "normalized": [] }, { "id": "PMID-12743037_T9", "type": "Gene_or_gene_product", "text": [ "Hog1" ], "offsets": [ [ 335, 339 ] ], "normalized": [] }, { "id": "PMID-12743037_T10", "type": "Gene_or_gene_product", "text": [ "Hot1" ], "offsets": [ [ 390, 394 ] ], "normalized": [] }, { "id": "PMID-12743037_T11", "type": "Gene_or_gene_product", "text": [ "Hog1" ], "offsets": [ [ 403, 407 ] ], "normalized": [] }, { "id": "PMID-12743037_T12", "type": "Gene_or_gene_product", "text": [ "Hot1" ], "offsets": [ [ 523, 527 ] ], "normalized": [] }, { "id": "PMID-12743037_T13", "type": "Gene_or_gene_product", "text": [ "Hot1" ], "offsets": [ [ 575, 579 ] ], "normalized": [] }, { "id": "PMID-12743037_T14", "type": "Gene_or_gene_product", "text": [ "Hog1 MAPK" ], "offsets": [ [ 591, 600 ] ], "normalized": [] }, { "id": "PMID-12743037_T15", "type": "Complex", "text": [ "RNA polymerase (Pol) II" ], "offsets": [ [ 631, 654 ] ], "normalized": [] }, { "id": "PMID-12743037_T16", "type": "Gene_or_gene_product", "text": [ "Hot1" ], "offsets": [ [ 729, 733 ] ], "normalized": [] }, { "id": "PMID-12743037_T17", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 751, 755 ] ], "normalized": [] }, { "id": "PMID-12743037_T18", "type": "Gene_or_gene_product", "text": [ "Hog1" ], "offsets": [ [ 757, 761 ] ], "normalized": [] }, { "id": "PMID-12743037_T19", "type": "Complex", "text": [ "RNA Pol II" ], "offsets": [ [ 781, 791 ] ], "normalized": [] }, { "id": "PMID-12743037_T20", "type": "Gene_or_gene_product", "text": [ "LexA" ], "offsets": [ [ 896, 900 ] ], "normalized": [] }, { "id": "PMID-12743037_T21", "type": "Gene_or_gene_product", "text": [ "Hog1" ], "offsets": [ [ 917, 921 ] ], "normalized": [] }, { "id": "PMID-12743037_T22", "type": "Gene_or_gene_product", "text": [ "Hog1" ], "offsets": [ [ 1003, 1007 ] ], "normalized": [] }, { "id": "PMID-12743037_T23", "type": "Gene_or_gene_product", "text": [ "Hot1" ], "offsets": [ [ 1028, 1032 ] ], "normalized": [] }, { "id": "PMID-12743037_T24", "type": "Complex", "text": [ "RNA Pol II" ], "offsets": [ [ 1090, 1100 ] ], "normalized": [] }, { "id": "PMID-12743037_T25", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1116, 1119 ] ], "normalized": [] }, { "id": "PMID-12743037_T26", "type": "Complex", "text": [ "RNA Pol II" ], "offsets": [ [ 1144, 1154 ] ], "normalized": [] }, { "id": "PMID-12743037_T27", "type": "Gene_or_gene_product", "text": [ "SAPKs" ], "offsets": [ [ 1235, 1240 ] ], "normalized": [] } ]

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[ { "id": "PMID-12743037_1", "entity_ids": [ "PMID-12743037_T4", "PMID-12743037_T5" ] } ]

[]

[ { "id": "PMID-12750288__text", "type": "abstract", "text": [ "p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells. \nThe negative-regulatory feedback loop between p53 and hdm2 forms part of a finely balanced regulatory network of proteins that controls cell cycle progression and commitment to apoptosis. Expression of hdm2, and its mouse orthologue mdm2, is known to be induced by p53, but recent evidence has demonstrated mdm2 expression can also be regulated via p53-independent pathways. However the p53 independent mechanisms that control transcription of the human hdm2 gene have not been studied. Differential levels of hdm2 mRNA and protein expression have been reported in several types of human malignancy, including breast cancers in which hdm2 expression correlates with positive estrogen receptor alpha (ERalpha) status. Experimental models have demonstrated that hdm2 overexpression can promote breast cancer development. Here, we show that the elevated level of hdm2 protein in ERalpha(+ve) breast cancer cell lines such as MCF-7 and T47D is because of transcription from the p53-inducible P2 promoter of hdm2. The P2 promoter is inactive in ERalpha(-ve) cell lines such as SKBr3. Hdm2-P2 promoter activity in T47D cells is independent of p53, as well as of known regulators of the mouse mdm2-P2 promoter, including ERalpha and ras-raf-mitogen-activated protein/extracellular signal-regulated kinase (MEK) mitogen-activated protein kinase (MAPK) signaling. We show that hdm2-P2 activity in T47D cells is dependent on the integrity of both an evolutionarily conserved composite binding site for AP1 and ETS family transcription factors (AP1-ETS) and a nonconserved upstream (nnGGGGC)(5) repeat sequence. Lack of hdm2-P2 activity in ERalpha(-ve) cells is shown to be a consequence of reduced transcriptional activation through the AP1-ETS element. Overexpression of ETS2 in SKBr3 cells reconstitutes AP1-ETS element-dependent hdm2-P2 promoter activity, resulting in increased levels of hdm2 protein in the cells. Our findings support the hypothesis that the elevated levels of hdm2 expression reported in cancers such as ERalpha(+ve) breast tumors play an important role in the development of these tumors.\n" ], "offsets": [ [ 0, 2304 ] ] } ]

[ { "id": "PMID-12750288_T1", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-12750288_T2", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 34, 38 ] ], "normalized": [] }, { "id": "PMID-12750288_T3", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 127, 131 ] ], "normalized": [] }, { "id": "PMID-12750288_T4", "type": "Gene_or_gene_product", "text": [ "estrogen receptor alpha" ], "offsets": [ [ 146, 169 ] ], "normalized": [] }, { "id": "PMID-12750288_T5", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 247, 250 ] ], "normalized": [] }, { "id": "PMID-12750288_T6", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 255, 259 ] ], "normalized": [] }, { "id": "PMID-12750288_T7", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 403, 407 ] ], "normalized": [] }, { "id": "PMID-12750288_T8", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 434, 438 ] ], "normalized": [] }, { "id": "PMID-12750288_T9", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 466, 469 ] ], "normalized": [] }, { "id": "PMID-12750288_T10", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 508, 512 ] ], "normalized": [] }, { "id": "PMID-12750288_T11", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 550, 553 ] ], "normalized": [] }, { "id": "PMID-12750288_T12", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 588, 591 ] ], "normalized": [] }, { "id": "PMID-12750288_T13", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 655, 659 ] ], "normalized": [] }, { "id": "PMID-12750288_T14", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 711, 715 ] ], "normalized": [] }, { "id": "PMID-12750288_T15", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 835, 839 ] ], "normalized": [] }, { "id": "PMID-12750288_T16", "type": "Gene_or_gene_product", "text": [ "estrogen receptor alpha" ], "offsets": [ [ 876, 899 ] ], "normalized": [] }, { "id": "PMID-12750288_T17", "type": "Gene_or_gene_product", "text": [ "ERalpha" ], "offsets": [ [ 901, 908 ] ], "normalized": [] }, { "id": "PMID-12750288_T18", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 961, 965 ] ], "normalized": [] }, { "id": "PMID-12750288_T19", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 1061, 1065 ] ], "normalized": [] }, { "id": "PMID-12750288_T20", "type": "Gene_or_gene_product", "text": [ "ERalpha" ], "offsets": [ [ 1077, 1084 ] ], "normalized": [] }, { "id": "PMID-12750288_T21", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1175, 1178 ] ], "normalized": [] }, { "id": "PMID-12750288_T22", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 1204, 1208 ] ], "normalized": [] }, { "id": "PMID-12750288_T23", "type": "Gene_or_gene_product", "text": [ "ERalpha" ], "offsets": [ [ 1241, 1248 ] ], "normalized": [] }, { "id": "PMID-12750288_T24", "type": "Gene_or_gene_product", "text": [ "Hdm2" ], "offsets": [ [ 1280, 1284 ] ], "normalized": [] }, { "id": "PMID-12750288_T25", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1338, 1341 ] ], "normalized": [] }, { "id": "PMID-12750288_T26", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 1387, 1391 ] ], "normalized": [] }, { "id": "PMID-12750288_T27", "type": "Gene_or_gene_product", "text": [ "ERalpha" ], "offsets": [ [ 1415, 1422 ] ], "normalized": [] }, { "id": "PMID-12750288_T28", "type": "Gene_or_gene_product", "text": [ "ras" ], "offsets": [ [ 1427, 1430 ] ], "normalized": [] }, { "id": "PMID-12750288_T29", "type": "Gene_or_gene_product", "text": [ "raf" ], "offsets": [ [ 1431, 1434 ] ], "normalized": [] }, { "id": "PMID-12750288_T30", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein/extracellular signal-regulated kinase" ], "offsets": [ [ 1435, 1498 ] ], "normalized": [] }, { "id": "PMID-12750288_T31", "type": "Gene_or_gene_product", "text": [ "MEK" ], "offsets": [ [ 1500, 1503 ] ], "normalized": [] }, { "id": "PMID-12750288_T32", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein kinase" ], "offsets": [ [ 1505, 1537 ] ], "normalized": [] }, { "id": "PMID-12750288_T33", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1539, 1543 ] ], "normalized": [] }, { "id": "PMID-12750288_T34", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 1569, 1573 ] ], "normalized": [] }, { "id": "PMID-12750288_T35", "type": "Gene_or_gene_product", "text": [ "AP1" ], "offsets": [ [ 1693, 1696 ] ], "normalized": [] }, { "id": "PMID-12750288_T36", "type": "Gene_or_gene_product", "text": [ "ETS" ], "offsets": [ [ 1701, 1704 ] ], "normalized": [] }, { "id": "PMID-12750288_T37", "type": "Gene_or_gene_product", "text": [ "AP1" ], "offsets": [ [ 1735, 1738 ] ], "normalized": [] }, { "id": "PMID-12750288_T38", "type": "Gene_or_gene_product", "text": [ "ETS" ], "offsets": [ [ 1739, 1742 ] ], "normalized": [] }, { "id": "PMID-12750288_T39", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 1810, 1814 ] ], "normalized": [] }, { "id": "PMID-12750288_T40", "type": "Gene_or_gene_product", "text": [ "ERalpha" ], "offsets": [ [ 1830, 1837 ] ], "normalized": [] }, { "id": "PMID-12750288_T41", "type": "Gene_or_gene_product", "text": [ "AP1" ], "offsets": [ [ 1928, 1931 ] ], "normalized": [] }, { "id": "PMID-12750288_T42", "type": "Gene_or_gene_product", "text": [ "ETS" ], "offsets": [ [ 1932, 1935 ] ], "normalized": [] }, { "id": "PMID-12750288_T43", "type": "Gene_or_gene_product", "text": [ "ETS2" ], "offsets": [ [ 1963, 1967 ] ], "normalized": [] }, { "id": "PMID-12750288_T44", "type": "Gene_or_gene_product", "text": [ "AP1" ], "offsets": [ [ 1997, 2000 ] ], "normalized": [] }, { "id": "PMID-12750288_T45", "type": "Gene_or_gene_product", "text": [ "ETS" ], "offsets": [ [ 2001, 2004 ] ], "normalized": [] }, { "id": "PMID-12750288_T46", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 2023, 2027 ] ], "normalized": [] }, { "id": "PMID-12750288_T47", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 2083, 2087 ] ], "normalized": [] }, { "id": "PMID-12750288_T48", "type": "Gene_or_gene_product", "text": [ "hdm2" ], "offsets": [ [ 2174, 2178 ] ], "normalized": [] }, { "id": "PMID-12750288_T49", "type": "Gene_or_gene_product", "text": [ "ERalpha" ], "offsets": [ [ 2218, 2225 ] ], "normalized": [] } ]

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"arguments": [ { "role": "Theme", "ref_id": "PMID-12750288_T3" } ] }, { "id": "PMID-12750288_E6", "type": "Negative_regulation", "trigger": { "text": [ "negative-regulatory" ], "offsets": [ [ 205, 224 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12750288_T5" }, { "role": "Theme", "ref_id": "PMID-12750288_E9" } ] }, { "id": "PMID-12750288_E7", "type": "Negative_regulation", "trigger": { "text": [ "negative-regulatory" ], "offsets": [ [ 205, 224 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12750288_T6" }, { "role": "Theme", "ref_id": "PMID-12750288_E8" } ] }, { "id": "PMID-12750288_E8", "type": "Regulation", "trigger": { "text": [ "regulatory" ], "offsets": [ [ 292, 302 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12750288_E11" } ] }, { "id": "PMID-12750288_E9", "type": "Regulation", "trigger": { "text": [ "regulatory" ], "offsets": [ [ 292, 302 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12750288_E10" } ] }, { "id": "PMID-12750288_E10", 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[]

[ { "id": "PMID-12755454__text", "type": "abstract", "text": [ "Molecular mechanisms and regulation of iron transport. \nIron homeostasis is primarily maintained through regulation of its transport. This review summarizes recent discoveries in the field of iron transport that have shed light on the molecular mechanisms of dietary iron uptake, pathways for iron efflux to and between peripheral tissues, proteins implicated in organellar transport of iron (particularly the mitochondrion), and novel regulators that have been proposed to control iron assimilation. The transport of both transferrin-bound and nontransferrin-bound iron to peripheral tissues is discussed. Finally, the regulation of iron transport is also considered at the molecular level, with posttranscriptional, transcriptional, and posttranslational control mechanisms being reviewed.\n" ], "offsets": [ [ 0, 792 ] ] } ]

[ { "id": "PMID-12755454_T1", "type": "Simple_chemical", "text": [ "iron" ], "offsets": [ [ 39, 43 ] ], "normalized": [] }, { "id": "PMID-12755454_T2", "type": "Simple_chemical", "text": [ "Iron" ], "offsets": [ [ 56, 60 ] ], "normalized": [] }, { "id": "PMID-12755454_T3", "type": "Simple_chemical", "text": [ "iron" ], "offsets": [ [ 192, 196 ] ], "normalized": [] }, { "id": "PMID-12755454_T4", "type": "Simple_chemical", "text": [ "iron" ], "offsets": [ [ 267, 271 ] ], "normalized": [] }, { "id": "PMID-12755454_T5", "type": "Simple_chemical", "text": [ "iron" ], "offsets": [ [ 293, 297 ] ], "normalized": [] }, { "id": "PMID-12755454_T6", "type": "Cellular_component", "text": [ "organellar" ], "offsets": [ [ 363, 373 ] ], "normalized": [] }, { "id": "PMID-12755454_T7", "type": "Simple_chemical", "text": [ "iron" ], "offsets": [ [ 387, 391 ] ], "normalized": [] }, { "id": "PMID-12755454_T8", "type": "Cellular_component", "text": [ "mitochondrion" ], "offsets": [ [ 410, 423 ] ], "normalized": [] }, { "id": "PMID-12755454_T9", "type": "Simple_chemical", "text": [ "iron" ], "offsets": [ [ 482, 486 ] ], "normalized": [] }, { "id": "PMID-12755454_T10", "type": "Gene_or_gene_product", "text": [ "transferrin" ], "offsets": [ [ 523, 534 ] ], "normalized": [] }, { "id": "PMID-12755454_T11", "type": "Gene_or_gene_product", "text": [ "transferrin" ], "offsets": [ [ 548, 559 ] ], "normalized": [] }, { "id": "PMID-12755454_T12", "type": "Simple_chemical", "text": [ "iron" ], "offsets": [ [ 566, 570 ] ], "normalized": [] }, { "id": "PMID-12755454_T13", "type": "Simple_chemical", "text": [ "iron" ], "offsets": [ [ 634, 638 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-12770767__text", "type": "abstract", "text": [ "The role of glucosidase II and endomannosidase in glucose trimming of asparagine-linked oligosaccharides. \nThis review covers various aspects of glucose trimming reactions occurring on asparagine-linked oligosaccharides. Structural and functional features of two enzymes, glucosidase II and endo-alpha-mannosidase, prominently involved in this process are summarized and their striking differences in terms of substrate specificities are highlighted. Recent results of analyses by immunoelectron microscopy of their distribution pattern are presented which demonstrate that glucose trimming is not restricted to the endoplasmic reticulum (ER) but additionally is a function accommodated by the Golgi apparatus. The mutually exclusive subcellular distribution of glucosidase II and endomannosidase are discussed in terms of their significance for quality control of protein folding and N-glycosylation.\n" ], "offsets": [ [ 0, 902 ] ] } ]

[ { "id": "PMID-12770767_T1", "type": "Gene_or_gene_product", "text": [ "glucosidase II" ], "offsets": [ [ 12, 26 ] ], "normalized": [] }, { "id": "PMID-12770767_T2", "type": "Gene_or_gene_product", "text": [ "endomannosidase" ], "offsets": [ [ 31, 46 ] ], "normalized": [] }, { "id": "PMID-12770767_T3", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 50, 57 ] ], "normalized": [] }, { "id": "PMID-12770767_T4", "type": "Simple_chemical", "text": [ "asparagine" ], "offsets": [ [ 70, 80 ] ], "normalized": [] }, { "id": "PMID-12770767_T5", "type": "Simple_chemical", "text": [ "oligosaccharides" ], "offsets": [ [ 88, 104 ] ], "normalized": [] }, { "id": "PMID-12770767_T6", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 145, 152 ] ], "normalized": [] }, { "id": "PMID-12770767_T7", "type": "Simple_chemical", "text": [ "asparagine" ], "offsets": [ [ 185, 195 ] ], "normalized": [] }, { "id": "PMID-12770767_T8", "type": "Simple_chemical", "text": [ "oligosaccharides" ], "offsets": [ [ 203, 219 ] ], "normalized": [] }, { "id": "PMID-12770767_T9", "type": "Gene_or_gene_product", "text": [ "glucosidase II" ], "offsets": [ [ 272, 286 ] ], "normalized": [] }, { "id": "PMID-12770767_T10", "type": "Gene_or_gene_product", "text": [ "endo-alpha-mannosidase" ], "offsets": [ [ 291, 313 ] ], "normalized": [] }, { "id": "PMID-12770767_T11", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 574, 581 ] ], "normalized": [] }, { "id": "PMID-12770767_T12", "type": "Cellular_component", "text": [ "endoplasmic reticulum" ], "offsets": [ [ 616, 637 ] ], "normalized": [] }, { "id": "PMID-12770767_T13", "type": "Cellular_component", "text": [ "ER" ], "offsets": [ [ 639, 641 ] ], "normalized": [] }, { "id": "PMID-12770767_T14", "type": "Cellular_component", "text": [ "Golgi apparatus" ], "offsets": [ [ 694, 709 ] ], "normalized": [] }, { "id": "PMID-12770767_T15", "type": "Cellular_component", "text": [ "subcellular" ], "offsets": [ [ 734, 745 ] ], "normalized": [] }, { "id": "PMID-12770767_T16", "type": "Gene_or_gene_product", "text": [ "glucosidase II" ], "offsets": [ [ 762, 776 ] ], "normalized": [] }, { "id": "PMID-12770767_T17", "type": "Gene_or_gene_product", "text": [ "endomannosidase" ], "offsets": [ [ 781, 796 ] ], "normalized": [] } ]

[ { "id": "PMID-12770767_E1", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 4, 8 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12770767_E3" }, { "role": "Cause", "ref_id": "PMID-12770767_T1" } ] }, { "id": "PMID-12770767_E2", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 4, 8 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12770767_E3" }, { "role": "Cause", "ref_id": "PMID-12770767_T2" } ] }, { "id": "PMID-12770767_E3", "type": "Dissociation", "trigger": { "text": [ "trimming" ], "offsets": [ [ 58, 66 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-12770767_T3" } ] }, { "id": "PMID-12770767_E4", "type": "Binding", "trigger": { "text": [ "linked" ], "offsets": [ [ 81, 87 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12770767_T4" }, { "role": "Theme", "ref_id": "PMID-12770767_T5" } ] }, { "id": "PMID-12770767_E5", "type": "Dissociation", "trigger": { "text": [ "trimming" ], "offsets": [ [ 153, 161 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-12770767_T6" } ] }, { "id": "PMID-12770767_E6", "type": "Binding", "trigger": { "text": [ "linked" ], "offsets": [ [ 196, 202 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12770767_T7" }, { "role": "Theme", "ref_id": "PMID-12770767_T8" } ] }, { "id": "PMID-12770767_E7", "type": "Dissociation", "trigger": { "text": [ "trimming" ], "offsets": [ [ 582, 590 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-12770767_T11" } ] }, { "id": "PMID-12770767_E8", "type": "Localization", "trigger": { "text": [ "restricted" ], "offsets": [ [ 598, 608 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12770767_T11" }, { "role": "AtLoc", "ref_id": "PMID-12770767_T13" } ] }, { "id": "PMID-12770767_E9", "type": "Localization", "trigger": { "text": [ "restricted" ], "offsets": [ [ 598, 608 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12770767_T11" }, { "role": "AtLoc", "ref_id": "PMID-12770767_T14" } ] }, { "id": "PMID-12770767_E10", "type": "Localization", "trigger": { "text": [ "distribution" ], "offsets": [ [ 746, 758 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-12770767_T15" }, { "role": "Theme", "ref_id": "PMID-12770767_T16" } ] }, { "id": "PMID-12770767_E11", "type": "Localization", "trigger": { "text": [ "distribution" ], "offsets": [ [ 746, 758 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-12770767_T15" }, { "role": "Theme", "ref_id": "PMID-12770767_T17" } ] } ]

[ { "id": "PMID-12770767_1", "entity_ids": [ "PMID-12770767_T12", "PMID-12770767_T13" ] } ]

[]

[ { "id": "PMID-12803540__text", "type": "abstract", "text": [ "Genomic identification and biochemical characterization of a second spermidine/spermine N1-acetyltransferase. \nIn the polyamine back-conversion pathway, spermine and spermidine are first acetylated by spermidine/spermine N(1) -acetyl-transferase (SSAT-1) and then oxidized by polyamine oxidase to produce spermidine and putrescine respectively. Herein we apply homology-search methods to identify novel sequences belonging to a second SSAT, SSAT-2, with a chromosomal location at 17p13.1, which is distinct from SSAT-1 at Xp22. Human SSAT-2 cDNA derived from small-cell lung carcinoma was deduced to encode a 170-amino-acid protein having 46% sequence identity and 64% sequence similarity with SSAT-1. When transiently transfected into HEK-293 cells, SSAT-1 decreased spermidine and spermine pools by approximately 30%, while, at the same time, significantly increasing putrescine, N (1)-acetylspermidine, N (1)-acetylspermine and N (1), N (12)-diacetylspermine pools. By contrast, transfected SSAT-2 had no effect on intracellular polyamine or acetylated polyamine pools. When enzyme activity was assayed on enzyme extracts from transfected cells, both SSAT-1 and SSAT-2 demonstrated much higher acetylating activity than vector-transfected cells. The data suggest that, in intact cells, SSAT-2 may be compartmentalized or it may be inefficient at low intracellular polyamine concentrations. By substituting candidate substrates in the enzyme assay, we determined that SSAT-1 shows the substrate preference norspermidine=spermidine>spermine> N (1)-acetylspermine>putrescine, whereas SSAT-2 shows the preference norspermidine>spermidine=spermine> N (1)-acetylspermine=putrescine. Analysis of mRNA levels in cell lines and ESTs (expressed sequence tags) from various tissues by digiNorthern (a web-based tool for virtually displaying expression profiles of query genes based on EST sequences) indicated that SSAT-1 tends to be more widely and highly expressed than SSAT-2. While SSAT-1 mRNA was inducible by polyamine analogues in a variety of cell lines, SSAT-2 was not. The existence of an active, but possibly sequestered, SSAT-2 enzyme suggests that, under certain conditions, it may be recruited into basal or perturbed polyamine metabolism.\n" ], "offsets": [ [ 0, 2246 ] ] } ]

[ { "id": "PMID-12803540_T1", "type": "Gene_or_gene_product", "text": [ "spermidine/spermine N1-acetyltransferase" ], "offsets": [ [ 68, 108 ] ], "normalized": [] }, { "id": "PMID-12803540_T2", "type": "Simple_chemical", "text": [ "polyamine" ], "offsets": [ [ 118, 127 ] ], "normalized": [] }, { "id": "PMID-12803540_T3", "type": "Simple_chemical", "text": [ "spermine" ], "offsets": [ [ 153, 161 ] ], "normalized": [] }, { "id": "PMID-12803540_T4", "type": "Simple_chemical", "text": [ "spermidine" ], "offsets": [ [ 166, 176 ] ], "normalized": [] }, { "id": "PMID-12803540_T5", "type": "Gene_or_gene_product", "text": [ "spermidine/spermine N(1) -acetyl-transferase" ], "offsets": [ [ 201, 245 ] ], "normalized": [] }, { "id": "PMID-12803540_T6", "type": "Gene_or_gene_product", "text": [ "SSAT-1" ], "offsets": [ [ 247, 253 ] ], "normalized": [] }, { "id": "PMID-12803540_T7", "type": "Gene_or_gene_product", "text": [ "polyamine oxidase" ], "offsets": [ [ 276, 293 ] ], "normalized": [] }, { "id": "PMID-12803540_T8", "type": "Simple_chemical", "text": [ "spermidine" ], "offsets": [ [ 305, 315 ] ], "normalized": [] }, { "id": "PMID-12803540_T9", "type": "Simple_chemical", "text": [ "putrescine" ], "offsets": [ [ 320, 330 ] ], "normalized": [] }, { "id": "PMID-12803540_T10", "type": "Gene_or_gene_product", "text": [ "SSAT" ], "offsets": [ [ 435, 439 ] ], "normalized": [] }, { "id": "PMID-12803540_T11", "type": "Gene_or_gene_product", "text": [ "SSAT-2" ], "offsets": [ [ 441, 447 ] ], "normalized": [] }, { "id": "PMID-12803540_T12", "type": "Cellular_component", "text": [ "chromosomal" ], "offsets": [ [ 456, 467 ] ], "normalized": [] }, { "id": "PMID-12803540_T13", "type": "Gene_or_gene_product", "text": [ "SSAT-1" ], "offsets": [ [ 512, 518 ] ], "normalized": [] }, { "id": "PMID-12803540_T14", "type": "Gene_or_gene_product", "text": [ "SSAT-2" ], "offsets": [ [ 534, 540 ] ], "normalized": [] }, { "id": "PMID-12803540_T15", "type": "Gene_or_gene_product", "text": [ "SSAT-1" ], "offsets": [ [ 694, 700 ] ], "normalized": [] }, { "id": "PMID-12803540_T16", "type": "Gene_or_gene_product", "text": [ "SSAT-1" ], "offsets": [ [ 751, 757 ] ], "normalized": [] }, { "id": "PMID-12803540_T17", "type": "Simple_chemical", "text": [ "spermidine" ], "offsets": [ [ 768, 778 ] ], "normalized": [] }, { "id": "PMID-12803540_T18", "type": "Simple_chemical", "text": [ "spermine" ], "offsets": [ [ 783, 791 ] ], "normalized": [] }, { "id": "PMID-12803540_T19", "type": "Simple_chemical", "text": [ "putrescine" ], "offsets": [ [ 870, 880 ] ], "normalized": [] }, { "id": "PMID-12803540_T20", "type": "Simple_chemical", "text": [ "N (1)-acetylspermidine" ], "offsets": [ [ 882, 904 ] ], "normalized": [] }, { "id": "PMID-12803540_T21", "type": "Simple_chemical", "text": [ "N (1)-acetylspermine" ], "offsets": [ [ 906, 926 ] ], "normalized": [] }, { "id": "PMID-12803540_T22", "type": "Simple_chemical", "text": [ "N (1), N (12)-diacetylspermine" ], "offsets": [ [ 931, 961 ] ], "normalized": [] }, { "id": "PMID-12803540_T23", "type": "Gene_or_gene_product", "text": [ "SSAT-2" ], "offsets": [ [ 994, 1000 ] ], "normalized": [] }, { "id": "PMID-12803540_T24", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 1018, 1031 ] ], "normalized": [] }, { "id": "PMID-12803540_T25", "type": "Simple_chemical", "text": [ "polyamine" ], "offsets": [ [ 1032, 1041 ] ], "normalized": [] }, { "id": "PMID-12803540_T26", "type": "Simple_chemical", "text": [ "polyamine" ], "offsets": [ [ 1056, 1065 ] ], "normalized": [] }, { "id": "PMID-12803540_T27", "type": "Gene_or_gene_product", "text": [ "SSAT-1" ], "offsets": [ [ 1154, 1160 ] ], "normalized": [] }, { "id": "PMID-12803540_T28", "type": "Gene_or_gene_product", "text": [ "SSAT-2" ], "offsets": [ [ 1165, 1171 ] ], "normalized": [] }, { "id": "PMID-12803540_T29", "type": "Gene_or_gene_product", "text": [ "SSAT-2" ], "offsets": [ [ 1289, 1295 ] ], "normalized": [] }, { "id": "PMID-12803540_T30", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 1353, 1366 ] ], "normalized": [] }, { "id": "PMID-12803540_T31", "type": "Simple_chemical", "text": [ "polyamine" ], "offsets": [ [ 1367, 1376 ] ], "normalized": [] }, { "id": "PMID-12803540_T32", "type": "Gene_or_gene_product", "text": [ "SSAT-1" ], "offsets": [ [ 1470, 1476 ] ], "normalized": [] }, { "id": "PMID-12803540_T33", "type": "Simple_chemical", "text": [ "norspermidine" ], "offsets": [ [ 1508, 1521 ] ], "normalized": [] }, { "id": "PMID-12803540_T34", "type": "Simple_chemical", "text": [ "spermidine" ], "offsets": [ [ 1522, 1532 ] ], "normalized": [] }, { "id": "PMID-12803540_T35", "type": "Simple_chemical", "text": [ "spermine" ], "offsets": [ [ 1533, 1541 ] ], "normalized": [] }, { "id": "PMID-12803540_T36", "type": "Simple_chemical", "text": [ "N (1)-acetylspermine" ], "offsets": [ [ 1543, 1563 ] ], "normalized": [] }, { "id": "PMID-12803540_T37", "type": "Simple_chemical", "text": [ "putrescine" ], "offsets": [ [ 1564, 1574 ] ], "normalized": [] }, { "id": "PMID-12803540_T38", "type": "Gene_or_gene_product", "text": [ "SSAT-2" ], "offsets": [ [ 1584, 1590 ] ], "normalized": [] }, { "id": "PMID-12803540_T39", "type": "Simple_chemical", "text": [ "norspermidine" ], "offsets": [ [ 1612, 1625 ] ], "normalized": [] }, { "id": "PMID-12803540_T40", "type": "Simple_chemical", "text": [ "spermidine" ], "offsets": [ [ 1626, 1636 ] ], "normalized": [] }, { "id": "PMID-12803540_T41", "type": "Simple_chemical", "text": [ "spermine" ], "offsets": [ [ 1637, 1645 ] ], "normalized": [] }, { "id": "PMID-12803540_T42", "type": "Simple_chemical", "text": [ "N (1)-acetylspermine" ], "offsets": [ [ 1647, 1667 ] ], "normalized": [] }, { "id": "PMID-12803540_T43", "type": "Simple_chemical", "text": [ "putrescine" ], "offsets": [ [ 1668, 1678 ] ], "normalized": [] }, { "id": "PMID-12803540_T44", "type": "Gene_or_gene_product", "text": [ "SSAT-1" ], "offsets": [ [ 1907, 1913 ] ], "normalized": [] }, { "id": "PMID-12803540_T45", "type": "Gene_or_gene_product", "text": [ "SSAT-2" ], "offsets": [ [ 1964, 1970 ] ], "normalized": [] }, { "id": "PMID-12803540_T46", "type": "Gene_or_gene_product", "text": [ "SSAT-1" ], "offsets": [ [ 1978, 1984 ] ], "normalized": [] }, { "id": "PMID-12803540_T47", "type": "Simple_chemical", "text": [ "polyamine" ], "offsets": [ [ 2007, 2016 ] ], "normalized": [] }, { "id": "PMID-12803540_T48", "type": "Gene_or_gene_product", "text": [ "SSAT-2" ], "offsets": [ [ 2055, 2061 ] ], "normalized": [] }, { "id": "PMID-12803540_T49", "type": "Gene_or_gene_product", "text": [ "SSAT-2" ], "offsets": [ [ 2125, 2131 ] ], "normalized": [] }, { "id": "PMID-12803540_T50", "type": "Simple_chemical", "text": [ "polyamine" ], "offsets": [ [ 2224, 2233 ] ], "normalized": [] } ]

[ { "id": "PMID-12803540_E1", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 187, 197 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T5" }, { "role": "Theme", "ref_id": "PMID-12803540_T3" } ] }, { "id": "PMID-12803540_E2", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 187, 197 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T5" }, { "role": "Theme", "ref_id": "PMID-12803540_T4" } ] }, { "id": "PMID-12803540_E3", "type": "Conversion", "trigger": { "text": [ "oxidized" ], "offsets": [ [ 264, 272 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12803540_T3" }, { "role": "Product", "ref_id": "PMID-12803540_T8" } ] }, { "id": "PMID-12803540_E4", "type": "Positive_regulation", "trigger": { "text": [ "oxidized" ], "offsets": [ [ 264, 272 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T7" }, { "role": "Theme", "ref_id": "PMID-12803540_E3" } ] }, { "id": "PMID-12803540_E5", "type": "Conversion", "trigger": { "text": [ "oxidized" ], "offsets": [ [ 264, 272 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12803540_T4" }, { "role": "Product", "ref_id": "PMID-12803540_T9" } ] }, { "id": "PMID-12803540_E6", "type": "Positive_regulation", "trigger": { "text": [ "oxidized" ], "offsets": [ [ 264, 272 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T7" }, { "role": "Theme", "ref_id": "PMID-12803540_E5" } ] }, { "id": "PMID-12803540_E7", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 758, 767 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T16" }, { "role": "Theme", "ref_id": "PMID-12803540_T17" } ] }, { "id": "PMID-12803540_E8", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 758, 767 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T16" }, { "role": "Theme", "ref_id": "PMID-12803540_T18" } ] }, { "id": "PMID-12803540_E9", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 859, 869 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T16" }, { "role": "Theme", "ref_id": "PMID-12803540_T19" } ] }, { "id": "PMID-12803540_E10", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 859, 869 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T16" }, { "role": "Theme", "ref_id": "PMID-12803540_T20" } ] }, { "id": "PMID-12803540_E11", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 859, 869 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T16" }, { "role": "Theme", "ref_id": "PMID-12803540_T21" } ] }, { "id": "PMID-12803540_E12", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 859, 869 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T16" }, { "role": "Theme", "ref_id": "PMID-12803540_T22" } ] }, { "id": "PMID-12803540_E13", "type": "Regulation", "trigger": { "text": [ "no effect" ], "offsets": [ [ 1005, 1014 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T23" }, { "role": "Theme", "ref_id": "PMID-12803540_T25" } ] }, { "id": "PMID-12803540_E14", "type": "Regulation", "trigger": { "text": [ "no effect" ], "offsets": [ [ 1005, 1014 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T23" }, { "role": "Theme", "ref_id": "PMID-12803540_T26" } ] }, { "id": "PMID-12803540_E15", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 1045, 1055 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12803540_T26" } ] }, { "id": "PMID-12803540_E16", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1949, 1958 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12803540_T44" } ] }, { "id": "PMID-12803540_E17", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1949, 1958 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12803540_T45" } ] }, { "id": "PMID-12803540_E18", "type": "Positive_regulation", "trigger": { "text": [ "inducible" ], "offsets": [ [ 1994, 2003 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T47" }, { "role": "Theme", "ref_id": "PMID-12803540_T46" } ] }, { "id": "PMID-12803540_E19", "type": "Positive_regulation", "trigger": { "text": [ "inducible" ], "offsets": [ [ 1994, 2003 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12803540_T47" }, { "role": "Theme", "ref_id": "PMID-12803540_T48" } ] }, { "id": "PMID-12803540_E20", "type": "Activation", "trigger": { "text": [ "active" ], "offsets": [ [ 2091, 2097 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12803540_T49" } ] }, { "id": "PMID-12803540_E21", "type": "Transport", "trigger": { "text": [ "sequestered" ], "offsets": [ [ 2112, 2123 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12803540_T49" } ] } ]

[ { "id": "PMID-12803540_1", "entity_ids": [ "PMID-12803540_T5", "PMID-12803540_T6" ] } ]

[]

[ { "id": "PMID-12835412__text", "type": "abstract", "text": [ "The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. \nProstaglandins are involved in a wide variety of physiological and pathophysiological processes, but the mechanism of prostaglandin release from cells is not completely understood. Although poorly membrane permeable, prostaglandins are believed to exit cells by passive diffusion. We have investigated the interaction between prostaglandins and members of the ATP-binding cassette (ABC) transporter ABCC [multidrug resistance protein (MRP)] family of membrane export pumps. In inside-out membrane vesicles derived from insect cells or HEK293 cells, MRP4 catalyzed the time- and ATP-dependent uptake of prostaglandin E1 (PGE1) and PGE2. In contrast, MRP1, MRP2, MRP3, and MRP5 did not transport PGE1 or PGE2. The MRP4-mediated transport of PGE1 and PGE2 displayed saturation kinetics, with Km values of 2.1 and 3.4 microM, respectively. Further studies showed that PGF1alpha, PGF2alpha, PGA1, and thromboxane B2 were high-affinity inhibitors (and therefore presumably substrates) of MRP4. Furthermore, several nonsteroidal antiinflammatory drugs were potent inhibitors of MRP4 at concentrations that did not inhibit MRP1. In cells expressing the prostaglandin transporter PGT, the steady-state accumulation of PGE1 and PGE2 was reduced proportional to MRP4 expression. Inhibition of MRP4 by an MRP4-specific RNA interference construct or by indomethacin reversed this accumulation deficit. Together, these data suggest that MRP4 can release prostaglandins from cells, and that, in addition to inhibiting prostaglandin synthesis, some nonsteroidal antiinflammatory drugs might also act by inhibiting this release.\n" ], "offsets": [ [ 0, 1762 ] ] } ]

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"text": [ "prostaglandins" ], "offsets": [ [ 476, 490 ] ], "normalized": [] }, { "id": "PMID-12835412_T9", "type": "Gene_or_gene_product", "text": [ "ATP-binding cassette (ABC) transporter ABCC" ], "offsets": [ [ 510, 553 ] ], "normalized": [] }, { "id": "PMID-12835412_T10", "type": "Gene_or_gene_product", "text": [ "multidrug resistance protein" ], "offsets": [ [ 555, 583 ] ], "normalized": [] }, { "id": "PMID-12835412_T11", "type": "Gene_or_gene_product", "text": [ "MRP" ], "offsets": [ [ 585, 588 ] ], "normalized": [] }, { "id": "PMID-12835412_T12", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 601, 609 ] ], "normalized": [] }, { "id": "PMID-12835412_T13", "type": "Cellular_component", "text": [ "membrane vesicles" ], "offsets": [ [ 638, 655 ] ], "normalized": [] }, { "id": "PMID-12835412_T14", "type": "Gene_or_gene_product", "text": [ "MRP4" ], "offsets": [ [ 699, 703 ] ], "normalized": [] }, { "id": "PMID-12835412_T15", "type": "Simple_chemical", "text": [ "ATP" ], "offsets": [ [ 728, 731 ] ], "normalized": [] }, { "id": "PMID-12835412_T16", "type": "Simple_chemical", "text": [ "prostaglandin E1" ], "offsets": [ [ 752, 768 ] ], "normalized": [] }, { "id": "PMID-12835412_T17", "type": "Simple_chemical", "text": [ "PGE1" ], "offsets": [ [ 770, 774 ] ], "normalized": [] }, { "id": "PMID-12835412_T18", "type": "Simple_chemical", "text": [ "PGE2" ], "offsets": [ [ 780, 784 ] ], "normalized": [] }, { "id": "PMID-12835412_T19", "type": "Gene_or_gene_product", "text": [ "MRP1" ], "offsets": [ [ 799, 803 ] ], "normalized": [] }, { "id": "PMID-12835412_T20", "type": "Gene_or_gene_product", "text": [ "MRP2" ], "offsets": [ [ 805, 809 ] ], "normalized": [] }, { "id": "PMID-12835412_T21", "type": "Gene_or_gene_product", "text": [ "MRP3" ], "offsets": [ [ 811, 815 ] ], "normalized": [] }, { "id": "PMID-12835412_T22", "type": "Gene_or_gene_product", "text": [ "MRP5" ], "offsets": [ [ 821, 825 ] ], "normalized": [] }, { "id": "PMID-12835412_T23", "type": "Simple_chemical", "text": [ "PGE1" ], "offsets": [ [ 844, 848 ] ], "normalized": [] }, { "id": "PMID-12835412_T24", "type": "Simple_chemical", "text": [ "PGE2" ], "offsets": [ [ 852, 856 ] ], "normalized": [] }, { "id": "PMID-12835412_T25", "type": "Gene_or_gene_product", "text": [ "MRP4" ], "offsets": [ [ 862, 866 ] ], "normalized": [] }, { "id": "PMID-12835412_T26", "type": "Simple_chemical", "text": [ "PGE1" ], "offsets": [ [ 889, 893 ] ], "normalized": [] }, { "id": "PMID-12835412_T27", "type": "Simple_chemical", "text": [ "PGE2" ], "offsets": [ [ 898, 902 ] ], "normalized": [] }, { "id": "PMID-12835412_T28", "type": "Simple_chemical", "text": [ "PGF1alpha" ], "offsets": [ [ 1014, 1023 ] ], "normalized": [] }, { "id": "PMID-12835412_T29", "type": "Simple_chemical", "text": [ "PGF2alpha" ], "offsets": [ [ 1025, 1034 ] ], "normalized": [] }, { "id": "PMID-12835412_T30", "type": "Simple_chemical", "text": [ "PGA1" ], "offsets": [ [ 1036, 1040 ] ], "normalized": [] }, { "id": "PMID-12835412_T31", "type": "Simple_chemical", "text": [ "thromboxane B2" ], "offsets": [ [ 1046, 1060 ] ], "normalized": [] }, { "id": "PMID-12835412_T32", "type": "Gene_or_gene_product", "text": [ "MRP4" ], "offsets": [ [ 1132, 1136 ] ], "normalized": [] }, { "id": "PMID-12835412_T33", "type": "Gene_or_gene_product", "text": [ "MRP4" ], "offsets": [ [ 1221, 1225 ] ], "normalized": [] }, { "id": "PMID-12835412_T34", "type": "Gene_or_gene_product", "text": [ "MRP1" ], "offsets": [ [ 1265, 1269 ] ], "normalized": [] }, { "id": "PMID-12835412_T35", "type": "Simple_chemical", "text": [ "prostaglandin" ], "offsets": [ [ 1295, 1308 ] ], "normalized": [] }, { "id": "PMID-12835412_T36", "type": "Gene_or_gene_product", "text": [ "PGT" ], "offsets": [ [ 1321, 1324 ] ], "normalized": [] }, { "id": "PMID-12835412_T37", "type": "Simple_chemical", "text": [ "PGE1" ], "offsets": [ [ 1359, 1363 ] ], "normalized": [] }, { "id": "PMID-12835412_T38", "type": "Simple_chemical", "text": [ "PGE2" ], 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[ { "id": "PMID-12835412_1", "entity_ids": [ "PMID-12835412_T10", "PMID-12835412_T11", "PMID-12835412_T9" ] }, { "id": "PMID-12835412_2", "entity_ids": [ "PMID-12835412_T16", "PMID-12835412_T17" ] } ]

[]

[ { "id": "PMID-12838312__text", "type": "abstract", "text": [ "ICBP90 belongs to a new family of proteins with an expression that is deregulated in cancer cells. \nICBP90 (Inverted CCAAT box Binding Protein of 90 kDa) is a recently identified nuclear protein that binds to one of the inverted CCAAT boxes of the topoisomerase IIalpha (TopoIIalpha) gene promoter. Here, we show that ICBP90 shares structural homology with several other proteins, including Np95, the human and mouse NIRF, suggesting the emergence of a new family of nuclear proteins. Towards elucidating the functions of this family, we analysed the expression of ICBP90 in various cancer or noncancer cell lines and in normal or breast carcinoma tissues. We found that cancer cell lines express higher levels of ICBP90 and TopoIIalpha than noncancer cell lines. By using cell-cycle phase-blocking drugs, we show that in primary cultured human lung fibroblasts, ICBP90 expression peaks at late G1 and during G2/M phases. In contrast, cancer cell lines such as HeLa, Jurkat and A549 show constant ICBP90 expression throughout the entire cell cycle. The effect of overexpression of E2F-1 is more efficient on ICBP90 and TopoIIalpha expression in noncancer cells (IMR90, WI38) than in cancer cells (U2OS, SaOs). Together, these results show that ICBP90 expression is altered in cancer cell lines and is upregulated by E2F-1 overexpression with an efficiency depending on the cancer status of the cell line.\n" ], "offsets": [ [ 0, 1405 ] ] } ]

[ { "id": "PMID-12838312_T1", "type": "Gene_or_gene_product", "text": [ "ICBP90" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "PMID-12838312_T2", "type": "Gene_or_gene_product", "text": [ "ICBP90" ], "offsets": [ [ 100, 106 ] ], "normalized": [] }, { "id": "PMID-12838312_T3", "type": "Gene_or_gene_product", "text": [ "Inverted CCAAT box Binding Protein of 90 kDa" ], "offsets": [ [ 108, 152 ] ], "normalized": [] }, { "id": "PMID-12838312_T4", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 179, 186 ] ], "normalized": [] }, { "id": "PMID-12838312_T5", "type": "Gene_or_gene_product", "text": [ "topoisomerase IIalpha" ], "offsets": [ [ 248, 269 ] ], "normalized": [] }, { "id": "PMID-12838312_T6", "type": "Gene_or_gene_product", "text": [ "TopoIIalpha" ], "offsets": [ [ 271, 282 ] ], "normalized": [] }, { "id": "PMID-12838312_T7", "type": "Gene_or_gene_product", "text": [ "ICBP90" ], "offsets": [ [ 318, 324 ] ], "normalized": [] }, { "id": "PMID-12838312_T8", "type": "Gene_or_gene_product", "text": [ "Np95" ], "offsets": [ [ 391, 395 ] ], "normalized": [] }, { "id": "PMID-12838312_T9", "type": "Gene_or_gene_product", "text": [ "NIRF" ], "offsets": [ [ 417, 421 ] ], "normalized": [] }, { "id": "PMID-12838312_T10", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 467, 474 ] ], "normalized": [] }, { "id": "PMID-12838312_T11", "type": "Gene_or_gene_product", "text": [ "ICBP90" ], "offsets": [ [ 565, 571 ] ], "normalized": [] }, { "id": "PMID-12838312_T12", "type": "Gene_or_gene_product", "text": [ "ICBP90" ], "offsets": [ [ 714, 720 ] ], "normalized": [] }, { "id": "PMID-12838312_T13", "type": "Gene_or_gene_product", "text": [ "TopoIIalpha" ], "offsets": [ [ 725, 736 ] ], "normalized": [] }, { "id": "PMID-12838312_T14", "type": "Gene_or_gene_product", "text": [ "ICBP90" ], "offsets": [ [ 863, 869 ] ], "normalized": [] }, { "id": "PMID-12838312_T15", "type": "Gene_or_gene_product", "text": [ "ICBP90" ], "offsets": [ [ 997, 1003 ] ], "normalized": [] }, { "id": "PMID-12838312_T16", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 1081, 1086 ] ], "normalized": [] }, { "id": "PMID-12838312_T17", "type": "Gene_or_gene_product", "text": [ "ICBP90" ], "offsets": [ [ 1108, 1114 ] ], "normalized": [] }, { "id": "PMID-12838312_T18", "type": "Gene_or_gene_product", "text": [ "TopoIIalpha" ], "offsets": [ [ 1119, 1130 ] ], "normalized": [] }, { "id": "PMID-12838312_T19", "type": "Gene_or_gene_product", "text": [ "ICBP90" ], "offsets": [ [ 1244, 1250 ] ], "normalized": [] }, { "id": "PMID-12838312_T20", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 1316, 1321 ] ], "normalized": [] } ]

[ { "id": "PMID-12838312_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 51, 61 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T1" } ] }, { "id": "PMID-12838312_E2", "type": "Regulation", "trigger": { "text": [ "deregulated" ], "offsets": [ [ 70, 81 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_E1" } ] }, { "id": "PMID-12838312_E3", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 200, 205 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T6" }, { "role": "Theme", "ref_id": "PMID-12838312_T2" } ] }, { "id": "PMID-12838312_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 551, 561 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T11" } ] }, { "id": "PMID-12838312_E5", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 689, 696 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T12" } ] }, { "id": "PMID-12838312_E6", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 689, 696 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T13" } ] }, { "id": "PMID-12838312_E7", "type": "Positive_regulation", "trigger": { "text": [ "higher" ], "offsets": [ [ 697, 703 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T12" } ] }, { "id": "PMID-12838312_E8", "type": "Positive_regulation", "trigger": { "text": [ "higher" ], "offsets": [ [ 697, 703 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T13" } ] }, { "id": "PMID-12838312_E9", "type": "Pathway", "trigger": { "text": [ "cell-cycle" ], "offsets": [ [ 773, 783 ] ] }, "arguments": [] }, { "id": "PMID-12838312_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 870, 880 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T14" } ] }, { "id": "PMID-12838312_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1004, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T15" } ] }, { "id": "PMID-12838312_E12", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1053, 1059 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12838312_E14" }, { "role": "Theme", "ref_id": "PMID-12838312_E16" } ] }, { "id": "PMID-12838312_E13", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1053, 1059 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12838312_E14" }, { "role": "Theme", "ref_id": "PMID-12838312_E15" } ] }, { "id": "PMID-12838312_E14", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1063, 1077 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T16" } ] }, { "id": "PMID-12838312_E15", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1131, 1141 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T18" } ] }, { "id": "PMID-12838312_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1131, 1141 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T17" } ] }, { "id": "PMID-12838312_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1251, 1261 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T19" } ] }, { "id": "PMID-12838312_E18", "type": "Regulation", "trigger": { "text": [ "altered" ], "offsets": [ [ 1265, 1272 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_E17" } ] }, { "id": "PMID-12838312_E19", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 1301, 1312 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12838312_E20" }, { "role": "Theme", "ref_id": "PMID-12838312_E17" } ] }, { "id": "PMID-12838312_E20", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1322, 1336 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12838312_T20" } ] } ]

[ { "id": "PMID-12838312_1", "entity_ids": [ "PMID-12838312_T2", "PMID-12838312_T3" ] }, { "id": "PMID-12838312_2", "entity_ids": [ "PMID-12838312_T6", "PMID-12838312_T5" ] } ]

[]

[ { "id": "PMID-12849978__text", "type": "abstract", "text": [ "Identification of a novel human uridine phosphorylase. \nUridine phosphorylase catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to uracil and ribose- or deoxyribose-1-phosphate. The enzyme has an important role in the metabolism of pyrimidine analogs used in cancer chemotherapy. The cDNA of a novel 317 amino acid human uridine phosphorylase approximately 60% identical to the previously identified human uridine phosphorylase was cloned. The novel enzyme, named uridine phosphorylase-2 (UPase-2), showed broad substrate specificity and accepted uridine, deoxyuridine, and thymidine as well as the two pyrimidine nucleoside analogs 5-fluorouridine and 5-fluoro-2(')-deoxyuridine. The human UPase-2 gene was mapped to chromosome 2q24.1 and the 2.2-kb mRNA was predominantly expressed in kidney. The mouse UPase-2 cDNA was also identified and shown to be predominantly expressed in liver. The identification of a novel uridine phosphorylase with broad substrate specificity is important for studies on both nucleoside metabolism as well as for studies on the pharmacological mechanisms of therapeutic pyrimidine nucleoside analogs.\n" ], "offsets": [ [ 0, 1158 ] ] } ]

[ { "id": "PMID-12849978_T1", "type": "Gene_or_gene_product", "text": [ "uridine phosphorylase" ], "offsets": [ [ 32, 53 ] ], "normalized": [] }, { "id": "PMID-12849978_T2", "type": "Gene_or_gene_product", "text": [ "Uridine phosphorylase" ], "offsets": [ [ 56, 77 ] ], "normalized": [] }, { "id": "PMID-12849978_T3", "type": "Simple_chemical", "text": [ "uridine" ], "offsets": [ [ 130, 137 ] ], "normalized": [] }, { "id": "PMID-12849978_T4", "type": "Simple_chemical", "text": [ "deoxyuridine" ], "offsets": [ [ 142, 154 ] ], "normalized": [] }, { "id": "PMID-12849978_T5", "type": "Simple_chemical", "text": [ "uracil" ], "offsets": [ [ 158, 164 ] ], "normalized": [] }, { "id": "PMID-12849978_T6", "type": "Simple_chemical", "text": [ "ribose" ], "offsets": [ [ 169, 175 ] ], "normalized": [] }, { "id": "PMID-12849978_T7", "type": "Simple_chemical", "text": [ "deoxyribose-1-phosphate" ], "offsets": [ [ 180, 203 ] ], "normalized": [] }, { "id": "PMID-12849978_T8", "type": "Simple_chemical", "text": [ "pyrimidine" ], "offsets": [ [ 259, 269 ] ], "normalized": [] }, { "id": "PMID-12849978_T9", "type": "Gene_or_gene_product", "text": [ "uridine phosphorylase" ], "offsets": [ [ 348, 369 ] ], "normalized": [] }, { "id": "PMID-12849978_T10", "type": "Gene_or_gene_product", "text": [ "uridine phosphorylase" ], "offsets": [ [ 433, 454 ] ], "normalized": [] }, { "id": "PMID-12849978_T11", "type": "Gene_or_gene_product", "text": [ "uridine phosphorylase-2" ], "offsets": [ [ 491, 514 ] ], "normalized": [] }, { "id": "PMID-12849978_T12", "type": "Gene_or_gene_product", "text": [ "UPase-2" ], "offsets": [ [ 516, 523 ] ], "normalized": [] }, { "id": "PMID-12849978_T13", "type": "Simple_chemical", "text": [ "uridine" ], "offsets": [ [ 574, 581 ] ], "normalized": [] }, { "id": "PMID-12849978_T14", "type": "Simple_chemical", "text": [ "deoxyuridine" ], "offsets": [ [ 583, 595 ] ], "normalized": [] }, { "id": "PMID-12849978_T15", "type": "Simple_chemical", "text": [ "thymidine" ], "offsets": [ [ 601, 610 ] ], "normalized": [] }, { "id": "PMID-12849978_T16", "type": "Simple_chemical", "text": [ "pyrimidine nucleoside" ], "offsets": [ [ 630, 651 ] ], "normalized": [] }, { "id": "PMID-12849978_T17", "type": "Simple_chemical", "text": [ "5-fluorouridine" ], "offsets": [ [ 660, 675 ] ], "normalized": [] }, { "id": "PMID-12849978_T18", "type": "Simple_chemical", "text": [ "5-fluoro-2(')-deoxyuridine" ], "offsets": [ [ 680, 706 ] ], "normalized": [] }, { "id": "PMID-12849978_T19", "type": "Gene_or_gene_product", "text": [ "UPase-2" ], "offsets": [ [ 718, 725 ] ], "normalized": [] }, { "id": "PMID-12849978_T20", "type": "Cellular_component", "text": [ "chromosome" ], "offsets": [ [ 745, 755 ] ], "normalized": [] }, { "id": "PMID-12849978_T21", "type": "Gene_or_gene_product", "text": [ "UPase-2" ], "offsets": [ [ 832, 839 ] ], "normalized": [] }, { "id": "PMID-12849978_T22", "type": "Gene_or_gene_product", "text": [ "uridine phosphorylase" ], "offsets": [ [ 945, 966 ] ], "normalized": [] }, { "id": "PMID-12849978_T23", "type": "Simple_chemical", "text": [ "pyrimidine nucleoside" ], "offsets": [ [ 1127, 1148 ] ], "normalized": [] } ]

[ { "id": "PMID-12849978_E1", "type": "Positive_regulation", "trigger": { "text": [ "catalyzes" ], "offsets": [ [ 78, 87 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12849978_T2" }, { "role": "Theme", "ref_id": "PMID-12849978_E3" } ] }, { "id": "PMID-12849978_E2", "type": "Positive_regulation", "trigger": { "text": [ "catalyzes" ], "offsets": [ [ 78, 87 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12849978_T2" }, { "role": "Theme", "ref_id": "PMID-12849978_E4" } ] }, { "id": "PMID-12849978_E3", "type": "Negative_regulation", "trigger": { "text": [ "reversible" ], "offsets": [ [ 92, 102 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12849978_E5" } ] }, { "id": "PMID-12849978_E4", "type": "Negative_regulation", "trigger": { "text": [ "reversible" ], "offsets": [ [ 92, 102 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12849978_E6" } ] }, { "id": "PMID-12849978_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylytic" ], "offsets": [ [ 103, 117 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12849978_T3" } ] }, { "id": "PMID-12849978_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylytic" ], "offsets": [ [ 103, 117 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12849978_T4" } ] }, { "id": "PMID-12849978_E7", "type": "Positive_regulation", "trigger": { "text": [ "important" ], "offsets": [ [ 223, 232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12849978_E8" }, { "role": "Cause", "ref_id": "PMID-12849978_T2" } ] }, { "id": "PMID-12849978_E8", "type": "Conversion", "trigger": { "text": [ "metabolism" ], "offsets": [ [ 245, 255 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12849978_T8" } ] }, { "id": "PMID-12849978_E9", "type": "Positive_regulation", "trigger": { "text": [ "accepted" ], "offsets": [ [ 565, 573 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12849978_T11" }, { "role": "Theme", "ref_id": "PMID-12849978_T13" } ] }, { "id": "PMID-12849978_E10", "type": "Positive_regulation", "trigger": { "text": [ "accepted" ], "offsets": [ [ 565, 573 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12849978_T11" }, { "role": "Theme", "ref_id": "PMID-12849978_T14" } ] }, { "id": "PMID-12849978_E11", "type": "Positive_regulation", "trigger": { "text": [ "accepted" ], "offsets": [ [ 565, 573 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12849978_T11" }, { "role": "Theme", "ref_id": "PMID-12849978_T15" } ] }, { "id": "PMID-12849978_E12", "type": "Positive_regulation", "trigger": { "text": [ "accepted" ], "offsets": [ [ 565, 573 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-12849978_T11" }, { "role": "Theme", "ref_id": "PMID-12849978_T16" } ] }, { "id": "PMID-12849978_E13", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 895, 904 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-12849978_T21" } ] } ]

[ { "id": "PMID-12849978_1", "entity_ids": [ "PMID-12849978_T11", "PMID-12849978_T12" ] } ]

[]

[ { "id": "PMID-12861053__text", "type": "abstract", "text": [ "Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage. \nPhosphorylation of NBS1, the product of the gene mutated in Nijmegen breakage syndrome (NBS), by ataxia telangiectasia mutated (ATM), the product of the gene mutated in ataxia telangiectasia, is required for activation of the S phase checkpoint in response to ionizing radiation (IR). However, NBS1 is also thought to play additional roles in the cellular response to DNA damage. To clarify these additional functions of NBS1, we generated NBS cell lines stably expressing various NBS1 mutants from retroviral vectors. The ATM-dependent activation of CHK2 by IR was defective in NBS cells but was restored by ectopic expression of wild-type NBS1. The defects in ATM-dependent activation of CHK2, S phase checkpoint control, IR-induced nuclear focus formation, and radiation sensitivity apparent in NBS cells were not corrected by expression of NBS1 mutants that lack an intact MRE11 binding domain, suggesting that formation of the NBS1-MRE11-RAD50 complex is required for the corresponding normal phenotypes. Expression of NBS1 proteins with mutated ATM-targeted phosphorylation sites (serines 278 or 343) did not restore S phase checkpoint control but did restore the ability of IR to activate CHK2 and to induce nuclear focus formation and normalized the radiation sensitivity of NBS cells. Expression of NBS1 containing mutations in the forkhead-associated or BRCA1 COOH terminus domains did not correct the defects in radiation sensitivity or nuclear focus formation but did restore S phase checkpoint control in NBS cells. Together, these data demonstrate that multiple functional domains of NBS1 are required for ATM-dependent activation of CHK2, nuclear focus formation, S phase checkpoint control, and cell survival after exposure to IR.\n" ], "offsets": [ [ 0, 1865 ] ] } ]

[ { "id": "PMID-12861053_T1", "type": "Gene_or_gene_product", "text": [ "NBS1" ], "offsets": [ [ 137, 141 ] ], "normalized": [] }, { "id": "PMID-12861053_T2", "type": "Gene_or_gene_product", "text": [ "ataxia telangiectasia mutated" ], "offsets": [ [ 215, 244 ] ], "normalized": [] }, { "id": "PMID-12861053_T3", "type": "Gene_or_gene_product", "text": [ "ATM" ], "offsets": [ [ 246, 249 ] ], "normalized": [] }, { "id": "PMID-12861053_T4", "type": "Gene_or_gene_product", "text": [ "NBS1" ], "offsets": [ [ 412, 416 ] ], "normalized": [] }, { "id": "PMID-12861053_T5", "type": "Gene_or_gene_product", "text": [ "NBS1" ], "offsets": [ [ 539, 543 ] ], "normalized": [] }, { "id": "PMID-12861053_T6", "type": "Gene_or_gene_product", "text": [ "NBS1" ], "offsets": [ [ 599, 603 ] ], "normalized": [] }, { "id": "PMID-12861053_T7", "type": "Gene_or_gene_product", "text": [ "ATM" ], "offsets": [ [ 641, 644 ] ], "normalized": [] }, { "id": "PMID-12861053_T8", "type": "Gene_or_gene_product", "text": [ "CHK2" ], "offsets": [ [ 669, 673 ] ], "normalized": [] }, { "id": "PMID-12861053_T9", "type": "Gene_or_gene_product", "text": [ "NBS1" ], "offsets": [ [ 759, 763 ] ], "normalized": [] }, { "id": "PMID-12861053_T10", "type": "Gene_or_gene_product", "text": [ "ATM" ], "offsets": [ [ 780, 783 ] ], "normalized": [] }, { "id": "PMID-12861053_T11", "type": "Gene_or_gene_product", "text": [ "CHK2" ], "offsets": [ [ 808, 812 ] ], "normalized": [] }, { "id": "PMID-12861053_T12", "type": "Cellular_component", "text": [ "nuclear focus" ], "offsets": [ [ 853, 866 ] ], "normalized": [] }, { "id": "PMID-12861053_T13", "type": "Gene_or_gene_product", "text": [ "NBS1" ], "offsets": [ [ 962, 966 ] ], "normalized": [] }, { "id": "PMID-12861053_T14", "type": "Gene_or_gene_product", "text": [ "MRE11" ], "offsets": [ [ 995, 1000 ] ], "normalized": [] }, { "id": "PMID-12861053_T15", "type": "Complex", "text": [ "NBS1-MRE11-RAD50" ], "offsets": [ [ 1050, 1066 ] ], "normalized": [] }, { "id": "PMID-12861053_T16", "type": "Gene_or_gene_product", "text": [ "NBS1" ], "offsets": [ [ 1142, 1146 ] ], "normalized": [] }, { "id": "PMID-12861053_T17", "type": "Gene_or_gene_product", "text": [ "ATM" ], "offsets": [ [ 1169, 1172 ] ], "normalized": [] }, { "id": "PMID-12861053_T18", "type": "Simple_chemical", "text": [ "serines 278" ], "offsets": [ [ 1205, 1216 ] ], "normalized": [] }, { "id": "PMID-12861053_T19", "type": "Simple_chemical", "text": [ "343" ], "offsets": [ [ 1220, 1223 ] ], "normalized": [] }, { "id": "PMID-12861053_T20", "type": "Gene_or_gene_product", "text": [ "CHK2" ], "offsets": [ [ 1314, 1318 ] ], "normalized": [] }, { "id": "PMID-12861053_T21", "type": "Cellular_component", "text": [ "nuclear focus" ], "offsets": [ [ 1333, 1346 ] ], "normalized": [] }, { "id": "PMID-12861053_T22", "type": "Gene_or_gene_product", "text": [ "NBS1" ], "offsets": [ [ 1426, 1430 ] ], "normalized": [] }, { "id": "PMID-12861053_T23", "type": "Gene_or_gene_product", "text": [ "BRCA1" ], "offsets": [ [ 1482, 1487 ] ], "normalized": [] }, { "id": "PMID-12861053_T24", "type": "Cellular_component", "text": [ "nuclear focus" ], "offsets": [ [ 1566, 1579 ] ], "normalized": [] }, { "id": "PMID-12861053_T25", "type": "Gene_or_gene_product", "text": [ "NBS1" ], "offsets": [ [ 1716, 1720 ] ], "normalized": [] }, { "id": "PMID-12861053_T26", "type": "Gene_or_gene_product", "text": [ "ATM" ], "offsets": [ [ 1738, 1741 ] ], "normalized": [] }, { "id": "PMID-12861053_T27", "type": "Gene_or_gene_product", "text": [ "CHK2" ], "offsets": [ [ 1766, 1770 ] ], "normalized": [] }, { "id": "PMID-12861053_T28", "type": "Cellular_component", "text": [ "nuclear focus" ], "offsets": [ [ 1772, 1785 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-12888566__text", "type": "abstract", "text": [ "Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88. \nThe Toll/interleukin 1 receptor (TIR) domain is a region found in the cytoplasmic tails of members of the Toll-like receptor/interleukin-1 receptor superfamily. The domain is essential for signaling and is also found in the adaptor proteins Mal (MyD88 adaptor-like) and MyD88, which function to couple activation of the receptor to downstream signaling components. Experimental structures of two Toll/interleukin 1 receptor domains reveal a alpha-beta-fold similar to that of the bacterial chemotaxis protein CheY, and other evidence suggests that the adaptors can make heterotypic interactions with both the receptors and themselves. Here we show that the purified TIR domains of Mal and MyD88 can form stable heterodimers and also that Mal homodimers and oligomers are dissociated in the presence of ATP. To identify structural features that may contribute to the formation of signaling complexes, we produced models of the TIR domains from human Toll-like receptor 4 (TLR4), Mal, and MyD88. We found that although the overall fold is conserved the electrostatic surface potentials are quite distinct. Docking studies of the models suggest that Mal and MyD88 bind to different regions in TLRs 2 and 4, a finding consistent with a cooperative role of the two adaptors in signaling. Mal and MyD88 are predicted to interact at a third non-overlapping site, suggesting that the receptor and adaptors may form heterotetrameric complexes. The theoretical model of the interactions is supported by experimental data from glutathione S-transferase pull-downs and co-immunoprecipitations. Neither theoretical nor experimental data suggest a direct role for the conserved proline in the BB-loop in the association of TLR4, Mal, and MyD88. Finally we show a sequence relationship between the Drosophila protein Tube and Mal that may indicate a functional equivalence of these two adaptors in the Drosophila and vertebrate Toll pathways.\n" ], "offsets": [ [ 0, 2050 ] ] } ]

[ { "id": "PMID-12888566_T1", "type": "Gene_or_gene_product", "text": [ "Toll/interleukin-1 receptor" ], "offsets": [ [ 30, 57 ] ], "normalized": [] }, { "id": "PMID-12888566_T2", "type": "Gene_or_gene_product", "text": [ "Toll-like receptors" ], "offsets": [ [ 69, 88 ] ], "normalized": [] }, { "id": "PMID-12888566_T3", "type": "Gene_or_gene_product", "text": [ "Mal" ], "offsets": [ [ 106, 109 ] ], "normalized": [] }, { "id": "PMID-12888566_T4", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 114, 119 ] ], "normalized": [] }, { "id": "PMID-12888566_T5", "type": "Gene_or_gene_product", "text": [ "Toll/interleukin 1 receptor" ], "offsets": [ [ 126, 153 ] ], "normalized": [] }, { "id": "PMID-12888566_T6", "type": "Gene_or_gene_product", "text": [ "TIR" ], "offsets": [ [ 155, 158 ] ], "normalized": [] }, { "id": "PMID-12888566_T7", "type": "Cellular_component", "text": [ "cytoplasmic" ], "offsets": [ [ 192, 203 ] ], "normalized": [] }, { "id": "PMID-12888566_T8", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor/interleukin-1 receptor" ], "offsets": [ [ 228, 269 ] ], "normalized": [] }, { "id": "PMID-12888566_T9", "type": "Gene_or_gene_product", "text": [ "Mal" ], "offsets": [ [ 363, 366 ] ], "normalized": [] }, { "id": "PMID-12888566_T10", "type": "Gene_or_gene_product", "text": [ "MyD88 adaptor-like" ], "offsets": [ [ 368, 386 ] ], "normalized": [] }, { "id": "PMID-12888566_T11", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 392, 397 ] ], "normalized": [] }, { "id": "PMID-12888566_T12", "type": "Gene_or_gene_product", "text": [ "Toll/interleukin 1 receptor" ], "offsets": [ [ 518, 545 ] ], "normalized": [] }, { "id": "PMID-12888566_T13", "type": "Gene_or_gene_product", "text": [ "CheY" ], "offsets": [ [ 631, 635 ] ], "normalized": [] }, { "id": "PMID-12888566_T14", "type": "Gene_or_gene_product", "text": [ "TIR" ], "offsets": [ [ 788, 791 ] ], "normalized": [] }, { "id": "PMID-12888566_T15", "type": "Gene_or_gene_product", "text": [ "Mal" ], "offsets": [ [ 803, 806 ] ], "normalized": [] }, { "id": "PMID-12888566_T16", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 811, 816 ] ], "normalized": [] }, { "id": "PMID-12888566_T17", "type": "Gene_or_gene_product", "text": [ "Mal" ], "offsets": [ [ 860, 863 ] ], "normalized": [] }, { "id": "PMID-12888566_T18", "type": "Simple_chemical", "text": [ "ATP" ], "offsets": [ [ 924, 927 ] ], "normalized": [] }, { "id": "PMID-12888566_T19", "type": "Gene_or_gene_product", "text": [ "TIR" ], "offsets": [ [ 1048, 1051 ] ], "normalized": [] }, { "id": "PMID-12888566_T20", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor 4" ], "offsets": [ [ 1071, 1091 ] ], "normalized": [] }, { "id": "PMID-12888566_T21", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 1093, 1097 ] ], "normalized": [] }, { "id": "PMID-12888566_T22", "type": "Gene_or_gene_product", "text": [ "Mal" ], "offsets": [ [ 1100, 1103 ] ], "normalized": [] }, { "id": "PMID-12888566_T23", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1109, 1114 ] ], "normalized": [] }, { "id": "PMID-12888566_T24", "type": "Gene_or_gene_product", "text": [ "Mal" ], "offsets": [ [ 1269, 1272 ] ], "normalized": [] }, { "id": "PMID-12888566_T25", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1277, 1282 ] ], "normalized": [] }, { "id": "PMID-12888566_T26", "type": "Gene_or_gene_product", "text": [ "TLRs 2" ], "offsets": [ [ 1312, 1318 ] ], "normalized": [] }, { "id": "PMID-12888566_T27", "type": "Gene_or_gene_product", "text": [ "4" ], "offsets": [ [ 1323, 1324 ] ], "normalized": [] }, { "id": "PMID-12888566_T28", "type": "Gene_or_gene_product", "text": [ "Mal" ], "offsets": [ [ 1405, 1408 ] ], "normalized": [] }, { "id": "PMID-12888566_T29", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1413, 1418 ] ], "normalized": [] }, { "id": "PMID-12888566_T30", "type": "Gene_or_gene_product", "text": [ "glutathione S-transferase" ], "offsets": [ [ 1638, 1663 ] ], "normalized": [] }, { "id": "PMID-12888566_T31", "type": "Simple_chemical", "text": [ "proline" ], "offsets": [ [ 1786, 1793 ] ], "normalized": [] }, { "id": "PMID-12888566_T32", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 1831, 1835 ] ], "normalized": [] }, { "id": "PMID-12888566_T33", "type": "Gene_or_gene_product", "text": [ "Mal" ], "offsets": [ [ 1837, 1840 ] ], "normalized": [] }, { "id": "PMID-12888566_T34", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1846, 1851 ] ], "normalized": [] }, { "id": "PMID-12888566_T35", "type": "Gene_or_gene_product", "text": [ "Tube" ], "offsets": [ [ 1924, 1928 ] ], "normalized": [] }, { "id": "PMID-12888566_T36", "type": "Gene_or_gene_product", "text": [ "Mal" ], "offsets": [ [ 1933, 1936 ] ], "normalized": [] }, { "id": "PMID-12888566_T37", "type": "Gene_or_gene_product", "text": [ "Toll" ], "offsets": [ [ 2035, 2039 ] ], "normalized": [] } ]

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[ { "id": "PMID-12888566_1", "entity_ids": [ "PMID-12888566_T5", "PMID-12888566_T6" ] }, { "id": "PMID-12888566_2", "entity_ids": [ "PMID-12888566_T9", "PMID-12888566_T10" ] }, { "id": "PMID-12888566_3", "entity_ids": [ "PMID-12888566_T20", "PMID-12888566_T21" ] } ]

[]

[ { "id": "PMID-1437141__text", "type": "abstract", "text": [ "Identification of complex formation between two intracellular tyrosine kinase substrates: human c-Rel and the p105 precursor of p50 NF-kappa B. \nImmune complexes of the product of the c-rel protooncogene and of p105, the p50 NF-kappa B precursor, isolated from human T-lymphoblastoid cell lines are comprised of multiple proteins. Only p105 and human c-Rel (hc-Rel) are common to complexes precipitated with antiserum directed against either p105 or hc-Rel. Both proteins are inducible by phytohemagglutinin (PHA) and phorbol 12-myristate 13-acetate (PMA) and their subcellular distribution is affected by this induction. We demonstrate that the Rel immune complex contains a protein with a molecular weight in the 40 kDa range (p40) which apparently is exclusively cytoplasmic. We were not able to detect p40 in the p105 immune complex, though hc-Rel is present. This indicates that hc-Rel exists in different multi-protein complexes and fits a model of functional regulation mediated by differential protein-protein interaction. We also demonstrate considerable isoform diversity of both hc-Rel and p105. We show that this heterogeneity is, in part, the result of phosphorylation. Furthermore, we demonstrate that p105 and hc-Rel are tyrosine kinase substrates. This finding indicates a role for both proteins in intracellular signal transduction pathways which are modulated by modification of their phosphorylation status.\n" ], "offsets": [ [ 0, 1427 ] ] } ]

[ { "id": "PMID-1437141_T1", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 48, 61 ] ], "normalized": [] }, { "id": "PMID-1437141_T2", "type": "Simple_chemical", "text": [ "tyrosine" ], "offsets": [ [ 62, 70 ] ], "normalized": [] }, { "id": "PMID-1437141_T3", "type": "Gene_or_gene_product", "text": [ "c-Rel" ], "offsets": [ [ 96, 101 ] ], "normalized": [] }, { "id": "PMID-1437141_T4", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 110, 114 ] ], "normalized": [] }, { "id": "PMID-1437141_T5", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 128, 131 ] ], "normalized": [] }, { "id": "PMID-1437141_T6", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 132, 142 ] ], "normalized": [] }, { "id": "PMID-1437141_T7", "type": "Gene_or_gene_product", "text": [ "c-rel" ], "offsets": [ [ 184, 189 ] ], "normalized": [] }, { "id": "PMID-1437141_T8", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 211, 215 ] ], "normalized": [] }, { "id": "PMID-1437141_T9", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 221, 224 ] ], "normalized": [] }, { "id": "PMID-1437141_T10", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 225, 235 ] ], "normalized": [] }, { "id": "PMID-1437141_T11", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 336, 340 ] ], "normalized": [] }, { "id": "PMID-1437141_T12", "type": "Gene_or_gene_product", "text": [ "c-Rel" ], "offsets": [ [ 351, 356 ] ], "normalized": [] }, { "id": "PMID-1437141_T13", "type": "Gene_or_gene_product", "text": [ "hc-Rel" ], "offsets": [ [ 358, 364 ] ], "normalized": [] }, { "id": "PMID-1437141_T14", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 442, 446 ] ], "normalized": [] }, { "id": "PMID-1437141_T15", "type": "Gene_or_gene_product", "text": [ "hc-Rel" ], "offsets": [ [ 450, 456 ] ], "normalized": [] }, { "id": "PMID-1437141_T16", "type": "Gene_or_gene_product", "text": [ "phytohemagglutinin" ], "offsets": [ [ 489, 507 ] ], "normalized": [] }, { "id": "PMID-1437141_T17", "type": "Gene_or_gene_product", "text": [ "PHA" ], "offsets": [ [ 509, 512 ] ], "normalized": [] }, { "id": "PMID-1437141_T18", "type": "Simple_chemical", "text": [ "phorbol 12-myristate 13-acetate" ], "offsets": [ [ 518, 549 ] ], "normalized": [] }, { "id": "PMID-1437141_T19", "type": "Simple_chemical", "text": [ "PMA" ], "offsets": [ [ 551, 554 ] ], "normalized": [] }, { "id": "PMID-1437141_T20", "type": "Cellular_component", "text": [ "subcellular" ], "offsets": [ [ 566, 577 ] ], "normalized": [] }, { "id": "PMID-1437141_T21", "type": "Gene_or_gene_product", "text": [ "Rel" ], "offsets": [ [ 646, 649 ] ], "normalized": [] }, { "id": "PMID-1437141_T22", "type": "Gene_or_gene_product", "text": [ "p40" ], "offsets": [ [ 729, 732 ] ], "normalized": [] }, { "id": "PMID-1437141_T23", "type": "Cellular_component", "text": [ "cytoplasmic" ], "offsets": [ [ 766, 777 ] ], "normalized": [] }, { "id": "PMID-1437141_T24", "type": "Gene_or_gene_product", "text": [ "p40" ], "offsets": [ [ 806, 809 ] ], "normalized": [] }, { "id": "PMID-1437141_T25", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 817, 821 ] ], "normalized": [] }, { "id": "PMID-1437141_T26", "type": "Gene_or_gene_product", "text": [ "hc-Rel" ], "offsets": [ [ 845, 851 ] ], "normalized": [] }, { "id": "PMID-1437141_T27", "type": "Gene_or_gene_product", "text": [ "hc-Rel" ], "offsets": [ [ 884, 890 ] ], "normalized": [] }, { "id": "PMID-1437141_T28", "type": "Gene_or_gene_product", "text": [ "hc-Rel" ], "offsets": [ [ 1090, 1096 ] ], "normalized": [] }, { "id": "PMID-1437141_T29", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 1101, 1105 ] ], "normalized": [] }, { "id": "PMID-1437141_T30", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 1216, 1220 ] ], "normalized": [] }, { "id": "PMID-1437141_T31", "type": "Gene_or_gene_product", "text": [ "hc-Rel" ], "offsets": [ [ 1225, 1231 ] ], "normalized": [] }, { "id": "PMID-1437141_T32", "type": "Simple_chemical", "text": [ "tyrosine" ], "offsets": [ [ 1236, 1244 ] ], "normalized": [] }, { "id": "PMID-1437141_T33", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 1315, 1328 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-14507663__text", "type": "abstract", "text": [ "Expression and localization of the multidrug resistance protein 5 (MRP5/ABCC5), a cellular export pump for cyclic nucleotides, in human heart. \nThe multidrug resistance protein 5 (MRP5/ABCC5) has been recently identified as cellular export pump for cyclic nucleotides with 3',5'-cyclic GMP (cGMP) as a high-affinity substrate. In view of the important role of cGMP for cardiovascular function, expression of this transport protein in human heart is of relevance. We analyzed the expression and localization of MRP5 in human heart [21 auricular (AS) and 15 left ventricular samples (LV) including 5 samples of dilated and ischemic cardiomyopathy]. Quantitative real-time polymerase chain reaction normalized to beta-actin revealed expression of the MRP5 gene in all samples (LV, 38.5 +/- 12.9; AS, 12.7 +/- 5.6; P < 0.001). An MRP5-specific polyclonal antibody detected a glycoprotein of approximately 190 kd in crude cell membrane fractions from these samples. Immunohistochemistry with the affinity-purified antibody revealed localization of MRP5 in cardiomyocytes as well as in cardiovascular endothelial and smooth muscle cells. Furthermore, we could detect MRP5 and ATP-dependent transport of [(3)H]cGMP in sarcolemma vesicles of human heart. Quantitative analysis of the immunoblots indicated an interindividual variability with a higher expression of MRP5 in the ischemic (104 +/- 38% of recombinant MRP5 standard) compared to normal ventricular samples (53 +/- 36%, P < 0.05). In addition, we screened genomic DNA from our samples for 20 single-nucleotide polymorphisms in the MRP5 gene. These results indicate that MRP5 is localized in cardiac and cardiovascular myocytes as well as endothelial cells with increased expression in ischemic cardiomyopathy. Therefore, MRP5-mediated cellular export may represent a novel, disease-dependent pathway for cGMP removal from cardiac cells.\n" ], "offsets": [ [ 0, 1890 ] ] } ]

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[]

[ { "id": "PMID-14517278__text", "type": "abstract", "text": [ "LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. \nToll-IL-1-resistance (TIR) domain-containing adaptor-inducing IFN-beta (TRIF)-related adaptor molecule (TRAM) is the fourth TIR domain-containing adaptor protein to be described that participates in Toll receptor signaling. Like TRIF, TRAM activates interferon regulatory factor (IRF)-3, IRF-7, and NF-kappaB-dependent signaling pathways. Toll-like receptor (TLR)3 and 4 activate these pathways to induce IFN-alpha/beta, regulated on activation, normal T cell expressed and secreted (RANTES), and gamma interferon-inducible protein 10 (IP-10) expression independently of the adaptor protein myeloid differentiation factor 88 (MyD88). Dominant negative and siRNA studies performed here demonstrate that TRIF functions downstream of both the TLR3 (dsRNA) and TLR4 (LPS) signaling pathways, whereas the function of TRAM is restricted to the TLR4 pathway. TRAM interacts with TRIF, MyD88 adaptor-like protein (Mal)/TIRAP, and TLR4 but not with TLR3. These studies suggest that TRIF and TRAM both function in LPS-TLR4 signaling to regulate the MyD88-independent pathway during the innate immune response to LPS.\n" ], "offsets": [ [ 0, 1194 ] ] } ]

[ { "id": "PMID-14517278_T1", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-14517278_T2", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 4, 8 ] ], "normalized": [] }, { "id": "PMID-14517278_T3", "type": "Gene_or_gene_product", "text": [ "IRF-3" ], "offsets": [ [ 22, 27 ] ], "normalized": [] }, { "id": "PMID-14517278_T4", "type": "Gene_or_gene_product", "text": [ "7" ], "offsets": [ [ 28, 29 ] ], "normalized": [] }, { "id": "PMID-14517278_T5", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 34, 43 ] ], "normalized": [] }, { "id": "PMID-14517278_T6", "type": "Gene_or_gene_product", "text": [ "TRAM" ], "offsets": [ [ 71, 75 ] ], "normalized": [] }, { "id": "PMID-14517278_T7", "type": "Gene_or_gene_product", "text": [ "TRIF" ], "offsets": [ [ 80, 84 ] ], "normalized": [] }, { "id": "PMID-14517278_T8", "type": "Gene_or_gene_product", "text": [ "Toll-IL-1-resistance (TIR) domain-containing adaptor-inducing IFN-beta (TRIF)-related adaptor molecule" ], "offsets": [ [ 87, 189 ] ], "normalized": [] }, { "id": "PMID-14517278_T9", "type": "Gene_or_gene_product", "text": [ "TRAM" ], "offsets": [ [ 191, 195 ] ], "normalized": [] }, { "id": "PMID-14517278_T10", "type": "Gene_or_gene_product", "text": [ "TIR" ], "offsets": [ [ 211, 214 ] ], "normalized": [] }, { "id": "PMID-14517278_T11", "type": "Gene_or_gene_product", "text": [ "Toll receptor" ], "offsets": [ [ 286, 299 ] ], "normalized": [] }, { "id": "PMID-14517278_T12", "type": "Gene_or_gene_product", "text": [ "TRIF" ], "offsets": [ [ 316, 320 ] ], "normalized": [] }, { "id": "PMID-14517278_T13", "type": "Gene_or_gene_product", "text": [ "TRAM" ], "offsets": [ [ 322, 326 ] ], "normalized": [] }, { "id": "PMID-14517278_T14", "type": "Gene_or_gene_product", "text": [ "interferon regulatory factor (IRF)-3" ], "offsets": [ [ 337, 373 ] ], "normalized": [] }, { "id": "PMID-14517278_T15", "type": "Gene_or_gene_product", "text": [ "IRF-7" ], "offsets": [ [ 375, 380 ] ], "normalized": [] }, { "id": "PMID-14517278_T16", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 386, 395 ] ], "normalized": [] }, { "id": "PMID-14517278_T17", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor (TLR)3" ], "offsets": [ [ 426, 451 ] ], "normalized": [] }, { "id": "PMID-14517278_T18", "type": "Gene_or_gene_product", "text": [ "4" ], "offsets": [ [ 456, 457 ] ], "normalized": [] }, { "id": "PMID-14517278_T19", "type": "Gene_or_gene_product", "text": [ "IFN-alpha/beta" ], "offsets": [ [ 492, 506 ] ], "normalized": [] }, { "id": "PMID-14517278_T20", "type": "Gene_or_gene_product", "text": [ "regulated on activation, normal T cell expressed and secreted" ], "offsets": [ [ 508, 569 ] ], "normalized": [] }, { "id": "PMID-14517278_T21", "type": "Gene_or_gene_product", "text": [ "RANTES" ], "offsets": [ [ 571, 577 ] ], "normalized": [] }, { "id": "PMID-14517278_T22", "type": "Gene_or_gene_product", "text": [ "gamma interferon-inducible protein 10" ], "offsets": [ [ 584, 621 ] ], "normalized": [] }, { "id": "PMID-14517278_T23", "type": "Gene_or_gene_product", "text": [ "IP-10" ], "offsets": [ [ 623, 628 ] ], "normalized": [] }, { "id": "PMID-14517278_T24", "type": "Gene_or_gene_product", "text": [ "myeloid differentiation factor 88" ], "offsets": [ [ 678, 711 ] ], "normalized": [] }, { "id": "PMID-14517278_T25", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 713, 718 ] ], "normalized": [] }, { "id": "PMID-14517278_T26", "type": "Gene_or_gene_product", "text": [ "TRIF" ], "offsets": [ [ 789, 793 ] ], "normalized": [] }, { "id": "PMID-14517278_T27", "type": "Gene_or_gene_product", "text": [ "TLR3" ], "offsets": [ [ 827, 831 ] ], "normalized": [] }, { "id": "PMID-14517278_T28", "type": "Gene_or_gene_product", "text": [ "TLR4" ], "offsets": [ [ 844, 848 ] ], "normalized": [] }, { "id": "PMID-14517278_T29", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 850, 853 ] ], 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[]

[ { "id": "PMID-14555292__text", "type": "abstract", "text": [ "Pharmacological analysis of signal transduction pathways required for oxidative burst in chicken heterophils stimulated by a Toll-like receptor 2 agonist. \nToll-like receptors (TLRs) play an important role in the innate immune response of avian heterophils. We previously used the pharmacological inhibitors genistein, verapamil, chelerythrine, and pertussis toxin to investigate the upstream signaling events involved in TLR2-mediated oxidative burst in chicken heterophils. Only chelerythrine, a protein kinase C inhibitor, was found to significantly inhibit oxidative burst stimulated by the TLR2 agonist lipoteichoic acid (LTA). In the present study, we used selective pharmacological inhibitors to investigate the roles of phosphatidylinositol-3'-kinase (PI3-K), phospholipase C (PLC), calcium-dependent protein kinase C (PKC), extra-cellular signal regulated kinase (ERK), and nuclear translocation factor kappa B (NF-kappaB) on TLR2-mediated oxidative burst. U-73122 (a PLC inhibitor), wortmannin (a PI3-K inhibitor), PD 98059 (an ERK inhibitor), Go 6976 (a PKC inhibitor) and Bay 11-7082 (a NF-kappaB inhibitor) significantly decreased LTA-stimulated oxidative burst in heterophils by 77%, 30%, 36%, 78%, and 61%, respectively. Activated TLR2 utilizes PI3-K, PLC, PKC, ERK, and NF-kappaB as signaling factors that mediate the oxidative burst of chicken heterophils.\n" ], "offsets": [ [ 0, 1374 ] ] } ]

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"Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 422, 426 ] ], "normalized": [] }, { "id": "PMID-14555292_T9", "type": "Simple_chemical", "text": [ "chelerythrine" ], "offsets": [ [ 481, 494 ] ], "normalized": [] }, { "id": "PMID-14555292_T10", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 498, 514 ] ], "normalized": [] }, { "id": "PMID-14555292_T11", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 595, 599 ] ], "normalized": [] }, { "id": "PMID-14555292_T12", "type": "Simple_chemical", "text": [ "lipoteichoic acid" ], "offsets": [ [ 608, 625 ] ], "normalized": [] }, { "id": "PMID-14555292_T13", "type": "Simple_chemical", "text": [ "LTA" ], "offsets": [ [ 627, 630 ] ], "normalized": [] }, { "id": "PMID-14555292_T14", "type": "Gene_or_gene_product", "text": [ "phosphatidylinositol-3'-kinase" ], "offsets": [ [ 728, 758 ] ], "normalized": [] }, { "id": "PMID-14555292_T15", "type": "Gene_or_gene_product", "text": [ "PI3-K" ], "offsets": [ [ 760, 765 ] ], "normalized": [] }, { "id": "PMID-14555292_T16", "type": "Gene_or_gene_product", "text": [ "phospholipase C" ], "offsets": [ [ 768, 783 ] ], "normalized": [] }, { "id": "PMID-14555292_T17", "type": "Gene_or_gene_product", "text": [ "PLC" ], "offsets": [ [ 785, 788 ] ], "normalized": [] }, { "id": "PMID-14555292_T18", "type": "Simple_chemical", "text": [ "calcium" ], "offsets": [ [ 791, 798 ] ], "normalized": [] }, { "id": "PMID-14555292_T19", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 809, 825 ] ], "normalized": [] }, { "id": "PMID-14555292_T20", "type": "Gene_or_gene_product", "text": [ "PKC" ], "offsets": [ [ 827, 830 ] ], "normalized": [] }, { "id": "PMID-14555292_T21", "type": "Gene_or_gene_product", "text": [ "extra-cellular signal regulated kinase" ], "offsets": [ [ 833, 871 ] ], "normalized": [] }, { "id": "PMID-14555292_T22", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 873, 876 ] ], "normalized": [] }, { "id": "PMID-14555292_T23", "type": "Complex", "text": [ "nuclear translocation factor kappa B" ], "offsets": [ [ 883, 919 ] ], "normalized": [] }, { "id": "PMID-14555292_T24", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 921, 930 ] ], "normalized": [] }, { "id": "PMID-14555292_T25", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 935, 939 ] ], "normalized": [] }, { "id": "PMID-14555292_T26", "type": "Simple_chemical", "text": [ "U-73122" ], "offsets": [ [ 966, 973 ] ], "normalized": [] }, { "id": "PMID-14555292_T27", "type": "Gene_or_gene_product", "text": [ "PLC" ], "offsets": [ [ 977, 980 ] ], "normalized": [] }, { "id": "PMID-14555292_T28", "type": "Simple_chemical", "text": [ "wortmannin" ], "offsets": [ [ 993, 1003 ] ], "normalized": [] }, { "id": "PMID-14555292_T29", "type": "Gene_or_gene_product", "text": [ "PI3-K" ], "offsets": [ [ 1007, 1012 ] ], "normalized": [] }, { "id": "PMID-14555292_T30", "type": "Simple_chemical", "text": [ "PD 98059" ], "offsets": [ [ 1025, 1033 ] ], "normalized": [] }, { "id": "PMID-14555292_T31", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 1038, 1041 ] ], "normalized": [] }, { "id": "PMID-14555292_T32", "type": "Simple_chemical", "text": [ "Go 6976" ], "offsets": [ [ 1054, 1061 ] ], "normalized": [] }, { "id": "PMID-14555292_T33", "type": "Gene_or_gene_product", "text": [ "PKC" ], "offsets": [ [ 1065, 1068 ] ], "normalized": [] }, { "id": "PMID-14555292_T34", "type": "Simple_chemical", "text": [ "Bay 11-7082" ], "offsets": [ [ 1084, 1095 ] ], "normalized": [] }, { "id": "PMID-14555292_T35", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1099, 1108 ] ], "normalized": [] }, { "id": "PMID-14555292_T36", "type": "Simple_chemical", "text": [ "LTA" ], "offsets": [ [ 1144, 1147 ] ], "normalized": [] }, { "id": "PMID-14555292_T37", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1246, 1250 ] ], "normalized": [] }, { "id": "PMID-14555292_T38", "type": "Gene_or_gene_product", "text": [ "PI3-K" ], "offsets": [ [ 1260, 1265 ] ], "normalized": [] }, { "id": "PMID-14555292_T39", "type": "Gene_or_gene_product", "text": [ "PLC" ], "offsets": [ [ 1267, 1270 ] ], "normalized": [] }, { "id": "PMID-14555292_T40", "type": "Gene_or_gene_product", "text": [ "PKC" ], "offsets": [ [ 1272, 1275 ] ], "normalized": [] }, { "id": "PMID-14555292_T41", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 1277, 1280 ] ], "normalized": [] }, { "id": "PMID-14555292_T42", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1286, 1295 ] ], "normalized": [] } ]

[ { "id": "PMID-14555292_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 515, 524 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555292_T10" }, { "role": "Cause", "ref_id": "PMID-14555292_T9" } ] }, { "id": "PMID-14555292_E2", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 799, 808 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-14555292_T18" }, { "role": "Theme", "ref_id": "PMID-14555292_T19" } ] }, { "id": "PMID-14555292_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 981, 990 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555292_T27" }, { "role": "Cause", "ref_id": "PMID-14555292_T26" } ] }, { "id": "PMID-14555292_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1013, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555292_T29" }, { "role": "Cause", "ref_id": "PMID-14555292_T28" } ] }, { "id": "PMID-14555292_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1042, 1051 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555292_T31" }, { "role": "Cause", "ref_id": "PMID-14555292_T30" } ] }, { "id": "PMID-14555292_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1069, 1078 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555292_T33" }, { "role": "Cause", "ref_id": "PMID-14555292_T32" } ] }, { "id": "PMID-14555292_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1109, 1118 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555292_T35" }, { "role": "Cause", "ref_id": "PMID-14555292_T34" } ] }, { "id": "PMID-14555292_E8", "type": "Activation", "trigger": { "text": [ "Activated" ], "offsets": [ [ 1236, 1245 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14555292_T37" } ] } ]

[ { "id": "PMID-14555292_1", "entity_ids": [ "PMID-14555292_T2", "PMID-14555292_T3" ] }, { "id": "PMID-14555292_2", "entity_ids": [ "PMID-14555292_T12", "PMID-14555292_T13" ] }, { "id": "PMID-14555292_3", "entity_ids": [ "PMID-14555292_T14", "PMID-14555292_T15" ] }, { "id": "PMID-14555292_4", "entity_ids": [ "PMID-14555292_T16", "PMID-14555292_T17" ] }, { "id": "PMID-14555292_5", "entity_ids": [ "PMID-14555292_T19", "PMID-14555292_T20" ] }, { "id": "PMID-14555292_6", "entity_ids": [ "PMID-14555292_T21", "PMID-14555292_T22" ] }, { "id": "PMID-14555292_7", "entity_ids": [ "PMID-14555292_T23", "PMID-14555292_T24" ] } ]

[]

[ { "id": "PMID-14560958__text", "type": "abstract", "text": [ "mTOR signaling to translation. \nOver the past few years, the target of rapamycin (TOR) pathway has been implicated in the control of translation, both in yeast and in higher eukaryotes. In this review, we provide an overview of translation in eukaryotes, and discuss the mechanisms and advantages of the regulation of translation. We then describe how the TOR pathway can modulate translation in yeast and in mammals, through the modulation of the phosphorylation of key translation components, and the regulation of the abundance of ribosomes and translation factors. \n" ], "offsets": [ [ 0, 570 ] ] } ]

[ { "id": "PMID-14560958_T1", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-14560958_T2", "type": "Gene_or_gene_product", "text": [ "target of rapamycin" ], "offsets": [ [ 61, 80 ] ], "normalized": [] }, { "id": "PMID-14560958_T3", "type": "Gene_or_gene_product", "text": [ "TOR" ], "offsets": [ [ 82, 85 ] ], "normalized": [] }, { "id": "PMID-14560958_T4", "type": "Gene_or_gene_product", "text": [ "TOR" ], "offsets": [ [ 356, 359 ] ], "normalized": [] }, { "id": "PMID-14560958_T5", "type": "Cellular_component", "text": [ "ribosomes" ], "offsets": [ [ 534, 543 ] ], "normalized": [] } ]

[ { "id": "PMID-14560958_E1", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 5, 14 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-14560958_T1" } ] }, { "id": "PMID-14560958_E2", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 87, 94 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-14560958_T2" } ] }, { "id": "PMID-14560958_E3", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 360, 367 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-14560958_T4" } ] }, { "id": "PMID-14560958_E4", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 503, 513 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-14560958_E3" }, { "role": "Theme", "ref_id": "PMID-14560958_T5" } ] } ]

[ { "id": "PMID-14560958_1", "entity_ids": [ "PMID-14560958_T3", "PMID-14560958_T2" ] } ]

[]

[ { "id": "PMID-14652114__text", "type": "abstract", "text": [ "Protein phosphatases that regulate multifunctional Ca2+/calmodulin-dependent protein kinases: from biochemistry to pharmacology. \nMultifunctional Ca(2+)/calmodulin-dependent protein kinases (CaMKs) play pivotal roles in Ca(2+) signaling pathways, such as the regulation of the neuronal functions of learning, memory, and neuronal cell death. The activities of the kinases are strictly regulated by protein phosphorylation/dephosphorylation. Although the activation mechanisms for multifunctional CaMKs through phosphorylation, which correspond to \"switch on,\" have been extensively studied, the negative regulatory mechanisms through dephosphorylation, which correspond to \"switch off,\" have not. In this review, we focused on the regulation of multifunctional CaMKs by the protein phosphatases responsible. We first summarized the current understanding of negative regulation of CaMKs by known protein phosphatases and their physiological significance. We then discussed newly developed methods for detection of protein phosphatases involved in the regulation of CaMKs. We also summarized the biochemical properties of a novel protein phosphatase, which we isolated with the new methods and designated as CaMK phosphatase (CaMKP), and its homologue. Pharmacological implications for neuronal functions including memory and neuronal cell death are discussed from the viewpoint that regulation of protein kinase activity can be elucidated by focusing on protein phosphatases involved in its \"switch off\" mechanism.\n" ], "offsets": [ [ 0, 1514 ] ] } ]

[ { "id": "PMID-14652114_T1", "type": "Gene_or_gene_product", "text": [ "Ca2+/calmodulin-dependent protein kinases" ], "offsets": [ [ 51, 92 ] ], "normalized": [] }, { "id": "PMID-14652114_T2", "type": "Gene_or_gene_product", "text": [ "Ca(2+)/calmodulin-dependent protein kinases" ], "offsets": [ [ 146, 189 ] ], "normalized": [] }, { "id": "PMID-14652114_T3", "type": "Gene_or_gene_product", "text": [ "CaMKs" ], "offsets": [ [ 191, 196 ] ], "normalized": [] }, { "id": "PMID-14652114_T4", "type": "Simple_chemical", "text": [ "Ca(2+)" ], "offsets": [ [ 220, 226 ] ], "normalized": [] }, { "id": "PMID-14652114_T5", "type": "Gene_or_gene_product", "text": [ "CaMKs" ], "offsets": [ [ 496, 501 ] ], "normalized": [] }, { "id": "PMID-14652114_T6", "type": "Gene_or_gene_product", "text": [ "CaMKs" ], "offsets": [ [ 761, 766 ] ], "normalized": [] }, { "id": "PMID-14652114_T7", "type": "Gene_or_gene_product", "text": [ "CaMKs" ], "offsets": [ [ 880, 885 ] ], "normalized": [] }, { "id": "PMID-14652114_T8", "type": "Gene_or_gene_product", "text": [ "CaMKs" ], "offsets": [ [ 1064, 1069 ] ], "normalized": [] }, { "id": "PMID-14652114_T9", "type": "Gene_or_gene_product", "text": [ "CaMK phosphatase" ], "offsets": [ [ 1206, 1222 ] ], "normalized": [] }, { "id": "PMID-14652114_T10", "type": "Gene_or_gene_product", "text": [ "CaMKP" ], "offsets": [ [ 1224, 1229 ] ], "normalized": [] } ]

[ { "id": "PMID-14652114_E1", "type": "Positive_regulation", "trigger": { "text": [ "play pivotal roles" ], "offsets": [ [ 198, 216 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-14652114_T2" }, { "role": "Theme", "ref_id": "PMID-14652114_E2" } ] }, { "id": "PMID-14652114_E2", "type": "Pathway", "trigger": { "text": [ "signaling pathways" ], "offsets": [ [ 227, 245 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-14652114_T4" } ] }, { "id": "PMID-14652114_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 510, 525 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14652114_T5" } ] }, { "id": "PMID-14652114_E4", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 731, 741 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14652114_T6" } ] }, { "id": "PMID-14652114_E5", "type": "Negative_regulation", "trigger": { "text": [ "negative regulation" ], "offsets": [ [ 857, 876 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14652114_T7" } ] }, { "id": "PMID-14652114_E6", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1050, 1060 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14652114_T8" } ] } ]

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[]

[ { "id": "PMID-14662871__text", "type": "abstract", "text": [ "Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk. \nDysregulation of the initial, innate immune response to bacterial infection may lead to septic shock and death. Toll-like receptors (TLRs) play a crucial role in this innate immune response, and yet the regulatory mechanisms controlling microbial-induced TLR triggering are still to be fully understood. We have therefore sought specific regulatory mechanisms that may modulate TLR signaling. In this study, we tested for the possible existence of a functionally active soluble form of TLR2. We demonstrated the existence of natural soluble forms of TLR2 (sTLR2), which we show to be capable of modulating cell activation. We found that blood monocytes released sTLR2 constitutively and that the kinetics of sTLR2 release increased upon cell activation. Analysis of cells expressing the human TLR2 cDNA or its c-myc-tagged version indicated that sTLR2 resulted from the posttranslational modification of the TLR2 protein in an intracellular compartment. Moreover, an intracellular pool of sTLR2 is maintained. sTLR2 was found naturally expressed in breast milk and plasma. Milk sTLR2 levels mirrored those of the TLR coreceptor soluble CD14. Depletion of sTLR2 from serum resulted in an increased cellular response to bacterial lipopeptide. Notably, serum sTLR2 was lower in tuberculosis patients. Coimmunoprecipitation experiments and computational molecular docking studies showed an interaction between sTLR2 and soluble CD14 in plasma and milk. These findings suggest the existence of a novel and specific innate immune mechanism regulating microbial-induced TLR triggering, and may lead to new therapeutics for the prevention and/or treatment of severe infectious diseases.\n" ], "offsets": [ [ 0, 1805 ] ] } ]

[ { "id": "PMID-14662871_T1", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor (TLR)2" ], "offsets": [ [ 17, 42 ] ], "normalized": [] }, { "id": "PMID-14662871_T2", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 65, 69 ] ], "normalized": [] }, { "id": "PMID-14662871_T3", "type": "Gene_or_gene_product", "text": [ "Toll-like receptors" ], "offsets": [ [ 238, 257 ] ], "normalized": [] }, { "id": "PMID-14662871_T4", "type": "Gene_or_gene_product", "text": [ "TLRs" ], "offsets": [ [ 259, 263 ] ], "normalized": [] }, { "id": "PMID-14662871_T5", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 381, 384 ] ], "normalized": [] }, { "id": "PMID-14662871_T6", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 504, 507 ] ], "normalized": [] }, { "id": "PMID-14662871_T7", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 612, 616 ] ], "normalized": [] }, { "id": "PMID-14662871_T8", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 676, 680 ] ], "normalized": [] }, { "id": "PMID-14662871_T9", "type": "Gene_or_gene_product", "text": [ "sTLR2" ], "offsets": [ [ 682, 687 ] ], "normalized": [] }, { "id": "PMID-14662871_T10", "type": "Gene_or_gene_product", "text": [ "sTLR2" ], "offsets": [ [ 788, 793 ] ], "normalized": [] }, { "id": "PMID-14662871_T11", "type": "Gene_or_gene_product", "text": [ "sTLR2" ], "offsets": [ [ 834, 839 ] ], "normalized": [] }, { "id": "PMID-14662871_T12", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 919, 923 ] ], "normalized": [] }, { "id": "PMID-14662871_T13", "type": "Gene_or_gene_product", "text": [ "c-myc" ], "offsets": [ [ 936, 941 ] ], "normalized": [] }, { "id": "PMID-14662871_T14", "type": "Gene_or_gene_product", "text": [ "sTLR2" ], "offsets": [ [ 972, 977 ] ], "normalized": [] }, { "id": "PMID-14662871_T15", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1034, 1038 ] ], "normalized": [] }, { "id": "PMID-14662871_T16", "type": "Cellular_component", "text": [ "intracellular compartment" ], "offsets": [ [ 1053, 1078 ] ], "normalized": [] }, { "id": "PMID-14662871_T17", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 1093, 1106 ] ], "normalized": [] }, { "id": "PMID-14662871_T18", "type": "Gene_or_gene_product", "text": [ "sTLR2" ], "offsets": [ [ 1115, 1120 ] ], "normalized": [] }, { "id": "PMID-14662871_T19", "type": "Gene_or_gene_product", "text": [ "sTLR2" ], "offsets": [ [ 1136, 1141 ] ], "normalized": [] }, { "id": "PMID-14662871_T20", "type": "Gene_or_gene_product", "text": [ "sTLR2" ], "offsets": [ [ 1204, 1209 ] ], "normalized": [] }, { "id": "PMID-14662871_T21", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 1239, 1242 ] ], "normalized": [] }, { "id": "PMID-14662871_T22", "type": "Gene_or_gene_product", "text": [ "CD14" ], "offsets": [ [ 1262, 1266 ] ], "normalized": [] }, { "id": "PMID-14662871_T23", "type": "Gene_or_gene_product", "text": [ "sTLR2" ], "offsets": [ [ 1281, 1286 ] ], "normalized": [] }, { "id": "PMID-14662871_T24", "type": "Simple_chemical", "text": [ "lipopeptide" ], "offsets": [ [ 1354, 1365 ] ], "normalized": [] }, { "id": "PMID-14662871_T25", "type": "Gene_or_gene_product", "text": [ "sTLR2" ], "offsets": [ [ 1382, 1387 ] ], "normalized": [] }, { "id": "PMID-14662871_T26", "type": "Gene_or_gene_product", "text": [ "sTLR2" ], "offsets": [ [ 1532, 1537 ] ], "normalized": [] }, { "id": "PMID-14662871_T27", "type": "Gene_or_gene_product", "text": [ "CD14" ], "offsets": [ [ 1550, 1554 ] ], "normalized": [] }, { "id": "PMID-14662871_T28", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 1689, 1692 ] ], "normalized": [] } ]

[ { "id": "PMID-14662871_E1", "type": "Positive_regulation", "trigger": { "text": [ "modulating" ], "offsets": [ [ 54, 64 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14662871_E2" }, { "role": "Cause", "ref_id": "PMID-14662871_T1" } ] }, { "id": "PMID-14662871_E2", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 70, 79 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-14662871_T2" } ] }, { "id": "PMID-14662871_E3", "type": "Positive_regulation", "trigger": { "text": [ "modulate" ], "offsets": [ [ 495, 503 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14662871_E4" } ] }, { "id": "PMID-14662871_E4", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 508, 517 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-14662871_T6" } ] }, { "id": "PMID-14662871_E5", "type": "Activation", "trigger": { "text": [ "active" ], "offsets": [ [ 589, 595 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14662871_T7" } ] }, { "id": "PMID-14662871_E6", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1162, 1171 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14662871_T19" } ] }, { "id": "PMID-14662871_E7", "type": "Negative_regulation", "trigger": { "text": [ "Depletion" ], "offsets": [ [ 1268, 1277 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14662871_T23" } ] }, { "id": "PMID-14662871_E8", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1512, 1523 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14662871_T26" }, { "role": "Theme", "ref_id": "PMID-14662871_T27" } ] } ]

[ { "id": "PMID-14662871_1", "entity_ids": [ "PMID-14662871_T3", "PMID-14662871_T4" ] }, { "id": "PMID-14662871_2", "entity_ids": [ "PMID-14662871_T8", "PMID-14662871_T9" ] } ]

[]

[ { "id": "PMID-14715500__text", "type": "abstract", "text": [ "Vasoactive effects of methylamine in isolated human blood vessels: role of semicarbazide-sensitive amine oxidase, formaldehyde, and hydrogen peroxide. \nIt is hypothesized that methylamine (MA) and semicarbazide-sensitive amine oxidase (SSAO) activity are involved in the cardiovascular complications in human diabetics. To test this, we 1) determined the acute vasoactive effects of MA (1-1,000 micromol/l) in uncontracted and norepinephrine (NE; 1 micromol/l)-precontracted human blood vessels used for coronary artery bypass grafts [left internal mammary artery (LIMA), radial artery (RA), and right saphenous vein (RSV)]; 2) tested whether MA effects in LIMA and RSV were dependent on SSAO activity using the SSAO inhibitor semicarbazide (1 mmol/l, 15 min); 3) determined the effects of MA metabolites formaldehyde and hydrogen peroxide in LIMA and RSV; 4) tested whether the MA response was nitric oxide, prostaglandin, or hyperpolarization dependent; 5) measured the LIMA and RSV cGMP levels after MA exposure; and 6) quantified SSAO activity in LIMA, RA, and RSV. In NE-precontracted vessels, MA stimulated a biphasic response in RA and RSV (rapid contraction followed by prolonged relaxation) and dominant relaxation in LIMA (mean +/- SE, %relaxation: 55.4 +/- 3.9, n = 30). The MA-induced relaxation in LIMA was repeatable, nontoxic, and age independent. Semicarbazide significantly blocked MA-induced relaxation (%inhibition: 82.5 +/- 4.8, n = 7) and SSAO activity (%inhibition: 98.1 +/- 1.3, n = 26) in LIMA. Formaldehyde (%relaxation: 37.3 +/- 18.6, n = 3) and H(2)O(2) (%relaxation: 55.6 +/- 9.0, n = 9) at 1 mmol/l relaxed NE-precontracted LIMA comparable with MA. MA-induced relaxation in LIMA was nitric oxide, prostaglandin, and possibly cGMP independent and blocked by hyperpolarization. We conclude that vascular SSAO activity may convert endogenous amines, like MA, to vasoactive metabolites.\n" ], "offsets": [ [ 0, 1912 ] ] } ]

[ { "id": "PMID-14715500_T1", "type": "Simple_chemical", "text": [ "methylamine" ], "offsets": [ [ 22, 33 ] ], "normalized": [] }, { "id": "PMID-14715500_T2", "type": "Gene_or_gene_product", "text": [ "semicarbazide-sensitive amine oxidase" ], "offsets": [ [ 75, 112 ] ], "normalized": [] }, { "id": "PMID-14715500_T3", "type": "Simple_chemical", "text": [ "formaldehyde" ], "offsets": [ [ 114, 126 ] ], "normalized": [] }, { "id": "PMID-14715500_T4", "type": "Simple_chemical", "text": [ "hydrogen peroxide" ], "offsets": [ [ 132, 149 ] ], "normalized": [] }, { "id": "PMID-14715500_T5", "type": "Simple_chemical", "text": [ "methylamine" ], "offsets": [ [ 176, 187 ] ], "normalized": [] }, { "id": "PMID-14715500_T6", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 189, 191 ] ], "normalized": [] }, { "id": "PMID-14715500_T7", "type": "Gene_or_gene_product", "text": [ "semicarbazide-sensitive amine oxidase" ], "offsets": [ [ 197, 234 ] ], "normalized": [] }, { "id": "PMID-14715500_T8", "type": "Gene_or_gene_product", "text": [ "SSAO" ], "offsets": [ [ 236, 240 ] ], "normalized": [] }, { "id": "PMID-14715500_T9", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 383, 385 ] ], "normalized": [] }, { "id": "PMID-14715500_T10", "type": "Simple_chemical", "text": [ "norepinephrine" ], "offsets": [ [ 427, 441 ] ], "normalized": [] }, { "id": "PMID-14715500_T11", "type": "Simple_chemical", "text": [ "NE" ], "offsets": [ [ 443, 445 ] ], "normalized": [] }, { "id": "PMID-14715500_T12", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 643, 645 ] ], "normalized": [] }, { "id": "PMID-14715500_T13", "type": "Gene_or_gene_product", "text": [ "SSAO" ], "offsets": [ [ 688, 692 ] ], "normalized": [] }, { "id": "PMID-14715500_T14", "type": "Gene_or_gene_product", "text": [ "SSAO" ], "offsets": [ [ 712, 716 ] ], "normalized": [] }, { "id": "PMID-14715500_T15", "type": "Simple_chemical", "text": [ "semicarbazide" ], "offsets": [ [ 727, 740 ] ], "normalized": [] }, { "id": "PMID-14715500_T16", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 790, 792 ] ], "normalized": [] }, { "id": "PMID-14715500_T17", "type": "Simple_chemical", "text": [ "formaldehyde" ], "offsets": [ [ 805, 817 ] ], "normalized": [] }, { "id": "PMID-14715500_T18", "type": "Simple_chemical", "text": [ "hydrogen peroxide" ], "offsets": [ [ 822, 839 ] ], "normalized": [] }, { "id": "PMID-14715500_T19", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 879, 881 ] ], "normalized": [] }, { "id": "PMID-14715500_T20", "type": "Simple_chemical", "text": [ "nitric oxide" ], "offsets": [ [ 895, 907 ] ], "normalized": [] }, { "id": "PMID-14715500_T21", "type": "Simple_chemical", "text": [ "prostaglandin" ], "offsets": [ [ 909, 922 ] ], "normalized": [] }, { "id": "PMID-14715500_T22", "type": "Simple_chemical", "text": [ "cGMP" ], "offsets": [ [ 985, 989 ] ], "normalized": [] }, { "id": "PMID-14715500_T23", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 1003, 1005 ] ], "normalized": [] }, { "id": "PMID-14715500_T24", "type": "Gene_or_gene_product", "text": [ "SSAO" ], "offsets": [ [ 1034, 1038 ] ], "normalized": [] }, { "id": "PMID-14715500_T25", "type": "Simple_chemical", "text": [ "NE" ], "offsets": [ [ 1073, 1075 ] ], "normalized": [] }, { "id": "PMID-14715500_T26", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 1099, 1101 ] ], "normalized": [] }, { "id": "PMID-14715500_T27", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 1286, 1288 ] ], "normalized": [] }, { "id": "PMID-14715500_T28", "type": "Simple_chemical", "text": [ "Semicarbazide" ], "offsets": [ [ 1363, 1376 ] ], "normalized": [] }, { "id": "PMID-14715500_T29", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 1399, 1401 ] ], "normalized": [] }, { "id": "PMID-14715500_T30", "type": "Gene_or_gene_product", "text": [ "SSAO" ], "offsets": [ [ 1460, 1464 ] ], "normalized": [] }, { "id": "PMID-14715500_T31", "type": "Simple_chemical", "text": [ "Formaldehyde" ], "offsets": [ [ 1519, 1531 ] ], "normalized": [] }, { "id": "PMID-14715500_T32", "type": "Simple_chemical", "text": [ "H(2)O(2)" ], "offsets": [ [ 1572, 1580 ] ], "normalized": [] }, { "id": "PMID-14715500_T33", "type": "Simple_chemical", "text": [ "NE" ], "offsets": [ [ 1636, 1638 ] ], "normalized": [] }, { "id": "PMID-14715500_T34", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 1674, 1676 ] ], "normalized": [] }, { "id": "PMID-14715500_T35", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 1678, 1680 ] ], "normalized": [] }, { "id": "PMID-14715500_T36", "type": "Simple_chemical", "text": [ "nitric oxide" ], "offsets": [ [ 1712, 1724 ] ], "normalized": [] }, { "id": "PMID-14715500_T37", "type": "Simple_chemical", "text": [ "prostaglandin" ], "offsets": [ [ 1726, 1739 ] ], "normalized": [] }, { "id": "PMID-14715500_T38", "type": "Simple_chemical", "text": [ "cGMP" ], "offsets": [ [ 1754, 1758 ] ], "normalized": [] }, { "id": "PMID-14715500_T39", "type": "Gene_or_gene_product", "text": [ "SSAO" ], "offsets": [ [ 1831, 1835 ] ], "normalized": [] }, { "id": "PMID-14715500_T40", "type": "Simple_chemical", "text": [ "amines" ], "offsets": [ [ 1868, 1874 ] ], "normalized": [] }, { "id": "PMID-14715500_T41", "type": "Simple_chemical", "text": [ "MA" ], "offsets": [ [ 1881, 1883 ] ], "normalized": [] } ]

[ { "id": "PMID-14715500_E1", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 675, 684 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-14715500_T13" }, { "role": "Theme", "ref_id": "PMID-14715500_T12" } ] }, { "id": "PMID-14715500_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 717, 726 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-14715500_T15" }, { "role": "Theme", "ref_id": "PMID-14715500_T14" } ] }, { "id": "PMID-14715500_E3", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 945, 954 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14715500_T19" }, { "role": "Cause", "ref_id": "PMID-14715500_T20" } ] }, { "id": "PMID-14715500_E4", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 945, 954 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14715500_T19" }, { "role": "Cause", "ref_id": "PMID-14715500_T21" } ] }, { "id": "PMID-14715500_E5", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1391, 1398 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14715500_T30" }, { "role": "Cause", "ref_id": "PMID-14715500_T28" } ] }, { "id": "PMID-14715500_E6", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 1759, 1770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14715500_T35" }, { "role": "Cause", "ref_id": "PMID-14715500_T36" } ] }, { "id": "PMID-14715500_E7", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 1759, 1770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14715500_T35" }, { "role": "Cause", "ref_id": "PMID-14715500_T37" } ] }, { "id": "PMID-14715500_E8", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 1759, 1770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14715500_T35" }, { "role": "Cause", "ref_id": "PMID-14715500_T38" } ] }, { "id": "PMID-14715500_E9", "type": "Conversion", "trigger": { "text": [ "convert" ], "offsets": [ [ 1849, 1856 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14715500_T41" } ] }, { "id": "PMID-14715500_E10", "type": "Positive_regulation", "trigger": { "text": [ "convert" ], "offsets": [ [ 1849, 1856 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14715500_E9" }, { "role": "Cause", "ref_id": "PMID-14715500_T39" } ] } ]

[ { "id": "PMID-14715500_1", "entity_ids": [ "PMID-14715500_T6", "PMID-14715500_T5" ] }, { "id": "PMID-14715500_2", "entity_ids": [ "PMID-14715500_T7", "PMID-14715500_T8" ] }, { "id": "PMID-14715500_3", "entity_ids": [ "PMID-14715500_T10", "PMID-14715500_T11" ] } ]

[]

[ { "id": "PMID-14966129__text", "type": "abstract", "text": [ "Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates. \nAminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and BW2315 are sulfamido-bridged 5,8-dideazafolate analogs with remarkably potent K(i) values of 8 and 6 nm, respectively, compared with most other antifolates. Crystal structures of ATIC at 2.55 and 2.60 A with each inhibitor, in the presence of substrate AICAR, revealed that the sulfonyl groups dominate inhibitor binding and orientation through interaction with the proposed oxyanion hole. These agents then appear to mimic the anionic transition state and now implicate Asn(431') in the reaction mechanism along with previously identified key catalytic residues Lys(266) and His(267). Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonyl-containing antifolates.\n" ], "offsets": [ [ 0, 1270 ] ] } ]

[ { "id": "PMID-14966129_T1", "type": "Gene_or_gene_product", "text": [ "aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase" ], "offsets": [ [ 48, 125 ] ], "normalized": [] }, { "id": "PMID-14966129_T2", "type": "Simple_chemical", "text": [ "sulfonyl" ], "offsets": [ [ 149, 157 ] ], "normalized": [] }, { "id": "PMID-14966129_T3", "type": "Simple_chemical", "text": [ "antifolates" ], "offsets": [ [ 169, 180 ] ], "normalized": [] }, { "id": "PMID-14966129_T4", "type": "Gene_or_gene_product", "text": [ "Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase" ], "offsets": [ [ 183, 268 ] ], "normalized": [] }, { "id": "PMID-14966129_T5", "type": "Gene_or_gene_product", "text": [ "ATIC" ], "offsets": [ [ 270, 274 ] ], "normalized": [] }, { "id": "PMID-14966129_T6", "type": "Simple_chemical", "text": [ "folate" ], "offsets": [ [ 306, 312 ] ], "normalized": [] }, { "id": "PMID-14966129_T7", "type": "Gene_or_gene_product", "text": [ "AICAR transformylase" ], "offsets": [ [ 323, 343 ] ], "normalized": [] }, { "id": "PMID-14966129_T8", "type": "Gene_or_gene_product", "text": [ "IMP cyclohydrolase" ], "offsets": [ [ 348, 366 ] ], "normalized": [] }, { "id": "PMID-14966129_T9", "type": "Simple_chemical", "text": [ "purine" ], "offsets": [ [ 415, 421 ] ], "normalized": [] }, { "id": "PMID-14966129_T10", "type": "Gene_or_gene_product", "text": [ "AICAR transformylase" ], "offsets": [ [ 440, 460 ] ], "normalized": [] }, { "id": "PMID-14966129_T11", "type": "Simple_chemical", "text": [ "BW1540" ], "offsets": [ [ 472, 478 ] ], "normalized": [] }, { "id": "PMID-14966129_T12", "type": "Simple_chemical", "text": [ "BW2315" ], "offsets": [ [ 483, 489 ] ], "normalized": [] }, { "id": "PMID-14966129_T13", "type": "Simple_chemical", "text": [ "sulfamido" ], "offsets": [ [ 494, 503 ] ], "normalized": [] }, { "id": "PMID-14966129_T14", "type": "Simple_chemical", "text": [ "5,8-dideazafolate" ], "offsets": [ [ 512, 529 ] ], "normalized": [] }, { "id": "PMID-14966129_T15", "type": "Simple_chemical", "text": [ "antifolates" ], "offsets": [ [ 627, 638 ] ], "normalized": [] }, { "id": "PMID-14966129_T16", "type": "Gene_or_gene_product", "text": [ "ATIC" ], "offsets": [ [ 662, 666 ] ], "normalized": [] }, { "id": "PMID-14966129_T17", "type": "Gene_or_gene_product", "text": [ "AICAR" ], "offsets": [ [ 736, 741 ] ], "normalized": [] }, { "id": "PMID-14966129_T18", "type": "Simple_chemical", "text": [ "sulfonyl" ], "offsets": [ [ 761, 769 ] ], "normalized": [] }, { "id": "PMID-14966129_T19", "type": "Simple_chemical", "text": [ "oxyanion" ], "offsets": [ [ 858, 866 ] ], "normalized": [] }, { "id": "PMID-14966129_T20", "type": "Simple_chemical", "text": [ "Asn(431')" ], "offsets": [ [ 954, 963 ] ], "normalized": [] }, { "id": "PMID-14966129_T21", "type": "Simple_chemical", "text": [ "Lys(266)" ], "offsets": [ [ 1046, 1054 ] ], "normalized": [] }, { "id": "PMID-14966129_T22", "type": "Simple_chemical", "text": [ "His(267)" ], "offsets": [ [ 1059, 1067 ] ], "normalized": [] }, { "id": "PMID-14966129_T23", "type": "Gene_or_gene_product", "text": [ "AICAR transformylase" ], "offsets": [ [ 1108, 1128 ] ], "normalized": [] }, { "id": "PMID-14966129_T24", "type": "Simple_chemical", "text": [ "folate" ], "offsets": [ [ 1162, 1168 ] ], "normalized": [] }, { "id": "PMID-14966129_T25", "type": "Simple_chemical", "text": [ "sulfonyl" ], "offsets": [ [ 1237, 1245 ] ], "normalized": [] }, { "id": "PMID-14966129_T26", "type": "Simple_chemical", "text": [ "antifolates" ], "offsets": [ [ 1257, 1268 ] ], "normalized": [] } ]

[ { "id": "PMID-14966129_E1", "type": "Binding", "trigger": { "text": [ "complex" ], "offsets": [ [ 129, 136 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14966129_T2" }, { "role": "Theme", "ref_id": "PMID-14966129_T3" }, { "role": "Theme", "ref_id": "PMID-14966129_T1" } ] }, { "id": "PMID-14966129_E2", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 313, 322 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-14966129_T6" }, { "role": "Theme", "ref_id": "PMID-14966129_T7" } ] }, { "id": "PMID-14966129_E3", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 313, 322 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-14966129_T6" }, { "role": "Theme", "ref_id": "PMID-14966129_T8" } ] }, { "id": "PMID-14966129_E4", "type": "Positive_regulation", "trigger": { "text": [ "catalyzes" ], "offsets": [ [ 383, 392 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14966129_E5" }, { "role": "Cause", "ref_id": "PMID-14966129_T4" } ] }, { "id": "PMID-14966129_E5", "type": "Conversion", "trigger": { "text": [ "biosynthesis" ], "offsets": [ [ 422, 434 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-14966129_T9" } ] }, { "id": "PMID-14966129_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 461, 471 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14966129_T10" }, { "role": "Cause", "ref_id": "PMID-14966129_T11" } ] }, { "id": "PMID-14966129_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 461, 471 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14966129_T10" }, { "role": "Cause", "ref_id": "PMID-14966129_T12" } ] }, { "id": "PMID-14966129_E8", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 696, 705 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14966129_T16" }, { "role": "Cause", "ref_id": "PMID-14966129_T11" } ] }, { "id": "PMID-14966129_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 696, 705 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14966129_T16" }, { "role": "Cause", "ref_id": "PMID-14966129_T12" } ] }, { "id": "PMID-14966129_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1090, 1100 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-14966129_T23" } ] } ]

[ { "id": "PMID-14966129_1", "entity_ids": [ "PMID-14966129_T4", "PMID-14966129_T5" ] } ]

[]

[ { "id": "PMID-15024086__text", "type": "abstract", "text": [ "A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. \nEukaryotic elongation factor 2 (eEF2) kinase is an unusual calcium- and calmodulin-dependent protein kinase that is regulated by insulin through the rapamycin-sensitive mTOR pathway. Here we show that insulin decreases the ability of eEF2 kinase to bind calmodulin in a rapamycin-sensitive manner. We identify a novel phosphorylation site in eEF2 kinase (Ser78) that is located immediately next to its calmodulin-binding motif. Phosphorylation of this site is increased by insulin in a rapamycin-sensitive fashion. Regulation of the phosphorylation of Ser78 also requires amino acids and the protein kinase phosphoinositide-dependent kinase 1. Mutation of this site to alanine strongly attenuates the effects of insulin and rapamycin both on the binding of calmodulin to eEF2 kinase and on eEF2 kinase activity. Phosphorylation of Ser78 is thus likely to link insulin and mTOR signaling to the control of eEF2 phosphorylation and chain elongation. This site is not a target for known kinases in the mTOR pathway, e.g., the S6 kinases, implying that it is phosphorylated by a novel mTOR-linked protein kinase that serves to couple hormones and amino acids to the control of translation elongation. eEF2 kinase is thus a target for mTOR signaling independently of previously known downstream components of the pathway. \n" ], "offsets": [ [ 0, 1461 ] ] } ]

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[]

[]

[ { "id": "PMID-15043811__text", "type": "abstract", "text": [ "The replication fork block protein Fob1 functions as a negative regulator of the FEAR network. \nBACKGROUND: The protein phosphatase Cdc14 is a key regulator of exit from mitosis in budding yeast. Its activation during anaphase is characterized by dissociation from its inhibitor Cfi1/Net1 in the nucleolus and is controlled by two regulatory networks. The Cdc14 early anaphase release (FEAR) network promotes activation of the phosphatase during early anaphase, whereas the mitotic exit network (MEN) activates Cdc14 during late stages of anaphase. RESULTS: Here we investigate how the FEAR network component Spo12 regulates Cdc14 activation. We identify the replication fork block protein Fob1 as a Spo12-interacting factor. Inactivation of FOB1 leads to premature release of Cdc14 from the nucleolus in metaphase-arrested cells. Conversely, high levels of FOB1 delay the release of Cdc14 from the nucleolus. Fob1 associates with Cfi1/Net1, and consistent with this observation, we find that the bulk of Cdc14 localizes to the Fob1 binding region within the rDNA repeats. Finally, we show that Spo12 phosphorylation is cell cycle regulated and affects its binding to Fob1. CONCLUSIONS: Fob1 functions as a negative regulator of the FEAR network. We propose that Fob1 helps to prevent the dissociation of Cdc14 from Cfi1/Net1 prior to anaphase and that Spo12 activation during early anaphase promotes the release of Cdc14 from its inhibitor by antagonizing Fob1 function.\n" ], "offsets": [ [ 0, 1472 ] ] } ]

[ { "id": "PMID-15043811_T1", "type": "Gene_or_gene_product", "text": [ "Fob1" ], "offsets": [ [ 35, 39 ] ], "normalized": [] }, { "id": "PMID-15043811_T2", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 132, 137 ] ], "normalized": [] }, { "id": "PMID-15043811_T3", "type": "Gene_or_gene_product", "text": [ "Cfi1" ], "offsets": [ [ 279, 283 ] ], "normalized": [] }, { "id": "PMID-15043811_T4", "type": "Gene_or_gene_product", "text": [ "Net1" ], "offsets": [ [ 284, 288 ] ], "normalized": [] }, { "id": "PMID-15043811_T5", "type": "Cellular_component", "text": [ "nucleolus" ], "offsets": [ [ 296, 305 ] ], "normalized": [] }, { "id": "PMID-15043811_T6", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 356, 361 ] ], "normalized": [] }, { "id": "PMID-15043811_T7", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 511, 516 ] ], "normalized": [] }, { "id": "PMID-15043811_T8", "type": "Gene_or_gene_product", "text": [ "Spo12" ], "offsets": [ [ 609, 614 ] ], "normalized": [] }, { "id": "PMID-15043811_T9", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 625, 630 ] ], "normalized": [] }, { "id": "PMID-15043811_T10", "type": "Gene_or_gene_product", "text": [ "Fob1" ], "offsets": [ [ 690, 694 ] ], "normalized": [] }, { "id": "PMID-15043811_T11", "type": "Gene_or_gene_product", "text": [ "Spo12" ], "offsets": [ [ 700, 705 ] ], "normalized": [] }, { "id": "PMID-15043811_T12", "type": "Gene_or_gene_product", "text": [ "FOB1" ], "offsets": [ [ 742, 746 ] ], "normalized": [] }, { "id": "PMID-15043811_T13", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 777, 782 ] ], "normalized": [] }, { "id": "PMID-15043811_T14", "type": "Cellular_component", "text": [ "nucleolus" ], "offsets": [ [ 792, 801 ] ], "normalized": [] }, { "id": "PMID-15043811_T15", "type": "Gene_or_gene_product", "text": [ "FOB1" ], "offsets": [ [ 858, 862 ] ], "normalized": [] }, { "id": "PMID-15043811_T16", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 884, 889 ] ], "normalized": [] }, { "id": "PMID-15043811_T17", "type": "Cellular_component", "text": [ "nucleolus" ], "offsets": [ [ 899, 908 ] ], "normalized": [] }, { "id": "PMID-15043811_T18", "type": "Gene_or_gene_product", "text": [ "Fob1" ], "offsets": [ [ 910, 914 ] ], "normalized": [] }, { "id": "PMID-15043811_T19", "type": "Gene_or_gene_product", "text": [ "Cfi1" ], "offsets": [ [ 931, 935 ] ], "normalized": [] }, { "id": "PMID-15043811_T20", "type": "Gene_or_gene_product", "text": [ "Net1" ], "offsets": [ [ 936, 940 ] ], "normalized": [] }, { "id": "PMID-15043811_T21", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 1005, 1010 ] ], "normalized": [] }, { "id": "PMID-15043811_T22", "type": "Gene_or_gene_product", "text": [ "Fob1" ], "offsets": [ [ 1028, 1032 ] ], "normalized": [] }, { "id": "PMID-15043811_T23", "type": "Gene_or_gene_product", "text": [ "Spo12" ], "offsets": [ [ 1095, 1100 ] ], "normalized": [] }, { "id": "PMID-15043811_T24", "type": "Gene_or_gene_product", "text": [ "Fob1" ], "offsets": [ [ 1168, 1172 ] ], "normalized": [] }, { "id": "PMID-15043811_T25", "type": "Gene_or_gene_product", "text": [ "Fob1" ], "offsets": [ [ 1187, 1191 ] ], "normalized": [] }, { "id": "PMID-15043811_T26", "type": "Gene_or_gene_product", "text": [ "Fob1" ], "offsets": [ [ 1263, 1267 ] ], "normalized": [] }, { "id": "PMID-15043811_T27", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 1305, 1310 ] ], "normalized": [] }, { "id": "PMID-15043811_T28", "type": "Gene_or_gene_product", "text": [ "Cfi1" ], "offsets": [ [ 1316, 1320 ] ], "normalized": [] }, { "id": "PMID-15043811_T29", "type": "Gene_or_gene_product", "text": [ "Net1" ], "offsets": [ [ 1321, 1325 ] ], "normalized": [] }, { "id": "PMID-15043811_T30", "type": "Gene_or_gene_product", "text": [ "Spo12" ], "offsets": [ [ 1353, 1358 ] ], "normalized": [] }, { "id": "PMID-15043811_T31", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 1416, 1421 ] ], "normalized": [] }, { "id": "PMID-15043811_T32", "type": "Gene_or_gene_product", "text": [ "Fob1" ], "offsets": [ [ 1457, 1461 ] ], "normalized": [] } ]

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"Negative_regulation", "trigger": { "text": [ "antagonizing" ], "offsets": [ [ 1444, 1456 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15043811_T32" } ] } ]

[ { "id": "PMID-15043811_1", "entity_ids": [ "PMID-15043811_T3", "PMID-15043811_T4" ] }, { "id": "PMID-15043811_2", "entity_ids": [ "PMID-15043811_T19", "PMID-15043811_T20" ] }, { "id": "PMID-15043811_3", "entity_ids": [ "PMID-15043811_T28", "PMID-15043811_T29" ] } ]

[]

[ { "id": "PMID-15105421__text", "type": "abstract", "text": [ "The proapoptotic gene SIVA is a direct transcriptional target for the tumor suppressors p53 and E2F1. \nThe p53 tumor suppressor gene is believed to play an important role in neuronal cell death in acute neurological disease and in neurodegeneration. The p53 signaling cascade is complex, and the mechanism by which p53 induces apoptosis is cell type-dependent. Using DNA microarray analysis, we have found a striking induction of the proapoptotic gene, SIVA. SIVA is a proapoptotic protein containing a death domain and interacts with members of the tumor necrosis factor receptor family as well as anti-apoptotic Bcl-2 family proteins. SIVA is induced following direct p53 gene delivery, treatment with a DNA-damaging agent camptothecin, and stroke injury in vivo. SIVA up-regulation is sufficient to initiate the apoptotic cascade in neurons. Through isolation and analysis of the SIVA promoter, we have identified response elements for both p53 and E2F1. Like p53, E2F1 is another tumor suppressor gene involved in the regulation of apoptosis, including neuronal injury models. We have identified E2F consensus sites in the promoter region, whereas p53 recognition sequences were found in intron1. Sequence analysis has shown that these consensus sites are also conserved between mouse and human SIVA genes. Electrophoretic mobility shift assays reveal that both transcription factors are capable of binding to putative consensus sites, and luciferase reporter assays reveal that E2F1 and p53 can activate transcription from the SIVA promoter. Here, we report that the proapoptotic gene, SIVA, which functions in a broad spectrum of cell types, is a direct transcriptional target for both tumor suppressors, p53 and E2F1.\n" ], "offsets": [ [ 0, 1725 ] ] } ]

[ { "id": "PMID-15105421_T1", "type": "Gene_or_gene_product", "text": [ "SIVA" ], "offsets": [ [ 22, 26 ] ], "normalized": [] }, { "id": "PMID-15105421_T2", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 88, 91 ] ], "normalized": [] }, { "id": "PMID-15105421_T3", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 96, 100 ] ], "normalized": [] }, { "id": "PMID-15105421_T4", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 107, 110 ] ], "normalized": [] }, { "id": "PMID-15105421_T5", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 254, 257 ] ], "normalized": [] }, { "id": "PMID-15105421_T6", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 315, 318 ] ], "normalized": [] }, { "id": "PMID-15105421_T7", "type": "Gene_or_gene_product", "text": [ "SIVA" ], "offsets": [ [ 453, 457 ] ], "normalized": [] }, { "id": "PMID-15105421_T8", "type": "Gene_or_gene_product", "text": [ "SIVA" ], "offsets": [ [ 459, 463 ] ], "normalized": [] }, { "id": "PMID-15105421_T9", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor receptor" ], "offsets": [ [ 550, 580 ] ], "normalized": [] }, { "id": "PMID-15105421_T10", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 614, 619 ] ], "normalized": [] }, { "id": "PMID-15105421_T11", "type": "Gene_or_gene_product", "text": [ "SIVA" ], "offsets": [ [ 637, 641 ] ], "normalized": [] }, { "id": "PMID-15105421_T12", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 670, 673 ] ], "normalized": [] }, { "id": "PMID-15105421_T13", "type": "Simple_chemical", "text": [ "camptothecin" ], "offsets": [ [ 725, 737 ] ], "normalized": [] }, { "id": "PMID-15105421_T14", "type": "Gene_or_gene_product", "text": [ "SIVA" ], "offsets": [ [ 766, 770 ] ], "normalized": [] }, { "id": "PMID-15105421_T15", "type": "Gene_or_gene_product", "text": [ "SIVA" ], "offsets": [ [ 883, 887 ] ], "normalized": [] }, { "id": "PMID-15105421_T16", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 944, 947 ] ], "normalized": [] }, { "id": "PMID-15105421_T17", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 952, 956 ] ], "normalized": [] }, { "id": "PMID-15105421_T18", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 963, 966 ] ], "normalized": [] }, { "id": "PMID-15105421_T19", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 968, 972 ] ], "normalized": [] }, { "id": "PMID-15105421_T20", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1100, 1103 ] ], "normalized": [] }, { "id": "PMID-15105421_T21", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1152, 1155 ] ], "normalized": [] }, { "id": "PMID-15105421_T22", "type": "Gene_or_gene_product", "text": [ "SIVA" ], "offsets": [ [ 1299, 1303 ] ], "normalized": [] }, { "id": "PMID-15105421_T23", "type": "Gene_or_gene_product", "text": [ "luciferase" ], "offsets": [ [ 1444, 1454 ] ], "normalized": [] }, { "id": "PMID-15105421_T24", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1483, 1487 ] ], "normalized": [] }, { "id": "PMID-15105421_T25", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1492, 1495 ] ], "normalized": [] }, { "id": "PMID-15105421_T26", "type": "Gene_or_gene_product", "text": [ "SIVA" ], "offsets": [ [ 1532, 1536 ] ], "normalized": [] }, { "id": "PMID-15105421_T27", "type": "Gene_or_gene_product", "text": [ "SIVA" ], "offsets": [ [ 1591, 1595 ] ], "normalized": [] }, { "id": "PMID-15105421_T28", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1711, 1714 ] ], "normalized": [] }, { "id": "PMID-15105421_T29", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1719, 1723 ] ], "normalized": [] } ]

[ { "id": "PMID-15105421_E1", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 55, 61 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15105421_T1" }, { "role": "Cause", "ref_id": "PMID-15105421_T2" } ] }, { "id": "PMID-15105421_E2", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 55, 61 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15105421_T1" }, { "role": "Cause", "ref_id": "PMID-15105421_T3" } ] }, { "id": "PMID-15105421_E3", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 258, 267 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15105421_T5" } ] }, { "id": "PMID-15105421_E4", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 319, 326 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15105421_T6" }, { "role": "Theme", "ref_id": "PMID-15105421_E5" } ] }, { "id": "PMID-15105421_E5", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 327, 336 ] ] }, "arguments": [] }, { "id": "PMID-15105421_E6", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 417, 426 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15105421_T7" } ] }, { "id": "PMID-15105421_E7", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 520, 529 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15105421_T8" }, { "role": "Theme", "ref_id": "PMID-15105421_T9" } ] }, { "id": "PMID-15105421_E8", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 520, 529 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15105421_T8" }, { "role": "Theme", "ref_id": "PMID-15105421_T10" } ] }, { "id": "PMID-15105421_E9", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 645, 652 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15105421_T11" } ] }, { "id": "PMID-15105421_E10", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 771, 784 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15105421_T14" } ] }, { "id": "PMID-15105421_E11", "type": "Positive_regulation", "trigger": { "text": [ "initiate" ], "offsets": [ [ 802, 810 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15105421_E10" }, { "role": "Theme", "ref_id": "PMID-15105421_E12" } ] }, { "id": "PMID-15105421_E12", "type": "Pathway", "trigger": { "text": [ "apoptotic" ], "offsets": [ [ 815, 824 ] ] }, "arguments": [] }, { "id": "PMID-15105421_E13", "type": "Positive_regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1006, 1014 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15105421_T19" }, { "role": "Theme", "ref_id": "PMID-15105421_E14" } ] }, { "id": "PMID-15105421_E14", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1022, 1032 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15105421_E15" } ] }, { "id": "PMID-15105421_E15", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1036, 1045 ] ] }, "arguments": [] }, { "id": "PMID-15105421_E16", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 1500, 1508 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15105421_E18" }, { "role": "Cause", "ref_id": "PMID-15105421_T24" } ] }, { "id": "PMID-15105421_E17", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 1500, 1508 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15105421_E18" }, { "role": "Cause", "ref_id": "PMID-15105421_T25" } ] }, { "id": "PMID-15105421_E18", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1509, 1522 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15105421_T26" } ] }, { "id": "PMID-15105421_E19", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 1676, 1682 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15105421_T27" }, { "role": "Theme", "ref_id": "PMID-15105421_T28" } ] }, { "id": "PMID-15105421_E20", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 1676, 1682 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15105421_T27" }, { "role": "Theme", "ref_id": "PMID-15105421_T29" } ] } ]

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[]

[ { "id": "PMID-15107615__text", "type": "abstract", "text": [ "Inactivating Cdc25, mitotic style. \nMitotic entry and exit require activation and inactivation of the Cdk1-cyclin B kinase complex, respectively. The Cdc25 protein phosphatase family activates Cdk1-cyclin B at the G2/M transition by removing inhibitory phosphate groups. Cdc25 family members, held inactive during interphase, are activated during mitotic progression in an amplification loop involving Cdk1-cyclin B. While Cdc25 activation at the G2/M transition is required for the timely initiation of mitosis, recent evidence suggests that the inactivation of Cdc25 in late mitosis may play a role in supporting Cdk1-cyclin B inactivation. Here, we discuss the mechanisms of Cdc25 regulation and how they pertain to both mitotic entry and exit.\n" ], "offsets": [ [ 0, 748 ] ] } ]

[ { "id": "PMID-15107615_T1", "type": "Gene_or_gene_product", "text": [ "Cdc25" ], "offsets": [ [ 13, 18 ] ], "normalized": [] }, { "id": "PMID-15107615_T2", "type": "Complex", "text": [ "Cdk1-cyclin B" ], "offsets": [ [ 102, 115 ] ], "normalized": [] }, { "id": "PMID-15107615_T3", "type": "Gene_or_gene_product", "text": [ "Cdc25" ], "offsets": [ [ 150, 155 ] ], "normalized": [] }, { "id": "PMID-15107615_T4", "type": "Complex", "text": [ "Cdk1-cyclin B" ], "offsets": [ [ 193, 206 ] ], "normalized": [] }, { "id": "PMID-15107615_T5", "type": "Gene_or_gene_product", "text": [ "Cdc25" ], "offsets": [ [ 271, 276 ] ], "normalized": [] }, { "id": "PMID-15107615_T6", "type": "Complex", "text": [ "Cdk1-cyclin B" ], "offsets": [ [ 402, 415 ] ], "normalized": [] }, { "id": "PMID-15107615_T7", "type": "Gene_or_gene_product", "text": [ "Cdc25" ], "offsets": [ [ 423, 428 ] ], "normalized": [] }, { "id": "PMID-15107615_T8", "type": "Gene_or_gene_product", "text": [ "Cdc25" ], "offsets": [ [ 563, 568 ] ], "normalized": [] }, { "id": "PMID-15107615_T9", "type": "Complex", "text": [ "Cdk1-cyclin B" ], "offsets": [ [ 615, 628 ] ], "normalized": [] }, { "id": "PMID-15107615_T10", "type": "Gene_or_gene_product", "text": [ "Cdc25" ], "offsets": [ [ 678, 683 ] ], "normalized": [] } ]

[ { "id": "PMID-15107615_E1", "type": "Inactivation", "trigger": { "text": [ "Inactivating" ], "offsets": [ [ 0, 12 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_T1" } ] }, { "id": "PMID-15107615_E2", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 67, 77 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_T2" } ] }, { "id": "PMID-15107615_E3", "type": "Inactivation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 82, 94 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_T2" } ] }, { "id": "PMID-15107615_E4", "type": "Activation", "trigger": { "text": [ "activates" ], "offsets": [ [ 183, 192 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_T4" }, { "role": "Cause", "ref_id": "PMID-15107615_T3" } ] }, { "id": "PMID-15107615_E5", "type": "Inactivation", "trigger": { "text": [ "inactive" ], "offsets": [ [ 298, 306 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_T5" } ] }, { "id": "PMID-15107615_E6", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 330, 339 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_T5" } ] }, { "id": "PMID-15107615_E7", "type": "Regulation", "trigger": { "text": [ "involving" ], "offsets": [ [ 392, 401 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_T6" } ] }, { "id": "PMID-15107615_E8", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 429, 439 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_T7" } ] }, { "id": "PMID-15107615_E9", "type": "Inactivation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 547, 559 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_T8" } ] }, { "id": "PMID-15107615_E10", "type": "Regulation", "trigger": { "text": [ "play a role" ], "offsets": [ [ 589, 600 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_E11" }, { "role": "Cause", "ref_id": "PMID-15107615_E9" } ] }, { "id": "PMID-15107615_E11", "type": "Inactivation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 629, 641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_T9" } ] }, { "id": "PMID-15107615_E12", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 684, 694 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15107615_T10" } ] } ]

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[ { "id": "PMID-15126619__text", "type": "abstract", "text": [ "Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. \nAlterations in transcription of genes regulated by members of the E2F family of transcription factors can be viewed as a measure of the ebb and flow in a constantly evolving battle between repressor and activator complexes. Various chromatin regulatory complexes have been linked to Rb/E2F proteins, and changes in histone modifications correlate with states of E2F-dependent transcription. E2F has traditionally been viewed in the context of cell-cycle control. However, several recent studies have revealed a new aspect of E2F function in which pRB/E2F-family proteins confer stable repression of transcription. Such repression is evident in both actively proliferating cells and in cells that have withdrawn from the cell cycle.\n" ], "offsets": [ [ 0, 811 ] ] } ]

[ { "id": "PMID-15126619_T1", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 24, 27 ] ], "normalized": [] }, { "id": "PMID-15126619_T2", "type": "Gene_or_gene_product", "text": [ "pRB" ], "offsets": [ [ 53, 56 ] ], "normalized": [] }, { "id": "PMID-15126619_T3", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 145, 148 ] ], "normalized": [] }, { "id": "PMID-15126619_T4", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 311, 320 ] ], "normalized": [] }, { "id": "PMID-15126619_T5", "type": "Gene_or_gene_product", "text": [ "Rb" ], "offsets": [ [ 362, 364 ] ], "normalized": [] }, { "id": "PMID-15126619_T6", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 365, 368 ] ], "normalized": [] }, { "id": "PMID-15126619_T7", "type": "Gene_or_gene_product", "text": [ "histone" ], "offsets": [ [ 394, 401 ] ], "normalized": [] }, { "id": "PMID-15126619_T8", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 441, 444 ] ], "normalized": [] }, { "id": "PMID-15126619_T9", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 470, 473 ] ], "normalized": [] }, { "id": "PMID-15126619_T10", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 604, 607 ] ], "normalized": [] }, { "id": "PMID-15126619_T11", "type": "Gene_or_gene_product", "text": [ "pRB" ], "offsets": [ [ 626, 629 ] ], "normalized": [] }, { "id": "PMID-15126619_T12", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 630, 633 ] ], "normalized": [] } ]

[ { "id": "PMID-15126619_E1", "type": "Pathway", "trigger": { "text": [ "cell-cycle" ], "offsets": [ [ 522, 532 ] ] }, "arguments": [] }, { "id": "PMID-15126619_E2", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 533, 540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15126619_E1" }, { "role": "Cause", "ref_id": "PMID-15126619_T9" } ] }, { "id": "PMID-15126619_E3", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 799, 809 ] ] }, "arguments": [] } ]

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[]

[ { "id": "PMID-15151990__text", "type": "abstract", "text": [ "nemo-like kinase is an essential co-activator of Wnt signaling during early zebrafish development. \nWnt/beta-catenin signaling regulates many aspects of early vertebrate development, including patterning of the mesoderm and neurectoderm during gastrulation. In zebrafish, Wnt signaling overcomes basal repression in the prospective caudal neurectoderm by Tcf homologs that act as inhibitors of Wnt target genes. The vertebrate homolog of Drosophila nemo, nemo-like kinase (Nlk), can phosphorylate Tcf/Lef proteins and inhibit the DNA-binding ability of beta-catenin/Tcf complexes, thereby blocking activation of Wnt targets. By contrast, mutations in a C. elegans homolog show that Nlk is required to activate Wnt targets that are constitutively repressed by Tcf. We show that overexpressed zebrafish nlk, in concert with wnt8, can downregulate two tcf3 homologs, tcf3a and tcf3b, that repress Wnt targets during neurectodermal patterning. Inhibition of nlk using morpholino oligos reveals essential roles in regulating ventrolateral mesoderm formation in conjunction with wnt8, and in patterning of the midbrain, possibly functioning with wnt8b. In both instances, nlk appears to function as a positive regulator of Wnt signaling. Additionally, nlk strongly enhances convergent/extension phenotypes associated with wnt11/silberblick, suggesting a role in modulating cell movements as well as cell fate.\n" ], "offsets": [ [ 0, 1404 ] ] } ]

[ { "id": "PMID-15151990_T1", "type": "Gene_or_gene_product", "text": [ "nemo-like kinase" ], "offsets": [ [ 0, 16 ] ], "normalized": [] }, { "id": "PMID-15151990_T2", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 49, 52 ] ], "normalized": [] }, { "id": "PMID-15151990_T3", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 100, 103 ] ], "normalized": [] }, { "id": "PMID-15151990_T4", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 104, 116 ] ], "normalized": [] }, { "id": "PMID-15151990_T5", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 272, 275 ] ], "normalized": [] }, { "id": "PMID-15151990_T6", "type": "Gene_or_gene_product", "text": [ "Tcf" ], "offsets": [ [ 355, 358 ] ], "normalized": [] }, { "id": "PMID-15151990_T7", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 394, 397 ] ], "normalized": [] }, { "id": "PMID-15151990_T8", "type": "Gene_or_gene_product", "text": [ "nemo" ], "offsets": [ [ 449, 453 ] ], "normalized": [] }, { "id": "PMID-15151990_T9", "type": "Gene_or_gene_product", "text": [ "nemo-like kinase" ], "offsets": [ [ 455, 471 ] ], "normalized": [] }, { "id": "PMID-15151990_T10", "type": "Gene_or_gene_product", "text": [ "Nlk" ], "offsets": [ [ 473, 476 ] ], "normalized": [] }, { "id": "PMID-15151990_T11", "type": "Gene_or_gene_product", "text": [ "Tcf/Lef" ], "offsets": [ [ 497, 504 ] ], "normalized": [] }, { "id": "PMID-15151990_T12", "type": "Complex", "text": [ "beta-catenin/Tcf" ], "offsets": [ [ 553, 569 ] ], "normalized": [] }, { "id": "PMID-15151990_T13", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 612, 615 ] ], "normalized": [] }, { "id": "PMID-15151990_T14", "type": "Gene_or_gene_product", "text": [ "Nlk" ], "offsets": [ [ 682, 685 ] ], "normalized": [] }, { "id": "PMID-15151990_T15", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 710, 713 ] ], "normalized": [] }, { "id": "PMID-15151990_T16", "type": "Gene_or_gene_product", "text": [ "Tcf" ], "offsets": [ [ 759, 762 ] ], "normalized": [] }, { "id": "PMID-15151990_T17", "type": "Gene_or_gene_product", "text": [ "nlk" ], "offsets": [ [ 801, 804 ] ], "normalized": [] }, { "id": "PMID-15151990_T18", "type": "Gene_or_gene_product", "text": [ "wnt8" ], "offsets": [ [ 822, 826 ] ], "normalized": [] }, { "id": "PMID-15151990_T19", "type": "Gene_or_gene_product", "text": [ "tcf3" ], "offsets": [ [ 849, 853 ] ], "normalized": [] }, { "id": "PMID-15151990_T20", "type": "Gene_or_gene_product", "text": [ "tcf3a" ], "offsets": [ [ 864, 869 ] ], "normalized": [] }, { "id": "PMID-15151990_T21", "type": "Gene_or_gene_product", "text": [ "tcf3b" ], "offsets": [ [ 874, 879 ] ], "normalized": [] }, { "id": "PMID-15151990_T22", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 894, 897 ] ], "normalized": [] }, { "id": "PMID-15151990_T23", "type": "Gene_or_gene_product", "text": [ "nlk" ], "offsets": [ [ 954, 957 ] ], "normalized": [] }, { "id": "PMID-15151990_T24", "type": "Gene_or_gene_product", "text": [ "wnt8" ], "offsets": [ [ 1073, 1077 ] ], "normalized": [] }, { "id": "PMID-15151990_T25", "type": "Gene_or_gene_product", "text": [ "wnt8b" ], "offsets": [ [ 1140, 1145 ] ], "normalized": [] }, { "id": "PMID-15151990_T26", "type": "Gene_or_gene_product", "text": [ "nlk" ], "offsets": [ [ 1166, 1169 ] ], "normalized": [] }, { "id": "PMID-15151990_T27", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 1217, 1220 ] ], "normalized": [] }, { "id": "PMID-15151990_T28", "type": "Gene_or_gene_product", "text": [ "nlk" ], "offsets": [ [ 1246, 1249 ] ], "normalized": [] }, { "id": "PMID-15151990_T29", "type": "Gene_or_gene_product", "text": [ "wnt11" ], "offsets": [ [ 1316, 1321 ] ], "normalized": [] }, { "id": "PMID-15151990_T30", "type": "Gene_or_gene_product", "text": [ "silberblick" ], "offsets": [ [ 1322, 1333 ] ], "normalized": [] } ]

[ { "id": "PMID-15151990_E1", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 23, 32 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15151990_T1" }, { "role": "Theme", "ref_id": "PMID-15151990_E2" } ] }, { "id": "PMID-15151990_E2", "type": "Positive_regulation", "trigger": { "text": [ "co-activator" ], "offsets": [ [ 33, 45 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15151990_E3" }, { "role": "Cause", "ref_id": "PMID-15151990_T1" } ] }, { "id": "PMID-15151990_E3", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 53, 62 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15151990_T2" } ] }, { "id": "PMID-15151990_E4", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 117, 126 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15151990_T3" }, { "role": "Participant", "ref_id": "PMID-15151990_T4" } ] }, { "id": "PMID-15151990_E5", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 276, 285 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15151990_T5" } ] }, { "id": "PMID-15151990_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylate" ], "offsets": [ [ 483, 496 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15151990_T9" }, { "role": "Theme", "ref_id": "PMID-15151990_T11" } ] }, { "id": "PMID-15151990_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 518, 525 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15151990_T9" }, { "role": "Theme", "ref_id": "PMID-15151990_E8" } ] }, { "id": "PMID-15151990_E8", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 534, 541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15151990_T12" } ] }, { "id": "PMID-15151990_E9", "type": "Gene_expression", "trigger": { "text": [ "overexpressed" ], "offsets": [ [ 777, 790 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15151990_T17" } ] }, { "id": "PMID-15151990_E10", "type": "Negative_regulation", "trigger": { "text": [ "downregulate" ], "offsets": [ [ 832, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15151990_T20" }, { "role": "Cause", "ref_id": "PMID-15151990_E9" } ] }, { "id": "PMID-15151990_E11", "type": "Negative_regulation", "trigger": { "text": [ "downregulate" ], "offsets": [ [ 832, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15151990_T21" }, { "role": "Cause", "ref_id": "PMID-15151990_E9" } ] }, { "id": "PMID-15151990_E12", "type": "Negative_regulation", "trigger": { "text": [ "downregulate" ], "offsets": [ [ 832, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15151990_T20" }, { "role": "Cause", "ref_id": "PMID-15151990_T18" } ] }, { "id": "PMID-15151990_E13", "type": "Negative_regulation", "trigger": { "text": [ "downregulate" ], "offsets": [ [ 832, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15151990_T21" }, { "role": "Cause", "ref_id": "PMID-15151990_T18" } ] }, { "id": "PMID-15151990_E14", "type": "Negative_regulation", "trigger": { "text": [ "Inhibition" ], "offsets": [ [ 940, 950 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15151990_T23" } ] }, { "id": "PMID-15151990_E15", "type": "Positive_regulation", "trigger": { "text": [ "positive regulator" ], "offsets": [ [ 1195, 1213 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15151990_T26" }, { "role": "Theme", "ref_id": "PMID-15151990_E16" } ] }, { "id": "PMID-15151990_E16", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1221, 1230 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15151990_T27" } ] } ]

[ { "id": "PMID-15151990_1", "entity_ids": [ "PMID-15151990_T9", "PMID-15151990_T10" ] }, { "id": "PMID-15151990_2", "entity_ids": [ "PMID-15151990_T29", "PMID-15151990_T30" ] } ]

[]

[ { "id": "PMID-15175242__text", "type": "abstract", "text": [ "Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics. \nTumor development is dependent upon the inactivation of two key tumor-suppressor networks, p16(Ink4a)-cycD/cdk4-pRB-E2F and p19(Arf)-mdm2-p53, that regulate cellular proliferation and the tumor surveillance response. These networks are known to intersect with one another, but the mechanisms are poorly understood. Here, we show that E2F directly participates in the transcriptional control of Arf in both normal and transformed cells. This occurs in a manner that is significantly different from the regulation of classic E2F-responsive targets. In wild-type mouse embryonic fibroblasts (MEFs), the Arf promoter is occupied by E2F3 and not other E2F family members. In quiescent cells, this role is largely fulfilled by E2F3b, an E2F3 isoform whose function was previously undetermined. E2f3 loss is sufficient to derepress Arf, triggering activation of p53 and expression of p21(Cip1). Thus, E2F3 is a key repressor of the p19(Arf)-p53 pathway in normal cells. Consistent with this notion, Arf mutation suppresses the activation of p53 and p21(Cip1) in E2f3-deficient MEFs. Arf loss also rescues the known cell cycle re-entry defect of E2f3(-/-) cells, and this correlates with restoration of appropriate activation of classic E2F-responsive genes. Our data also demonstrate a direct role for E2F in the oncogenic activation of Arf. Specifically, we observe recruitment of the endogenous activating E2Fs, E2F1, and E2F3a, to the Arf promoter. Thus, distinct E2F complexes directly contribute to the normal repression and oncogenic activation of Arf. We propose that monitoring of E2F levels and/or activity is a key component of Arf's ability to respond to inappropriate, but not normal cellular proliferation.\n" ], "offsets": [ [ 0, 1805 ] ] } ]

[ { "id": "PMID-15175242_T1", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 18, 21 ] ], "normalized": [] }, { "id": "PMID-15175242_T2", "type": "Gene_or_gene_product", "text": [ "E2F3" ], "offsets": [ [ 42, 46 ] ], "normalized": [] }, { "id": "PMID-15175242_T3", "type": "Gene_or_gene_product", "text": [ "p16" ], "offsets": [ [ 183, 186 ] ], "normalized": [] }, { "id": "PMID-15175242_T4", "type": "Gene_or_gene_product", "text": [ "Ink4a" ], "offsets": [ [ 187, 192 ] ], "normalized": [] }, { "id": "PMID-15175242_T5", "type": "Complex", "text": [ "cycD/cdk4" ], "offsets": [ [ 194, 203 ] ], "normalized": [] }, { "id": "PMID-15175242_T6", "type": "Gene_or_gene_product", "text": [ "pRB" ], "offsets": [ [ 204, 207 ] ], "normalized": [] }, { "id": "PMID-15175242_T7", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 208, 211 ] ], "normalized": [] }, { "id": "PMID-15175242_T8", "type": "Gene_or_gene_product", "text": [ "p19" ], "offsets": [ [ 216, 219 ] ], "normalized": [] }, { "id": "PMID-15175242_T9", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 220, 223 ] ], "normalized": [] }, { "id": "PMID-15175242_T10", "type": "Gene_or_gene_product", "text": [ "mdm2" ], "offsets": [ [ 225, 229 ] ], "normalized": [] }, { "id": "PMID-15175242_T11", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 230, 233 ] ], "normalized": [] }, { "id": "PMID-15175242_T12", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 426, 429 ] ], "normalized": [] }, { "id": "PMID-15175242_T13", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 486, 489 ] ], "normalized": [] }, { "id": "PMID-15175242_T14", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 615, 618 ] ], "normalized": [] }, { "id": "PMID-15175242_T15", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 692, 695 ] ], "normalized": [] }, { "id": "PMID-15175242_T16", "type": "Gene_or_gene_product", "text": [ "E2F3" ], "offsets": [ [ 720, 724 ] ], "normalized": [] }, { "id": "PMID-15175242_T17", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 739, 742 ] ], "normalized": [] }, { "id": "PMID-15175242_T18", "type": "Gene_or_gene_product", "text": [ "E2F3b" ], "offsets": [ [ 813, 818 ] ], "normalized": [] }, { "id": "PMID-15175242_T19", "type": "Gene_or_gene_product", "text": [ "E2F3" ], "offsets": [ [ 823, 827 ] ], "normalized": [] }, { "id": "PMID-15175242_T20", "type": "Gene_or_gene_product", "text": [ "E2f3" ], "offsets": [ [ 880, 884 ] ], "normalized": [] }, { "id": "PMID-15175242_T21", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 917, 920 ] ], "normalized": [] }, { "id": "PMID-15175242_T22", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 947, 950 ] ], "normalized": [] }, { "id": "PMID-15175242_T23", "type": "Gene_or_gene_product", "text": [ "p21" ], "offsets": [ [ 969, 972 ] ], "normalized": [] }, { "id": "PMID-15175242_T24", "type": "Gene_or_gene_product", "text": [ "Cip1" ], "offsets": [ [ 973, 977 ] ], "normalized": [] }, { "id": "PMID-15175242_T25", "type": "Gene_or_gene_product", "text": [ "E2F3" ], "offsets": [ [ 986, 990 ] ], "normalized": [] }, { "id": "PMID-15175242_T26", "type": "Gene_or_gene_product", "text": [ "p19" ], "offsets": [ [ 1017, 1020 ] ], "normalized": [] }, { "id": "PMID-15175242_T27", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 1021, 1024 ] ], "normalized": [] }, { "id": "PMID-15175242_T28", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1026, 1029 ] ], "normalized": [] }, { "id": "PMID-15175242_T29", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 1084, 1087 ] ], "normalized": [] }, { "id": "PMID-15175242_T30", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1126, 1129 ] ], "normalized": [] }, { "id": "PMID-15175242_T31", "type": "Gene_or_gene_product", "text": [ "p21" ], "offsets": [ [ 1134, 1137 ] ], "normalized": [] }, { "id": "PMID-15175242_T32", "type": "Gene_or_gene_product", "text": [ "Cip1" ], "offsets": [ [ 1138, 1142 ] ], "normalized": [] }, { "id": "PMID-15175242_T33", "type": "Gene_or_gene_product", "text": [ "E2f3" ], "offsets": [ [ 1147, 1151 ] ], "normalized": [] }, { "id": "PMID-15175242_T34", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 1168, 1171 ] ], "normalized": [] }, { "id": "PMID-15175242_T35", "type": "Gene_or_gene_product", "text": [ "E2f3" ], "offsets": [ [ 1230, 1234 ] ], "normalized": [] }, { "id": "PMID-15175242_T36", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1321, 1324 ] ], "normalized": [] }, { "id": "PMID-15175242_T37", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1387, 1390 ] ], "normalized": [] }, { "id": "PMID-15175242_T38", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 1422, 1425 ] ], "normalized": [] }, { "id": "PMID-15175242_T39", "type": "Gene_or_gene_product", "text": [ "E2Fs" ], "offsets": [ [ 1493, 1497 ] ], "normalized": [] }, { "id": "PMID-15175242_T40", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1499, 1503 ] ], "normalized": [] }, { "id": "PMID-15175242_T41", "type": "Gene_or_gene_product", "text": [ "E2F3a" ], "offsets": [ [ 1509, 1514 ] ], "normalized": [] }, { "id": "PMID-15175242_T42", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 1523, 1526 ] ], "normalized": [] }, { "id": "PMID-15175242_T43", "type": "Complex", "text": [ "E2F complexes" ], "offsets": [ [ 1552, 1565 ] ], "normalized": [] }, { "id": "PMID-15175242_T44", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 1639, 1642 ] ], "normalized": [] }, { "id": "PMID-15175242_T45", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1674, 1677 ] ], "normalized": [] }, { "id": "PMID-15175242_T46", "type": "Gene_or_gene_product", "text": [ "Arf" ], "offsets": [ [ 1723, 1726 ] ], "normalized": [] } ]

[ { "id": "PMID-15175242_E1", "type": "Negative_regulation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 132, 144 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15175242_E4" } ] }, { "id": "PMID-15175242_E2", "type": "Negative_regulation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 132, 144 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15175242_E3" } ] }, { "id": "PMID-15175242_E3", "type": "Pathway", "trigger": { "text": [ "networks" ], "offsets": [ [ 173, 181 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15175242_T4" }, { "role": "Participant", "ref_id": "PMID-15175242_T5" }, { "role": "Participant", "ref_id": "PMID-15175242_T6" }, { "role": "Participant", "ref_id": "PMID-15175242_T7" } ] }, { "id": "PMID-15175242_E4", "type": "Pathway", "trigger": { "text": [ "networks" ], "offsets": [ [ 173, 181 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15175242_T9" }, { "role": "Participant", "ref_id": "PMID-15175242_T10" }, { "role": "Participant", "ref_id": "PMID-15175242_T11" } ] }, { "id": "PMID-15175242_E5", "type": "Regulation", "trigger": { "text": [ "participates" ], "offsets": [ [ 439, 451 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15175242_T12" }, { "role": "Theme", "ref_id": "PMID-15175242_E7" } ] }, { "id": "PMID-15175242_E6", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 459, 474 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15175242_T13" } ] }, { "id": "PMID-15175242_E7", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 475, 482 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15175242_E6" } ] }, { "id": "PMID-15175242_E8", "type": "Binding", "trigger": { "text": [ "occupied" ], "offsets": [ [ 708, 716 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15175242_T15" }, { "role": "Theme", "ref_id": "PMID-15175242_T16" } ] }, { "id": "PMID-15175242_E9", "type": "Binding", 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[]

[ { "id": "PMID-15271987__text", "type": "abstract", "text": [ "Aberrant regulation of survivin by the RB/E2F family of proteins. \nSurvivin is a putative oncogene that is aberrantly expressed in cancer cells. It has been hypothesized to play a central role in cancer progression and resistance to therapy in diverse tumor types. Although some of the transcriptional processes regulating its expression have been established, the diversity of genes that may be controlling the levels of its expression in both normal cells as well as in cancer cells has not been fully explored. The most common genetically mutated pathways in human malignancies are the p53 tumor suppressor pathway and the RB/E2F pathway. Both of these pathways, when intact, provide essential checkpoints in the maintenance of normal cell growth and protect the cell from DNA damage. Using non-transformed embryonic fibroblasts, we provide evidence of a molecular link between the regulation of survivin transcription and the RB/E2F family of proteins. We demonstrate that both pRB and p130 can interact with the survivin promoter and can repress survivin transcription. We also show that the E2F activators (E2F1, E2F2, and E2F3) can bind to the survivin promoter and induce survivin transcription. Genetically modified cells that harbor deletions in various members of the RB/E2F family confirm our data from the wild-type cells. Our findings implicate several members of the RB/E2F pathway in an intricate mechanism of survivin gene regulation that, when genetically altered during the process of tumorigenesis, may function within cancer cells to aberrantly alter survivin levels and enhance tumor progression.\n" ], "offsets": [ [ 0, 1619 ] ] } ]

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[]

[]

[ { "id": "PMID-15334086__text", "type": "abstract", "text": [ "The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. \nA20 is a cytoplasmic protein required for the termination of tumor necrosis factor (TNF)-induced signals. We show here that mice doubly deficient in either A20 and TNF or A20 and TNF receptor 1 developed spontaneous inflammation, indicating that A20 is also critical for the regulation of TNF-independent signals in vivo. A20 was required for the termination of Toll-like receptor-induced activity of the transcription factor NF-kappaB and proinflammatory gene expression in macrophages, and this function protected mice from endotoxic shock. A20 accomplished this biochemically by directly removing ubiquitin moieties from the signaling molecule TRAF6. The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance of the regulation of ubiquitin conjugation in innate immune cells.\n" ], "offsets": [ [ 0, 932 ] ] } ]

[ { "id": "PMID-15334086_T1", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 4, 13 ] ], "normalized": [] }, { "id": "PMID-15334086_T2", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 31, 34 ] ], "normalized": [] }, { "id": "PMID-15334086_T3", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor" ], "offsets": [ [ 66, 84 ] ], "normalized": [] }, { "id": "PMID-15334086_T4", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 97, 100 ] ], "normalized": [] }, { "id": "PMID-15334086_T5", "type": "Cellular_component", "text": [ "cytoplasmic" ], "offsets": [ [ 106, 117 ] ], "normalized": [] }, { "id": "PMID-15334086_T6", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor" ], "offsets": [ [ 158, 179 ] ], "normalized": [] }, { "id": "PMID-15334086_T7", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 181, 184 ] ], "normalized": [] }, { "id": "PMID-15334086_T8", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 253, 256 ] ], "normalized": [] }, { "id": "PMID-15334086_T9", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 261, 264 ] ], "normalized": [] }, { "id": "PMID-15334086_T10", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 268, 271 ] ], "normalized": [] }, { "id": "PMID-15334086_T11", "type": "Gene_or_gene_product", "text": [ "TNF receptor 1" ], "offsets": [ [ 276, 290 ] ], "normalized": [] }, { "id": "PMID-15334086_T12", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 343, 346 ] ], "normalized": [] }, { "id": "PMID-15334086_T13", "type": "Gene_or_gene_product", "text": [ "TNF" ], "offsets": [ [ 386, 389 ] ], "normalized": [] }, { "id": "PMID-15334086_T14", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 419, 422 ] ], "normalized": [] }, { "id": "PMID-15334086_T15", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor" ], "offsets": [ [ 459, 477 ] ], "normalized": [] }, { "id": "PMID-15334086_T16", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 523, 532 ] ], "normalized": [] }, { "id": "PMID-15334086_T17", "type": "Gene_or_gene_product", "text": [ "A20" ], "offsets": [ [ 640, 643 ] ], "normalized": [] }, { "id": "PMID-15334086_T18", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 697, 706 ] ], "normalized": [] }, { "id": "PMID-15334086_T19", "type": "Gene_or_gene_product", "text": [ "TRAF6" ], "offsets": [ [ 744, 749 ] ], "normalized": [] }, { "id": "PMID-15334086_T20", "type": "Gene_or_gene_product", "text": [ "TLR" ], "offsets": [ [ 827, 830 ] ], "normalized": [] }, { "id": "PMID-15334086_T21", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 886, 895 ] ], "normalized": [] } ]

[ { "id": "PMID-15334086_E1", "type": "Transport", "trigger": { "text": [ "modifying" ], "offsets": [ [ 14, 23 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15334086_T1" } ] }, { "id": "PMID-15334086_E2", "type": "Positive_regulation", "trigger": { "text": [ "modifying" ], "offsets": [ [ 14, 23 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15334086_E1" }, { "role": "Cause", "ref_id": "PMID-15334086_T2" } ] }, { "id": "PMID-15334086_E3", "type": "Transport", "trigger": { "text": [ "removing" ], "offsets": [ [ 688, 696 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15334086_T18" } ] }, { "id": "PMID-15334086_E4", "type": "Positive_regulation", "trigger": { "text": [ "removing" ], "offsets": [ [ 688, 696 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15334086_E3" }, { "role": "Cause", "ref_id": "PMID-15334086_T17" } ] }, { "id": "PMID-15334086_E5", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 872, 882 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15334086_E6" } ] }, { "id": "PMID-15334086_E6", "type": "Binding", "trigger": { "text": [ "conjugation" ], "offsets": [ [ 896, 907 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15334086_T21" } ] } ]

[ { "id": "PMID-15334086_1", "entity_ids": [ "PMID-15334086_T6", "PMID-15334086_T7" ] } ]

[]

[ { "id": "PMID-15460900__text", "type": "abstract", "text": [ "The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression. \nThe p16INK4a tumor suppressor protein functions as an inhibitor of CDK4 and CDK6, the D-type cyclin-dependent kinases that initiate the phosphorylation of the retinoblastoma tumor suppressor protein, RB. Thus, p16INK4a has the capacity to arrest cells in the G1-phase of the cell cycle and its probable physiological role is in the implementation of irreversible growth arrest termed cellular senescence. Cellular senescence is a state of permanent growth arrest that can be induced by a variety of stresses such as DNA-damage and aberrant mitogenic signaling in human primary cells. In contrast to normal cells, the function of the p16INK4a gene or its downstream mediators is frequently deregulated in many types of human cancers, illustrating the importance of cellular senescence in tumor suppression. Here we discuss the molecular mechanisms that direct cellular senescence and reveal its potential for tumor suppression.\n" ], "offsets": [ [ 0, 1019 ] ] } ]

[ { "id": "PMID-15460900_T1", "type": "Gene_or_gene_product", "text": [ "p16INK4a" ], "offsets": [ [ 4, 12 ] ], "normalized": [] }, { "id": "PMID-15460900_T2", "type": "Gene_or_gene_product", "text": [ "RB" ], "offsets": [ [ 13, 15 ] ], "normalized": [] }, { "id": "PMID-15460900_T3", "type": "Gene_or_gene_product", "text": [ "p16INK4a" ], "offsets": [ [ 96, 104 ] ], "normalized": [] }, { "id": "PMID-15460900_T4", "type": "Gene_or_gene_product", "text": [ "CDK4" ], "offsets": [ [ 159, 163 ] ], "normalized": [] }, { "id": "PMID-15460900_T5", "type": "Gene_or_gene_product", "text": [ "CDK6" ], "offsets": [ [ 168, 172 ] ], "normalized": [] }, { "id": "PMID-15460900_T6", "type": "Gene_or_gene_product", "text": [ "D-type cyclin-dependent kinases" ], "offsets": [ [ 178, 209 ] ], "normalized": [] }, { "id": "PMID-15460900_T7", "type": "Gene_or_gene_product", "text": [ "RB" ], "offsets": [ [ 292, 294 ] ], "normalized": [] }, { "id": "PMID-15460900_T8", "type": "Gene_or_gene_product", "text": [ "p16INK4a" ], "offsets": [ [ 302, 310 ] ], "normalized": [] }, { "id": "PMID-15460900_T9", "type": "Gene_or_gene_product", "text": [ "p16INK4a" ], "offsets": [ [ 725, 733 ] ], "normalized": [] } ]

[ { "id": "PMID-15460900_E1", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 16, 23 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15460900_T1" }, { "role": "Participant", "ref_id": "PMID-15460900_T2" } ] }, { "id": "PMID-15460900_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 146, 155 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15460900_T3" }, { "role": "Theme", "ref_id": "PMID-15460900_T4" } ] }, { "id": "PMID-15460900_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 146, 155 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15460900_T3" }, { "role": "Theme", "ref_id": "PMID-15460900_T5" } ] }, { "id": "PMID-15460900_E4", "type": "Positive_regulation", "trigger": { "text": [ "initiate" ], "offsets": [ [ 215, 223 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15460900_T6" }, { "role": "Theme", "ref_id": "PMID-15460900_E5" } ] }, { "id": "PMID-15460900_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 228, 243 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15460900_T7" } ] }, { "id": "PMID-15460900_E6", "type": "Negative_regulation", "trigger": { "text": [ "arrest" ], "offsets": [ [ 331, 337 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15460900_E7" }, { "role": "Cause", "ref_id": "PMID-15460900_T8" } ] }, { "id": "PMID-15460900_E7", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 367, 377 ] ] }, "arguments": [] }, { "id": "PMID-15460900_E8", "type": "Regulation", "trigger": { "text": [ "deregulated" ], "offsets": [ [ 781, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15460900_T9" } ] } ]

[]

[]

[ { "id": "PMID-15466942__text", "type": "abstract", "text": [ "11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. \n11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative \"11beta-HSD1 knockout state\" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.\n" ], "offsets": [ [ 0, 1367 ] ] } ]

[ { "id": "PMID-15466942_T1", "type": "Gene_or_gene_product", "text": [ "11beta-hydroxysteroid dehydrogenase type 1" ], "offsets": [ [ 0, 42 ] ], "normalized": [] }, { "id": "PMID-15466942_T2", "type": "Simple_chemical", "text": [ "glucocorticoid" ], "offsets": [ [ 75, 89 ] ], "normalized": [] }, { "id": "PMID-15466942_T3", "type": "Gene_or_gene_product", "text": [ "11beta-hydroxysteroid dehydrogenase type 1" ], "offsets": [ [ 101, 143 ] ], "normalized": [] }, { "id": "PMID-15466942_T4", "type": "Gene_or_gene_product", "text": [ "11beta-HSD1" ], "offsets": [ [ 145, 156 ] ], "normalized": [] }, { "id": "PMID-15466942_T5", "type": "Simple_chemical", "text": [ "cortisone" ], "offsets": [ [ 181, 190 ] ], "normalized": [] }, { "id": "PMID-15466942_T6", "type": "Simple_chemical", "text": [ "cortisol" ], "offsets": [ [ 202, 210 ] ], "normalized": [] }, { "id": "PMID-15466942_T7", "type": "Simple_chemical", "text": [ "glucocorticoid" ], "offsets": [ [ 304, 318 ] ], "normalized": [] }, { "id": "PMID-15466942_T8", "type": "Gene_or_gene_product", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 353, 376 ] ], "normalized": [] }, { "id": "PMID-15466942_T9", "type": "Gene_or_gene_product", "text": [ "11beta-HSD1" ], "offsets": [ [ 467, 478 ] ], "normalized": [] }, { "id": "PMID-15466942_T10", "type": "Gene_or_gene_product", "text": [ "cortisone reductase" ], "offsets": [ [ 591, 610 ] ], "normalized": [] }, { "id": "PMID-15466942_T11", "type": "Gene_or_gene_product", "text": [ "11beta-HSD1" ], "offsets": [ [ 637, 648 ] ], "normalized": [] }, { "id": "PMID-15466942_T12", "type": "Gene_or_gene_product", "text": [ "HSD11B1" ], "offsets": [ [ 732, 739 ] ], "normalized": [] }, { "id": "PMID-15466942_T13", "type": "Gene_or_gene_product", "text": [ "hexose-6-phosphate dehydrogenase" ], "offsets": [ [ 800, 832 ] ], "normalized": [] }, { "id": "PMID-15466942_T14", "type": "Simple_chemical", "text": [ "nicotinamide-adenine dinucleotide phosphate" ], "offsets": [ [ 878, 921 ] ], "normalized": [] }, { "id": "PMID-15466942_T15", "type": "Gene_or_gene_product", "text": [ "11beta-HSD1" ], "offsets": [ [ 937, 948 ] ], "normalized": [] }, { "id": "PMID-15466942_T16", "type": "Gene_or_gene_product", "text": [ "hexose-6-phosphate dehydrogenase" ], "offsets": [ [ 997, 1029 ] ], "normalized": [] }, { "id": "PMID-15466942_T17", "type": "Simple_chemical", "text": [ "nicotinamide-adenine dinucleotide phosphate" ], "offsets": [ [ 1061, 1104 ] ], "normalized": [] }, { "id": "PMID-15466942_T18", "type": "Gene_or_gene_product", "text": [ "11beta-HSD1" ], "offsets": [ [ 1164, 1175 ] ], "normalized": [] }, { "id": "PMID-15466942_T19", "type": "Gene_or_gene_product", "text": [ "11beta-HSD1" ], "offsets": [ [ 1212, 1223 ] ], "normalized": [] } ]

[ { "id": "PMID-15466942_E1", "type": "Regulation", "trigger": { "text": [ "regulator" ], "offsets": [ [ 62, 71 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15466942_T1" }, { "role": "Theme", "ref_id": "PMID-15466942_T2" } ] }, { "id": "PMID-15466942_E2", "type": "Conversion", "trigger": { "text": [ "interconverts" ], "offsets": [ [ 158, 171 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_T5" }, { "role": "Product", "ref_id": "PMID-15466942_T6" } ] }, { "id": "PMID-15466942_E3", "type": "Conversion", "trigger": { "text": [ "interconverts" ], "offsets": [ [ 158, 171 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_T6" }, { "role": "Product", "ref_id": "PMID-15466942_T5" } ] }, { "id": "PMID-15466942_E4", "type": "Positive_regulation", "trigger": { "text": [ "interconverts" ], "offsets": [ [ 158, 171 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15466942_T3" }, { "role": "Theme", "ref_id": "PMID-15466942_E2" } ] }, { "id": "PMID-15466942_E5", "type": "Positive_regulation", "trigger": { "text": [ "interconverts" ], "offsets": [ [ 158, 171 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15466942_T3" }, { "role": "Theme", "ref_id": "PMID-15466942_E3" } ] }, { "id": "PMID-15466942_E6", "type": "Inactivation", "trigger": { "text": [ "inactive" ], "offsets": [ [ 172, 180 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_T5" } ] }, { "id": "PMID-15466942_E7", "type": "Activation", "trigger": { "text": [ "active" ], "offsets": [ [ 195, 201 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_T6" } ] }, { "id": "PMID-15466942_E8", "type": "Conversion", "trigger": { "text": [ "generating" ], "offsets": [ [ 286, 296 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-15466942_T7" } ] }, { "id": "PMID-15466942_E9", "type": "Positive_regulation", "trigger": { "text": [ "generating" ], "offsets": [ [ 286, 296 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_E8" }, { "role": "Cause", "ref_id": "PMID-15466942_T3" } ] }, { "id": "PMID-15466942_E10", "type": "Activation", "trigger": { "text": [ "active" ], "offsets": [ [ 297, 303 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_T7" } ] }, { "id": "PMID-15466942_E11", "type": "Positive_regulation", "trigger": { "text": [ "enhancing" ], "offsets": [ [ 343, 352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_E12" }, { "role": "Cause", "ref_id": "PMID-15466942_T3" } ] }, { "id": "PMID-15466942_E12", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 377, 387 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_T8" } ] }, { "id": "PMID-15466942_E13", "type": "Inactivation", "trigger": { "text": [ "deficiency" ], "offsets": [ [ 611, 621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_T10" } ] }, { "id": "PMID-15466942_E14", "type": "Inactivation", "trigger": { "text": [ "knockout" ], "offsets": [ [ 649, 657 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_T11" } ] }, { "id": "PMID-15466942_E15", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 700, 706 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_E13" } ] }, { "id": "PMID-15466942_E16", "type": "Positive_regulation", "trigger": { "text": [ "crucial" ], "offsets": [ [ 1119, 1126 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_T18" }, { "role": "Cause", "ref_id": "PMID-15466942_T17" } ] }, { "id": "PMID-15466942_E17", "type": "Positive_regulation", "trigger": { "text": [ "crucial" ], "offsets": [ [ 1119, 1126 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_T18" }, { "role": "Cause", "ref_id": "PMID-15466942_T16" } ] }, { "id": "PMID-15466942_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1198, 1208 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15466942_T19" } ] } ]

[ { "id": "PMID-15466942_1", "entity_ids": [ "PMID-15466942_T3", "PMID-15466942_T4" ] } ]

[]

[ { "id": "PMID-15494392__text", "type": "abstract", "text": [ "A role for 14-3-3 tau in E2F1 stabilization and DNA damage-induced apoptosis. \nGenotoxic stress triggers apoptosis through multiple signaling pathways. Recent studies have demonstrated a specific induction of E2F1 accumulation and a role for E2F1 in apoptosis upon DNA damage. Induction of E2F1 is mediated by phosphorylation events that are dependent on DNA damage-responsive protein kinases, such as ATM. How ATM phosphorylation leads to E2F1 stabilization is unknown. We now show that 14-3-3 tau, a phosphoserine-binding protein, mediates E2F1 stabilization. 14-3-3 tau interacts with ATM-phosphorylated E2F1 during DNA damage and inhibits E2F1 ubiquitination. Depletion of 14-3-3 tau or E2F1, but not E2F2 or E2F3, blocks adriamycin-induced apoptosis. 14-3-3 tau is also required for expression and induction of E2F1 apoptotic targets, such as p73, Apaf-1, and caspases, during DNA damage. Together, these data demonstrate a novel function for 14-3-3 tau in the regulation of E2F1 protein stability and apoptosis during DNA damage.\n" ], "offsets": [ [ 0, 1036 ] ] } ]

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"PMID-15494392_E20" } ] }, { "id": "PMID-15494392_E25", "type": "Negative_regulation", "trigger": { "text": [ "blocks" ], "offsets": [ [ 719, 725 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15494392_E26" }, { "role": "Cause", "ref_id": "PMID-15494392_E21" } ] }, { "id": "PMID-15494392_E26", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 745, 754 ] ] }, "arguments": [] }, { "id": "PMID-15494392_E27", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 775, 783 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15494392_T20" }, { "role": "Theme", "ref_id": "PMID-15494392_E33" } ] }, { "id": "PMID-15494392_E28", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 775, 783 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15494392_T20" }, { "role": "Theme", "ref_id": "PMID-15494392_E36" } ] }, { "id": "PMID-15494392_E29", "type": "Positive_regulation", "trigger": { "text": [ 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[]

[]

[ { "id": "PMID-15510213__text", "type": "abstract", "text": [ "E2Fs link the control of G1/S and G2/M transcription. \nPrevious work has provided evidence for E2F-dependent transcription control of both G1/S- and G2/M-regulated genes. Analysis of the G2-regulated cdc2 and cyclin B1 genes reveals the presence of both positive- and negative-acting E2F promoter elements. Additional elements provide both positive (CCAAT and Myb) and negative (CHR) control. Chromatin immunoprecipitation assays identify multiple interactions of E2F proteins that include those previously shown to activate and repress transcription. We find that E2F1, E2F2, and E2F3 bind to the positive-acting E2F site in the cdc2 promoter, whereas E2F4 binds to the negative-acting site. We also find that binding of an activator E2F is dependent on an adjacent CCAAT site that is bound by the NF-Y transcription factor and binding of a repressor E2F is dependent on an adjacent CHR element, suggesting a role for cooperative interactions in determining both activation and repression. Finally, the kinetics of B-Myb interaction with the G2-regulated promoters coincides with the activation of the genes, and RNAi-mediated reduction of B-Myb inhibits expression of cyclin B1 and cdc2. The ability of B-Myb to interact with the cdc2 promoter is dependent on an intact E2F binding site. These results thus point to a role for E2Fs, together with B-Myb, which is an E2F-regulated gene expressed at G1/S, in linking the regulation of genes at G1/S and G2/M.\n" ], "offsets": [ [ 0, 1459 ] ] } ]

[ { "id": "PMID-15510213_T1", "type": "Gene_or_gene_product", "text": [ "E2Fs" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-15510213_T2", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 95, 98 ] ], "normalized": [] }, { "id": "PMID-15510213_T3", "type": "Gene_or_gene_product", "text": [ "cdc2" ], "offsets": [ [ 200, 204 ] ], "normalized": [] }, { "id": "PMID-15510213_T4", "type": "Gene_or_gene_product", "text": [ "cyclin B1" ], "offsets": [ [ 209, 218 ] ], "normalized": [] }, { "id": "PMID-15510213_T5", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 284, 287 ] ], "normalized": [] }, { "id": "PMID-15510213_T6", "type": "Cellular_component", "text": [ "Chromatin" ], "offsets": [ [ 393, 402 ] ], "normalized": [] }, { "id": "PMID-15510213_T7", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 464, 467 ] ], "normalized": [] }, { "id": "PMID-15510213_T8", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 565, 569 ] ], "normalized": [] }, { "id": "PMID-15510213_T9", "type": "Gene_or_gene_product", "text": [ "E2F2" ], "offsets": [ [ 571, 575 ] ], "normalized": [] }, { "id": "PMID-15510213_T10", "type": "Gene_or_gene_product", "text": [ "E2F3" ], "offsets": [ [ 581, 585 ] ], "normalized": [] }, { "id": "PMID-15510213_T11", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 614, 617 ] ], "normalized": [] }, { "id": "PMID-15510213_T12", "type": "Gene_or_gene_product", "text": [ "cdc2" ], "offsets": [ [ 630, 634 ] ], "normalized": [] }, { "id": "PMID-15510213_T13", "type": "Gene_or_gene_product", "text": [ "E2F4" ], "offsets": [ [ 653, 657 ] ], "normalized": [] }, { "id": "PMID-15510213_T14", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 735, 738 ] ], "normalized": [] }, { "id": "PMID-15510213_T15", "type": "Complex", "text": [ "NF-Y" ], "offsets": [ [ 799, 803 ] ], "normalized": [] }, { "id": "PMID-15510213_T16", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 852, 855 ] ], "normalized": [] }, { "id": "PMID-15510213_T17", "type": "Gene_or_gene_product", "text": [ "B-Myb" ], "offsets": [ [ 1016, 1021 ] ], "normalized": [] }, { "id": "PMID-15510213_T18", "type": "Gene_or_gene_product", "text": [ "B-Myb" ], "offsets": [ [ 1141, 1146 ] ], "normalized": [] }, { "id": "PMID-15510213_T19", "type": "Gene_or_gene_product", "text": [ "cyclin B1" ], "offsets": [ [ 1170, 1179 ] ], "normalized": [] }, { "id": "PMID-15510213_T20", "type": "Gene_or_gene_product", "text": [ "cdc2" ], "offsets": [ [ 1184, 1188 ] ], "normalized": [] }, { "id": "PMID-15510213_T21", "type": "Gene_or_gene_product", "text": [ "B-Myb" ], "offsets": [ [ 1205, 1210 ] ], "normalized": [] }, { "id": "PMID-15510213_T22", "type": "Gene_or_gene_product", "text": [ "cdc2" ], "offsets": [ [ 1232, 1236 ] ], "normalized": [] }, { "id": "PMID-15510213_T23", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1272, 1275 ] ], "normalized": [] }, { "id": "PMID-15510213_T24", "type": "Gene_or_gene_product", "text": [ "E2Fs" ], "offsets": [ [ 1329, 1333 ] ], "normalized": [] }, { "id": "PMID-15510213_T25", "type": "Gene_or_gene_product", "text": [ "B-Myb" ], "offsets": [ [ 1349, 1354 ] ], "normalized": [] }, { "id": "PMID-15510213_T26", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1368, 1371 ] ], "normalized": [] } ]

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[ { "id": "PMID-15536069__text", "type": "abstract", "text": [ "A novel repressive E2F6 complex containing the polycomb group protein, EPC1, that interacts with EZH2 in a proliferation-specific manner. \nThe transcriptional repressor E2F6 has been identified as a component of two distinct polycomb group protein (PcG)-containing complexes, suggesting a mechanism for the recruitment of repressive complexes to target sequences in DNA. Whereas one complex is involved in the repression of classic E2F target genes in G0, a role for E2F6 within the cell cycle has yet to be defined. We searched for novel E2F6-binding proteins using a yeast two-hybrid screen and identified the PcG protein, EPC1. We showed that, both in vitro and in vivo, E2F6, DP1, and EPC1 form a stable core complex with repressive activity. Furthermore, we identified the proliferation-specific PcG, EZH2, as an EPC1-interacting protein. Using affinity purification, we showed that E2F6, DP1, EPC1, EZH2, and Sin3B co-elute, suggesting the identification of a novel E2F6 complex that exists in vivo in both normal and transformed human cell lines. EZH2 is required for cellular proliferation and consistent with this, EZH2 elutes with the E2F6-EPC1 complex only in proliferating cells. Thus we have identified a novel E2F6-PcG complex (E2F6-EPC1) that interacts with EZH2 and may regulate genes required for cell cycle progression.\n" ], "offsets": [ [ 0, 1338 ] ] } ]

[ { "id": "PMID-15536069_T1", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 19, 23 ] ], "normalized": [] }, { "id": "PMID-15536069_T2", "type": "Gene_or_gene_product", "text": [ "polycomb group protein" ], "offsets": [ [ 47, 69 ] ], "normalized": [] }, { "id": "PMID-15536069_T3", "type": "Gene_or_gene_product", "text": [ "EPC1" ], "offsets": [ [ 71, 75 ] ], "normalized": [] }, { "id": "PMID-15536069_T4", "type": "Gene_or_gene_product", "text": [ "EZH2" ], "offsets": [ [ 97, 101 ] ], "normalized": [] }, { "id": "PMID-15536069_T5", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 169, 173 ] ], "normalized": [] }, { "id": "PMID-15536069_T6", "type": "Gene_or_gene_product", "text": [ "polycomb group protein" ], "offsets": [ [ 225, 247 ] ], "normalized": [] }, { "id": "PMID-15536069_T7", "type": "Gene_or_gene_product", "text": [ "PcG" ], "offsets": [ [ 249, 252 ] ], "normalized": [] }, { "id": "PMID-15536069_T8", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 432, 435 ] ], "normalized": [] }, { "id": "PMID-15536069_T9", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 467, 471 ] ], "normalized": [] }, { "id": "PMID-15536069_T10", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 539, 543 ] ], "normalized": [] }, { "id": "PMID-15536069_T11", "type": "Gene_or_gene_product", "text": [ "PcG" ], "offsets": [ [ 612, 615 ] ], "normalized": [] }, { "id": "PMID-15536069_T12", "type": "Gene_or_gene_product", "text": [ "EPC1" ], "offsets": [ [ 625, 629 ] ], "normalized": [] }, { "id": "PMID-15536069_T13", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 674, 678 ] ], "normalized": [] }, { "id": "PMID-15536069_T14", "type": "Gene_or_gene_product", "text": [ "DP1" ], "offsets": [ [ 680, 683 ] ], "normalized": [] }, { "id": "PMID-15536069_T15", "type": "Gene_or_gene_product", "text": [ "EPC1" ], "offsets": [ [ 689, 693 ] ], "normalized": [] }, { "id": "PMID-15536069_T16", "type": "Gene_or_gene_product", "text": [ "PcG" ], "offsets": [ [ 801, 804 ] ], "normalized": [] }, { "id": "PMID-15536069_T17", "type": "Gene_or_gene_product", "text": [ "EZH2" ], "offsets": [ [ 806, 810 ] ], "normalized": [] }, { "id": "PMID-15536069_T18", "type": "Gene_or_gene_product", "text": [ "EPC1" ], "offsets": [ [ 818, 822 ] ], "normalized": [] }, { "id": "PMID-15536069_T19", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 888, 892 ] ], "normalized": [] }, { "id": "PMID-15536069_T20", "type": "Gene_or_gene_product", "text": [ "DP1" ], "offsets": [ [ 894, 897 ] ], "normalized": [] }, { "id": "PMID-15536069_T21", "type": "Gene_or_gene_product", "text": [ "EPC1" ], "offsets": [ [ 899, 903 ] ], "normalized": [] }, { "id": "PMID-15536069_T22", "type": "Gene_or_gene_product", "text": [ "EZH2" ], "offsets": [ [ 905, 909 ] ], "normalized": [] }, { "id": "PMID-15536069_T23", "type": "Gene_or_gene_product", "text": [ "Sin3B" ], "offsets": [ [ 915, 920 ] ], "normalized": [] }, { "id": "PMID-15536069_T24", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 972, 976 ] ], "normalized": [] }, { "id": "PMID-15536069_T25", "type": "Gene_or_gene_product", "text": [ "EZH2" ], "offsets": [ [ 1054, 1058 ] ], "normalized": [] }, { "id": "PMID-15536069_T26", "type": "Gene_or_gene_product", "text": [ "EZH2" ], "offsets": [ [ 1124, 1128 ] ], "normalized": [] }, { "id": "PMID-15536069_T27", "type": "Complex", "text": [ "E2F6-EPC1" ], "offsets": [ [ 1145, 1154 ] ], "normalized": [] }, { "id": "PMID-15536069_T28", "type": "Complex", "text": [ "E2F6-PcG" ], "offsets": [ [ 1224, 1232 ] ], "normalized": [] }, { "id": "PMID-15536069_T29", "type": "Complex", "text": [ "E2F6-EPC1" ], "offsets": [ [ 1242, 1251 ] ], "normalized": [] }, { "id": "PMID-15536069_T30", "type": "Gene_or_gene_product", "text": [ "EZH2" ], "offsets": [ [ 1273, 1277 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-15558284__text", "type": "abstract", "text": [ "Differential regulation of Tec1 by Fus3 and Kss1 confers signaling specificity in yeast development. \nTranscriptional regulation by mitogen-activated protein (MAP) kinase signaling cascades is a major control mechanism for eukaryotic development. In budding yeast, Fus3 and Kss1 are two MAP kinases that control two distinct developmental programs-mating and invasive growth. We investigated whether signal-specific activation of mating and invasive growth involves regulation of the transcription factor Tec1 by Fus3 and Kss1. We present evidence that, during mating, Fus3 phosphorylates Tec1 to downregulate this invasive growth-specific transcription factor and its target genes. This function of Fus3 is essential for correct execution of the mating program and is not shared by Kss1. We find that Kss1 controls the activity of Tec1 mainly during invasive growth by control of TEC1 gene expression. Our study suggests that signaling specificity can arise from differential regulation of a single transcription factor by two MAP kinases with shared functions in distinct developmental programs.\n" ], "offsets": [ [ 0, 1098 ] ] } ]

[ { "id": "PMID-15558284_T1", "type": "Gene_or_gene_product", "text": [ "Tec1" ], "offsets": [ [ 27, 31 ] ], "normalized": [] }, { "id": "PMID-15558284_T2", "type": "Gene_or_gene_product", "text": [ "Fus3" ], "offsets": [ [ 35, 39 ] ], "normalized": [] }, { "id": "PMID-15558284_T3", "type": "Gene_or_gene_product", "text": [ "Kss1" ], "offsets": [ [ 44, 48 ] ], "normalized": [] }, { "id": "PMID-15558284_T4", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein (MAP) kinase" ], "offsets": [ [ 132, 170 ] ], "normalized": [] }, { "id": "PMID-15558284_T5", "type": "Gene_or_gene_product", "text": [ "Fus3" ], "offsets": [ [ 265, 269 ] ], "normalized": [] }, { "id": "PMID-15558284_T6", "type": "Gene_or_gene_product", "text": [ "Kss1" ], "offsets": [ [ 274, 278 ] ], "normalized": [] }, { "id": "PMID-15558284_T7", "type": "Gene_or_gene_product", "text": [ "MAP kinases" ], "offsets": [ [ 287, 298 ] ], "normalized": [] }, { "id": "PMID-15558284_T8", "type": "Gene_or_gene_product", "text": [ "Tec1" ], "offsets": [ [ 505, 509 ] ], "normalized": [] }, { "id": "PMID-15558284_T9", "type": "Gene_or_gene_product", "text": [ "Fus3" ], "offsets": [ [ 513, 517 ] ], "normalized": [] }, { "id": "PMID-15558284_T10", "type": "Gene_or_gene_product", "text": [ "Kss1" ], "offsets": [ [ 522, 526 ] ], "normalized": [] }, { "id": "PMID-15558284_T11", "type": "Gene_or_gene_product", "text": [ "Fus3" ], "offsets": [ [ 569, 573 ] ], "normalized": [] }, { "id": "PMID-15558284_T12", "type": "Gene_or_gene_product", "text": [ "Tec1" ], "offsets": [ [ 589, 593 ] ], "normalized": [] }, { "id": "PMID-15558284_T13", "type": "Gene_or_gene_product", "text": [ "Fus3" ], "offsets": [ [ 700, 704 ] ], "normalized": [] }, { "id": "PMID-15558284_T14", "type": "Gene_or_gene_product", "text": [ "Kss1" ], "offsets": [ [ 783, 787 ] ], "normalized": [] }, { "id": "PMID-15558284_T15", "type": "Gene_or_gene_product", "text": [ "Kss1" ], "offsets": [ [ 802, 806 ] ], "normalized": [] }, { "id": "PMID-15558284_T16", "type": "Gene_or_gene_product", "text": [ "Tec1" ], "offsets": [ [ 832, 836 ] ], "normalized": [] }, { "id": "PMID-15558284_T17", "type": "Gene_or_gene_product", "text": [ "TEC1" ], "offsets": [ [ 881, 885 ] ], "normalized": [] }, { "id": "PMID-15558284_T18", "type": "Gene_or_gene_product", "text": [ "MAP kinases" ], "offsets": [ [ 1028, 1039 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-15642694__text", "type": "abstract", "text": [ "DNA binding of repressor nuclear factor-kappaB p50/p50 depends on phosphorylation of Ser337 by the protein kinase A catalytic subunit. \nThe NF-kappaB p50/p50 homodimer is mainly associated with transcriptional repression. Previously, we demonstrated that phosphorylation of NF-kappaB p50 Ser(337) is critical for DNA binding. Here, we report that p50 Ser(337) is constitutively phosphorylated by the protein kinase A catalytic subunit (PKAc) in three different cell types, which may account for the constant binding of p50/p50 to DNA in unstimulated cells. This was demonstrated first by showing that treatment of cells with PKAc-specific inhibitors blocked p50/p50 DNA binding. Second, phosphorylation of p50 by PKAc was prevented by substitution of Ser(337) to alanine. Third, both p50 and PKAc proteins as well as kinase activity that phosphorylates p50 were found to co-fractionate following gel filtration chromatography. Finally, PKAc and p50 were shown to be able to reciprocally co-immunoprecipitate one another, and their physical association was blocked by a PKA catalytic site inhibitory peptide. This indicates that phosphorylation of p50 Ser(337) involves direct contact with the PKAc catalytic center. In contrast to the dramatic elevation of nuclear p50/p65 heterodimers induced by tumor necrosis factor alpha, DNA binding of p50/p50 homodimers was not greatly altered. Taken together, these findings reveal for the first time that there is a direct interaction between PKAc and p50 that accounts for constitutive phosphorylation of p50 Ser(337) and the existence of DNA bound p50/p50 in the nuclei of most resting cells. This mechanism of DNA binding by p50/p50 following phosphorylation of Ser(337) by PKAc may represent an important means for maintaining stable negative regulation of NF-kappaB gene expression in the absence of extracellular stimulation.\n" ], "offsets": [ [ 0, 1874 ] ] } ]

[ { "id": "PMID-15642694_T1", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 25, 46 ] ], "normalized": [] }, { "id": "PMID-15642694_T2", "type": "Complex", "text": [ "p50/p50" ], "offsets": [ [ 47, 54 ] ], "normalized": [] }, { "id": "PMID-15642694_T3", "type": "Simple_chemical", "text": [ "Ser337" ], "offsets": [ [ 85, 91 ] ], "normalized": [] }, { "id": "PMID-15642694_T4", "type": "Gene_or_gene_product", "text": [ "protein kinase A catalytic subunit" ], "offsets": [ [ 99, 133 ] ], "normalized": [] }, { "id": "PMID-15642694_T5", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 140, 149 ] ], "normalized": [] }, { "id": "PMID-15642694_T6", "type": "Complex", "text": [ "p50/p50" ], "offsets": [ [ 150, 157 ] ], "normalized": [] }, { "id": "PMID-15642694_T7", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 274, 283 ] ], "normalized": [] }, { "id": "PMID-15642694_T8", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 284, 287 ] ], "normalized": [] }, { "id": "PMID-15642694_T9", "type": "Simple_chemical", "text": [ "Ser(337)" ], "offsets": [ [ 288, 296 ] ], "normalized": [] }, { "id": "PMID-15642694_T10", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 347, 350 ] ], "normalized": [] }, { "id": "PMID-15642694_T11", "type": "Simple_chemical", "text": [ "Ser(337)" ], "offsets": [ [ 351, 359 ] ], "normalized": [] }, { "id": "PMID-15642694_T12", "type": "Gene_or_gene_product", "text": [ "protein kinase A catalytic subunit" ], "offsets": [ [ 400, 434 ] ], "normalized": [] }, { "id": "PMID-15642694_T13", "type": "Gene_or_gene_product", "text": [ "PKAc" ], "offsets": [ [ 436, 440 ] ], "normalized": [] }, { "id": "PMID-15642694_T14", "type": "Complex", "text": [ "p50/p50" ], "offsets": [ [ 519, 526 ] ], "normalized": [] }, { "id": "PMID-15642694_T15", "type": "Gene_or_gene_product", "text": [ "PKAc" ], "offsets": [ [ 625, 629 ] ], "normalized": [] }, { "id": "PMID-15642694_T16", "type": "Complex", "text": [ "p50/p50" ], "offsets": [ [ 658, 665 ] ], "normalized": [] }, { "id": "PMID-15642694_T17", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 706, 709 ] ], "normalized": [] }, { "id": "PMID-15642694_T18", "type": "Gene_or_gene_product", "text": [ "PKAc" ], "offsets": [ [ 713, 717 ] ], "normalized": [] }, { "id": "PMID-15642694_T19", "type": "Simple_chemical", "text": [ "Ser(337)" ], "offsets": [ [ 751, 759 ] ], "normalized": [] }, { "id": "PMID-15642694_T20", "type": "Simple_chemical", "text": [ "alanine" ], "offsets": [ [ 763, 770 ] ], "normalized": [] }, { "id": "PMID-15642694_T21", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 784, 787 ] ], "normalized": [] }, { "id": "PMID-15642694_T22", "type": "Gene_or_gene_product", "text": [ "PKAc" ], "offsets": [ [ 792, 796 ] ], "normalized": [] }, { "id": "PMID-15642694_T23", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 853, 856 ] ], "normalized": [] }, { "id": "PMID-15642694_T24", "type": "Gene_or_gene_product", "text": [ "PKAc" ], "offsets": [ [ 936, 940 ] ], "normalized": [] }, { "id": "PMID-15642694_T25", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 945, 948 ] ], "normalized": [] }, { "id": "PMID-15642694_T26", "type": "Complex", "text": [ "PKA" ], "offsets": [ [ 1069, 1072 ] ], "normalized": [] }, { "id": "PMID-15642694_T27", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 1147, 1150 ] ], "normalized": [] }, { "id": "PMID-15642694_T28", "type": "Simple_chemical", "text": [ "Ser(337)" ], "offsets": [ [ 1151, 1159 ] ], "normalized": [] }, { "id": "PMID-15642694_T29", "type": "Gene_or_gene_product", "text": [ "PKAc" ], "offsets": [ [ 1193, 1197 ] ], "normalized": [] }, { "id": "PMID-15642694_T30", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1257, 1264 ] ], "normalized": [] }, { "id": "PMID-15642694_T31", "type": "Complex", "text": [ "p50/p65" ], "offsets": [ [ 1265, 1272 ] ], "normalized": [] }, { "id": "PMID-15642694_T32", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 1297, 1324 ] ], "normalized": [] }, { "id": "PMID-15642694_T33", "type": "Complex", "text": [ "p50/p50" ], "offsets": [ [ 1341, 1348 ] ], "normalized": [] }, { "id": "PMID-15642694_T34", "type": "Gene_or_gene_product", "text": [ "PKAc" ], "offsets": [ [ 1485, 1489 ] ], "normalized": [] }, { "id": "PMID-15642694_T35", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 1494, 1497 ] ], "normalized": [] }, { "id": "PMID-15642694_T36", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 1548, 1551 ] ], "normalized": [] }, { "id": "PMID-15642694_T37", "type": "Simple_chemical", "text": [ "Ser(337)" ], "offsets": [ [ 1552, 1560 ] ], "normalized": [] }, { "id": "PMID-15642694_T38", "type": "Complex", "text": [ "p50/p50" ], "offsets": [ [ 1592, 1599 ] ], "normalized": [] }, { "id": "PMID-15642694_T39", "type": "Cellular_component", "text": [ "nuclei" ], "offsets": [ [ 1607, 1613 ] ], "normalized": [] }, { "id": "PMID-15642694_T40", "type": "Complex", "text": [ "p50/p50" ], "offsets": [ [ 1670, 1677 ] ], "normalized": [] }, { "id": "PMID-15642694_T41", "type": "Simple_chemical", "text": [ "Ser(337)" ], "offsets": [ [ 1707, 1715 ] ], "normalized": [] }, { "id": "PMID-15642694_T42", "type": "Gene_or_gene_product", "text": [ "PKAc" ], "offsets": [ [ 1719, 1723 ] ], "normalized": [] }, { "id": "PMID-15642694_T43", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1803, 1812 ] ], "normalized": [] }, { "id": "PMID-15642694_T44", "type": "Cellular_component", "text": [ "extracellular" ], "offsets": [ [ 1847, 1860 ] ], "normalized": [] } ]

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"role": "Theme", "ref_id": "PMID-15642694_E2" }, { "role": "Cause", "ref_id": "PMID-15642694_E8" } ] }, { "id": "PMID-15642694_E6", "type": "Positive_regulation", "trigger": { "text": [ "depends" ], "offsets": [ [ 55, 62 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_E1" }, { "role": "Cause", "ref_id": "PMID-15642694_E8" } ] }, { "id": "PMID-15642694_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 66, 81 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15642694_T4" }, { "role": "Site", "ref_id": "PMID-15642694_T3" }, { "role": "Theme", "ref_id": "PMID-15642694_T1" } ] }, { "id": "PMID-15642694_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 66, 81 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15642694_T4" }, { "role": "Site", "ref_id": "PMID-15642694_T3" }, { "role": "Theme", "ref_id": "PMID-15642694_T2" } ] }, { "id": "PMID-15642694_E9", "type": "Binding", 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"text": [ "phosphorylates" ], "offsets": [ [ 838, 852 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_T23" } ] }, { "id": "PMID-15642694_E27", "type": "Binding", "trigger": { "text": [ "association" ], "offsets": [ [ 1040, 1051 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_T24" }, { "role": "Theme", "ref_id": "PMID-15642694_T25" } ] }, { "id": "PMID-15642694_E28", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1056, 1063 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_E27" } ] }, { "id": "PMID-15642694_E29", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1128, 1143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_T27" }, { "role": "Site", "ref_id": "PMID-15642694_T28" } ] }, { "id": "PMID-15642694_E30", "type": "Positive_regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 1160, 1168 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_E31" }, { "role": "Cause", "ref_id": "PMID-15642694_E29" } ] }, { "id": "PMID-15642694_E31", "type": "Binding", "trigger": { "text": [ "contact" ], "offsets": [ [ 1176, 1183 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_T27" }, { "role": "Theme", "ref_id": "PMID-15642694_T29" } ] }, { "id": "PMID-15642694_E32", "type": "Positive_regulation", "trigger": { "text": [ "elevation" ], "offsets": [ [ 1244, 1253 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_E33" } ] }, { "id": "PMID-15642694_E33", "type": "Binding", "trigger": { "text": [ "heterodimers" ], "offsets": [ [ 1273, 1285 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_T31" } ] }, { "id": "PMID-15642694_E34", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1286, 1293 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_E32" }, { "role": "Cause", "ref_id": "PMID-15642694_T32" } ] }, { "id": "PMID-15642694_E35", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1330, 1337 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_T33" } ] }, { "id": "PMID-15642694_E36", "type": "Binding", "trigger": { "text": [ "homodimers" ], "offsets": [ [ 1349, 1359 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_T33" } ] }, { "id": "PMID-15642694_E37", "type": "Regulation", "trigger": { "text": [ "altered" ], "offsets": [ [ 1376, 1383 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_E35" } ] }, { "id": "PMID-15642694_E38", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1465, 1476 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_T34" }, { "role": "Theme", "ref_id": "PMID-15642694_T35" } ] }, { "id": "PMID-15642694_E39", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1529, 1544 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_T36" }, { "role": "Site", "ref_id": "PMID-15642694_T37" }, { "role": "Cause", "ref_id": "PMID-15642694_T34" } ] }, { "id": "PMID-15642694_E40", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 1586, 1591 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_T38" } ] }, { "id": "PMID-15642694_E41", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1688, 1703 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15642694_T40" }, { "role": "Site", "ref_id": "PMID-15642694_T41" }, { "role": "Cause", "ref_id": "PMID-15642694_T42" } ] } ]

[ { "id": "PMID-15642694_1", "entity_ids": [ "PMID-15642694_T12", "PMID-15642694_T13" ] } ]

[]

[ { "id": "PMID-15701789__text", "type": "abstract", "text": [ "Ran GTPase regulates Mad2 localization to the nuclear pore complex. \nIn yeast and mammalian cells, the spindle assembly checkpoint proteins Mad1p and Mad2p localize to the nuclear pore complex (NPC) during interphase. Deletion of MAD1 or MAD2 did not affect steady-state nucleocytoplasmic distribution of a classical nuclear localization signal-containing reporter, a nuclear export signal-containing reporter, or Ran localization. We utilized cells with conditional mutations in the yeast Ran GTPase pathway to examine the relationship between Ran and targeting of checkpoint regulators to the NPC. Mutations that disrupt the concentration of Ran in the nucleus displaced Mad2p but not Mad1p from the NPC. The displacement of Mad2p in M-phase cells was correlated with activation of the spindle checkpoint. Our observations demonstrate that Mad2p localization at NPCs is sensitive to nuclear levels of Ran and suggest that release of Mad2p from NPCs is closely linked with spindle assembly checkpoint activation in yeast. This is the first evidence indicating that Ran affects the localization of Mad2p to the NPC.\n" ], "offsets": [ [ 0, 1116 ] ] } ]

[ { "id": "PMID-15701789_T1", "type": "Gene_or_gene_product", "text": [ "Ran" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-15701789_T2", "type": "Gene_or_gene_product", "text": [ "Mad2" ], "offsets": [ [ 21, 25 ] ], "normalized": [] }, { "id": "PMID-15701789_T3", "type": "Cellular_component", "text": [ "nuclear pore complex" ], "offsets": [ [ 46, 66 ] ], "normalized": [] }, { "id": "PMID-15701789_T4", "type": "Cellular_component", "text": [ "spindle" ], "offsets": [ [ 103, 110 ] ], "normalized": [] }, { "id": "PMID-15701789_T5", "type": "Gene_or_gene_product", "text": [ "Mad1p" ], "offsets": [ [ 140, 145 ] ], "normalized": [] }, { "id": "PMID-15701789_T6", "type": "Gene_or_gene_product", "text": [ "Mad2p" ], "offsets": [ [ 150, 155 ] ], "normalized": [] }, { "id": "PMID-15701789_T7", "type": "Cellular_component", "text": [ "nuclear pore complex" ], "offsets": [ [ 172, 192 ] ], "normalized": [] }, { "id": "PMID-15701789_T8", "type": "Cellular_component", "text": [ "NPC" ], "offsets": [ [ 194, 197 ] ], "normalized": [] }, { "id": "PMID-15701789_T9", "type": "Gene_or_gene_product", "text": [ "MAD1" ], "offsets": [ [ 230, 234 ] ], "normalized": [] }, { "id": "PMID-15701789_T10", "type": "Gene_or_gene_product", "text": [ "MAD2" ], "offsets": [ [ 238, 242 ] ], "normalized": [] }, { "id": "PMID-15701789_T11", "type": "Cellular_component", "text": [ "nucleocytoplasmic" ], "offsets": [ [ 271, 288 ] ], "normalized": [] }, { "id": "PMID-15701789_T12", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 317, 324 ] ], "normalized": [] }, { "id": "PMID-15701789_T13", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 368, 375 ] ], "normalized": [] }, { "id": "PMID-15701789_T14", "type": "Gene_or_gene_product", "text": [ "Ran" ], "offsets": [ [ 414, 417 ] ], "normalized": [] }, { "id": "PMID-15701789_T15", "type": "Gene_or_gene_product", "text": [ "Ran" ], "offsets": [ [ 490, 493 ] ], "normalized": [] }, { "id": "PMID-15701789_T16", "type": "Gene_or_gene_product", "text": [ "Ran" ], "offsets": [ [ 545, 548 ] ], "normalized": [] }, { "id": "PMID-15701789_T17", "type": "Cellular_component", "text": [ "NPC" ], "offsets": [ [ 595, 598 ] ], "normalized": [] }, { "id": "PMID-15701789_T18", "type": "Gene_or_gene_product", "text": [ "Ran" ], "offsets": [ [ 644, 647 ] ], "normalized": [] }, { "id": "PMID-15701789_T19", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 655, 662 ] ], "normalized": [] }, { "id": "PMID-15701789_T20", "type": "Gene_or_gene_product", "text": [ "Mad2p" ], "offsets": [ [ 673, 678 ] ], "normalized": [] }, { "id": "PMID-15701789_T21", "type": "Gene_or_gene_product", "text": [ "Mad1p" ], "offsets": [ [ 687, 692 ] ], "normalized": [] }, { "id": "PMID-15701789_T22", "type": "Cellular_component", "text": [ "NPC" ], "offsets": [ [ 702, 705 ] ], "normalized": [] }, { "id": "PMID-15701789_T23", "type": "Gene_or_gene_product", "text": [ "Mad2p" ], "offsets": [ [ 727, 732 ] ], "normalized": [] }, { "id": "PMID-15701789_T24", "type": "Cellular_component", "text": [ "spindle" ], "offsets": [ [ 788, 795 ] ], "normalized": [] }, { "id": "PMID-15701789_T25", "type": "Gene_or_gene_product", "text": [ "Mad2p" ], "offsets": [ [ 842, 847 ] ], "normalized": [] }, { "id": "PMID-15701789_T26", "type": "Cellular_component", "text": [ "NPCs" ], "offsets": [ [ 864, 868 ] ], "normalized": [] }, { "id": "PMID-15701789_T27", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 885, 892 ] ], "normalized": [] }, { "id": "PMID-15701789_T28", "type": "Gene_or_gene_product", "text": [ "Ran" ], "offsets": [ [ 903, 906 ] ], "normalized": [] }, { "id": "PMID-15701789_T29", "type": "Gene_or_gene_product", "text": [ "Mad2p" ], "offsets": [ [ 935, 940 ] ], "normalized": [] }, { "id": "PMID-15701789_T30", "type": "Cellular_component", "text": [ "NPCs" ], "offsets": [ [ 946, 950 ] ], "normalized": [] }, { "id": "PMID-15701789_T31", "type": "Cellular_component", "text": [ "spindle" ], "offsets": [ [ 974, 981 ] ], "normalized": [] }, { "id": "PMID-15701789_T32", "type": "Gene_or_gene_product", "text": [ "Ran" ], "offsets": [ [ 1066, 1069 ] ], "normalized": [] }, { "id": "PMID-15701789_T33", "type": "Gene_or_gene_product", "text": [ "Mad2p" ], "offsets": [ [ 1098, 1103 ] ], "normalized": [] }, { "id": "PMID-15701789_T34", "type": "Cellular_component", "text": [ "NPC" ], "offsets": [ [ 1111, 1114 ] ], "normalized": [] } ]

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[ { "id": "PMID-15701789_1", "entity_ids": [ "PMID-15701789_T7", "PMID-15701789_T8" ] } ]

[]

[ { "id": "PMID-15744308__text", "type": "abstract", "text": [ "Cyclin specificity in the phosphorylation of cyclin-dependent kinase substrates. \nCell-cycle events are controlled by cyclin-dependent kinases (CDKs), whose periodic activation is driven by cyclins. Different cyclins promote distinct cell-cycle events, but the molecular basis for these differences remains unclear. Here we compare the specificity of two budding yeast cyclins, the S-phase cyclin Clb5 and the M-phase cyclin Clb2, in the phosphorylation of 150 Cdk1 (Cdc28) substrates. About 24% of these proteins were phosphorylated more efficiently by Clb5-Cdk1 than Clb2-Cdk1. The Clb5-specific targets include several proteins (Sld2, Cdc6, Orc6, Mcm3 and Cdh1) involved in early S-phase events. Clb5 specificity depended on an interaction between a hydrophobic patch in Clb5 and a short sequence in the substrate (the RXL or Cy motif). Phosphorylation of Clb5-specific targets during S phase was reduced by replacing Clb5 with Clb2 or by mutating the substrate RXL motif, confirming the importance of Clb5 specificity in vivo. Although we did not identify any highly Clb2-specific substrates, we found that Clb2-Cdk1 possessed higher intrinsic kinase activity than Clb5-Cdk1, enabling efficient phosphorylation of a broad range of mitotic Cdk1 targets. Thus, Clb5 and Clb2 use distinct mechanisms to enhance the phosphorylation of S-phase and M-phase substrates.\n" ], "offsets": [ [ 0, 1367 ] ] } ]

[ { "id": "PMID-15744308_T1", "type": "Gene_or_gene_product", "text": [ "Cyclin" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "PMID-15744308_T2", "type": "Gene_or_gene_product", "text": [ "cyclin-dependent kinase" ], "offsets": [ [ 45, 68 ] ], "normalized": [] }, { "id": "PMID-15744308_T3", "type": "Gene_or_gene_product", "text": [ "cyclin-dependent kinases" ], "offsets": [ [ 118, 142 ] ], "normalized": [] }, { "id": "PMID-15744308_T4", "type": "Gene_or_gene_product", "text": [ "CDKs" ], "offsets": [ [ 144, 148 ] ], "normalized": [] }, { "id": "PMID-15744308_T5", "type": "Gene_or_gene_product", "text": [ "cyclins" ], "offsets": [ [ 190, 197 ] ], "normalized": [] }, { "id": "PMID-15744308_T6", "type": "Gene_or_gene_product", "text": [ "cyclins" ], "offsets": [ [ 209, 216 ] ], "normalized": [] }, { "id": "PMID-15744308_T7", "type": "Gene_or_gene_product", "text": [ "cyclins" ], "offsets": [ [ 369, 376 ] ], "normalized": [] }, { "id": "PMID-15744308_T8", "type": "Gene_or_gene_product", "text": [ "cyclin Clb5" ], "offsets": [ [ 390, 401 ] ], "normalized": [] }, { "id": "PMID-15744308_T9", "type": "Gene_or_gene_product", "text": [ "cyclin Clb2" ], "offsets": [ [ 418, 429 ] ], "normalized": [] }, { "id": "PMID-15744308_T10", "type": "Gene_or_gene_product", "text": [ "Cdk1" ], "offsets": [ [ 461, 465 ] ], "normalized": [] }, { "id": "PMID-15744308_T11", "type": "Gene_or_gene_product", "text": [ "Cdc28" ], "offsets": [ [ 467, 472 ] ], "normalized": [] }, { "id": "PMID-15744308_T12", "type": "Complex", "text": [ "Clb5-Cdk1" ], "offsets": [ [ 554, 563 ] ], "normalized": [] }, { "id": "PMID-15744308_T13", "type": "Complex", "text": [ "Clb2-Cdk1" ], "offsets": [ [ 569, 578 ] ], "normalized": [] }, { "id": "PMID-15744308_T14", "type": "Gene_or_gene_product", "text": [ "Clb5" ], "offsets": [ [ 584, 588 ] ], "normalized": [] }, { "id": "PMID-15744308_T15", "type": "Gene_or_gene_product", "text": [ "Sld2" ], "offsets": [ [ 632, 636 ] ], "normalized": [] }, { "id": "PMID-15744308_T16", "type": "Gene_or_gene_product", "text": [ "Cdc6" ], "offsets": [ [ 638, 642 ] ], "normalized": [] }, { "id": "PMID-15744308_T17", "type": "Gene_or_gene_product", "text": [ "Orc6" ], "offsets": [ [ 644, 648 ] ], "normalized": [] }, { "id": "PMID-15744308_T18", "type": "Gene_or_gene_product", "text": [ "Mcm3" ], "offsets": [ [ 650, 654 ] ], "normalized": [] }, { "id": "PMID-15744308_T19", "type": "Gene_or_gene_product", "text": [ "Cdh1" ], "offsets": [ [ 659, 663 ] ], "normalized": [] }, { "id": "PMID-15744308_T20", "type": "Gene_or_gene_product", "text": [ "Clb5" ], "offsets": [ [ 699, 703 ] ], "normalized": [] }, { "id": "PMID-15744308_T21", "type": "Gene_or_gene_product", "text": [ "Clb5" ], "offsets": [ [ 774, 778 ] ], "normalized": [] }, { "id": "PMID-15744308_T22", "type": "Gene_or_gene_product", "text": [ "Clb5" ], "offsets": [ [ 859, 863 ] ], "normalized": [] }, { "id": "PMID-15744308_T23", "type": "Gene_or_gene_product", "text": [ "Clb5" ], "offsets": [ [ 921, 925 ] ], "normalized": [] }, { "id": "PMID-15744308_T24", "type": "Gene_or_gene_product", "text": [ "Clb2" ], "offsets": [ [ 931, 935 ] ], "normalized": [] }, { "id": "PMID-15744308_T25", "type": "Gene_or_gene_product", "text": [ "Clb5" ], "offsets": [ [ 1005, 1009 ] ], "normalized": [] }, { "id": "PMID-15744308_T26", "type": "Gene_or_gene_product", "text": [ "Clb2" ], "offsets": [ [ 1071, 1075 ] ], "normalized": [] }, { "id": "PMID-15744308_T27", "type": "Complex", "text": [ "Clb2-Cdk1" ], "offsets": [ [ 1111, 1120 ] ], "normalized": [] }, { "id": "PMID-15744308_T28", "type": "Complex", "text": [ "Clb5-Cdk1" ], "offsets": [ [ 1169, 1178 ] ], "normalized": [] }, { "id": "PMID-15744308_T29", "type": "Gene_or_gene_product", "text": [ "Cdk1" ], "offsets": [ [ 1243, 1247 ] ], "normalized": [] }, { "id": "PMID-15744308_T30", "type": "Gene_or_gene_product", "text": [ "Clb5" ], "offsets": [ [ 1263, 1267 ] ], "normalized": [] }, { "id": "PMID-15744308_T31", "type": "Gene_or_gene_product", "text": [ "Clb2" ], "offsets": [ [ 1272, 1276 ] ], "normalized": [] } ]

[ { "id": "PMID-15744308_E1", "type": "Pathway", "trigger": { "text": [ "Cell-cycle" ], "offsets": [ [ 82, 92 ] ] }, "arguments": [] }, { "id": "PMID-15744308_E2", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 104, 114 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_T3" }, { "role": "Theme", "ref_id": "PMID-15744308_E1" } ] }, { "id": "PMID-15744308_E3", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 166, 176 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15744308_T3" } ] }, { "id": "PMID-15744308_E4", "type": "Positive_regulation", "trigger": { "text": [ "driven" ], "offsets": [ [ 180, 186 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15744308_E3" }, { "role": "Cause", "ref_id": "PMID-15744308_T5" } ] }, { "id": "PMID-15744308_E5", "type": "Positive_regulation", "trigger": { "text": [ "promote" ], "offsets": [ [ 217, 224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15744308_E6" }, { "role": "Cause", "ref_id": "PMID-15744308_T6" } ] }, { "id": "PMID-15744308_E6", "type": "Pathway", "trigger": { "text": [ "cell-cycle" ], "offsets": [ [ 234, 244 ] ] }, "arguments": [] }, { "id": "PMID-15744308_E7", "type": "Positive_regulation", "trigger": { "text": [ "targets" ], "offsets": [ [ 598, 605 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_T14" }, { "role": "Theme", "ref_id": "PMID-15744308_T15" } ] }, { "id": "PMID-15744308_E8", "type": "Positive_regulation", "trigger": { "text": [ "targets" ], "offsets": [ [ 598, 605 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_T14" }, { "role": "Theme", "ref_id": "PMID-15744308_T16" } ] }, { "id": "PMID-15744308_E9", "type": "Positive_regulation", "trigger": { "text": [ "targets" ], "offsets": [ [ 598, 605 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_T14" }, { "role": "Theme", "ref_id": "PMID-15744308_T17" } ] }, { "id": "PMID-15744308_E10", "type": "Positive_regulation", "trigger": { "text": [ "targets" ], "offsets": [ [ 598, 605 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_T14" }, { "role": "Theme", "ref_id": "PMID-15744308_T18" } ] }, { "id": "PMID-15744308_E11", "type": "Positive_regulation", "trigger": { "text": [ "targets" ], "offsets": [ [ 598, 605 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_T14" }, { "role": "Theme", "ref_id": "PMID-15744308_T19" } ] }, { "id": "PMID-15744308_E12", "type": "Positive_regulation", "trigger": { "text": [ "depended" ], "offsets": [ [ 716, 724 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15744308_T20" }, { "role": "Cause", "ref_id": "PMID-15744308_E13" } ] }, { "id": "PMID-15744308_E13", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 731, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15744308_T21" } ] }, { "id": "PMID-15744308_E14", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 840, 855 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_T22" }, { "role": "Theme", "ref_id": "PMID-15744308_T15" } ] }, { "id": "PMID-15744308_E15", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 840, 855 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_T22" }, { "role": "Theme", "ref_id": "PMID-15744308_T16" } ] }, { "id": "PMID-15744308_E16", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 840, 855 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_T22" }, { "role": "Theme", "ref_id": "PMID-15744308_T17" } ] }, { "id": "PMID-15744308_E17", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 840, 855 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_T22" }, { "role": "Theme", "ref_id": "PMID-15744308_T18" } ] }, { "id": "PMID-15744308_E18", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 840, 855 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_T22" }, { "role": "Theme", "ref_id": "PMID-15744308_T19" } ] }, { "id": "PMID-15744308_E19", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 900, 907 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_E24" }, { "role": "Theme", "ref_id": "PMID-15744308_E14" } ] }, { "id": "PMID-15744308_E20", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 900, 907 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_E24" }, { "role": "Theme", "ref_id": "PMID-15744308_E15" } ] }, { "id": "PMID-15744308_E21", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 900, 907 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_E24" }, { "role": "Theme", "ref_id": "PMID-15744308_E16" } ] }, { "id": "PMID-15744308_E22", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 900, 907 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_E24" }, { "role": "Theme", "ref_id": "PMID-15744308_E17" } ] }, { "id": "PMID-15744308_E23", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 900, 907 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15744308_E24" }, { "role": "Theme", "ref_id": "PMID-15744308_E18" } ] }, { "id": "PMID-15744308_E24", "type": "Inactivation", "trigger": { "text": [ "replacing" ], "offsets": [ [ 911, 920 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15744308_T23" } ] } ]

[ { "id": "PMID-15744308_1", "entity_ids": [ "PMID-15744308_T4", "PMID-15744308_T3" ] }, { "id": "PMID-15744308_2", "entity_ids": [ "PMID-15744308_T10", "PMID-15744308_T11" ] } ]

[]

[ { "id": "PMID-15766563__text", "type": "abstract", "text": [ "E2F1 up-regulates the expression of the tumour suppressor axin2 both by activation of transcription and by mRNA stabilisation. \nAxin2 is a negative regulator of Wnt/beta-catenin signalling with roles in early development and tumour suppression. Axin2 is induced by E2F1 and therefore acts as a point of cross-talk between the pRb/E2F and Wnt/beta-catenin pathways: two of the most frequently deregulated pathways in human cancers. In this study, we show that E2F1 up-regulates axin2 by two independent mechanisms. The human axin2 gene allows transcription of messages with three different 5' untranslated regions and in the first mechanism E2F1 directly activates the transcription of only one of these species by acting at canonical E2F binding sites. Second, E2F1 induces stabilisation of axin2 mRNAs. We discuss this regulation with respect to other known E2F targets.\n" ], "offsets": [ [ 0, 872 ] ] } ]

[ { "id": "PMID-15766563_T1", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-15766563_T2", "type": "Gene_or_gene_product", "text": [ "axin2" ], "offsets": [ [ 58, 63 ] ], "normalized": [] }, { "id": "PMID-15766563_T3", "type": "Gene_or_gene_product", "text": [ "Axin2" ], "offsets": [ [ 128, 133 ] ], "normalized": [] }, { "id": "PMID-15766563_T4", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 161, 164 ] ], "normalized": [] }, { "id": "PMID-15766563_T5", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 165, 177 ] ], "normalized": [] }, { "id": "PMID-15766563_T6", "type": "Gene_or_gene_product", "text": [ "Axin2" ], "offsets": [ [ 245, 250 ] ], "normalized": [] }, { "id": "PMID-15766563_T7", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 265, 269 ] ], "normalized": [] }, { "id": "PMID-15766563_T8", "type": "Gene_or_gene_product", "text": [ "pRb" ], "offsets": [ [ 326, 329 ] ], "normalized": [] }, { "id": "PMID-15766563_T9", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 330, 333 ] ], "normalized": [] }, { "id": "PMID-15766563_T10", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 338, 341 ] ], "normalized": [] }, { "id": "PMID-15766563_T11", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 342, 354 ] ], "normalized": [] }, { "id": "PMID-15766563_T12", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 459, 463 ] ], "normalized": [] }, { "id": "PMID-15766563_T13", "type": "Gene_or_gene_product", "text": [ "axin2" ], "offsets": [ [ 477, 482 ] ], "normalized": [] }, { "id": "PMID-15766563_T14", "type": "Gene_or_gene_product", "text": [ "axin2" ], "offsets": [ [ 524, 529 ] ], "normalized": [] }, { "id": "PMID-15766563_T15", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 640, 644 ] ], "normalized": [] }, { "id": "PMID-15766563_T16", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 734, 737 ] ], "normalized": [] }, { "id": "PMID-15766563_T17", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 761, 765 ] ], "normalized": [] }, { "id": "PMID-15766563_T18", "type": "Gene_or_gene_product", "text": [ "axin2" ], "offsets": [ [ 791, 796 ] ], "normalized": [] }, { "id": "PMID-15766563_T19", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 859, 862 ] ], "normalized": [] } ]

[ { "id": "PMID-15766563_E1", "type": "Positive_regulation", "trigger": { "text": [ "up-regulates" ], "offsets": [ [ 5, 17 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15766563_T1" }, { "role": "Theme", "ref_id": "PMID-15766563_E2" } ] }, { "id": "PMID-15766563_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 22, 32 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15766563_T2" } ] }, { "id": "PMID-15766563_E3", "type": "Negative_regulation", "trigger": { "text": [ "negative regulator" ], "offsets": [ [ 139, 157 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15766563_T3" }, { "role": "Theme", "ref_id": "PMID-15766563_E4" } ] }, { "id": "PMID-15766563_E4", "type": "Pathway", "trigger": { "text": [ "signalling" ], "offsets": [ [ 178, 188 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15766563_T4" }, { "role": "Participant", "ref_id": "PMID-15766563_T5" } ] }, { "id": "PMID-15766563_E5", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 254, 261 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15766563_T6" }, { "role": "Cause", "ref_id": "PMID-15766563_T7" } ] }, { "id": "PMID-15766563_E6", "type": "Pathway", "trigger": { "text": [ "pathways" ], "offsets": [ [ 355, 363 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15766563_T8" }, { "role": "Participant", "ref_id": "PMID-15766563_T9" } ] }, { "id": "PMID-15766563_E7", "type": "Pathway", "trigger": { "text": [ "pathways" ], "offsets": [ [ 355, 363 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15766563_T10" }, { "role": "Participant", "ref_id": "PMID-15766563_T11" } ] }, { "id": "PMID-15766563_E8", "type": "Negative_regulation", "trigger": { "text": [ "deregulated" ], "offsets": [ [ 392, 403 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15766563_E6" } ] }, { "id": "PMID-15766563_E9", "type": "Negative_regulation", "trigger": { "text": [ "deregulated" ], "offsets": [ [ 392, 403 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15766563_E7" } ] }, { "id": "PMID-15766563_E10", "type": "Positive_regulation", "trigger": { "text": [ "up-regulates" ], "offsets": [ [ 464, 476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15766563_T12" }, { "role": "Theme", "ref_id": "PMID-15766563_T13" } ] }, { "id": "PMID-15766563_E11", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 766, 773 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15766563_T17" }, { "role": "Theme", "ref_id": "PMID-15766563_E12" } ] }, { "id": "PMID-15766563_E12", "type": "Regulation", "trigger": { "text": [ "stabilisation" ], "offsets": [ [ 774, 787 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15766563_T18" } ] }, { "id": "PMID-15766563_E13", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 820, 830 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15766563_E11" } ] } ]

[]

[]

[ { "id": "PMID-15767663__text", "type": "abstract", "text": [ "Distinct signaling events downstream of mTOR cooperate to mediate the effects of amino acids and insulin on initiation factor 4E-binding proteins. \nSignaling through the mammalian target of rapamycin (mTOR) controls cell size and growth as well as other functions, and it is a potential therapeutic target for graft rejection, certain cancers, and disorders characterized by inappropriate cell or tissue growth. mTOR signaling is positively regulated by hormones or growth factors and amino acids. mTOR signaling regulates the phosphorylation of several proteins, the best characterized being ones that control mRNA translation. Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) undergoes phosphorylation at multiple sites. Here we show that amino acids regulate the N-terminal phosphorylation sites in 4E-BP1 through the RAIP motif in a rapamycin-insensitive manner. Several criteria indicate this reflects a rapamycin-insensitive output from mTOR. In contrast, the insulin-stimulated phosphorylation of the C-terminal site Ser64/65 is generally sensitive to rapamycin, as is phosphorylation of another well-characterized target for mTOR signaling, S6K1. Our data imply that it is unlikely that mTOR directly phosphorylates Thr69/70 in 4E-BP1. Although 4E-BP1 and S6K1 bind the mTOR partner, raptor, our data indicate that the outputs from mTOR to 4E-BP1 and S6K1 are distinct. In cells, efficient phosphorylation of 4E-BP1 requires it to be able to bind to eIF4E, whereas phosphorylation of 4E-BP1 by mTOR in vitro shows no such preference. These data have important implications for understanding signaling downstream of mTOR and the development of new strategies to impair mTOR signaling. \n" ], "offsets": [ [ 0, 1703 ] ] } ]

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"PMID-15767663_T31" } ] }, { "id": "PMID-15767663_E27", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1483, 1498 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15767663_T33" }, { "role": "Cause", "ref_id": "PMID-15767663_T34" } ] }, { "id": "PMID-15767663_E28", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1691, 1700 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15767663_T36" } ] } ]

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[]

[ { "id": "PMID-15838516__text", "type": "abstract", "text": [ "Pocket proteins and cell cycle control. \nThe retinoblastoma protein (pRB) and the pRB-related p107 and p130 comprise the 'pocket protein' family of cell cycle regulators. These proteins are best known for their roles in restraining the G1-S transition through the regulation of E2F-responsive genes. pRB and the p107/p130 pair are required for the repression of distinct sets of genes, potentially due to their selective interactions with E2Fs that are engaged at specific promoter elements. In addition to regulating E2F-responsive genes in a reversible manner, pocket proteins contribute to silencing of such genes in cells that are undergoing senescence or differentiation. Pocket proteins also affect the G1-S transition through E2F-independent mechanisms, such as by inhibiting Cdk2 or by stabilizing p27(Kip1), and they are implicated in the control of G0 exit, the spatial organization of replication, and genomic rereplication. New insights into pocket protein regulation have also been obtained. Kinases previously thought to be crucial to pocket protein phosphorylation have been shown to be redundant, and new modes of phosphorylation and dephosphorylation have been identified. Despite these advances, much remains to be learned about the pocket proteins, particularly with regard to their developmental and tumor suppressor functions. Thus continues the story of the pocket proteins and the cell cycle.\n" ], "offsets": [ [ 0, 1416 ] ] } ]

[ { "id": "PMID-15838516_T1", "type": "Gene_or_gene_product", "text": [ "Pocket proteins" ], "offsets": [ [ 0, 15 ] ], "normalized": [] }, { "id": "PMID-15838516_T2", "type": "Gene_or_gene_product", "text": [ "retinoblastoma protein" ], "offsets": [ [ 45, 67 ] ], "normalized": [] }, { "id": "PMID-15838516_T3", "type": "Gene_or_gene_product", "text": [ "pRB" ], "offsets": [ [ 69, 72 ] ], "normalized": [] }, { "id": "PMID-15838516_T4", "type": "Gene_or_gene_product", "text": [ "pRB" ], "offsets": [ [ 82, 85 ] ], "normalized": [] }, { "id": "PMID-15838516_T5", "type": "Gene_or_gene_product", "text": [ "p107" ], "offsets": [ [ 94, 98 ] ], "normalized": [] }, { "id": "PMID-15838516_T6", "type": "Gene_or_gene_product", "text": [ "p130" ], "offsets": [ [ 103, 107 ] ], "normalized": [] }, { "id": "PMID-15838516_T7", "type": "Gene_or_gene_product", "text": [ "pocket protein" ], "offsets": [ [ 122, 136 ] ], "normalized": [] }, { "id": "PMID-15838516_T8", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 278, 281 ] ], "normalized": [] }, { "id": "PMID-15838516_T9", "type": "Gene_or_gene_product", "text": [ "pRB" ], "offsets": [ [ 300, 303 ] ], "normalized": [] }, { "id": "PMID-15838516_T10", "type": "Gene_or_gene_product", "text": [ "p107" ], "offsets": [ [ 312, 316 ] ], "normalized": [] }, { "id": "PMID-15838516_T11", "type": "Gene_or_gene_product", "text": [ "p130" ], "offsets": [ [ 317, 321 ] ], "normalized": [] }, { "id": "PMID-15838516_T12", "type": "Gene_or_gene_product", "text": [ "E2Fs" ], "offsets": [ [ 439, 443 ] ], "normalized": [] }, { "id": "PMID-15838516_T13", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 518, 521 ] ], "normalized": [] }, { "id": "PMID-15838516_T14", "type": "Gene_or_gene_product", "text": [ "pocket proteins" ], "offsets": [ [ 563, 578 ] ], "normalized": [] }, { "id": "PMID-15838516_T15", "type": "Gene_or_gene_product", "text": [ "Pocket proteins" ], "offsets": [ [ 677, 692 ] ], "normalized": [] }, { "id": "PMID-15838516_T16", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 733, 736 ] ], "normalized": [] }, { "id": "PMID-15838516_T17", "type": "Gene_or_gene_product", "text": [ "Cdk2" ], "offsets": [ [ 783, 787 ] ], "normalized": [] }, { "id": "PMID-15838516_T18", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 806, 809 ] ], "normalized": [] }, { "id": "PMID-15838516_T19", "type": "Gene_or_gene_product", "text": [ "Kip1" ], "offsets": [ [ 810, 814 ] ], "normalized": [] }, { "id": "PMID-15838516_T20", "type": "Gene_or_gene_product", "text": [ "pocket protein" ], "offsets": [ [ 954, 968 ] ], "normalized": [] }, { "id": "PMID-15838516_T21", "type": "Gene_or_gene_product", "text": [ "pocket protein" ], "offsets": [ [ 1049, 1063 ] ], "normalized": [] }, { "id": "PMID-15838516_T22", "type": "Gene_or_gene_product", "text": [ "pocket proteins" ], "offsets": [ [ 1251, 1266 ] ], "normalized": [] }, { "id": "PMID-15838516_T23", "type": "Gene_or_gene_product", "text": [ "pocket proteins" ], "offsets": [ [ 1380, 1395 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-15850991__text", "type": "abstract", "text": [ "LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders. \nThe LDL receptor-related protein 5 (LRP5) is a member of the LDL receptor family, which also includes the VLDL receptor and the apolipoprotein E receptor 2. The LRP5 is a co-receptor of Wnt located on the osteoblast membrane between two other receptors, Frizzled and Kremen. Frizzled and LRP5 bind to Wnt, thereby stabilizing beta-catenin and activating bone formation. When the dickkopf protein (Dkk) binds to Kremen and LRP5, this last undergoes internalization and therefore becomes unable to bind Wnt; this leads to degradation of beta-catenin and to inhibition of bone formation. In humans, loss of LRP5 function causes osteoporosis-pseudoglioma syndrome, which is characterized by congenital blindness and extremely severe childhood-onset osteoporosis (lumbar spine Z-score often < -4) with fractures. The G171V mutation prevents Dkk from binding to LRP5, thereby increasing LRP5 function; the result is high bone mass due to uncoupling of bone formation and resorption. The Z-scores in this condition can exceed +6 at the hip and spine. The LRP5 and Wnt/beta-catenin reflect the level of bone formation and play a central role in bone mass accrual and normal distribution. Furthermore, LRP5 may contribute to mediate mechanical loads within bone tissue. Identification of the Wnt/beta-catenin pathway is a breakthrough in the elucidation of pathophysiological mechanisms affecting bone tissue and suggests new treatment targets for patients with osteoporosis or specific malignant conditions such as myeloma and sclerotic bone metastases.\n" ], "offsets": [ [ 0, 1630 ] ] } ]

[ { "id": "PMID-15850991_T1", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-15850991_T2", "type": "Gene_or_gene_product", "text": [ "LDL receptor-related protein 5" ], "offsets": [ [ 88, 118 ] ], "normalized": [] }, { "id": "PMID-15850991_T3", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 120, 124 ] ], "normalized": [] }, { "id": "PMID-15850991_T4", "type": "Gene_or_gene_product", "text": [ "LDL receptor" ], "offsets": [ [ 145, 157 ] ], "normalized": [] }, { "id": "PMID-15850991_T5", "type": "Gene_or_gene_product", "text": [ "VLDL receptor" ], "offsets": [ [ 190, 203 ] ], "normalized": [] }, { "id": "PMID-15850991_T6", "type": "Gene_or_gene_product", "text": [ "apolipoprotein E receptor 2" ], "offsets": [ [ 212, 239 ] ], "normalized": [] }, { "id": "PMID-15850991_T7", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 245, 249 ] ], "normalized": [] }, { "id": "PMID-15850991_T8", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 270, 273 ] ], "normalized": [] }, { "id": "PMID-15850991_T9", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 300, 308 ] ], "normalized": [] }, { "id": "PMID-15850991_T10", "type": "Gene_or_gene_product", "text": [ "Frizzled" ], "offsets": [ [ 338, 346 ] ], "normalized": [] }, { "id": "PMID-15850991_T11", "type": "Gene_or_gene_product", "text": [ "Kremen" ], "offsets": [ [ 351, 357 ] ], "normalized": [] }, { "id": "PMID-15850991_T12", "type": "Gene_or_gene_product", "text": [ "Frizzled" ], "offsets": [ [ 359, 367 ] ], "normalized": [] }, { "id": "PMID-15850991_T13", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 372, 376 ] ], "normalized": [] }, { "id": "PMID-15850991_T14", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 385, 388 ] ], "normalized": [] }, { "id": "PMID-15850991_T15", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 410, 422 ] ], "normalized": [] }, { "id": "PMID-15850991_T16", "type": "Gene_or_gene_product", "text": [ "dickkopf" ], "offsets": [ [ 463, 471 ] ], "normalized": [] }, { "id": "PMID-15850991_T17", "type": "Gene_or_gene_product", "text": [ "Dkk" ], "offsets": [ [ 481, 484 ] ], "normalized": [] }, { "id": "PMID-15850991_T18", "type": "Gene_or_gene_product", "text": [ "Kremen" ], "offsets": [ [ 495, 501 ] ], "normalized": [] }, { "id": "PMID-15850991_T19", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 506, 510 ] ], "normalized": [] }, { "id": "PMID-15850991_T20", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 585, 588 ] ], "normalized": [] }, { "id": "PMID-15850991_T21", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 619, 631 ] ], "normalized": [] }, { "id": "PMID-15850991_T22", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 688, 692 ] ], "normalized": [] }, { "id": "PMID-15850991_T23", "type": "Gene_or_gene_product", "text": [ "Dkk" ], "offsets": [ [ 920, 923 ] ], "normalized": [] }, { "id": "PMID-15850991_T24", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 940, 944 ] ], "normalized": [] }, { "id": "PMID-15850991_T25", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 965, 969 ] ], "normalized": [] }, { "id": "PMID-15850991_T26", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 1132, 1136 ] ], "normalized": [] }, { "id": "PMID-15850991_T27", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 1141, 1144 ] ], "normalized": [] }, { "id": "PMID-15850991_T28", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1145, 1157 ] ], "normalized": [] }, { "id": "PMID-15850991_T29", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 1277, 1281 ] ], "normalized": [] }, { "id": "PMID-15850991_T30", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 1367, 1370 ] ], "normalized": [] }, { "id": "PMID-15850991_T31", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1371, 1383 ] ], "normalized": [] } ]

[ { "id": "PMID-15850991_E1", "type": "Localization", "trigger": { "text": [ "located" ], "offsets": [ [ 274, 281 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15850991_T9" }, { "role": "Theme", "ref_id": "PMID-15850991_T7" } ] }, { "id": "PMID-15850991_E2", "type": "Localization", "trigger": { "text": [ "located" ], "offsets": [ [ 274, 281 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15850991_T9" }, { "role": "Theme", "ref_id": "PMID-15850991_T10" } ] }, { "id": "PMID-15850991_E3", "type": "Localization", "trigger": { "text": [ "located" ], "offsets": [ [ 274, 281 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-15850991_T9" }, { "role": "Theme", "ref_id": "PMID-15850991_T11" } ] }, { "id": "PMID-15850991_E4", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 377, 381 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15850991_T13" }, { "role": "Theme", "ref_id": "PMID-15850991_T14" }, { "role": "Theme", "ref_id": "PMID-15850991_T12" } ] }, { "id": "PMID-15850991_E5", "type": "Regulation", "trigger": { "text": [ "stabilizing" ], "offsets": [ [ 398, 409 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15850991_T15" }, { "role": "Cause", "ref_id": "PMID-15850991_E4" } ] }, { "id": "PMID-15850991_E6", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 486, 491 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15850991_T16" }, { "role": "Theme", "ref_id": "PMID-15850991_T18" }, { "role": "Theme", "ref_id": "PMID-15850991_T19" } ] }, { "id": "PMID-15850991_E7", "type": "Transport", "trigger": { "text": [ "internalization" ], "offsets": [ [ 532, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15850991_T19" } ] }, { "id": "PMID-15850991_E8", "type": "Negative_regulation", "trigger": { "text": [ "becomes" ], "offsets": [ [ 562, 569 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15850991_E7" }, { "role": "Theme", "ref_id": "PMID-15850991_E9" } ] }, { "id": "PMID-15850991_E9", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 580, 584 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15850991_T20" }, { "role": "Theme", "ref_id": "PMID-15850991_T19" } ] }, { "id": "PMID-15850991_E10", "type": "Positive_regulation", "trigger": { "text": [ "leads" ], "offsets": [ [ 595, 600 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15850991_E9" }, { "role": "Theme", "ref_id": "PMID-15850991_E11" } ] }, { "id": "PMID-15850991_E11", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 604, 615 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15850991_T21" } ] }, { "id": "PMID-15850991_E12", "type": "Inactivation", "trigger": { "text": [ "loss" ], "offsets": [ [ 680, 684 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15850991_T22" } ] }, { "id": "PMID-15850991_E13", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 911, 919 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15850991_E14" } ] }, { "id": "PMID-15850991_E14", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 929, 936 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15850991_T23" }, { "role": "Theme", "ref_id": "PMID-15850991_T24" } ] }, { "id": "PMID-15850991_E15", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 954, 964 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15850991_E13" }, { "role": "Theme", "ref_id": "PMID-15850991_T25" } ] }, { "id": "PMID-15850991_E16", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1384, 1391 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15850991_T30" }, { "role": "Participant", "ref_id": "PMID-15850991_T31" } ] } ]

[ { "id": "PMID-15850991_1", "entity_ids": [ "PMID-15850991_T2", "PMID-15850991_T3" ] }, { "id": "PMID-15850991_2", "entity_ids": [ "PMID-15850991_T16", "PMID-15850991_T17" ] } ]

[]

[ { "id": "PMID-15897325__text", "type": "abstract", "text": [ "Selection of novel mediators of E2F1-induced apoptosis through retroviral expression of an antisense cDNA library. \nThe E2F1 transcription factor is an essential mediator of p53-dependent and p53-independent apoptosis as part of an anti-tumour safeguard mechanism. In this study, a functional so-called technical knockout (TKO) approach was applied to Saos-2ERE2F1 cells that conditionally activate E2F1 by the addition of 4-hydroxytamoxifen to search for p53-independent pro-apoptotic E2F1 targets. The approach was based on random inactivation of genes after retroviral transfer of an antisense cDNA library enriched of E2F1-induced genes, followed by the selection of Saos-2ERE2F1 cells that survive in the presence of the apoptotic stimulus. We identified 13 novel E2F1 target genes encoding proteins of known cellular function, including apoptosis and RNA binding. FACS analysis revealed that E2F1-induced apoptosis was significantly attenuated in cell clones containing the antisense cDNA fragments of these genes, demonstrating their participation in E2F1 death pathways. Moreover, inactivation of the target genes resulted in a clear increase of cell viability (>80%) in response to E2F1 activation compared with controls (approximately 30%). Four genes showed an increase in expression intensity in the presence of cycloheximide, suggesting a direct effect of E2F1 on gene transcription, whereas one gene was identified as an indirect target. Our data provide new insight in the regulation of E2F1-induced apoptosis.\n" ], "offsets": [ [ 0, 1526 ] ] } ]

[ { "id": "PMID-15897325_T1", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 32, 36 ] ], "normalized": [] }, { "id": "PMID-15897325_T2", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 120, 124 ] ], "normalized": [] }, { "id": "PMID-15897325_T3", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 174, 177 ] ], "normalized": [] }, { "id": "PMID-15897325_T4", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 192, 195 ] ], "normalized": [] }, { "id": "PMID-15897325_T5", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 399, 403 ] ], "normalized": [] }, { "id": "PMID-15897325_T6", "type": "Simple_chemical", "text": [ "4-hydroxytamoxifen" ], "offsets": [ [ 423, 441 ] ], "normalized": [] }, { "id": "PMID-15897325_T7", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 456, 459 ] ], "normalized": [] }, { "id": "PMID-15897325_T8", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 486, 490 ] ], "normalized": [] }, { "id": "PMID-15897325_T9", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 622, 626 ] ], "normalized": [] }, { "id": "PMID-15897325_T10", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 769, 773 ] ], "normalized": [] }, { "id": "PMID-15897325_T11", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 898, 902 ] ], "normalized": [] }, { "id": "PMID-15897325_T12", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1058, 1062 ] ], "normalized": [] }, { "id": "PMID-15897325_T13", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1191, 1195 ] ], "normalized": [] }, { "id": "PMID-15897325_T14", "type": "Simple_chemical", "text": [ "cycloheximide" ], "offsets": [ [ 1324, 1337 ] ], "normalized": [] }, { "id": "PMID-15897325_T15", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1369, 1373 ] ], "normalized": [] }, { "id": "PMID-15897325_T16", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1502, 1506 ] ], "normalized": [] } ]

[ { "id": "PMID-15897325_E1", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 37, 44 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15897325_T1" }, { "role": "Theme", "ref_id": "PMID-15897325_E2" } ] }, { "id": "PMID-15897325_E2", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 45, 54 ] ] }, "arguments": [] }, { "id": "PMID-15897325_E3", "type": "Positive_regulation", "trigger": { "text": [ "essential mediator" ], "offsets": [ [ 152, 170 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15897325_T2" }, { "role": "Theme", "ref_id": "PMID-15897325_E6" } ] }, { "id": "PMID-15897325_E4", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 178, 187 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15897325_E6" }, { "role": "Cause", "ref_id": "PMID-15897325_T3" } ] }, { "id": "PMID-15897325_E5", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 196, 207 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15897325_T4" }, { "role": "Theme", "ref_id": "PMID-15897325_E6" } ] }, { "id": "PMID-15897325_E6", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 208, 217 ] ] }, "arguments": [] }, { "id": "PMID-15897325_E7", "type": "Activation", "trigger": { "text": [ "activate" ], "offsets": [ [ 390, 398 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15897325_T5" } ] }, { "id": "PMID-15897325_E8", "type": "Pathway", "trigger": { "text": [ "apoptotic" ], "offsets": [ [ 726, 735 ] ] }, "arguments": [] }, { "id": "PMID-15897325_E9", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 843, 852 ] ] }, "arguments": [] }, { "id": "PMID-15897325_E10", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 903, 910 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15897325_E11" }, { "role": "Cause", "ref_id": "PMID-15897325_T11" } ] }, { "id": "PMID-15897325_E11", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 911, 920 ] ] }, "arguments": [] }, { "id": "PMID-15897325_E12", "type": "Negative_regulation", "trigger": { "text": [ "attenuated" ], "offsets": [ [ 939, 949 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15897325_E11" } ] }, { "id": "PMID-15897325_E13", "type": "Regulation", "trigger": { "text": [ "participation" ], "offsets": [ [ 1041, 1054 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15897325_E14" } ] }, { "id": "PMID-15897325_E14", "type": "Pathway", "trigger": { "text": [ "death pathways" ], "offsets": [ [ 1063, 1077 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-15897325_T12" } ] }, { "id": "PMID-15897325_E15", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1196, 1206 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15897325_T13" } ] }, { "id": "PMID-15897325_E16", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1488, 1498 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-15897325_E18" } ] }, { "id": "PMID-15897325_E17", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1507, 1514 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-15897325_T16" }, { "role": "Theme", "ref_id": "PMID-15897325_E18" } ] }, { "id": "PMID-15897325_E18", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1515, 1524 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-15972957__text", "type": "abstract", "text": [ "Aberrant beta-catenin signaling in tuberous sclerosis. \nThe pathology associated with tuberous sclerosis complex (TSC) shows diverse phenotypes that suggest abnormal signaling of multiple pathways. Besides the negative regulatory role of the TSC1/TSC2 proteins on mTOR, we have reported an effect on beta-catenin signaling at the level of the degradation complex in vitro. The TSC1/TSC2 complex associates with GSK3 and Axin and promotes beta-catenin degradation to inhibit Wnt-stimulated TCF/LEF-dependent transcription. Here, we show that beta-catenin and its effectors, cyclin D1 and connexin 43, were up-regulated in TSC-related angiomyolipomas and lymphangioleiomyomatosis. This was supported by the failure of three disease-causing TSC2 missense mutants to inhibit Wnt signaling. Further, the interaction between TSC1/TSC2 and components of the beta-catenin degradation complex was dependent on Wnt stimulation such that binding of tuberin to GSK3 and Axin was reduced in the presence of Wnt whereas the tuberin-Dishevelled interaction was increased. GSK3 activity played a role in regulating the assembly/stability of the degradation complex. Inhibition of GSK3 by lithium chloride reduced its association with TSC1 whereas disruption of GSK3-phosphorylation sites in TSC1 reduced interaction between TSC2 and TSC1. Collectively, our data provide further evidence that beta-catenin signaling plays a role in TSC pathogenesis in vivo and suggest a novel role of GSK3 in modulating the TSC1/TSC2 complex through TSC1 phosphorylation. \n" ], "offsets": [ [ 0, 1540 ] ] } ]

[ { "id": "PMID-15972957_T1", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 9, 21 ] ], "normalized": [] }, { "id": "PMID-15972957_T2", "type": "Gene_or_gene_product", "text": [ "TSC1" ], "offsets": [ [ 242, 246 ] ], "normalized": [] }, { "id": "PMID-15972957_T3", "type": "Gene_or_gene_product", "text": [ "TSC2" ], "offsets": [ [ 247, 251 ] ], "normalized": [] }, { "id": "PMID-15972957_T4", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 264, 268 ] ], "normalized": [] }, { "id": "PMID-15972957_T5", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 300, 312 ] ], "normalized": [] }, { "id": "PMID-15972957_T6", "type": "Complex", "text": [ "TSC1/TSC2" ], "offsets": [ [ 377, 386 ] ], "normalized": [] }, { "id": "PMID-15972957_T7", "type": "Gene_or_gene_product", "text": [ "GSK3" ], "offsets": [ [ 411, 415 ] ], "normalized": [] }, { "id": "PMID-15972957_T8", "type": "Gene_or_gene_product", "text": [ "Axin" ], "offsets": [ [ 420, 424 ] ], "normalized": [] }, { "id": "PMID-15972957_T9", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 438, 450 ] ], "normalized": [] }, { "id": "PMID-15972957_T10", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 474, 477 ] ], "normalized": [] }, { "id": "PMID-15972957_T11", "type": "Gene_or_gene_product", "text": [ "TCF" ], "offsets": [ [ 489, 492 ] ], "normalized": [] }, { "id": "PMID-15972957_T12", "type": "Gene_or_gene_product", "text": [ "LEF" ], "offsets": [ [ 493, 496 ] ], "normalized": [] }, { "id": "PMID-15972957_T13", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 541, 553 ] ], "normalized": [] }, { "id": "PMID-15972957_T14", "type": "Gene_or_gene_product", "text": [ "cyclin D1" ], "offsets": [ [ 573, 582 ] ], "normalized": [] }, { "id": "PMID-15972957_T15", "type": "Gene_or_gene_product", "text": [ "connexin 43" ], "offsets": [ [ 587, 598 ] ], "normalized": [] }, { "id": "PMID-15972957_T16", "type": "Gene_or_gene_product", "text": [ "TSC2" ], "offsets": [ [ 738, 742 ] ], "normalized": [] }, { "id": "PMID-15972957_T17", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 771, 774 ] ], "normalized": [] }, { "id": "PMID-15972957_T18", "type": "Complex", "text": [ "TSC1/TSC2" ], "offsets": [ [ 819, 828 ] ], "normalized": [] }, { "id": "PMID-15972957_T19", "type": "Complex", "text": [ "beta-catenin degradation complex" ], "offsets": [ [ 851, 883 ] ], "normalized": [] }, { "id": "PMID-15972957_T20", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 901, 904 ] ], "normalized": [] }, { "id": "PMID-15972957_T21", "type": "Gene_or_gene_product", "text": [ "tuberin" ], "offsets": [ [ 938, 945 ] ], "normalized": [] }, { "id": "PMID-15972957_T22", "type": "Gene_or_gene_product", "text": [ "GSK3" ], "offsets": [ [ 949, 953 ] ], "normalized": [] }, { "id": "PMID-15972957_T23", "type": "Gene_or_gene_product", "text": [ "Axin" ], "offsets": [ [ 958, 962 ] ], 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[]

[]

[ { "id": "PMID-15993039__text", "type": "abstract", "text": [ "RhoA-mediated Phospholipase D1 signaling is not required for the formation of stress fibers and focal adhesions. \nThe small GTPase RhoA regulates a wide spectrum of cellular functions including transformation and cytoskeletal reorganization. A large number of proteins have been identified as targets of RhoA, but their specific roles in these processes are not clear. Phospholipase D (PLD) was shown to be one such target several years ago; more recent work from our laboratory and others has demonstrated that of the two mammalian PLD isozymes, PLD1 but not PLD2 is activated by RhoA and this activation proceeds through direct binding both in vitro and in vivo. In this study, using a series of RhoA mutants, we have defined a PLD1-specific interacting site on RhoA composed of the residues Asn41, Trp58 and Asp76, using the yeast two-hybrid system, co-immunoprecipitation, and a PLD in vivo assay. The results further substantiate our previous finding that RhoA activates PLD1 through direct interaction. These mutants were then used to investigate the role of PLD1 in the cytoskeletal reorganization stimulated by RhoA signaling. Our results show that PLD1 is not required for the RhoA-mediated stress fiber and focal adhesion formation. The lack of importance of PLD1 signaling in RhoA-mediated cytoskeletal reorganization is further supported by the observation that PLD1 depletion using an shRNA approach and tetracycline-induced overexpression of the wild-type and the catalytically inactive mutant of PLD1 in stable cell lines do not alter stress fiber and focal adhesion formation.\n" ], "offsets": [ [ 0, 1593 ] ] } ]

[ { "id": "PMID-15993039_T1", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-15993039_T2", "type": "Gene_or_gene_product", "text": [ "Phospholipase D1" ], "offsets": [ [ 14, 30 ] ], "normalized": [] }, { "id": "PMID-15993039_T3", "type": "Cellular_component", "text": [ "stress fibers" ], "offsets": [ [ 78, 91 ] ], "normalized": [] }, { "id": "PMID-15993039_T4", "type": "Cellular_component", "text": [ "focal adhesions" ], "offsets": [ [ 96, 111 ] ], "normalized": [] }, { "id": "PMID-15993039_T5", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 131, 135 ] ], "normalized": [] }, { "id": "PMID-15993039_T6", "type": "Cellular_component", "text": [ "cytoskeletal" ], "offsets": [ [ 213, 225 ] ], "normalized": [] }, { "id": "PMID-15993039_T7", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 304, 308 ] ], "normalized": [] }, { "id": "PMID-15993039_T8", "type": "Gene_or_gene_product", "text": [ "Phospholipase D" ], "offsets": [ [ 369, 384 ] ], "normalized": [] }, { "id": "PMID-15993039_T9", "type": "Gene_or_gene_product", "text": [ "PLD" ], "offsets": [ [ 386, 389 ] ], "normalized": [] }, { "id": "PMID-15993039_T10", "type": "Gene_or_gene_product", "text": [ "PLD" ], "offsets": [ [ 533, 536 ] ], "normalized": [] }, { "id": "PMID-15993039_T11", "type": "Gene_or_gene_product", "text": [ "PLD1" ], "offsets": [ [ 547, 551 ] ], "normalized": [] }, { "id": "PMID-15993039_T12", "type": "Gene_or_gene_product", "text": [ "PLD2" ], "offsets": [ [ 560, 564 ] ], "normalized": [] }, { "id": "PMID-15993039_T13", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 581, 585 ] ], "normalized": [] }, { "id": "PMID-15993039_T14", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 698, 702 ] ], "normalized": [] }, { "id": "PMID-15993039_T15", "type": "Gene_or_gene_product", "text": [ "PLD1" ], "offsets": [ [ 730, 734 ] ], "normalized": [] }, { "id": "PMID-15993039_T16", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 764, 768 ] ], "normalized": [] }, { "id": "PMID-15993039_T17", "type": "Simple_chemical", "text": [ "Asn41" ], "offsets": [ [ 794, 799 ] ], "normalized": [] }, { "id": "PMID-15993039_T18", "type": "Simple_chemical", "text": [ "Trp58" ], "offsets": [ [ 801, 806 ] ], "normalized": [] }, { "id": "PMID-15993039_T19", "type": "Simple_chemical", "text": [ "Asp76" ], "offsets": [ [ 811, 816 ] ], "normalized": [] }, { "id": "PMID-15993039_T20", "type": "Gene_or_gene_product", "text": [ "PLD" ], "offsets": [ [ 883, 886 ] ], "normalized": [] }, { "id": "PMID-15993039_T21", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 961, 965 ] ], "normalized": [] }, { "id": "PMID-15993039_T22", "type": "Gene_or_gene_product", "text": [ "PLD1" ], "offsets": [ [ 976, 980 ] ], "normalized": [] }, { "id": "PMID-15993039_T23", "type": "Gene_or_gene_product", "text": [ "PLD1" ], "offsets": [ [ 1065, 1069 ] ], "normalized": [] }, { "id": "PMID-15993039_T24", "type": "Cellular_component", "text": [ "cytoskeletal" ], "offsets": [ [ 1077, 1089 ] ], "normalized": [] }, { "id": "PMID-15993039_T25", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 1119, 1123 ] ], "normalized": [] }, { "id": "PMID-15993039_T26", "type": "Gene_or_gene_product", "text": [ "PLD1" ], "offsets": [ [ 1157, 1161 ] ], "normalized": [] }, { "id": "PMID-15993039_T27", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 1186, 1190 ] ], "normalized": [] }, { "id": "PMID-15993039_T28", "type": "Cellular_component", "text": [ "stress fiber" ], "offsets": [ [ 1200, 1212 ] ], "normalized": [] }, { "id": "PMID-15993039_T29", "type": "Cellular_component", "text": [ "focal adhesion" ], "offsets": [ [ 1217, 1231 ] ], "normalized": [] }, { "id": "PMID-15993039_T30", "type": "Gene_or_gene_product", "text": [ "PLD1" ], "offsets": [ [ 1269, 1273 ] ], "normalized": [] }, { "id": "PMID-15993039_T31", "type": "Gene_or_gene_product", "text": [ "RhoA" ], "offsets": [ [ 1287, 1291 ] ], "normalized": [] }, { "id": "PMID-15993039_T32", "type": "Cellular_component", "text": [ "cytoskeletal" ], "offsets": [ [ 1301, 1313 ] ], "normalized": [] }, { "id": "PMID-15993039_T33", "type": "Gene_or_gene_product", "text": [ "PLD1" ], "offsets": [ [ 1374, 1378 ] ], "normalized": [] }, { "id": "PMID-15993039_T34", "type": "Simple_chemical", "text": [ "tetracycline" ], "offsets": [ [ 1417, 1429 ] ], "normalized": [] }, { "id": "PMID-15993039_T35", "type": "Gene_or_gene_product", "text": [ "PLD1" ], "offsets": [ [ 1511, 1515 ] ], "normalized": [] }, { "id": "PMID-15993039_T36", "type": "Cellular_component", "text": [ "stress fiber" ], "offsets": [ [ 1550, 1562 ] ], "normalized": [] }, { "id": "PMID-15993039_T37", "type": "Cellular_component", "text": [ "focal adhesion" ], "offsets": [ [ 1567, 1581 ] ], "normalized": [] } ]

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[ { "id": "PMID-15993039_1", "entity_ids": [ "PMID-15993039_T8", "PMID-15993039_T9" ] } ]

[]

[ { "id": "PMID-16107498__text", "type": "abstract", "text": [ "Activating E2Fs mediate transcriptional regulation of human E2F6 repressor. \nE2F6 is believed to repress E2F-responsive genes and therefore serve a role in cell cycle regulation. Analysis of the human E2F6 promoter region revealed the presence of two putative E2F binding sites, both of which were found to be functionally critical because deletion or mutations of these sites abolished promoter activity. Ectopic expression of E2F1 protein was found to increase E2F6 mRNA levels and significantly upregulate E2F6 promoter activity. Deletion or mutation of the putative E2F binding sites nullified the effects of E2F1 on the E2F6 promoter activity. Studies on the temporal induction of E2F family members demonstrated that the activating E2Fs, and most notably E2F1, were upregulated before E2F6 during cell cycle progression at the G1/S phase, and this coincided with the time course of induction experienced by the E2F6 promoter during the course of the cell cycle. EMSAs indicated the specific binding of nuclear complexes to the E2F6 promoter that contained E2F1-related species whose binding was specifically competed by the consensus E2F binding site. Chromatin immunoprecipitation assays with anti-E2Fs demonstrated the association of E2F family members with the E2F6 promoter in vivo. These data indicate that the expression of the E2F6 repressor is influenced at the transcriptional level by E2F family members and suggest that interplay among these transcriptional regulators, especially E2F1, may be critical for cell cycle regulation.\n" ], "offsets": [ [ 0, 1547 ] ] } ]

[ { "id": "PMID-16107498_T1", "type": "Gene_or_gene_product", "text": [ "E2Fs" ], "offsets": [ [ 11, 15 ] ], "normalized": [] }, { "id": "PMID-16107498_T2", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 60, 64 ] ], "normalized": [] }, { "id": "PMID-16107498_T3", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 77, 81 ] ], "normalized": [] }, { "id": "PMID-16107498_T4", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 105, 108 ] ], "normalized": [] }, { "id": "PMID-16107498_T5", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 201, 205 ] ], "normalized": [] }, { "id": "PMID-16107498_T6", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 260, 263 ] ], "normalized": [] }, { "id": "PMID-16107498_T7", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 428, 432 ] ], "normalized": [] }, { "id": "PMID-16107498_T8", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 463, 467 ] ], "normalized": [] }, { "id": "PMID-16107498_T9", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 509, 513 ] ], "normalized": [] }, { "id": "PMID-16107498_T10", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 570, 573 ] ], "normalized": [] }, { "id": "PMID-16107498_T11", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 613, 617 ] ], "normalized": [] }, { "id": "PMID-16107498_T12", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 625, 629 ] ], "normalized": [] }, { "id": "PMID-16107498_T13", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 686, 689 ] ], "normalized": [] }, { "id": "PMID-16107498_T14", "type": "Gene_or_gene_product", "text": [ "E2Fs" ], "offsets": [ [ 738, 742 ] ], "normalized": [] }, { "id": "PMID-16107498_T15", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 761, 765 ] ], "normalized": [] }, { "id": "PMID-16107498_T16", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 791, 795 ] ], "normalized": [] }, { "id": "PMID-16107498_T17", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 917, 921 ] ], "normalized": [] }, { "id": "PMID-16107498_T18", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1008, 1015 ] ], "normalized": [] }, { "id": "PMID-16107498_T19", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 1033, 1037 ] ], "normalized": [] }, { "id": "PMID-16107498_T20", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1062, 1066 ] ], "normalized": [] }, { "id": "PMID-16107498_T21", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1140, 1143 ] ], "normalized": [] }, { "id": "PMID-16107498_T22", "type": "Cellular_component", "text": [ "Chromatin" ], "offsets": [ [ 1158, 1167 ] ], "normalized": [] }, { "id": "PMID-16107498_T23", "type": "Gene_or_gene_product", "text": [ "E2Fs" ], "offsets": [ [ 1205, 1209 ] ], "normalized": [] }, { "id": "PMID-16107498_T24", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1242, 1245 ] ], "normalized": [] }, { "id": "PMID-16107498_T25", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 1270, 1274 ] ], "normalized": [] }, { "id": "PMID-16107498_T26", "type": "Gene_or_gene_product", "text": [ "E2F6" ], "offsets": [ [ 1340, 1344 ] ], "normalized": [] }, { "id": "PMID-16107498_T27", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1401, 1404 ] ], "normalized": [] }, { "id": "PMID-16107498_T28", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1498, 1502 ] ], "normalized": [] } ]

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"ref_id": "PMID-16107498_E7" }, { "role": "Cause", "ref_id": "PMID-16107498_T3" } ] }, { "id": "PMID-16107498_E6", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 156, 166 ] ] }, "arguments": [] }, { "id": "PMID-16107498_E7", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 167, 177 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_E6" } ] }, { "id": "PMID-16107498_E8", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 264, 271 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T6" }, { "role": "Theme", "ref_id": "PMID-16107498_T5" } ] }, { "id": "PMID-16107498_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 414, 424 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T7" } ] }, { "id": "PMID-16107498_E10", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 454, 462 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T8" }, { "role": "Cause", "ref_id": "PMID-16107498_E9" } ] }, { "id": "PMID-16107498_E11", "type": "Positive_regulation", "trigger": { "text": [ "upregulate" ], "offsets": [ [ 498, 508 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T9" }, { "role": "Cause", "ref_id": "PMID-16107498_E10" } ] }, { "id": "PMID-16107498_E12", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 574, 581 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T10" } ] }, { "id": "PMID-16107498_E13", "type": "Negative_regulation", "trigger": { "text": [ "nullified" ], "offsets": [ [ 588, 597 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_E14" } ] }, { "id": "PMID-16107498_E14", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 602, 609 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16107498_T11" }, { "role": "Theme", "ref_id": "PMID-16107498_T12" } ] }, { "id": "PMID-16107498_E15", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 673, 682 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T13" } ] }, { "id": "PMID-16107498_E16", "type": "Activation", "trigger": { "text": [ "activating" ], "offsets": [ [ 727, 737 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T14" } ] }, { "id": "PMID-16107498_E17", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 772, 783 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T15" } ] }, { "id": "PMID-16107498_E18", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 803, 813 ] ] }, "arguments": [] }, { "id": "PMID-16107498_E19", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 997, 1004 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T19" } ] }, { "id": "PMID-16107498_E20", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1144, 1151 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T21" } ] }, { "id": "PMID-16107498_E21", "type": "Binding", "trigger": { "text": [ "association" ], "offsets": [ [ 1227, 1238 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T24" }, { "role": "Theme", "ref_id": "PMID-16107498_T25" } ] }, { "id": "PMID-16107498_E22", "type": "Negative_regulation", "trigger": { "text": [ "repressor" ], "offsets": [ [ 1345, 1354 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_T26" } ] }, { "id": "PMID-16107498_E23", "type": "Positive_regulation", "trigger": { "text": [ "critical" ], "offsets": [ [ 1511, 1519 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_E25" }, { "role": "Cause", "ref_id": "PMID-16107498_T28" } ] }, { "id": "PMID-16107498_E24", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1524, 1534 ] ] }, "arguments": [] }, { "id": "PMID-16107498_E25", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1535, 1545 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16107498_E24" } ] } ]

[]

[]

[ { "id": "PMID-16155345__text", "type": "abstract", "text": [ "DNA damage induces cdk2 protein levels and histone H2B phosphorylation in SH-SY5Y neuroblastoma cells. \nDNA damage and activation of the cell cycle have been implicated in numerous neurodegenerative diseases, including Alzheimer disease, Parkinson's disease, and amyotrophic lateral sclerosis. To better understand the role of cell cycle proteins in DNA-damage induced neuronal cell death, we examined various cell cycle proteins during camptothecin-induced death of human neuroblastoma cells. We report a rapid induction of p53 and increased expression of p21, concurrent with reduced levels of many cell cycle proteins that regulate G1 to S phase cell cycle progression. However, we found increased levels of cdk2 and cyclin E, and formation of a cyclin E-cdk2-p21 protein complex. DNA damage failed to induce activation and progression of the cell cycle. Finally, camptothecin-induced neuronal cell death occurred concurrent with phosphorylation of histone H2B. Pretreatment of cells with cdk inhibitor olomoucine impeded cdk2-cyclin E accumulation, but not the induction of p53. Olomucine concurrently delayed histone H2B phosphorylation, caspase-3 activation and cell death. These findings suggest that DNA-damage of differentiated neuroblastoma cells induces a rapid p53-mediated inhibition of cell cycle progression and induction of cdk2-cyclin E, followed by caspase-3 activation, phosphorylation of histone and cell death.\n" ], "offsets": [ [ 0, 1432 ] ] } ]

[ { "id": "PMID-16155345_T1", "type": "Gene_or_gene_product", "text": [ "cdk2" ], "offsets": [ [ 19, 23 ] ], "normalized": [] }, { "id": "PMID-16155345_T2", "type": "Gene_or_gene_product", "text": [ "histone H2B" ], "offsets": [ [ 43, 54 ] ], "normalized": [] }, { "id": "PMID-16155345_T3", "type": "Simple_chemical", "text": [ "camptothecin" ], "offsets": [ [ 437, 449 ] ], "normalized": [] }, { "id": "PMID-16155345_T4", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 525, 528 ] ], "normalized": [] }, { "id": "PMID-16155345_T5", "type": "Gene_or_gene_product", "text": [ "p21" ], "offsets": [ [ 557, 560 ] ], "normalized": [] }, { "id": "PMID-16155345_T6", "type": "Gene_or_gene_product", "text": [ "cdk2" ], "offsets": [ [ 711, 715 ] ], "normalized": [] }, { "id": "PMID-16155345_T7", "type": "Gene_or_gene_product", "text": [ "cyclin E" ], "offsets": [ [ 720, 728 ] ], "normalized": [] }, { "id": "PMID-16155345_T8", "type": "Complex", "text": [ "cyclin E-cdk2-p21" ], "offsets": [ [ 749, 766 ] ], "normalized": [] }, { "id": "PMID-16155345_T9", "type": "Simple_chemical", "text": [ "camptothecin" ], "offsets": [ [ 867, 879 ] ], "normalized": [] }, { "id": "PMID-16155345_T10", "type": "Gene_or_gene_product", "text": [ "histone H2B" ], "offsets": [ [ 952, 963 ] ], "normalized": [] }, { "id": "PMID-16155345_T11", "type": "Gene_or_gene_product", "text": [ "cdk" ], "offsets": [ [ 992, 995 ] ], "normalized": [] }, { "id": "PMID-16155345_T12", "type": "Simple_chemical", "text": [ "olomoucine" ], "offsets": [ [ 1006, 1016 ] ], "normalized": [] }, { "id": "PMID-16155345_T13", "type": "Complex", "text": [ "cdk2-cyclin E" ], "offsets": [ [ 1025, 1038 ] ], "normalized": [] }, { "id": "PMID-16155345_T14", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1078, 1081 ] ], "normalized": [] }, { "id": "PMID-16155345_T15", "type": "Simple_chemical", "text": [ "Olomucine" ], "offsets": [ [ 1083, 1092 ] ], "normalized": [] }, { "id": "PMID-16155345_T16", "type": "Gene_or_gene_product", "text": [ "histone H2B" ], "offsets": [ [ 1114, 1125 ] ], "normalized": [] }, { "id": "PMID-16155345_T17", "type": "Gene_or_gene_product", "text": [ "caspase-3" ], "offsets": [ [ 1143, 1152 ] ], "normalized": [] }, { "id": "PMID-16155345_T18", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1273, 1276 ] ], "normalized": [] }, { "id": "PMID-16155345_T19", "type": "Complex", "text": [ "cdk2-cyclin E" ], "offsets": [ [ 1340, 1353 ] ], "normalized": [] }, { "id": "PMID-16155345_T20", "type": "Gene_or_gene_product", "text": [ "caspase-3" ], "offsets": [ [ 1367, 1376 ] ], "normalized": [] }, { "id": "PMID-16155345_T21", "type": "Gene_or_gene_product", "text": [ "histone" ], "offsets": [ [ 1408, 1415 ] ], "normalized": [] } ]

[ { "id": "PMID-16155345_E1", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 11, 18 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T1" } ] }, { "id": "PMID-16155345_E2", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 11, 18 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_E3" } ] }, { "id": "PMID-16155345_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 55, 70 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T2" } ] }, { "id": "PMID-16155345_E4", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 119, 129 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_E5" } ] }, { "id": "PMID-16155345_E5", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 137, 147 ] ] }, "arguments": [] }, { "id": "PMID-16155345_E6", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 327, 337 ] ] }, "arguments": [] }, { "id": "PMID-16155345_E7", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 410, 420 ] ] }, "arguments": [] }, { "id": "PMID-16155345_E8", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 512, 521 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T4" } ] }, { "id": "PMID-16155345_E9", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 533, 542 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_E10" } ] }, { "id": "PMID-16155345_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 543, 553 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T5" } ] }, { "id": "PMID-16155345_E11", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 601, 611 ] ] }, "arguments": [] }, { "id": "PMID-16155345_E12", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 649, 659 ] ] }, "arguments": [] }, { "id": "PMID-16155345_E13", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 691, 700 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T6" } ] }, { "id": "PMID-16155345_E14", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 691, 700 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T7" } ] }, { "id": "PMID-16155345_E15", "type": "Binding", "trigger": { "text": [ "formation" ], "offsets": [ [ 734, 743 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-16155345_T8" } ] }, { "id": "PMID-16155345_E16", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 805, 811 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_E17" } ] }, { "id": "PMID-16155345_E17", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 812, 822 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_E18" } ] }, { "id": "PMID-16155345_E18", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 846, 856 ] ] }, "arguments": [] }, { "id": "PMID-16155345_E19", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 933, 948 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T10" } ] }, { "id": "PMID-16155345_E20", "type": "Negative_regulation", "trigger": { "text": [ "impeded" ], "offsets": [ [ 1017, 1024 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16155345_T12" }, { "role": "Theme", "ref_id": "PMID-16155345_T13" } ] }, { "id": "PMID-16155345_E21", "type": "Negative_regulation", "trigger": { "text": [ "impeded" ], "offsets": [ [ 1017, 1024 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16155345_T12" }, { "role": "Theme", "ref_id": "PMID-16155345_E22" } ] }, { "id": "PMID-16155345_E22", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1065, 1074 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T14" } ] }, { "id": "PMID-16155345_E23", "type": "Negative_regulation", "trigger": { "text": [ "delayed" ], "offsets": [ [ 1106, 1113 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16155345_T15" }, { "role": "Theme", "ref_id": "PMID-16155345_E25" } ] }, { "id": "PMID-16155345_E24", "type": "Negative_regulation", "trigger": { "text": [ "delayed" ], "offsets": [ [ 1106, 1113 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16155345_T15" }, { "role": "Theme", "ref_id": "PMID-16155345_E26" } ] }, { "id": "PMID-16155345_E25", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1126, 1141 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T16" } ] }, { "id": "PMID-16155345_E26", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1153, 1163 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T17" } ] }, { "id": "PMID-16155345_E27", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 1257, 1264 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_E30" } ] }, { "id": "PMID-16155345_E28", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 1257, 1264 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_E32" } ] }, { "id": "PMID-16155345_E29", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1277, 1285 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16155345_T18" }, { "role": "Theme", "ref_id": "PMID-16155345_E30" } ] }, { "id": "PMID-16155345_E30", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1286, 1296 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_E31" } ] }, { "id": "PMID-16155345_E31", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1300, 1310 ] ] }, "arguments": [] }, { "id": "PMID-16155345_E32", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1327, 1336 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T19" } ] }, { "id": "PMID-16155345_E33", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1377, 1387 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T20" } ] }, { "id": "PMID-16155345_E34", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1389, 1404 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16155345_T21" } ] } ]

[]

[]

[ { "id": "PMID-16158053__text", "type": "abstract", "text": [ "E2F-HDAC complexes negatively regulate the tumor suppressor gene ARHI in breast cancer. \nARHI is a maternally imprinted tumor suppressor gene whose expression is markedly downregulated in breast cancer. Reactivation of ARHI expression in breast cancer cells is associated with increased histone H3 acetylation and decreased lysine 9 methylation of histone H3. An ARHI promoter segment that spanned bases -420 to +58 (designated the P2 region) exhibits significantly higher promoter activity in normal cells than in cancer cells. To better understand the molecular mechanisms contributing to this differential transcriptional activity, we sought to identify transcription factors that bind to the P2 region of the ARHI promoter and regulate its activity. Sequence analysis and oligonucleotide competition in electrophoretic mobility shift assays identified an A2 fragment containing an E2F-binding site. Using specific antibodies in supershift assays, we have shown that anti-E2F1 and 4 antibodies can supershift the A2-protein complexes, whereas anti-E2F2 and 6 antibodies cannot, demonstrating that the A2 fragment interacts with specific members of the E2F family proteins. When compared with normal breast epithelial cells, breast cancer cells have significantly elevated expression of E2F1, 4 and increased E2F DNA-binding activity. Moreover, chromatin immunoprecipitation experiments revealed that both E2F1 and 4 bind to the ARHI promoter in breast cancer cells in vivo. This binding was reduced when the cells were treated with the histone deacetylase (HDAC) inhibitor--trichostatin A (TSA). When SKBr3 cells were cotransfected with an ARHI/luciferase reporter and E2F-expression vectors, E2F1 and 4 reduced ARHI promoter activity 2-3-fold, and this reduction could be reversed by TSA treatment. The negative regulation by E2F-HDAC complexes could also be reduced by small interfering RNA of E2F1 and 4. While the retinoblastoma protein, pRB, alone had no effect on ARHI promoter activity, repression by E2F1, but not E2F4, was enhanced by the coexpression of pRB. Taken together, our results suggest that E2F1, 4 and their complexes with HDAC play an important role in downregulating the expression of the tumor suppressor gene ARHI in breast cancer cells.\n" ], "offsets": [ [ 0, 2265 ] ] } ]

[ { "id": "PMID-16158053_T1", "type": "Complex", "text": [ "E2F-HDAC" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-16158053_T2", "type": "Gene_or_gene_product", "text": [ "ARHI" ], "offsets": [ [ 65, 69 ] ], "normalized": [] }, { "id": "PMID-16158053_T3", "type": "Gene_or_gene_product", "text": [ "ARHI" ], "offsets": [ [ 89, 93 ] ], "normalized": [] }, { "id": "PMID-16158053_T4", "type": "Gene_or_gene_product", "text": [ "ARHI" ], "offsets": [ [ 219, 223 ] ], "normalized": [] }, { "id": "PMID-16158053_T5", "type": "Gene_or_gene_product", "text": [ "histone H3" ], "offsets": [ [ 287, 297 ] ], "normalized": [] }, { "id": "PMID-16158053_T6", "type": "Simple_chemical", "text": [ "lysine 9" ], "offsets": [ [ 324, 332 ] ], "normalized": [] }, { "id": "PMID-16158053_T7", "type": "Gene_or_gene_product", "text": [ "histone H3" ], "offsets": [ [ 348, 358 ] ], "normalized": [] }, { "id": "PMID-16158053_T8", "type": "Gene_or_gene_product", "text": [ "ARHI" ], "offsets": [ [ 363, 367 ] ], "normalized": [] }, { "id": "PMID-16158053_T9", "type": "Gene_or_gene_product", "text": [ "ARHI" ], "offsets": [ [ 713, 717 ] ], "normalized": [] }, { "id": "PMID-16158053_T10", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 885, 888 ] ], "normalized": [] }, { "id": "PMID-16158053_T11", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 975, 979 ] ], "normalized": [] }, { "id": "PMID-16158053_T12", "type": "Gene_or_gene_product", "text": [ "4" ], "offsets": [ [ 984, 985 ] ], "normalized": [] }, { "id": "PMID-16158053_T13", "type": "Gene_or_gene_product", "text": [ "E2F2" ], "offsets": [ [ 1051, 1055 ] ], "normalized": [] }, { "id": "PMID-16158053_T14", "type": "Gene_or_gene_product", "text": [ "6" ], "offsets": [ [ 1060, 1061 ] ], "normalized": [] }, { "id": "PMID-16158053_T15", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1155, 1158 ] ], "normalized": [] }, { "id": "PMID-16158053_T16", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1289, 1293 ] ], "normalized": [] }, { "id": "PMID-16158053_T17", "type": "Gene_or_gene_product", "text": [ "4" ], "offsets": [ [ 1295, 1296 ] ], "normalized": [] }, { "id": "PMID-16158053_T18", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1311, 1314 ] ], "normalized": [] }, { "id": "PMID-16158053_T19", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 1347, 1356 ] ], "normalized": [] }, { "id": "PMID-16158053_T20", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1408, 1412 ] ], "normalized": [] }, { "id": "PMID-16158053_T21", "type": "Gene_or_gene_product", "text": [ "4" ], "offsets": [ [ 1417, 1418 ] ], "normalized": [] }, { "id": "PMID-16158053_T22", "type": "Gene_or_gene_product", "text": [ "ARHI" ], "offsets": [ [ 1431, 1435 ] ], "normalized": [] }, { "id": "PMID-16158053_T23", "type": "Gene_or_gene_product", "text": [ "histone deacetylase" ], "offsets": [ [ 1539, 1558 ] ], "normalized": [] }, { "id": "PMID-16158053_T24", "type": "Gene_or_gene_product", "text": [ "HDAC" ], "offsets": [ [ 1560, 1564 ] ], "normalized": [] }, { "id": "PMID-16158053_T25", "type": "Simple_chemical", "text": [ "trichostatin A" ], "offsets": [ [ 1577, 1591 ] ], "normalized": [] }, { "id": "PMID-16158053_T26", "type": "Simple_chemical", "text": [ "TSA" ], "offsets": [ [ 1593, 1596 ] ], "normalized": [] }, { "id": "PMID-16158053_T27", "type": "Gene_or_gene_product", "text": [ "ARHI" ], "offsets": [ [ 1643, 1647 ] ], "normalized": [] }, { "id": "PMID-16158053_T28", "type": "Gene_or_gene_product", "text": [ "luciferase" ], "offsets": [ [ 1648, 1658 ] ], "normalized": [] }, { "id": "PMID-16158053_T29", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1672, 1675 ] ], "normalized": [] }, { "id": "PMID-16158053_T30", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1696, 1700 ] ], "normalized": [] }, { "id": "PMID-16158053_T31", "type": "Gene_or_gene_product", "text": [ "4" ], "offsets": [ [ 1705, 1706 ] ], "normalized": [] }, { "id": "PMID-16158053_T32", "type": "Gene_or_gene_product", "text": [ "ARHI" ], "offsets": [ [ 1715, 1719 ] ], "normalized": [] }, { "id": "PMID-16158053_T33", "type": "Simple_chemical", "text": [ "TSA" ], "offsets": [ [ 1788, 1791 ] ], "normalized": [] }, { "id": "PMID-16158053_T34", "type": "Complex", "text": [ "E2F-HDAC" ], "offsets": [ [ 1830, 1838 ] ], "normalized": [] }, { "id": "PMID-16158053_T35", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 1899, 1903 ] ], "normalized": [] }, { "id": "PMID-16158053_T36", "type": "Gene_or_gene_product", "text": [ "4" ], "offsets": [ [ 1908, 1909 ] ], "normalized": [] }, { "id": "PMID-16158053_T37", "type": "Gene_or_gene_product", "text": [ "retinoblastoma protein" ], "offsets": [ [ 1921, 1943 ] ], "normalized": [] }, { "id": "PMID-16158053_T38", "type": "Gene_or_gene_product", "text": [ "pRB" ], "offsets": [ [ 1945, 1948 ] ], "normalized": [] }, { "id": "PMID-16158053_T39", "type": "Gene_or_gene_product", "text": [ "ARHI" ], "offsets": [ [ 1973, 1977 ] ], "normalized": [] }, { "id": "PMID-16158053_T40", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 2011, 2015 ] ], "normalized": [] }, { "id": "PMID-16158053_T41", "type": "Gene_or_gene_product", "text": [ "E2F4" ], "offsets": [ [ 2025, 2029 ] ], "normalized": [] }, { "id": "PMID-16158053_T42", "type": "Gene_or_gene_product", "text": [ "pRB" ], "offsets": [ [ 2067, 2070 ] ], "normalized": [] }, { "id": "PMID-16158053_T43", "type": "Gene_or_gene_product", "text": [ "E2F1" ], "offsets": [ [ 2113, 2117 ] ], "normalized": [] }, { "id": "PMID-16158053_T44", "type": "Gene_or_gene_product", "text": [ "4" ], "offsets": [ [ 2119, 2120 ] ], "normalized": [] }, { "id": "PMID-16158053_T45", "type": "Gene_or_gene_product", "text": [ "HDAC" ], "offsets": [ [ 2146, 2150 ] ], "normalized": [] }, { "id": "PMID-16158053_T46", "type": "Gene_or_gene_product", "text": [ "ARHI" ], "offsets": [ [ 2236, 2240 ] ], "normalized": [] } ]

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"role": "Theme", "ref_id": "PMID-16158053_T4" } ] }, { "id": "PMID-16158053_E6", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 261, 271 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16158053_E4" }, { "role": "Theme", "ref_id": "PMID-16158053_E10" } ] }, { "id": "PMID-16158053_E7", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 261, 271 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16158053_E4" }, { "role": "Theme", "ref_id": "PMID-16158053_E8" } ] }, { "id": "PMID-16158053_E8", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 277, 286 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16158053_E9" } ] }, { "id": "PMID-16158053_E9", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 298, 309 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16158053_T5" } ] }, { "id": "PMID-16158053_E10", "type": "Negative_regulation", "trigger": { 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"role": "Theme", "ref_id": "PMID-16158053_T24" }, { "role": "Cause", "ref_id": "PMID-16158053_T26" } ] }, { "id": "PMID-16158053_E20", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1676, 1686 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16158053_T29" } ] }, { "id": "PMID-16158053_E21", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1707, 1714 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16158053_T30" }, { "role": "Theme", "ref_id": "PMID-16158053_T31" } ] }, { "id": "PMID-16158053_E22", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1707, 1714 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16158053_T30" }, { "role": "Theme", "ref_id": "PMID-16158053_T32" } ] }, { "id": "PMID-16158053_E23", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1963, 1969 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16158053_T39" }, { "role": "Cause", "ref_id": "PMID-16158053_T38" } ] }, { "id": "PMID-16158053_E24", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 1997, 2007 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16158053_T40" }, { "role": "Theme", "ref_id": "PMID-16158053_T39" } ] }, { "id": "PMID-16158053_E25", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 2035, 2043 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16158053_E26" }, { "role": "Theme", "ref_id": "PMID-16158053_T39" } ] }, { "id": "PMID-16158053_E26", "type": "Gene_expression", "trigger": { "text": [ "coexpression" ], "offsets": [ [ 2051, 2063 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16158053_T42" } ] }, { "id": "PMID-16158053_E27", "type": "Positive_regulation", "trigger": { "text": [ "play an important role" ], "offsets": [ [ 2151, 2173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16158053_E30" }, { "role": "Cause", "ref_id": "PMID-16158053_T43" } ] }, { "id": "PMID-16158053_E28", "type": "Positive_regulation", "trigger": { "text": [ "play an important role" ], "offsets": [ [ 2151, 2173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16158053_E30" }, { "role": "Cause", "ref_id": "PMID-16158053_T44" } ] }, { "id": "PMID-16158053_E29", "type": "Positive_regulation", "trigger": { "text": [ "play an important role" ], "offsets": [ [ 2151, 2173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16158053_E30" }, { "role": "Cause", "ref_id": "PMID-16158053_T45" } ] }, { "id": "PMID-16158053_E30", "type": "Negative_regulation", "trigger": { "text": [ "downregulating" ], "offsets": [ [ 2177, 2191 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16158053_E31" } ] }, { "id": "PMID-16158053_E31", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2196, 2206 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16158053_T46" } ] } ]

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[]

[ { "id": "PMID-16179649__text", "type": "abstract", "text": [ "Characterization of E2F8, a novel E2F-like cell-cycle regulated repressor of E2F-activated transcription. \nThe E2F family of transcription factors are downstream effectors of the retinoblastoma protein, pRB, pathway and are essential for the timely regulation of genes necessary for cell-cycle progression. Here we describe the characterization of human and murine E2F8, a new member of the E2F family. Sequence analysis of E2F8 predicts the presence of two distinct E2F-related DNA binding domains suggesting that E2F8 and, the recently, identified E2F7 form a subgroup within the E2F family. We show that E2F transcription factors bind the E2F8 promoter in vivo and that expression of E2F8 is being induced at the G1/S transition. Purified recombinant E2F8 binds specifically to a consensus E2F-DNA-binding site indicating that E2F8, like E2F7, binds DNA without the requirement of co-factors such as DP1. E2F8 inhibits E2F-driven promoters suggesting that E2F8 is transcriptional repressor like E2F7. Ectopic expression of E2F8 in diploid human fibroblasts reduces expression of E2F-target genes and inhibits cell growth consistent with a role for repressing E2F transcriptional activity. Taken together, these data suggest that E2F8 has an important role in turning of the expression of E2F-target genes in the S-phase of the cell cycle.\n" ], "offsets": [ [ 0, 1342 ] ] } ]

[ { "id": "PMID-16179649_T1", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 20, 24 ] ], "normalized": [] }, { "id": "PMID-16179649_T2", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 34, 37 ] ], "normalized": [] }, { "id": "PMID-16179649_T3", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 77, 80 ] ], "normalized": [] }, { "id": "PMID-16179649_T4", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 111, 114 ] ], "normalized": [] }, { "id": "PMID-16179649_T5", "type": "Gene_or_gene_product", "text": [ "retinoblastoma protein" ], "offsets": [ [ 179, 201 ] ], "normalized": [] }, { "id": "PMID-16179649_T6", "type": "Gene_or_gene_product", "text": [ "pRB" ], "offsets": [ [ 203, 206 ] ], "normalized": [] }, { "id": "PMID-16179649_T7", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 365, 369 ] ], "normalized": [] }, { "id": "PMID-16179649_T8", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 391, 394 ] ], "normalized": [] }, { "id": "PMID-16179649_T9", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 424, 428 ] ], "normalized": [] }, { "id": "PMID-16179649_T10", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 467, 470 ] ], "normalized": [] }, { "id": "PMID-16179649_T11", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 515, 519 ] ], "normalized": [] }, { "id": "PMID-16179649_T12", "type": "Gene_or_gene_product", "text": [ "E2F7" ], "offsets": [ [ 550, 554 ] ], "normalized": [] }, { "id": "PMID-16179649_T13", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 582, 585 ] ], "normalized": [] }, { "id": "PMID-16179649_T14", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 607, 610 ] ], "normalized": [] }, { "id": "PMID-16179649_T15", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 642, 646 ] ], "normalized": [] }, { "id": "PMID-16179649_T16", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 687, 691 ] ], "normalized": [] }, { "id": "PMID-16179649_T17", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 754, 758 ] ], "normalized": [] }, { "id": "PMID-16179649_T18", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 793, 796 ] ], "normalized": [] }, { "id": "PMID-16179649_T19", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 830, 834 ] ], "normalized": [] }, { "id": "PMID-16179649_T20", "type": "Gene_or_gene_product", "text": [ "E2F7" ], "offsets": [ [ 841, 845 ] ], "normalized": [] }, { "id": "PMID-16179649_T21", "type": "Gene_or_gene_product", "text": [ "DP1" ], "offsets": [ [ 903, 906 ] ], "normalized": [] }, { "id": "PMID-16179649_T22", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 908, 912 ] ], "normalized": [] }, { "id": "PMID-16179649_T23", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 922, 925 ] ], "normalized": [] }, { "id": "PMID-16179649_T24", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 959, 963 ] ], "normalized": [] }, { "id": "PMID-16179649_T25", "type": "Gene_or_gene_product", "text": [ "E2F7" ], "offsets": [ [ 998, 1002 ] ], "normalized": [] }, { "id": "PMID-16179649_T26", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 1026, 1030 ] ], "normalized": [] }, { "id": "PMID-16179649_T27", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1082, 1085 ] ], "normalized": [] }, { "id": "PMID-16179649_T28", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1162, 1165 ] ], "normalized": [] }, { "id": "PMID-16179649_T29", "type": "Gene_or_gene_product", "text": [ "E2F8" ], "offsets": [ [ 1232, 1236 ] ], "normalized": [] }, { "id": "PMID-16179649_T30", "type": "Gene_or_gene_product", "text": [ "E2F" ], "offsets": [ [ 1291, 1294 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-16281053__text", "type": "abstract", "text": [ "A dual role for PP1 in shaping the Msn2-dependent transcriptional response to glucose starvation. \nIn yeast, glucose depletion elicits a quick response in the transcription of stress-related genes. The main transcriptional activator that orchestrates this response is Msn2, whose nuclear localization and DNA binding are negatively controlled by the cAMP-dependent protein kinase (PKA). Msn2 activation by sudden glucose depletion correlates with a fast but transient decrease in phosphorylation of several sites in its nuclear localization signal (NLS). Here we show that protein phosphatase 1 (PP1) is the direct antagonist of PKA-dependent phosphorylation at the Msn2 nuclear import domain and therefore a potential mediator of glucose starvation signals that target this transcription factor. Apart from PKA, the protein kinase Snf1 can also directly modify one of the Msn2 phosphorylation sites (S582) and thereby repress Msn2 function. Consequently, in snf1 mutants, rephosphorylation of the NLS happens to be much slower during prolonged starvation. Thus, a second, Reg1-dependent form of PP1 indirectly influences Msn2 functionality by modulating Snf1 kinase activation and repression. Different activities of PP1 are therefore involved in shaping induction and adaptation of the transcriptional stress response during acute glucose starvation.\n" ], "offsets": [ [ 0, 1353 ] ] } ]

[ { "id": "PMID-16281053_T1", "type": "Gene_or_gene_product", "text": [ "PP1" ], "offsets": [ [ 16, 19 ] ], "normalized": [] }, { "id": "PMID-16281053_T2", "type": "Gene_or_gene_product", "text": [ "Msn2" ], "offsets": [ [ 35, 39 ] ], "normalized": [] }, { "id": "PMID-16281053_T3", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 78, 85 ] ], "normalized": [] }, { "id": "PMID-16281053_T4", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 109, 116 ] ], "normalized": [] }, { "id": "PMID-16281053_T5", "type": "Gene_or_gene_product", "text": [ "Msn2" ], "offsets": [ [ 268, 272 ] ], "normalized": [] }, { "id": "PMID-16281053_T6", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 280, 287 ] ], "normalized": [] }, { "id": "PMID-16281053_T7", "type": "Gene_or_gene_product", "text": [ "cAMP-dependent protein kinase" ], "offsets": [ [ 350, 379 ] ], "normalized": [] }, { "id": "PMID-16281053_T8", "type": "Gene_or_gene_product", "text": [ "PKA" ], "offsets": [ [ 381, 384 ] ], "normalized": [] }, { "id": "PMID-16281053_T9", "type": "Gene_or_gene_product", "text": [ "Msn2" ], "offsets": [ [ 387, 391 ] ], "normalized": [] }, { "id": "PMID-16281053_T10", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 413, 420 ] ], "normalized": [] }, { "id": "PMID-16281053_T11", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 520, 527 ] ], "normalized": [] }, { "id": "PMID-16281053_T12", "type": "Gene_or_gene_product", "text": [ "protein phosphatase 1" ], "offsets": [ [ 573, 594 ] ], "normalized": [] }, { "id": "PMID-16281053_T13", "type": "Gene_or_gene_product", "text": [ "PP1" ], "offsets": [ [ 596, 599 ] ], "normalized": [] }, { "id": "PMID-16281053_T14", "type": "Gene_or_gene_product", "text": [ "PKA" ], "offsets": [ [ 629, 632 ] ], "normalized": [] }, { "id": "PMID-16281053_T15", "type": "Gene_or_gene_product", "text": [ "Msn2" ], "offsets": [ [ 666, 670 ] ], "normalized": [] }, { "id": "PMID-16281053_T16", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 671, 678 ] ], "normalized": [] }, { "id": "PMID-16281053_T17", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 731, 738 ] ], "normalized": [] }, { "id": "PMID-16281053_T18", "type": "Gene_or_gene_product", "text": [ "PKA" ], "offsets": [ [ 808, 811 ] ], "normalized": [] }, { "id": "PMID-16281053_T19", "type": "Gene_or_gene_product", "text": [ "Snf1" ], "offsets": [ [ 832, 836 ] ], "normalized": [] }, { "id": "PMID-16281053_T20", "type": "Gene_or_gene_product", "text": [ "Msn2" ], "offsets": [ [ 873, 877 ] ], "normalized": [] }, { "id": "PMID-16281053_T21", "type": "Simple_chemical", "text": [ "S582" ], "offsets": [ [ 901, 905 ] ], "normalized": [] }, { "id": "PMID-16281053_T22", "type": "Gene_or_gene_product", "text": [ "Msn2" ], "offsets": [ [ 927, 931 ] ], "normalized": [] }, { "id": "PMID-16281053_T23", "type": "Gene_or_gene_product", "text": [ "snf1" ], "offsets": [ [ 959, 963 ] ], "normalized": [] }, { "id": "PMID-16281053_T24", "type": "Gene_or_gene_product", "text": [ "Reg1" ], "offsets": [ [ 1073, 1077 ] ], "normalized": [] }, { "id": "PMID-16281053_T25", "type": "Gene_or_gene_product", "text": [ "PP1" ], "offsets": [ [ 1096, 1099 ] ], "normalized": [] }, { "id": "PMID-16281053_T26", "type": "Gene_or_gene_product", "text": [ "Msn2" ], "offsets": [ [ 1122, 1126 ] ], "normalized": [] }, { "id": "PMID-16281053_T27", "type": "Gene_or_gene_product", "text": [ "Snf1" ], "offsets": [ [ 1155, 1159 ] ], "normalized": [] }, { "id": "PMID-16281053_T28", "type": "Gene_or_gene_product", "text": [ "PP1" ], "offsets": [ [ 1218, 1221 ] ], "normalized": [] }, { "id": "PMID-16281053_T29", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 1333, 1340 ] ], "normalized": [] } ]

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"ref_id": "PMID-16281053_T8" }, { "role": "Theme", "ref_id": "PMID-16281053_E3" } ] }, { "id": "PMID-16281053_E6", "type": "Negative_regulation", "trigger": { "text": [ "negatively controlled" ], "offsets": [ [ 321, 342 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16281053_T8" }, { "role": "Theme", "ref_id": "PMID-16281053_E4" } ] }, { "id": "PMID-16281053_E7", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 392, 402 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16281053_T9" }, { "role": "Cause", "ref_id": "PMID-16281053_E8" } ] }, { "id": "PMID-16281053_E8", "type": "Negative_regulation", "trigger": { "text": [ "depletion" ], "offsets": [ [ 421, 430 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16281053_T10" } ] }, { "id": "PMID-16281053_E9", "type": "Regulation", "trigger": { "text": [ "correlates" ], "offsets": [ [ 431, 441 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16281053_E7" }, { "role": "Theme", "ref_id": "PMID-16281053_E10" } ] }, { "id": "PMID-16281053_E10", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 468, 476 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16281053_E11" } ] }, { "id": "PMID-16281053_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 480, 495 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16281053_T9" } ] }, { "id": "PMID-16281053_E12", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 633, 642 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16281053_T14" }, { "role": "Theme", "ref_id": "PMID-16281053_E13" } ] }, { "id": "PMID-16281053_E13", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 643, 658 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16281053_T15" } ] }, { "id": "PMID-16281053_E14", "type": "Phosphorylation", "trigger": { "text": [ "modify" ], "offsets": [ [ 855, 861 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16281053_T19" }, { "role": "Site", "ref_id": "PMID-16281053_T21" }, { "role": "Theme", "ref_id": "PMID-16281053_T20" } ] }, { "id": "PMID-16281053_E15", "type": "Negative_regulation", "trigger": { "text": [ "repress" ], "offsets": [ [ 919, 926 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16281053_T22" }, { "role": "Cause", "ref_id": "PMID-16281053_E14" } ] }, { "id": "PMID-16281053_E16", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1078, 1087 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16281053_T24" }, { "role": "Theme", "ref_id": "PMID-16281053_T25" } ] }, { "id": "PMID-16281053_E17", "type": "Regulation", "trigger": { "text": [ "influences" ], "offsets": [ [ 1111, 1121 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16281053_T26" }, { "role": "Cause", "ref_id": "PMID-16281053_T25" } ] }, { "id": "PMID-16281053_E18", "type": "Positive_regulation", "trigger": { "text": [ "modulating" ], "offsets": [ [ 1144, 1154 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16281053_E17" }, { "role": "Theme", "ref_id": "PMID-16281053_E20" } ] }, { "id": "PMID-16281053_E19", "type": "Positive_regulation", "trigger": { "text": [ "modulating" ], "offsets": [ [ 1144, 1154 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16281053_E17" }, { "role": "Theme", "ref_id": "PMID-16281053_E21" } ] }, { "id": "PMID-16281053_E20", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1167, 1177 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16281053_T27" } ] }, { "id": "PMID-16281053_E21", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 1182, 1192 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16281053_T27" } ] }, { "id": "PMID-16281053_E22", "type": "Negative_regulation", "trigger": { "text": [ "starvation" ], "offsets": [ [ 1341, 1351 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16281053_T29" } ] } ]

[ { "id": "PMID-16281053_1", "entity_ids": [ "PMID-16281053_T7", "PMID-16281053_T8" ] }, { "id": "PMID-16281053_2", "entity_ids": [ "PMID-16281053_T12", "PMID-16281053_T13" ] } ]

[]

[ { "id": "PMID-16286006__text", "type": "abstract", "text": [ "mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. \nIn response to nutrients, energy sufficiency, hormones, and mitogenic agents, S6K1 phosphorylates several targets linked to translation. However, the molecular mechanisms whereby S6K1 is activated, encounters substrate, and contributes to translation initiation are poorly understood. We show that mTOR and S6K1 maneuver on and off the eukaryotic initiation factor 3 (eIF3) translation initiation complex in a signal-dependent, choreographed fashion. When inactive, S6K1 associates with the eIF3 complex, while the S6K1 activator mTOR/raptor does not. Cell stimulation promotes mTOR/raptor binding to the eIF3 complex and phosphorylation of S6K1 at its hydrophobic motif. Phosphorylation results in S6K1 dissociation, activation, and subsequent phosphorylation of its translational targets, including eIF4B, which is then recruited into the complex in a phosphorylation-dependent manner. Thus, the eIF3 preinitiation complex acts as a scaffold to coordinate a dynamic sequence of events in response to stimuli that promote efficient protein synthesis. \n" ], "offsets": [ [ 0, 1198 ] ] } ]

[ { "id": "PMID-16286006_T1", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-16286006_T2", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 9, 13 ] ], "normalized": [] }, { "id": "PMID-16286006_T3", "type": "Complex", "text": [ "translation preinitiation complex" ], "offsets": [ [ 38, 71 ] ], "normalized": [] }, { "id": "PMID-16286006_T4", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 223, 227 ] ], "normalized": [] }, { "id": "PMID-16286006_T5", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 324, 328 ] ], "normalized": [] }, { "id": "PMID-16286006_T6", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 443, 447 ] ], "normalized": [] }, { "id": "PMID-16286006_T7", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 452, 456 ] ], "normalized": [] }, { "id": "PMID-16286006_T8", "type": "Complex", "text": [ "eukaryotic initiation factor 3 (eIF3) translation initiation complex" ], "offsets": [ [ 481, 549 ] ], "normalized": [] }, { "id": "PMID-16286006_T9", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 611, 615 ] ], "normalized": [] }, { "id": "PMID-16286006_T10", "type": "Complex", "text": [ "eIF3 complex" ], "offsets": [ [ 636, 648 ] ], "normalized": [] }, { "id": "PMID-16286006_T11", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 660, 664 ] ], "normalized": [] }, { "id": "PMID-16286006_T12", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 675, 679 ] ], "normalized": [] }, { "id": "PMID-16286006_T13", "type": "Gene_or_gene_product", "text": [ "raptor" ], "offsets": [ [ 680, 686 ] ], "normalized": [] }, { "id": "PMID-16286006_T14", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 723, 727 ] ], "normalized": [] }, { "id": "PMID-16286006_T15", "type": "Gene_or_gene_product", "text": [ "raptor" ], "offsets": [ [ 728, 734 ] ], "normalized": [] }, { "id": "PMID-16286006_T16", "type": "Complex", "text": [ "eIF3 complex" ], "offsets": [ [ 750, 762 ] ], "normalized": [] }, { "id": "PMID-16286006_T17", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 786, 790 ] ], "normalized": [] }, { "id": "PMID-16286006_T18", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 844, 848 ] ], "normalized": [] }, { "id": "PMID-16286006_T19", "type": "Gene_or_gene_product", "text": [ "eIF4B" ], "offsets": [ [ 946, 951 ] ], "normalized": [] }, { "id": "PMID-16286006_T20", "type": "Complex", "text": [ "eIF3 preinitiation complex" ], "offsets": [ [ 1043, 1069 ] ], "normalized": [] } ]

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"role": "Theme", "ref_id": "PMID-16286006_T6" }, { "role": "Theme", "ref_id": "PMID-16286006_T8" } ] }, { "id": "PMID-16286006_E6", "type": "Binding", "trigger": { "text": [ "maneuver on" ], "offsets": [ [ 457, 468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T7" }, { "role": "Theme", "ref_id": "PMID-16286006_T8" } ] }, { "id": "PMID-16286006_E7", "type": "Dissociation", "trigger": { "text": [ "maneuver on and off" ], "offsets": [ [ 457, 476 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-16286006_T6" }, { "role": "Theme", "ref_id": "PMID-16286006_T8" } ] }, { "id": "PMID-16286006_E8", "type": "Dissociation", "trigger": { "text": [ "maneuver on and off" ], "offsets": [ [ 457, 476 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-16286006_T7" }, { "role": "Theme", "ref_id": "PMID-16286006_T8" } ] }, { "id": "PMID-16286006_E9", "type": "Inactivation", "trigger": { "text": [ "inactive" ], "offsets": [ [ 601, 609 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T9" } ] }, { "id": "PMID-16286006_E10", "type": "Binding", "trigger": { "text": [ "associates" ], "offsets": [ [ 616, 626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T9" }, { "role": "Theme", "ref_id": "PMID-16286006_T10" } ] }, { "id": "PMID-16286006_E11", "type": "Binding", "trigger": { "text": [ "associates" ], "offsets": [ [ 616, 626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T10" }, { "role": "Theme", "ref_id": "PMID-16286006_T13" } ] }, { "id": "PMID-16286006_E12", "type": "Binding", "trigger": { "text": [ "associates" ], "offsets": [ [ 616, 626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T10" }, { "role": "Theme", "ref_id": "PMID-16286006_T12" } ] }, { "id": "PMID-16286006_E13", "type": "Activation", "trigger": { "text": [ "activator" ], "offsets": [ [ 665, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T11" }, { "role": "Cause", "ref_id": "PMID-16286006_T12" } ] }, { "id": "PMID-16286006_E14", "type": "Activation", "trigger": { "text": [ "activator" ], "offsets": [ [ 665, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T11" }, { "role": "Cause", "ref_id": "PMID-16286006_T13" } ] }, { "id": "PMID-16286006_E15", "type": "Positive_regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 714, 722 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_E19" } ] }, { "id": "PMID-16286006_E16", "type": "Positive_regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 714, 722 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_E18" } ] }, { "id": "PMID-16286006_E17", "type": "Positive_regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 714, 722 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_E20" } ] }, { "id": "PMID-16286006_E18", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 735, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T14" }, { "role": "Theme", "ref_id": "PMID-16286006_T16" } ] }, { "id": "PMID-16286006_E19", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 735, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T15" }, { "role": "Theme", "ref_id": "PMID-16286006_T16" } ] }, { "id": "PMID-16286006_E20", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 767, 782 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T17" } ] }, { "id": "PMID-16286006_E21", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 817, 832 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T17" } ] }, { "id": "PMID-16286006_E22", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 833, 840 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16286006_E21" }, { "role": "Theme", "ref_id": "PMID-16286006_E25" } ] }, { "id": "PMID-16286006_E23", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 833, 840 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16286006_E21" }, { "role": "Theme", "ref_id": "PMID-16286006_E26" } ] }, { "id": "PMID-16286006_E24", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 833, 840 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16286006_E21" }, { "role": "Theme", "ref_id": "PMID-16286006_E27" } ] }, { "id": "PMID-16286006_E25", "type": "Dissociation", "trigger": { "text": [ "dissociation" ], "offsets": [ [ 849, 861 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-16286006_T18" }, { "role": "Theme", "ref_id": "PMID-16286006_T16" } ] }, { "id": "PMID-16286006_E26", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 863, 873 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T18" } ] }, { "id": "PMID-16286006_E27", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 890, 905 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T19" } ] }, { "id": "PMID-16286006_E28", "type": "Binding", "trigger": { "text": [ "recruited" ], "offsets": [ [ 967, 976 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T19" }, { "role": "Theme", "ref_id": "PMID-16286006_T16" } ] }, { "id": "PMID-16286006_E29", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 999, 1014 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16286006_T19" } ] }, { "id": "PMID-16286006_E30", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1015, 1024 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16286006_E29" }, { "role": "Theme", "ref_id": "PMID-16286006_E28" } ] } ]

[]

[]

[ { "id": "PMID-1628831__text", "type": "abstract", "text": [ "Signal transduction in Saccharomyces cerevisiae requires tyrosine and threonine phosphorylation of FUS3 and KSS1. \nThe FUS3 and KSS1 kinases are components of the pheromone-dependent signal transduction pathway in yeast. We show that FUS3 and KSS1 become rapidly phosphorylated after pheromone treatment. Similar to mammalian MAP kinases, this modification occurs at two amino acids of FUS3, threonine-180 and tyrosine-182. A mutation introduced at either position results in complete loss of function in vivo. Amino acid substitutions that destroy catalytic activity of the kinase do not prevent phosphorylation of the mutant products, a result that excludes an autocatalytic activation pathway. The modification of FUS3 is dependent on kinases encoded by the STE11 and STE7 genes. Furthermore, a hyperactive allele of STE11 causes increased phosphorylation of FUS3 in the absence of pheromone stimulation. Thus, either STE7 or STE11 could be the kinase responsible for the phosphorylation of FUS3.\n" ], "offsets": [ [ 0, 1000 ] ] } ]

[ { "id": "PMID-1628831_T1", "type": "Simple_chemical", "text": [ "tyrosine" ], "offsets": [ [ 57, 65 ] ], "normalized": [] }, { "id": "PMID-1628831_T2", "type": "Simple_chemical", "text": [ "threonine" ], "offsets": [ [ 70, 79 ] ], "normalized": [] }, { "id": "PMID-1628831_T3", "type": "Gene_or_gene_product", "text": [ "FUS3" ], "offsets": [ [ 99, 103 ] ], "normalized": [] }, { "id": "PMID-1628831_T4", "type": "Gene_or_gene_product", "text": [ "KSS1" ], "offsets": [ [ 108, 112 ] ], "normalized": [] }, { "id": "PMID-1628831_T5", "type": "Gene_or_gene_product", "text": [ "FUS3" ], "offsets": [ [ 119, 123 ] ], "normalized": [] }, { "id": "PMID-1628831_T6", "type": "Gene_or_gene_product", "text": [ "KSS1" ], "offsets": [ [ 128, 132 ] ], "normalized": [] }, { "id": "PMID-1628831_T7", "type": "Gene_or_gene_product", "text": [ "FUS3" ], "offsets": [ [ 234, 238 ] ], "normalized": [] }, { "id": "PMID-1628831_T8", "type": "Gene_or_gene_product", "text": [ "KSS1" ], "offsets": [ [ 243, 247 ] ], "normalized": [] }, { "id": "PMID-1628831_T9", "type": "Gene_or_gene_product", "text": [ "MAP kinases" ], "offsets": [ [ 326, 337 ] ], "normalized": [] }, { "id": "PMID-1628831_T10", "type": "Gene_or_gene_product", "text": [ "FUS3" ], "offsets": [ [ 386, 390 ] ], "normalized": [] }, { "id": "PMID-1628831_T11", "type": "Simple_chemical", "text": [ "threonine-180" ], "offsets": [ [ 392, 405 ] ], "normalized": [] }, { "id": "PMID-1628831_T12", "type": "Simple_chemical", "text": [ "tyrosine-182" ], "offsets": [ [ 410, 422 ] ], "normalized": [] }, { "id": "PMID-1628831_T13", "type": "Gene_or_gene_product", "text": [ "FUS3" ], "offsets": [ [ 717, 721 ] ], "normalized": [] }, { "id": "PMID-1628831_T14", "type": "Gene_or_gene_product", "text": [ "STE11" ], "offsets": [ [ 761, 766 ] ], "normalized": [] }, { "id": "PMID-1628831_T15", "type": "Gene_or_gene_product", "text": [ "STE7" ], "offsets": [ [ 771, 775 ] ], "normalized": [] }, { "id": "PMID-1628831_T16", "type": "Gene_or_gene_product", "text": [ "STE11" ], "offsets": [ [ 820, 825 ] ], "normalized": [] }, { "id": "PMID-1628831_T17", "type": "Gene_or_gene_product", "text": [ "FUS3" ], "offsets": [ [ 862, 866 ] ], "normalized": [] }, { "id": "PMID-1628831_T18", "type": "Gene_or_gene_product", "text": [ "STE7" ], "offsets": [ [ 921, 925 ] ], "normalized": [] }, { "id": "PMID-1628831_T19", "type": "Gene_or_gene_product", "text": [ "STE11" ], "offsets": [ [ 929, 934 ] ], "normalized": [] }, { "id": "PMID-1628831_T20", "type": "Gene_or_gene_product", "text": [ "FUS3" ], "offsets": [ [ 994, 998 ] ], "normalized": [] } ]

[ { "id": "PMID-1628831_E1", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 80, 95 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T3" }, { "role": "Site", "ref_id": "PMID-1628831_T2" } ] }, { "id": "PMID-1628831_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 80, 95 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T4" }, { "role": "Site", "ref_id": "PMID-1628831_T2" } ] }, { "id": "PMID-1628831_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 80, 95 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T3" }, { "role": "Site", "ref_id": "PMID-1628831_T1" } ] }, { "id": "PMID-1628831_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 80, 95 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T4" }, { "role": "Site", "ref_id": "PMID-1628831_T1" } ] }, { "id": "PMID-1628831_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 263, 277 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T8" } ] }, { "id": "PMID-1628831_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 263, 277 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T7" } ] }, { "id": "PMID-1628831_E7", "type": "Phosphorylation", "trigger": { "text": [ "modification" ], "offsets": [ [ 344, 356 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T10" }, { "role": "Site", "ref_id": "PMID-1628831_T11" } ] }, { "id": "PMID-1628831_E8", "type": "Phosphorylation", "trigger": { "text": [ "modification" ], "offsets": [ [ 344, 356 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T10" }, { "role": "Site", "ref_id": "PMID-1628831_T12" } ] }, { "id": "PMID-1628831_E9", "type": "Phosphorylation", "trigger": { "text": [ "modification" ], "offsets": [ [ 701, 713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T13" } ] }, { "id": "PMID-1628831_E10", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 725, 734 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_E9" }, { "role": "Cause", "ref_id": "PMID-1628831_T14" } ] }, { "id": "PMID-1628831_E11", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 725, 734 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_E9" }, { "role": "Cause", "ref_id": "PMID-1628831_T15" } ] }, { "id": "PMID-1628831_E12", "type": "Activation", "trigger": { "text": [ "hyperactive" ], "offsets": [ [ 798, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T16" } ] }, { "id": "PMID-1628831_E13", "type": "Positive_regulation", "trigger": { "text": [ "causes" ], "offsets": [ [ 826, 832 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_E14" }, { "role": "Cause", "ref_id": "PMID-1628831_E12" } ] }, { "id": "PMID-1628831_E14", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 833, 842 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_E15" } ] }, { "id": "PMID-1628831_E15", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 843, 858 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T17" } ] }, { "id": "PMID-1628831_E16", "type": "Positive_regulation", "trigger": { "text": [ "responsible" ], "offsets": [ [ 955, 966 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_E18" }, { "role": "Cause", "ref_id": "PMID-1628831_T18" } ] }, { "id": "PMID-1628831_E17", "type": "Positive_regulation", "trigger": { "text": [ "responsible" ], "offsets": [ [ 955, 966 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_E18" }, { "role": "Cause", "ref_id": "PMID-1628831_T19" } ] }, { "id": "PMID-1628831_E18", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 975, 990 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1628831_T20" } ] } ]

[]

[]

[ { "id": "PMID-16407284__text", "type": "abstract", "text": [ "Blockade of NFAT activation by the second calcineurin binding site. \nActivation of NFAT transcription factors requires their dephosphorylation by the phosphatase calcineurin (CN). NFATs contain two CN binding motifs: PxIxIT and CnBP-B/CNBR2 (which we call LxVP). Here we carry out a detailed comparative analysis of the CN binding activity displayed by the PxIxIT and LxVP sites from different NFATs. Dose-response CN binding experiments with GST fusion proteins of NFATc1 and NFATc2 showed that NFATc1 binds CN in vitro more efficiently than does NFATc2. This difference in binding appears to be caused by the different CN binding potencies of the corresponding LxVP sites; thus while the LxVPc2 peptide fused to GST did not bind CN, GST-LxVPc1 bound it more efficiently than did GST-PxIxITc1 or GST-PxIxITc2. Furthermore, an NFATc2 chimera protein containing the LxVP motif from NFATc1 interacted with CN much more potently than did wild-type NFATc2. Free peptides spanning the LxVP motifs from NFATc1, c3 or c4 displaced CN from GST-NFATc1 and GST-NFATc2 more efficiently than any PxIxIT peptide. PxIxITc2 and LxVPc1 peptides were each able to cross-compete GST-LxVPc1-CN and GST-PxIxITc2-CN binding. In contrast with PxIxITc2, the LxVP peptide not only blocked CN-NFAT binding but also inhibited CN phosphatase activity in vitro. Furthermore, exogenous LxVPc1 blocked NFATc2 phosphorylation and nuclear translocation in vivo. These results suggest a model in which the different CN binding characteristics of the PxIxIT and LxVP sites enable different NFAT members to influence each others activities in cells where they are co-expressed.\n" ], "offsets": [ [ 0, 1643 ] ] } ]

[ { "id": "PMID-16407284_T1", "type": "Gene_or_gene_product", "text": [ "NFAT" ], "offsets": [ [ 12, 16 ] ], "normalized": [] }, { "id": "PMID-16407284_T2", "type": "Complex", "text": [ "calcineurin" ], "offsets": [ [ 42, 53 ] ], "normalized": [] }, { "id": "PMID-16407284_T3", "type": "Gene_or_gene_product", "text": [ "NFAT" ], "offsets": [ [ 83, 87 ] ], "normalized": [] }, { "id": "PMID-16407284_T4", "type": "Complex", "text": [ "calcineurin" ], "offsets": [ [ 162, 173 ] ], "normalized": [] }, { "id": "PMID-16407284_T5", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 175, 177 ] ], "normalized": [] }, { "id": "PMID-16407284_T6", "type": "Gene_or_gene_product", "text": [ "NFATs" ], "offsets": [ [ 180, 185 ] ], "normalized": [] }, { "id": "PMID-16407284_T7", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 198, 200 ] ], "normalized": [] }, { "id": "PMID-16407284_T8", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 320, 322 ] ], "normalized": [] }, { "id": "PMID-16407284_T9", "type": "Gene_or_gene_product", "text": [ "NFATs" ], "offsets": [ [ 394, 399 ] ], "normalized": [] }, { "id": "PMID-16407284_T10", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 415, 417 ] ], "normalized": [] }, { "id": "PMID-16407284_T11", "type": "Gene_or_gene_product", "text": [ "GST" ], "offsets": [ [ 443, 446 ] ], "normalized": [] }, { "id": "PMID-16407284_T12", "type": "Gene_or_gene_product", "text": [ "NFATc1" ], "offsets": [ [ 466, 472 ] ], "normalized": [] }, { "id": "PMID-16407284_T13", "type": "Gene_or_gene_product", "text": [ "NFATc2" ], "offsets": [ [ 477, 483 ] ], "normalized": [] }, { "id": "PMID-16407284_T14", "type": "Gene_or_gene_product", "text": [ "NFATc1" ], "offsets": [ [ 496, 502 ] ], "normalized": [] }, { "id": "PMID-16407284_T15", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 509, 511 ] ], "normalized": [] }, { "id": "PMID-16407284_T16", "type": "Gene_or_gene_product", "text": [ "NFATc2" ], "offsets": [ [ 548, 554 ] ], "normalized": [] }, { "id": "PMID-16407284_T17", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 621, 623 ] ], "normalized": [] }, { "id": "PMID-16407284_T18", "type": "Gene_or_gene_product", "text": [ "LxVPc2" ], "offsets": [ [ 690, 696 ] ], "normalized": [] }, { "id": "PMID-16407284_T19", "type": "Gene_or_gene_product", "text": [ "GST" ], "offsets": [ [ 714, 717 ] ], "normalized": [] }, { "id": "PMID-16407284_T20", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 731, 733 ] ], "normalized": [] }, { "id": "PMID-16407284_T21", "type": "Gene_or_gene_product", "text": [ "GST-LxVPc1" ], "offsets": [ [ 735, 745 ] ], "normalized": [] }, { "id": "PMID-16407284_T22", "type": "Gene_or_gene_product", "text": [ "GST-PxIxITc1" ], "offsets": [ [ 781, 793 ] ], "normalized": [] }, { "id": "PMID-16407284_T23", "type": "Gene_or_gene_product", "text": [ "GST-PxIxITc2" ], "offsets": [ [ 797, 809 ] ], "normalized": [] }, { "id": "PMID-16407284_T24", "type": "Gene_or_gene_product", "text": [ "NFATc2" ], "offsets": [ [ 827, 833 ] ], "normalized": [] }, { "id": "PMID-16407284_T25", "type": "Gene_or_gene_product", "text": [ "NFATc1" ], "offsets": [ [ 881, 887 ] ], "normalized": [] }, { "id": "PMID-16407284_T26", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 904, 906 ] ], "normalized": [] }, { "id": "PMID-16407284_T27", "type": "Gene_or_gene_product", "text": [ "NFATc2" ], "offsets": [ [ 945, 951 ] ], "normalized": [] }, { "id": "PMID-16407284_T28", "type": "Gene_or_gene_product", "text": [ "NFATc1" ], "offsets": [ [ 997, 1003 ] ], "normalized": [] }, { "id": "PMID-16407284_T29", "type": "Gene_or_gene_product", "text": [ "c3" ], "offsets": [ [ 1005, 1007 ] ], "normalized": [] }, { "id": "PMID-16407284_T30", "type": "Gene_or_gene_product", "text": [ "c4" ], "offsets": [ [ 1011, 1013 ] ], "normalized": [] }, { "id": "PMID-16407284_T31", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 1024, 1026 ] ], "normalized": [] }, { "id": "PMID-16407284_T32", "type": "Complex", "text": [ "GST-NFATc1" ], "offsets": [ [ 1032, 1042 ] ], "normalized": [] }, { "id": "PMID-16407284_T33", "type": "Complex", "text": [ "GST-NFATc2" ], "offsets": [ [ 1047, 1057 ] ], "normalized": [] }, { "id": "PMID-16407284_T34", "type": "Gene_or_gene_product", "text": [ "PxIxIT" ], "offsets": [ [ 1084, 1090 ] ], "normalized": [] }, { "id": "PMID-16407284_T35", "type": "Gene_or_gene_product", "text": [ "PxIxITc2" ], "offsets": [ [ 1100, 1108 ] ], "normalized": [] }, { "id": "PMID-16407284_T36", "type": "Gene_or_gene_product", "text": [ "LxVPc1" ], "offsets": [ [ 1113, 1119 ] ], "normalized": [] }, { "id": "PMID-16407284_T37", "type": "Complex", "text": [ "GST-LxVPc1-CN" ], "offsets": [ [ 1161, 1174 ] ], "normalized": [] }, { "id": "PMID-16407284_T38", "type": "Complex", "text": [ "GST-PxIxITc2-CN" ], "offsets": [ [ 1179, 1194 ] ], "normalized": [] }, { "id": "PMID-16407284_T39", "type": "Gene_or_gene_product", "text": [ "PxIxITc2" ], "offsets": [ [ 1221, 1229 ] ], "normalized": [] }, { "id": "PMID-16407284_T40", "type": "Gene_or_gene_product", "text": [ "LxVP" ], "offsets": [ [ 1235, 1239 ] ], "normalized": [] }, { "id": "PMID-16407284_T41", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 1265, 1267 ] ], "normalized": [] }, { "id": "PMID-16407284_T42", "type": "Gene_or_gene_product", "text": [ "NFAT" ], "offsets": [ [ 1268, 1272 ] ], "normalized": [] }, { "id": "PMID-16407284_T43", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 1300, 1302 ] ], "normalized": [] }, { "id": "PMID-16407284_T44", "type": "Gene_or_gene_product", "text": [ "LxVPc1" ], "offsets": [ [ 1357, 1363 ] ], "normalized": [] }, { "id": "PMID-16407284_T45", "type": "Gene_or_gene_product", "text": [ "NFATc2" ], "offsets": [ [ 1372, 1378 ] ], "normalized": [] }, { "id": "PMID-16407284_T46", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1399, 1406 ] ], "normalized": [] }, { "id": "PMID-16407284_T47", "type": "Complex", "text": [ "CN" ], "offsets": [ [ 1483, 1485 ] ], "normalized": [] }, { "id": "PMID-16407284_T48", "type": "Gene_or_gene_product", "text": [ "NFAT" ], "offsets": [ [ 1556, 1560 ] ], "normalized": [] } ]

[ { "id": "PMID-16407284_E1", "type": "Negative_regulation", "trigger": { "text": [ "Blockade" ], "offsets": [ [ 0, 8 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_E2" } ] }, { "id": "PMID-16407284_E2", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 17, 27 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T1" } ] }, { "id": "PMID-16407284_E3", "type": "Activation", "trigger": { "text": [ "Activation" ], "offsets": [ [ 69, 79 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T3" } ] }, { "id": "PMID-16407284_E4", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 110, 118 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16407284_E5" }, { "role": "Theme", "ref_id": "PMID-16407284_E3" } ] }, { "id": "PMID-16407284_E5", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylation" ], "offsets": [ [ 125, 142 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T3" }, { "role": "Cause", "ref_id": "PMID-16407284_T4" } ] }, { "id": "PMID-16407284_E6", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 323, 330 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T8" }, { "role": "Theme", "ref_id": "PMID-16407284_T9" } ] }, { "id": "PMID-16407284_E7", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 418, 425 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T10" } ] }, { "id": "PMID-16407284_E8", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 503, 508 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T14" }, { "role": "Theme", "ref_id": "PMID-16407284_T15" } ] }, { "id": "PMID-16407284_E9", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 503, 508 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T16" }, { "role": "Theme", "ref_id": "PMID-16407284_T15" } ] }, { "id": "PMID-16407284_E10", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 575, 582 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T14" }, { "role": "Theme", "ref_id": "PMID-16407284_T15" } ] }, { "id": "PMID-16407284_E11", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 575, 582 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T16" }, { "role": "Theme", "ref_id": "PMID-16407284_T15" } ] }, { "id": "PMID-16407284_E12", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 624, 631 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T17" } ] }, { "id": "PMID-16407284_E13", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 726, 730 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T20" }, { "role": "Theme", "ref_id": "PMID-16407284_T18" } ] }, { "id": "PMID-16407284_E14", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 746, 751 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T21" }, { "role": "Theme", "ref_id": "PMID-16407284_T20" } ] }, { "id": "PMID-16407284_E15", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 746, 751 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T22" }, { "role": "Theme", "ref_id": "PMID-16407284_T20" } ] }, { "id": "PMID-16407284_E16", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 746, 751 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T23" }, { "role": "Theme", "ref_id": "PMID-16407284_T20" } ] }, { "id": "PMID-16407284_E17", "type": "Binding", "trigger": { "text": [ "interacted" ], "offsets": [ [ 888, 898 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T26" }, { "role": "Theme", "ref_id": "PMID-16407284_T24" } ] }, { "id": "PMID-16407284_E18", "type": "Binding", "trigger": { "text": [ "interacted" ], "offsets": [ [ 888, 898 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T27" }, { "role": "Theme", "ref_id": "PMID-16407284_T26" } ] }, { "id": "PMID-16407284_E19", "type": "Dissociation", "trigger": { "text": [ "displaced" ], "offsets": [ [ 1014, 1023 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-16407284_T31" }, { "role": "Product", "ref_id": "PMID-16407284_T32" } ] }, { "id": "PMID-16407284_E20", "type": "Dissociation", "trigger": { "text": [ "displaced" ], "offsets": [ [ 1014, 1023 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-16407284_T31" }, { "role": "Product", "ref_id": "PMID-16407284_T33" } ] }, { "id": "PMID-16407284_E21", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1257, 1264 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16407284_T40" }, { "role": "Theme", "ref_id": "PMID-16407284_E23" } ] }, { "id": "PMID-16407284_E22", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1257, 1264 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16407284_T39" }, { "role": "Theme", "ref_id": "PMID-16407284_E23" } ] }, { "id": "PMID-16407284_E23", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1273, 1280 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T41" }, { "role": "Theme", "ref_id": "PMID-16407284_T42" } ] }, { "id": "PMID-16407284_E24", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1290, 1299 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T43" }, { "role": "Cause", "ref_id": "PMID-16407284_T40" } ] }, { "id": "PMID-16407284_E25", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1290, 1299 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T43" }, { "role": "Cause", "ref_id": "PMID-16407284_T39" } ] }, { "id": "PMID-16407284_E26", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1364, 1371 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16407284_T44" }, { "role": "Theme", "ref_id": "PMID-16407284_E28" } ] }, { "id": "PMID-16407284_E27", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1364, 1371 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16407284_T44" }, { "role": "Theme", "ref_id": "PMID-16407284_E29" } ] }, { "id": "PMID-16407284_E28", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1379, 1394 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T45" } ] }, { "id": "PMID-16407284_E29", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 1407, 1420 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-16407284_T46" }, { "role": "Theme", "ref_id": "PMID-16407284_T45" } ] }, { "id": "PMID-16407284_E30", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1486, 1493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16407284_T47" } ] } ]

[ { "id": "PMID-16407284_1", "entity_ids": [ "PMID-16407284_T4", "PMID-16407284_T5" ] } ]

[]

[ { "id": "PMID-16672979__text", "type": "abstract", "text": [ "Rec8 phosphorylation and recombination promote the step-wise loss of cohesins in meiosis. \nDuring meiosis, cohesins--protein complexes that hold sister chromatids together--are lost from chromosomes in a step-wise manner. Loss of cohesins from chromosome arms is necessary for homologous chromosomes to segregate during meiosis I. Retention of cohesins around centromeres until meiosis II is required for the accurate segregation of sister chromatids. Here we show that phosphorylation of the cohesin subunit Rec8 contributes to step-wise cohesin removal. Our data further implicate two other key regulators of meiotic chromosome segregation, the cohesin protector Sgo1 and meiotic recombination in bringing about the step-wise loss of cohesins and thus the establishment of the meiotic chromosome segregation pattern. Understanding the interplay between these processes should provide insight into the events underlying meiotic chromosome mis-segregation, the leading cause of miscarriages and mental retardation in humans.\n" ], "offsets": [ [ 0, 1025 ] ] } ]

[ { "id": "PMID-16672979_T1", "type": "Gene_or_gene_product", "text": [ "Rec8" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-16672979_T2", "type": "Complex", "text": [ "cohesins" ], "offsets": [ [ 69, 77 ] ], "normalized": [] }, { "id": "PMID-16672979_T3", "type": "Complex", "text": [ "cohesins" ], "offsets": [ [ 107, 115 ] ], "normalized": [] }, { "id": "PMID-16672979_T4", "type": "Cellular_component", "text": [ "chromatids" ], "offsets": [ [ 152, 162 ] ], "normalized": [] }, { "id": "PMID-16672979_T5", "type": "Cellular_component", "text": [ "chromosomes" ], "offsets": [ [ 187, 198 ] ], "normalized": [] }, { "id": "PMID-16672979_T6", "type": "Complex", "text": [ "cohesins" ], "offsets": [ [ 230, 238 ] ], "normalized": [] }, { "id": "PMID-16672979_T7", "type": "Cellular_component", "text": [ "chromosome arms" ], "offsets": [ [ 244, 259 ] ], "normalized": [] }, { "id": "PMID-16672979_T8", "type": "Cellular_component", "text": [ "chromosomes" ], "offsets": [ [ 288, 299 ] ], "normalized": [] }, { "id": "PMID-16672979_T9", "type": "Complex", "text": [ "cohesins" ], "offsets": [ [ 344, 352 ] ], "normalized": [] }, { "id": "PMID-16672979_T10", "type": "Cellular_component", "text": [ "chromatids" ], "offsets": [ [ 440, 450 ] ], "normalized": [] }, { "id": "PMID-16672979_T11", "type": "Complex", "text": [ "cohesin" ], "offsets": [ [ 493, 500 ] ], "normalized": [] }, { "id": "PMID-16672979_T12", "type": "Gene_or_gene_product", "text": [ "Rec8" ], "offsets": [ [ 509, 513 ] ], "normalized": [] }, { "id": "PMID-16672979_T13", "type": "Complex", "text": [ "cohesin" ], "offsets": [ [ 539, 546 ] ], "normalized": [] }, { "id": "PMID-16672979_T14", "type": "Cellular_component", "text": [ "chromosome" ], "offsets": [ [ 619, 629 ] ], "normalized": [] }, { "id": "PMID-16672979_T15", "type": "Complex", "text": [ "cohesin" ], "offsets": [ [ 647, 654 ] ], "normalized": [] }, { "id": "PMID-16672979_T16", "type": "Gene_or_gene_product", "text": [ "Sgo1" ], "offsets": [ [ 665, 669 ] ], "normalized": [] }, { "id": "PMID-16672979_T17", "type": "Complex", "text": [ "cohesins" ], "offsets": [ [ 736, 744 ] ], "normalized": [] }, { "id": "PMID-16672979_T18", "type": "Cellular_component", "text": [ "chromosome" ], "offsets": [ [ 787, 797 ] ], "normalized": [] }, { "id": "PMID-16672979_T19", "type": "Cellular_component", "text": [ "chromosome" ], "offsets": [ [ 929, 939 ] ], "normalized": [] } ]

[ { "id": "PMID-16672979_E1", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 5, 20 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16672979_T1" } ] }, { "id": "PMID-16672979_E2", "type": "Positive_regulation", "trigger": { "text": [ "promote" ], "offsets": [ [ 39, 46 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16672979_E1" }, { "role": "Theme", "ref_id": "PMID-16672979_E3" } ] }, { "id": "PMID-16672979_E3", "type": "Dissociation", "trigger": { "text": [ "loss" ], "offsets": [ [ 61, 65 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16672979_T2" } ] }, { "id": "PMID-16672979_E4", "type": "Dissociation", "trigger": { "text": [ "Loss" ], "offsets": [ [ 222, 226 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16672979_T6" } ] }, { "id": "PMID-16672979_E5", "type": "Positive_regulation", "trigger": { "text": [ "Retention" ], "offsets": [ [ 331, 340 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16672979_T9" } ] }, { "id": "PMID-16672979_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 470, 485 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16672979_T12" } ] }, { "id": "PMID-16672979_E7", "type": "Positive_regulation", "trigger": { "text": [ "contributes" ], "offsets": [ [ 514, 525 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16672979_E8" }, { "role": "Cause", "ref_id": "PMID-16672979_E6" } ] }, { "id": "PMID-16672979_E8", "type": "Dissociation", "trigger": { "text": [ "removal" ], "offsets": [ [ 547, 554 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16672979_T13" } ] }, { "id": "PMID-16672979_E9", "type": "Dissociation", "trigger": { "text": [ "loss" ], "offsets": [ [ 728, 732 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16672979_T17" } ] } ]

[]

[]

[ { "id": "PMID-16741925__text", "type": "abstract", "text": [ "Regulation of the Pur-alpha promoter by E2F-1. \nPuralpha is a ubiquitously expressed multifunctional nucleic acid-binding protein that is involved in many cellular processes including transcriptional regulation, the cell cycle, oncogenic transformation, and post-natal brain development. Previously, Puralpha protein was found to bind to E2F-1, inhibit E2F-1 transcriptional activity, and reverse the effects of ectopic E2F-1 expression on cell growth. Also Puralpha binds to a GC/GA-rich sequence within its own promoter and inhibits gene expression, that is, Puralpha is autoregulated. We now report that the Puralpha promoter (pPuralpha) is induced by E2F-1 and that this activity maps to a consensus E2F-1 binding motif that is juxtaposed to the Puralpha binding site. Deletion mutants of the E2F-1 protein showed that the region between amino acid residues 88-241 is important for this activity. E2F-1-associated activation of the pPuralpha was inhibited by co-expression of Puralpha, pRb, and an RNA species with specific binding to E2F-1. Chromatin immunoprecipitation (ChIP) assay using primers that flanked the juxtaposed Puralpha and E2F-1 binding sites verified the presence of Puralpha and E2F-1 on the pPuralpha in vivo. In a Tet-inducible cell line, Puralpha delayed cell cycle progression. Thus, E2F-1 and Puralpha interplay appears to be involved in the regulation of Puralpha expression and the cell cycle.\n" ], "offsets": [ [ 0, 1424 ] ] } ]

[ { "id": "PMID-16741925_T1", "type": "Gene_or_gene_product", "text": [ "Pur-alpha" ], "offsets": [ [ 18, 27 ] ], "normalized": [] }, { "id": "PMID-16741925_T2", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 40, 45 ] ], "normalized": [] }, { "id": "PMID-16741925_T3", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 48, 56 ] ], "normalized": [] }, { "id": "PMID-16741925_T4", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 300, 308 ] ], "normalized": [] }, { "id": "PMID-16741925_T5", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 338, 343 ] ], "normalized": [] }, { "id": "PMID-16741925_T6", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 353, 358 ] ], "normalized": [] }, { "id": "PMID-16741925_T7", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 420, 425 ] ], "normalized": [] }, { "id": "PMID-16741925_T8", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 458, 466 ] ], "normalized": [] }, { "id": "PMID-16741925_T9", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 561, 569 ] ], "normalized": [] }, { "id": "PMID-16741925_T10", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 611, 619 ] ], "normalized": [] }, { "id": "PMID-16741925_T11", "type": "Gene_or_gene_product", "text": [ "pPuralpha" ], "offsets": [ [ 630, 639 ] ], "normalized": [] }, { "id": "PMID-16741925_T12", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 655, 660 ] ], "normalized": [] }, { "id": "PMID-16741925_T13", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 704, 709 ] ], "normalized": [] }, { "id": "PMID-16741925_T14", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 750, 758 ] ], "normalized": [] }, { "id": "PMID-16741925_T15", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 797, 802 ] ], "normalized": [] }, { "id": "PMID-16741925_T16", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 901, 906 ] ], "normalized": [] }, { "id": "PMID-16741925_T17", "type": "Gene_or_gene_product", "text": [ "pPuralpha" ], "offsets": [ [ 936, 945 ] ], "normalized": [] }, { "id": "PMID-16741925_T18", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 980, 988 ] ], "normalized": [] }, { "id": "PMID-16741925_T19", "type": "Gene_or_gene_product", "text": [ "pRb" ], "offsets": [ [ 990, 993 ] ], "normalized": [] }, { "id": "PMID-16741925_T20", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 1039, 1044 ] ], "normalized": [] }, { "id": "PMID-16741925_T21", "type": "Cellular_component", "text": [ "Chromatin" ], "offsets": [ [ 1046, 1055 ] ], "normalized": [] }, { "id": "PMID-16741925_T22", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 1131, 1139 ] ], "normalized": [] }, { "id": "PMID-16741925_T23", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 1144, 1149 ] ], "normalized": [] }, { "id": "PMID-16741925_T24", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 1189, 1197 ] ], "normalized": [] }, { "id": "PMID-16741925_T25", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 1202, 1207 ] ], "normalized": [] }, { "id": "PMID-16741925_T26", "type": "Gene_or_gene_product", "text": [ "pPuralpha" ], "offsets": [ [ 1215, 1224 ] ], "normalized": [] }, { "id": "PMID-16741925_T27", "type": "Gene_or_gene_product", "text": [ "Tet" ], "offsets": [ [ 1239, 1242 ] ], "normalized": [] }, { "id": "PMID-16741925_T28", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 1264, 1272 ] ], "normalized": [] }, { "id": "PMID-16741925_T29", "type": "Gene_or_gene_product", "text": [ "E2F-1" ], "offsets": [ [ 1311, 1316 ] ], "normalized": [] }, { "id": "PMID-16741925_T30", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 1321, 1329 ] ], "normalized": [] }, { "id": "PMID-16741925_T31", "type": "Gene_or_gene_product", "text": [ "Puralpha" ], "offsets": [ [ 1384, 1392 ] ], "normalized": [] } ]

[ { "id": "PMID-16741925_E1", "type": "Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T1" }, { "role": "Cause", "ref_id": "PMID-16741925_T2" } ] }, { "id": "PMID-16741925_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitously" ], "offsets": [ [ 62, 74 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T3" } ] }, { "id": "PMID-16741925_E3", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 75, 84 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T3" } ] }, { "id": "PMID-16741925_E4", "type": "Positive_regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 138, 146 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_E5" }, { "role": "Cause", "ref_id": "PMID-16741925_T3" } ] }, { "id": "PMID-16741925_E5", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 216, 226 ] ] }, "arguments": [] }, { "id": "PMID-16741925_E6", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 330, 334 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T4" }, { "role": "Theme", "ref_id": "PMID-16741925_T5" } ] }, { "id": "PMID-16741925_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 345, 352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_E8" }, { "role": "Cause", "ref_id": "PMID-16741925_T4" } ] }, { "id": "PMID-16741925_E8", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 359, 374 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T6" } ] }, { "id": "PMID-16741925_E9", "type": "Negative_regulation", "trigger": { "text": [ "reverse" ], "offsets": [ [ 389, 396 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_E10" }, { "role": "Cause", "ref_id": "PMID-16741925_T4" } ] }, { "id": "PMID-16741925_E10", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 401, 408 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_E11" } ] }, { "id": "PMID-16741925_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 426, 436 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T7" } ] }, { "id": "PMID-16741925_E12", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 467, 472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T8" } ] }, { "id": "PMID-16741925_E13", "type": "Regulation", "trigger": { "text": [ "autoregulated" ], "offsets": [ [ 573, 586 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T9" } ] }, { "id": "PMID-16741925_E14", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 644, 651 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16741925_T12" }, { "role": "Theme", "ref_id": "PMID-16741925_T11" } ] }, { "id": "PMID-16741925_E15", "type": "Positive_regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 907, 917 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16741925_T16" }, { "role": "Theme", "ref_id": "PMID-16741925_E16" } ] }, { "id": "PMID-16741925_E16", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 918, 928 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T17" } ] }, { "id": "PMID-16741925_E17", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 950, 959 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_E16" }, { "role": "Cause", "ref_id": "PMID-16741925_E19" } ] }, { "id": "PMID-16741925_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 950, 959 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_E16" }, { "role": "Cause", "ref_id": "PMID-16741925_E20" } ] }, { "id": "PMID-16741925_E19", "type": "Gene_expression", "trigger": { "text": [ "co-expression" ], "offsets": [ [ 963, 976 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T18" } ] }, { "id": "PMID-16741925_E20", "type": "Gene_expression", "trigger": { "text": [ "co-expression" ], "offsets": [ [ 963, 976 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T19" } ] }, { "id": "PMID-16741925_E21", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1028, 1035 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T20" } ] }, { "id": "PMID-16741925_E22", "type": "Negative_regulation", "trigger": { "text": [ "delayed" ], "offsets": [ [ 1273, 1280 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_E23" }, { "role": "Cause", "ref_id": "PMID-16741925_T28" } ] }, { "id": "PMID-16741925_E23", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1281, 1291 ] ] }, "arguments": [] }, { "id": "PMID-16741925_E24", "type": "Positive_regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1354, 1362 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16741925_T30" }, { "role": "Theme", "ref_id": "PMID-16741925_E28" } ] }, { "id": "PMID-16741925_E25", "type": "Positive_regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1354, 1362 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16741925_T29" }, { "role": "Theme", "ref_id": "PMID-16741925_E28" } ] }, { "id": "PMID-16741925_E26", "type": "Positive_regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1354, 1362 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16741925_T29" }, { "role": "Theme", "ref_id": "PMID-16741925_E29" } ] }, { "id": "PMID-16741925_E27", "type": "Positive_regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 1354, 1362 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16741925_T30" }, { "role": "Theme", "ref_id": "PMID-16741925_E29" } ] }, { "id": "PMID-16741925_E28", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1370, 1380 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_E30" } ] }, { "id": "PMID-16741925_E29", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1370, 1380 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_E31" } ] }, { "id": "PMID-16741925_E30", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1393, 1403 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16741925_T31" } ] }, { "id": "PMID-16741925_E31", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1412, 1422 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-16753024__text", "type": "abstract", "text": [ "Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. \nUNLABELLED: Wnt/beta-catenin signaling has been proven to play a central role in bone biology. Unexpectedly, the Wnt antagonist Dkk2 is required for terminal osteoblast differentiation and mineralized matrix formation. We show that Dkk1, unlike Dkk2, negatively regulates osteoblast differentiation and bone formation. INTRODUCTION: The Wnt co-receptor LRP5 is a critical regulator of bone mass. Dickkopf (Dkk) proteins act as natural Wnt antagonists by bridging LRP5/6 and Kremen, inducing the internalization of the complex. Wnt antagonists are thus expected to negatively regulation bone formation. However, Dkk2 deficiency results in increased bone, questioning the precise role of Dkks in bone metabolism. MATERIALS AND METHODS: In this study, we investigated specifically the role of Dkk1 in bone in vitro and in vivo. Using rat primary calvaria cells, we studied the effect of retroviral expression of Dkk1 on osteoblast differentiation. In addition, the effect of Dkk1 osteoblast was studied in MC3T3-E1 cells by means of recombinant protein. Finally, to address the role of Dkk1 in vivo, we analyzed the bone phenotype of Dkk1(+/-) animals. RESULTS: Retroviral expression of Dkk1 in rat primary calvaria cells resulted in a complete inhibition of osteoblast differentiation and formation of mineralized nodules, with a marked decrease in the expression of alkaline phosphatase. Dkk1 expression also increased adipocyte differentiation in these cell cultures. Recombinant murine Dkk1 (rmDkk1) inhibited spontaneous and induced osteoblast differentiation of MC3T3-E1 cells. To determine the role of Dkk1 in vivo and overcome the embryonic lethality of homozygous deletion, we studied the bone phenotype in heterozygous Dkk1-deficient mice. Structural, dynamic, and cellular analysis of bone remodeling in Dkk1(+/-) mice showed an increase in all bone formation parameters, with no change in bone resorption, leading to a marked increase in bone mass. Importantly, the number of osteoblasts, mineral apposition, and bone formation rate were all increased several fold. CONCLUSIONS: We conclude that Dkk1 protein is a potent negative regulator of osteoblasts in vitro and in vivo. Given that a heterozygous decrease in Dkk1 expression is sufficient to induce a significant increase in bone mass, antagonizing Dkk1 should result in a potent anabolic effect.\n" ], "offsets": [ [ 0, 2462 ] ] } ]

[ { "id": "PMID-16753024_T1", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 35, 39 ] ], "normalized": [] }, { "id": "PMID-16753024_T2", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 112, 115 ] ], "normalized": [] }, { "id": "PMID-16753024_T3", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 116, 128 ] ], "normalized": [] }, { "id": "PMID-16753024_T4", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 213, 216 ] ], "normalized": [] }, { "id": "PMID-16753024_T5", "type": "Gene_or_gene_product", "text": [ "Dkk2" ], "offsets": [ [ 228, 232 ] ], "normalized": [] }, { "id": "PMID-16753024_T6", "type": "Cellular_component", "text": [ "matrix" ], "offsets": [ [ 301, 307 ] ], "normalized": [] }, { "id": "PMID-16753024_T7", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 332, 336 ] ], "normalized": [] }, { "id": "PMID-16753024_T8", "type": "Gene_or_gene_product", "text": [ "Dkk2" ], "offsets": [ [ 345, 349 ] ], "normalized": [] }, { "id": "PMID-16753024_T9", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 437, 440 ] ], "normalized": [] }, { "id": "PMID-16753024_T10", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 453, 457 ] ], "normalized": [] }, { "id": "PMID-16753024_T11", "type": "Gene_or_gene_product", "text": [ "Dickkopf" ], "offsets": [ [ 496, 504 ] ], "normalized": [] }, { "id": "PMID-16753024_T12", "type": "Gene_or_gene_product", "text": [ "Dkk" ], "offsets": [ [ 506, 509 ] ], "normalized": [] }, { "id": "PMID-16753024_T13", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 535, 538 ] ], "normalized": [] }, { "id": "PMID-16753024_T14", "type": "Gene_or_gene_product", "text": [ "LRP5" ], "offsets": [ [ 563, 567 ] ], "normalized": [] }, { "id": "PMID-16753024_T15", "type": "Gene_or_gene_product", "text": [ "6" ], "offsets": [ [ 568, 569 ] ], "normalized": [] }, { "id": "PMID-16753024_T16", "type": "Gene_or_gene_product", "text": [ "Kremen" ], "offsets": [ [ 574, 580 ] ], "normalized": [] }, { "id": "PMID-16753024_T17", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 627, 630 ] ], "normalized": [] }, { "id": "PMID-16753024_T18", "type": "Gene_or_gene_product", "text": [ "Dkk2" ], "offsets": [ [ 711, 715 ] ], "normalized": [] }, { "id": "PMID-16753024_T19", "type": "Gene_or_gene_product", "text": [ "Dkks" ], "offsets": [ [ 786, 790 ] ], "normalized": [] }, { "id": "PMID-16753024_T20", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 890, 894 ] ], "normalized": [] }, { "id": "PMID-16753024_T21", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 1009, 1013 ] ], "normalized": [] }, { "id": "PMID-16753024_T22", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 1072, 1076 ] ], "normalized": [] }, { "id": "PMID-16753024_T23", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 1183, 1187 ] ], "normalized": [] }, { "id": "PMID-16753024_T24", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 1231, 1235 ] ], "normalized": [] }, { "id": "PMID-16753024_T25", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 1284, 1288 ] ], "normalized": [] }, { "id": "PMID-16753024_T26", "type": "Gene_or_gene_product", "text": [ "alkaline phosphatase" ], "offsets": [ [ 1465, 1485 ] ], "normalized": [] }, { "id": "PMID-16753024_T27", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 1487, 1491 ] ], "normalized": [] }, { "id": "PMID-16753024_T28", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 1587, 1591 ] ], "normalized": [] }, { "id": "PMID-16753024_T29", "type": "Gene_or_gene_product", "text": [ "rmDkk1" ], "offsets": [ [ 1593, 1599 ] ], "normalized": [] }, { "id": "PMID-16753024_T30", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 1706, 1710 ] ], "normalized": [] }, { "id": "PMID-16753024_T31", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 1826, 1830 ] ], "normalized": [] }, { "id": "PMID-16753024_T32", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 1912, 1916 ] ], "normalized": [] }, { "id": "PMID-16753024_T33", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 2205, 2209 ] ], "normalized": [] }, { "id": "PMID-16753024_T34", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 2324, 2328 ] ], "normalized": [] }, { "id": "PMID-16753024_T35", "type": "Gene_or_gene_product", "text": [ "Dkk1" ], "offsets": [ [ 2414, 2418 ] ], "normalized": [] } ]

[ { "id": "PMID-16753024_E1", "type": "Inactivation", "trigger": { "text": [ "Deletion" ], "offsets": [ [ 0, 8 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16753024_T1" } ] }, { "id": "PMID-16753024_E2", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 129, 138 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-16753024_T2" }, { "role": "Participant", "ref_id": "PMID-16753024_T3" } ] }, { "id": "PMID-16753024_E3", "type": "Negative_regulation", "trigger": { "text": [ "deficiency" ], "offsets": [ [ 716, 726 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16753024_T18" } ] }, { "id": "PMID-16753024_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 995, 1005 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16753024_T21" } ] }, { "id": "PMID-16753024_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1270, 1280 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16753024_T25" } ] }, { "id": "PMID-16753024_E6", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1435, 1443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16753024_E7" } ] }, { "id": "PMID-16753024_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1451, 1461 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16753024_T26" } ] }, { "id": "PMID-16753024_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1492, 1502 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16753024_T27" } ] }, { "id": "PMID-16753024_E9", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 2312, 2320 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16753024_E10" } ] }, { "id": "PMID-16753024_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2329, 2339 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16753024_T34" } ] }, { "id": "PMID-16753024_E11", "type": "Negative_regulation", "trigger": { "text": [ "antagonizing" ], "offsets": [ [ 2401, 2413 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16753024_T35" } ] } ]

[ { "id": "PMID-16753024_1", "entity_ids": [ "PMID-16753024_T11", "PMID-16753024_T12" ] }, { "id": "PMID-16753024_2", "entity_ids": [ "PMID-16753024_T28", "PMID-16753024_T29" ] } ]

[]

[ { "id": "PMID-16785567__text", "type": "abstract", "text": [ "Peptidoglycan-induced IL-6 production in RAW 264.7 macrophages is mediated by cyclooxygenase-2, PGE2/PGE4 receptors, protein kinase A, I kappa B kinase, and NF-kappa B. \nIn this study, we investigated the signaling pathway involved in IL-6 production caused by peptidoglycan (PGN), a cell wall component of the Gram-positive bacterium, Staphylococcus aureus, in RAW 264.7 macrophages. PGN caused concentration- and time-dependent increases in IL-6, PGE(2), and cAMP production. PGN-mediated IL-6 production was inhibited by a nonselective cyclooxygenase (COX) inhibitor (indomethacin), a selective COX-2 inhibitor (NS398), a PGE(2) (EP2) antagonist (AH6809), a PGE(4) (EP4) antagonist (AH23848), and a protein kinase A (PKA) inhibitor (KT5720), but not by a nonselective NO synthase inhibitor (N(G)-nitro-l-arginine methyl ester). Furthermore, PGE(2), an EP2 agonist (butaprost), an EP2/PGE(3) (EP3)/EP4 agonist (misoprostol), and misoprostol in the presence of AH6809 all induced IL-6 production, whereas an EP1/EP3 agonist (sulprostone) did not. PGN caused time-dependent activations of IkappaB kinase alphabeta (IKKdbeta) and p65 phosphorylation at Ser(276), and these effects were inhibited by NS398 and KT5720. Both PGE(2) and 8-bromo-cAMP also caused IKKdbeta kinase alphabeta phosphorylation. PGN resulted in two waves of the formation of NF-kappaB-specific DNA-protein complexes. The first wave of NF-kappaB activation occurred at 10-60 min of treatment, whereas the later wave occurred at 2-12 h of treatment. The PGN-induced increase in kappaB luciferase activity was inhibited by NS398, AH6809, AH23848, KT5720, a protein kinase C inhibitor (Ro31-8220), and a p38 MAPK inhibitor (SB203580). These results suggest that PGN-induced IL-6 production involves COX-2-generated PGE(2), activation of the EP2 and EP4 receptors, cAMP formation, and the activation of PKA, protein kinase C, p38 MAPK, IKKdbeta, kinase alphabeta, p65 phosphorylation, and NF-kappaB. However, PGN-induced NO release is not involved in the signaling pathway of PGN-induced IL-6 production.\n" ], "offsets": [ [ 0, 2071 ] ] } ]

[ { "id": "PMID-16785567_T1", "type": "Simple_chemical", "text": [ "Peptidoglycan" ], "offsets": [ [ 0, 13 ] ], "normalized": [] }, { "id": "PMID-16785567_T2", "type": "Gene_or_gene_product", "text": [ "IL-6" ], "offsets": [ [ 22, 26 ] ], "normalized": [] }, { "id": "PMID-16785567_T3", "type": "Gene_or_gene_product", "text": [ "cyclooxygenase-2" ], "offsets": [ [ 78, 94 ] ], "normalized": [] }, { "id": "PMID-16785567_T4", "type": "Gene_or_gene_product", "text": [ "PGE2" ], "offsets": [ [ 96, 100 ] ], "normalized": [] }, { "id": "PMID-16785567_T5", "type": "Gene_or_gene_product", "text": [ "PGE4 receptors" ], "offsets": [ [ 101, 115 ] ], "normalized": [] }, { "id": "PMID-16785567_T6", "type": "Complex", "text": [ "protein kinase A" ], "offsets": [ [ 117, 133 ] ], "normalized": [] }, { "id": "PMID-16785567_T7", "type": "Complex", "text": [ "I kappa B kinase" ], "offsets": [ [ 135, 151 ] ], "normalized": [] }, { "id": "PMID-16785567_T8", "type": "Complex", "text": [ "NF-kappa B" ], 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[]

[ { "id": "PMID-16861226__text", "type": "abstract", "text": [ "Direct phosphorylation and activation of a Nim1-related kinase Gin4 by Elm1 in budding yeast. \nIn budding yeast, Gin4, a Nim1-related kinase, plays an important role in proper organization of the septin ring at the mother-bud neck, a filamentous structure that is critical for diverse cellular processes including mitotic entry and cytokinesis. How Gin4 kinase activity is regulated is not known. Here we showed that a neck-associated Ser/Thr kinase Elm1, which is important for septin assembly, is critical for proper modification of Gin4 and its physiological substrate Shs1. In vitro studies with purified recombinant proteins demonstrated that Elm1 directly phosphorylates and activates Gin4, which in turn phosphorylates Shs1. Consistent with these observations, acute inhibition of Elm1 activity abolished mitotic Gin4 phosphorylation and Gin4-dependent Shs1 modification in vivo. In addition, a gin4 mutant lacking the Elm1-dependent phosphorylation sites exhibited an impaired localization to the bud-neck and, as a result, induced a significant growth defect with an elongated bud morphology. Thus, Elm1 regulates the septin assembly-dependent cellular events by directly phosphorylating and activating the Gin4-dependent pathway(s).\n" ], "offsets": [ [ 0, 1243 ] ] } ]

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"Positive_regulation", "trigger": { "text": [ "plays an important role" ], "offsets": [ [ 142, 165 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_E6" }, { "role": "Cause", "ref_id": "PMID-16861226_T4" } ] }, { "id": "PMID-16861226_E6", "type": "Binding", "trigger": { "text": [ "organization" ], "offsets": [ [ 176, 188 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_T6" } ] }, { "id": "PMID-16861226_E7", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 373, 382 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_T8" } ] }, { "id": "PMID-16861226_E8", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 424, 434 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16861226_T9" }, { "role": "Theme", "ref_id": "PMID-16861226_T12" } ] }, { "id": "PMID-16861226_E9", "type": "Positive_regulation", "trigger": { "text": [ "important" ], "offsets": [ [ 465, 474 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16861226_T12" }, { "role": "Theme", "ref_id": "PMID-16861226_E10" } ] }, { "id": "PMID-16861226_E10", "type": "Binding", "trigger": { "text": [ "assembly" ], "offsets": [ [ 486, 494 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_T13" } ] }, { "id": "PMID-16861226_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 662, 676 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16861226_T16" }, { "role": "Theme", "ref_id": "PMID-16861226_T17" } ] }, { "id": "PMID-16861226_E12", "type": "Activation", "trigger": { "text": [ "activates" ], "offsets": [ [ 681, 690 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16861226_T16" }, { "role": "Theme", "ref_id": "PMID-16861226_T17" } ] }, { "id": "PMID-16861226_E13", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 711, 725 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_T18" } ] }, { "id": "PMID-16861226_E14", "type": "Positive_regulation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 711, 725 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_E13" }, { "role": "Cause", "ref_id": "PMID-16861226_E12" } ] }, { "id": "PMID-16861226_E15", "type": "Positive_regulation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 711, 725 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_E13" }, { "role": "Cause", "ref_id": "PMID-16861226_E11" } ] }, { "id": "PMID-16861226_E16", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 774, 784 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_T19" } ] }, { "id": "PMID-16861226_E17", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 802, 811 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_E18" }, { "role": "Cause", "ref_id": "PMID-16861226_E16" } ] }, { "id": "PMID-16861226_E18", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 825, 840 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_T20" } ] }, { "id": "PMID-16861226_E19", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 931, 940 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16861226_T24" }, { "role": "Theme", "ref_id": "PMID-16861226_E20" } ] }, { "id": "PMID-16861226_E20", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 941, 956 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_T23" } ] }, { "id": "PMID-16861226_E21", "type": "Negative_regulation", "trigger": { "text": [ "impaired" ], "offsets": [ [ 976, 984 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_E22" } ] }, { "id": "PMID-16861226_E22", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 985, 997 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-16861226_T25" }, { "role": "Theme", "ref_id": "PMID-16861226_T23" } ] }, { "id": "PMID-16861226_E23", "type": "Binding", "trigger": { "text": [ "assembly" ], "offsets": [ [ 1134, 1142 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861226_T28" } ] } ]

[]

[]

[ { "id": "PMID-16959561__text", "type": "abstract", "text": [ "Mind the GAP: Wnt steps onto the mTORC1 train. \nThe TSC1/2 tumor-suppressor complex controls protein synthesis through the regulation of mTOR. In this issue of Cell, Inoki et al. (2006) report that the kinases GSK3 and AMPK cooperate in the activation of TSC2 to inhibit mTOR activity. Surprisingly, the phosphorylation of TSC2 by GSK3 is markedly suppressed by Wnt signaling. This suggests that components of the mTOR pathway may be therapeutic targets for diseases linked to hyperactive Wnt signaling. \n" ], "offsets": [ [ 0, 505 ] ] } ]

[ { "id": "PMID-16959561_T1", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 14, 17 ] ], "normalized": [] }, { "id": "PMID-16959561_T2", "type": "Complex", "text": [ "mTORC1" ], "offsets": [ [ 33, 39 ] ], "normalized": [] }, { "id": "PMID-16959561_T3", "type": "Complex", "text": [ "TSC1/2" ], "offsets": [ [ 52, 58 ] ], "normalized": [] }, { "id": "PMID-16959561_T4", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 137, 141 ] ], "normalized": [] }, { "id": "PMID-16959561_T5", "type": "Gene_or_gene_product", "text": [ "GSK3" ], "offsets": [ [ 210, 214 ] ], "normalized": [] }, { "id": "PMID-16959561_T6", "type": "Gene_or_gene_product", "text": [ "AMPK" ], "offsets": [ [ 219, 223 ] ], "normalized": [] }, { "id": "PMID-16959561_T7", "type": "Gene_or_gene_product", "text": [ "TSC2" ], "offsets": [ [ 255, 259 ] ], "normalized": [] }, { "id": "PMID-16959561_T8", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 271, 275 ] ], "normalized": [] }, { "id": "PMID-16959561_T9", "type": "Gene_or_gene_product", "text": [ "TSC2" ], "offsets": [ [ 323, 327 ] ], "normalized": [] }, { "id": "PMID-16959561_T10", "type": "Gene_or_gene_product", "text": [ "GSK3" ], "offsets": [ [ 331, 335 ] ], "normalized": [] }, { "id": "PMID-16959561_T11", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 362, 365 ] ], "normalized": [] }, { "id": "PMID-16959561_T12", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 414, 418 ] ], "normalized": [] }, { "id": "PMID-16959561_T13", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 489, 492 ] ], "normalized": [] } ]

[ { "id": "PMID-16959561_E1", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 123, 133 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16959561_T4" }, { "role": "Cause", "ref_id": "PMID-16959561_T3" } ] }, { "id": "PMID-16959561_E2", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 241, 251 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16959561_T5" }, { "role": "Theme", "ref_id": "PMID-16959561_T7" } ] }, { "id": "PMID-16959561_E3", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 241, 251 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16959561_T6" }, { "role": "Theme", "ref_id": "PMID-16959561_T7" } ] }, { "id": "PMID-16959561_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 263, 270 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16959561_T8" }, { "role": "Cause", "ref_id": "PMID-16959561_E2" } ] }, { "id": "PMID-16959561_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 263, 270 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-16959561_E3" }, { "role": "Theme", "ref_id": "PMID-16959561_T8" } ] }, { "id": "PMID-16959561_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 304, 319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16959561_T9" }, { "role": "Cause", "ref_id": "PMID-16959561_T10" } ] }, { "id": "PMID-16959561_E7", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 348, 358 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16959561_E6" }, { "role": "Cause", "ref_id": "PMID-16959561_E8" } ] }, { "id": "PMID-16959561_E8", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 366, 375 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-16959561_T11" } ] }, { "id": "PMID-16959561_E9", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 419, 426 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-16959561_T12" } ] }, { "id": "PMID-16959561_E10", "type": "Positive_regulation", "trigger": { "text": [ "hyperactive" ], "offsets": [ [ 477, 488 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16959561_E11" } ] }, { "id": "PMID-16959561_E11", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 493, 502 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-16959561_T13" } ] } ]

[]

[]

[ { "id": "PMID-17122856__text", "type": "abstract", "text": [ "Polo kinase controls cell-cycle-dependent transcription by targeting a coactivator protein. \nPolo kinases have crucial conserved functions in controlling the eukaryotic cell cycle through orchestrating several events during mitosis. An essential element of cell cycle control is exerted by altering the expression of key regulators. Here we show an important function for the polo kinase Cdc5p in controlling cell-cycle-dependent gene expression that is crucial for the execution of mitosis in the model eukaryote Saccharomyces cerevisiae. In particular, we find that Cdc5p is temporally recruited to promoters of the cell-cycle-regulated CLB2 gene cluster, where it targets the Mcm1p-Fkh2p-Ndd1p transcription factor complex, through direct phosphorylation of the coactivator protein Ndd1p. This phosphorylation event is required for the normal temporal expression of cell-cycle-regulated genes such as CLB2 and SWI5 in G2/M phases. Furthermore, severe defects in cell division occur in the absence of Cdc5p-mediated phosphorylation of Ndd1p. Thus, polo kinase is required for the production of key mitotic regulators, in addition to previously defined roles in controlling other mitotic events.\n" ], "offsets": [ [ 0, 1197 ] ] } ]

[ { "id": "PMID-17122856_T1", "type": "Gene_or_gene_product", "text": [ "Polo kinase" ], "offsets": [ [ 0, 11 ] ], "normalized": [] }, { "id": "PMID-17122856_T2", "type": "Gene_or_gene_product", "text": [ "Polo kinases" ], "offsets": [ [ 93, 105 ] ], "normalized": [] }, { "id": "PMID-17122856_T3", "type": "Gene_or_gene_product", "text": [ "polo kinase" ], "offsets": [ [ 376, 387 ] ], "normalized": [] }, { "id": "PMID-17122856_T4", "type": "Gene_or_gene_product", "text": [ "Cdc5p" ], "offsets": [ [ 388, 393 ] ], "normalized": [] }, { "id": "PMID-17122856_T5", "type": "Gene_or_gene_product", "text": [ "Cdc5p" ], "offsets": [ [ 568, 573 ] ], "normalized": [] }, { "id": "PMID-17122856_T6", "type": "Gene_or_gene_product", "text": [ "CLB2" ], "offsets": [ [ 639, 643 ] ], "normalized": [] }, { "id": "PMID-17122856_T7", "type": "Complex", "text": [ "Mcm1p-Fkh2p-Ndd1p" ], "offsets": [ [ 679, 696 ] ], "normalized": [] }, { "id": "PMID-17122856_T8", "type": "Gene_or_gene_product", "text": [ "Ndd1p" ], "offsets": [ [ 785, 790 ] ], "normalized": [] }, { "id": "PMID-17122856_T9", "type": "Gene_or_gene_product", "text": [ "CLB2" ], "offsets": [ [ 904, 908 ] ], "normalized": [] }, { "id": "PMID-17122856_T10", "type": "Gene_or_gene_product", "text": [ "SWI5" ], "offsets": [ [ 913, 917 ] ], "normalized": [] }, { "id": "PMID-17122856_T11", "type": "Gene_or_gene_product", "text": [ "Cdc5p" ], "offsets": [ [ 1003, 1008 ] ], "normalized": [] }, { "id": "PMID-17122856_T12", "type": "Gene_or_gene_product", "text": [ "Ndd1p" ], "offsets": [ [ 1037, 1042 ] ], "normalized": [] }, { "id": "PMID-17122856_T13", "type": "Gene_or_gene_product", "text": [ "polo kinase" ], "offsets": [ [ 1050, 1061 ] ], "normalized": [] } ]

[ { "id": "PMID-17122856_E1", "type": "Pathway", "trigger": { "text": [ "cell-cycle" ], "offsets": [ [ 21, 31 ] ] }, "arguments": [] }, { "id": "PMID-17122856_E2", "type": "Regulation", "trigger": { "text": [ "controlling" ], "offsets": [ [ 142, 153 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17122856_E3" }, { "role": "Cause", "ref_id": "PMID-17122856_T2" } ] }, { "id": "PMID-17122856_E3", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 169, 179 ] ] }, "arguments": [] }, { "id": "PMID-17122856_E4", "type": "Pathway", "trigger": { "text": [ "cell-cycle" ], "offsets": [ [ 409, 419 ] ] }, "arguments": [] }, { "id": "PMID-17122856_E5", "type": "Transport", "trigger": { "text": [ "recruited" ], "offsets": [ [ 588, 597 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17122856_T5" } ] }, { "id": "PMID-17122856_E6", "type": "Pathway", "trigger": { "text": [ "cell-cycle" ], "offsets": [ [ 618, 628 ] ] }, "arguments": [] }, { "id": "PMID-17122856_E7", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 629, 638 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17122856_E6" }, { "role": "Theme", "ref_id": "PMID-17122856_T6" } ] }, { "id": "PMID-17122856_E8", "type": "Regulation", "trigger": { "text": [ "targets" ], "offsets": [ [ 667, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17122856_T7" }, { "role": "Cause", "ref_id": "PMID-17122856_T5" } ] }, { "id": "PMID-17122856_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 742, 757 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17122856_T8" }, { "role": "Cause", "ref_id": "PMID-17122856_T5" } ] }, { "id": "PMID-17122856_E10", "type": "Activation", "trigger": { "text": [ "coactivator" ], "offsets": [ [ 765, 776 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17122856_T8" } ] }, { "id": "PMID-17122856_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 797, 812 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17122856_T8" } ] }, { "id": "PMID-17122856_E12", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 822, 830 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17122856_E11" }, { "role": "Theme", "ref_id": "PMID-17122856_E14" } ] }, { "id": "PMID-17122856_E13", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 822, 830 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17122856_E11" }, { "role": "Theme", "ref_id": "PMID-17122856_E15" } ] }, { "id": "PMID-17122856_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 855, 865 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17122856_T9" } ] }, { "id": "PMID-17122856_E15", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 855, 865 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17122856_T10" } ] }, { "id": "PMID-17122856_E16", "type": "Pathway", "trigger": { "text": [ "cell-cycle" ], "offsets": [ [ 869, 879 ] ] }, "arguments": [] }, { "id": "PMID-17122856_E17", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 880, 889 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17122856_E16" }, { "role": "Theme", "ref_id": "PMID-17122856_T9" } ] }, { "id": "PMID-17122856_E18", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 880, 889 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17122856_E16" }, { "role": "Theme", "ref_id": "PMID-17122856_T10" } ] }, { "id": "PMID-17122856_E19", "type": "Negative_regulation", "trigger": { "text": [ "absence" ], "offsets": [ [ 992, 999 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17122856_E21" } ] }, { "id": "PMID-17122856_E20", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1009, 1017 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17122856_E21" }, { "role": "Cause", "ref_id": "PMID-17122856_T11" } ] }, { "id": "PMID-17122856_E21", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1018, 1033 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17122856_T12" } ] } ]

[]

[]

[ { "id": "PMID-1717476__text", "type": "abstract", "text": [ "Human cyclins A and B1 are differentially located in the cell and undergo cell cycle-dependent nuclear transport. \nWe have used immunofluorescence staining to study the subcellular distribution of cyclin A and B1 during the somatic cell cycle. In both primary human fibroblasts and in epithelial tumor cells, we find that cyclin A is predominantly nuclear from S phase onwards. Cyclin A may associated with condensing chromosomes in prophase, but is not associated with condensed chromosomes in metaphase. By contrast, cyclin B1 accumulates in the cytoplasm of interphase cells and only enters the nucleus at the beginning of mitosis, before nuclear lamina breakdown. In mitotic cells, cyclin B1 associates with condensed chromosomes in prophase and metaphase, and with the mitotic apparatus. Cyclin A is degraded during metaphase and cyclin B1 is precipitously destroyed at the metaphase----anaphase transition. Cell fractionation and immunoprecipitation studies showed that both cyclin A and cyclin B1 are associated with PSTAIRE-containing proteins. The nuclear, but not the cytoplasmic form, of cyclin A is associated with a 33-kD PSTAIRE-containing protein. Cyclin B1 is associated with p34cdc2 in the cytoplasm. Thus we propose that the different localization of cyclin A and cyclin B1 in the cell cycle could be the means by which the two types of mitotic cyclin confer substrate specificity upon their associated PSTAIRE-containing protein kinase subunit.\n" ], "offsets": [ [ 0, 1464 ] ] } ]

[ { "id": "PMID-1717476_T1", "type": "Gene_or_gene_product", "text": [ "cyclins A" ], "offsets": [ [ 6, 15 ] ], "normalized": [] }, { "id": "PMID-1717476_T2", "type": "Gene_or_gene_product", "text": [ "B1" ], "offsets": [ [ 20, 22 ] ], "normalized": [] }, { "id": "PMID-1717476_T3", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 95, 102 ] ], "normalized": [] }, { "id": "PMID-1717476_T4", "type": "Cellular_component", "text": [ "subcellular" ], "offsets": [ [ 169, 180 ] ], "normalized": [] }, { "id": "PMID-1717476_T5", "type": "Gene_or_gene_product", "text": [ "cyclin A" ], "offsets": [ [ 197, 205 ] ], "normalized": [] }, { "id": "PMID-1717476_T6", "type": "Gene_or_gene_product", "text": [ "B1" ], "offsets": [ [ 210, 212 ] ], "normalized": [] }, { "id": "PMID-1717476_T7", "type": "Gene_or_gene_product", "text": [ "cyclin A" ], "offsets": [ [ 322, 330 ] ], "normalized": [] }, { "id": "PMID-1717476_T8", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 348, 355 ] ], "normalized": [] }, { "id": "PMID-1717476_T9", "type": "Gene_or_gene_product", "text": [ "Cyclin A" ], "offsets": [ [ 378, 386 ] ], "normalized": [] }, { "id": "PMID-1717476_T10", "type": "Cellular_component", "text": [ "chromosomes" ], "offsets": [ [ 418, 429 ] ], "normalized": [] }, { "id": "PMID-1717476_T11", "type": "Cellular_component", "text": [ "chromosomes" ], "offsets": [ [ 480, 491 ] ], "normalized": [] }, { "id": "PMID-1717476_T12", "type": "Gene_or_gene_product", "text": [ "cyclin B1" ], "offsets": [ [ 519, 528 ] ], "normalized": [] }, { "id": "PMID-1717476_T13", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 548, 557 ] ], "normalized": [] }, { "id": "PMID-1717476_T14", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 598, 605 ] ], "normalized": [] }, { "id": "PMID-1717476_T15", "type": "Cellular_component", "text": [ "nuclear lamina" ], "offsets": [ [ 642, 656 ] ], "normalized": [] }, { "id": "PMID-1717476_T16", "type": "Gene_or_gene_product", "text": [ "cyclin B1" ], "offsets": [ [ 686, 695 ] ], "normalized": [] }, { "id": "PMID-1717476_T17", "type": "Cellular_component", "text": [ "chromosomes" ], "offsets": [ [ 722, 733 ] ], "normalized": [] }, { "id": "PMID-1717476_T18", "type": "Cellular_component", "text": [ "mitotic apparatus" ], "offsets": [ [ 774, 791 ] ], "normalized": [] }, { "id": "PMID-1717476_T19", "type": "Gene_or_gene_product", "text": [ "Cyclin A" ], "offsets": [ [ 793, 801 ] ], "normalized": [] }, { "id": "PMID-1717476_T20", "type": "Gene_or_gene_product", "text": [ "cyclin B1" ], "offsets": [ [ 835, 844 ] ], "normalized": [] }, { "id": "PMID-1717476_T21", "type": "Gene_or_gene_product", "text": [ "cyclin A" ], "offsets": [ [ 981, 989 ] ], "normalized": [] }, { "id": "PMID-1717476_T22", "type": "Gene_or_gene_product", "text": [ "cyclin B1" ], "offsets": [ [ 994, 1003 ] ], "normalized": [] }, { "id": "PMID-1717476_T23", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1057, 1064 ] ], "normalized": [] }, { "id": "PMID-1717476_T24", "type": "Cellular_component", "text": [ "cytoplasmic" ], "offsets": [ [ 1078, 1089 ] ], "normalized": [] }, { "id": "PMID-1717476_T25", "type": "Gene_or_gene_product", "text": [ "cyclin A" ], "offsets": [ [ 1099, 1107 ] ], "normalized": [] }, { "id": "PMID-1717476_T26", "type": "Gene_or_gene_product", "text": [ "Cyclin B1" ], "offsets": [ [ 1163, 1172 ] ], "normalized": [] }, { "id": "PMID-1717476_T27", "type": "Gene_or_gene_product", "text": [ "p34cdc2" ], "offsets": [ [ 1192, 1199 ] ], "normalized": [] }, { "id": "PMID-1717476_T28", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 1207, 1216 ] ], "normalized": [] }, { "id": "PMID-1717476_T29", "type": "Gene_or_gene_product", "text": [ "cyclin A" ], "offsets": [ [ 1269, 1277 ] ], "normalized": [] }, { "id": "PMID-1717476_T30", "type": "Gene_or_gene_product", "text": [ "cyclin B1" ], "offsets": [ [ 1282, 1291 ] ], "normalized": [] }, { "id": "PMID-1717476_T31", "type": "Gene_or_gene_product", "text": [ "cyclin" ], "offsets": [ [ 1363, 1369 ] ], "normalized": [] } ]

[ { "id": "PMID-1717476_E1", "type": "Localization", "trigger": { "text": [ "located" ], "offsets": [ [ 42, 49 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1717476_T1" } ] }, { "id": "PMID-1717476_E2", "type": "Localization", "trigger": { "text": [ "located" ], "offsets": [ [ 42, 49 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1717476_T2" } ] }, { "id": "PMID-1717476_E3", "type": "Pathway", "trigger": { "text": [ "cell cycle-" ], "offsets": [ [ 74, 85 ] ] }, "arguments": [] }, { "id": "PMID-1717476_E4", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 85, 94 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1717476_E3" }, { "role": "Theme", "ref_id": "PMID-1717476_E6" } ] }, { "id": "PMID-1717476_E5", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 85, 94 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1717476_E3" }, { "role": "Theme", "ref_id": "PMID-1717476_E7" } ] }, { "id": "PMID-1717476_E6", "type": "Transport", "trigger": { "text": [ "transport" ], "offsets": [ [ 103, 112 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-1717476_T3" }, { "role": "Theme", "ref_id": "PMID-1717476_T1" } ] }, { "id": "PMID-1717476_E7", "type": "Transport", "trigger": { "text": [ "transport" ], "offsets": [ [ 103, 112 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-1717476_T3" }, { "role": "Theme", "ref_id": "PMID-1717476_T2" } ] }, { "id": "PMID-1717476_E8", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 391, 401 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1717476_T9" }, { "role": "Theme", "ref_id": "PMID-1717476_T10" } ] }, { "id": "PMID-1717476_E9", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 454, 464 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1717476_T9" }, { "role": "Theme", "ref_id": "PMID-1717476_T11" } ] }, { "id": "PMID-1717476_E10", "type": "Positive_regulation", "trigger": { "text": [ "accumulates" ], "offsets": [ [ 529, 540 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1717476_T12" }, { "role": "Theme", "ref_id": "PMID-1717476_T13" } ] }, { "id": "PMID-1717476_E11", "type": "Regulation", "trigger": { "text": [ "associates" ], "offsets": [ [ 696, 706 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1717476_T16" }, { "role": "Theme", "ref_id": "PMID-1717476_T17" } ] }, { "id": "PMID-1717476_E12", "type": "Regulation", "trigger": { "text": [ "associates" ], "offsets": [ [ 696, 706 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1717476_T16" }, { "role": "Theme", "ref_id": "PMID-1717476_T18" } ] }, { "id": "PMID-1717476_E13", "type": "Negative_regulation", "trigger": { "text": [ "degraded" ], "offsets": [ [ 805, 813 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1717476_T19" } ] }, { "id": "PMID-1717476_E14", "type": "Degradation", "trigger": { "text": [ "destroyed" ], "offsets": [ [ 862, 871 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1717476_T20" } ] }, { "id": "PMID-1717476_E15", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 1176, 1186 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1717476_T26" }, { "role": "Theme", "ref_id": "PMID-1717476_T27" } ] }, { "id": "PMID-1717476_E16", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 1253, 1265 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1717476_T29" } ] }, { "id": "PMID-1717476_E17", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 1253, 1265 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1717476_T30" } ] }, { "id": "PMID-1717476_E18", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1299, 1309 ] ] }, "arguments": [] } ]

[]

[]

[ { "id": "PMID-17189191__text", "type": "abstract", "text": [ "The checkpoint clamp activates Mec1 kinase during initiation of the DNA damage checkpoint. \nYeast Mec1/Ddc2 protein kinase, the ortholog of human ATR/ATRIP, plays a central role in the DNA damage checkpoint. The PCNA-like clamp Rad17/Mec3/Ddc1 (the 9-1-1 complex in human) and its loader Rad24-RFC are also essential components of this signal transduction pathway. Here we have studied the role of the clamp in regulating Mec1, and we delineate how the signal generated by DNA lesions is transduced to the Rad53 effector kinase. The checkpoint clamp greatly activates the kinase activity of Mec1, but only if the clamp is appropriately loaded upon partial duplex DNA. Activated Mec1 phosphorylates the Ddc1 and Mec3 subunits of the clamp, the Rad24 subunit of the loader, and the Rpa1 and Rpa2 subunits of RPA. Phosphorylation of Rad53, and of human PHAS-1, a nonspecific target, also requires a properly loaded clamp. Phosphorylation and binding studies with individual clamp subunits indicate that the Ddc1 subunit mediates the functional interactions with Mec1.\n" ], "offsets": [ [ 0, 1065 ] ] } ]

[ { "id": "PMID-17189191_T1", "type": "Gene_or_gene_product", "text": [ "Mec1" ], "offsets": [ [ 31, 35 ] ], "normalized": [] }, { "id": "PMID-17189191_T2", "type": "Complex", "text": [ "Mec1/Ddc2" ], "offsets": [ [ 98, 107 ] ], "normalized": [] }, { "id": "PMID-17189191_T3", "type": "Complex", "text": [ "ATR/ATRIP" ], "offsets": [ [ 146, 155 ] ], "normalized": [] }, { "id": "PMID-17189191_T4", "type": "Complex", "text": [ "Rad17/Mec3/Ddc1" ], "offsets": [ [ 228, 243 ] ], "normalized": [] }, { "id": "PMID-17189191_T5", "type": "Complex", "text": [ "9-1-1" ], "offsets": [ [ 249, 254 ] ], "normalized": [] }, { "id": "PMID-17189191_T6", "type": "Complex", "text": [ "Rad24-RFC" ], "offsets": [ [ 288, 297 ] ], "normalized": [] }, { "id": "PMID-17189191_T7", "type": "Gene_or_gene_product", "text": [ "Mec1" ], "offsets": [ [ 422, 426 ] ], "normalized": [] }, { "id": "PMID-17189191_T8", "type": "Gene_or_gene_product", "text": [ "Rad53" ], "offsets": [ [ 506, 511 ] ], "normalized": [] }, { "id": "PMID-17189191_T9", "type": "Gene_or_gene_product", "text": [ "Mec1" ], "offsets": [ [ 591, 595 ] ], "normalized": [] }, { "id": "PMID-17189191_T10", "type": "Gene_or_gene_product", "text": [ "Mec1" ], "offsets": [ [ 678, 682 ] ], "normalized": [] }, { "id": "PMID-17189191_T11", "type": "Gene_or_gene_product", "text": [ "Ddc1" ], "offsets": [ [ 702, 706 ] ], "normalized": [] }, { "id": "PMID-17189191_T12", "type": "Gene_or_gene_product", "text": [ "Mec3" ], "offsets": [ [ 711, 715 ] ], "normalized": [] }, { "id": "PMID-17189191_T13", "type": "Gene_or_gene_product", "text": [ "Rad24" ], "offsets": [ [ 743, 748 ] ], "normalized": [] }, { "id": "PMID-17189191_T14", "type": "Gene_or_gene_product", "text": [ "Rpa1" ], "offsets": [ [ 780, 784 ] ], "normalized": [] }, { "id": "PMID-17189191_T15", "type": "Gene_or_gene_product", "text": [ "Rpa2" ], "offsets": [ [ 789, 793 ] ], "normalized": [] }, { "id": "PMID-17189191_T16", "type": "Complex", "text": [ "RPA" ], "offsets": [ [ 806, 809 ] ], "normalized": [] }, { "id": "PMID-17189191_T17", "type": "Gene_or_gene_product", "text": [ "Rad53" ], "offsets": [ [ 830, 835 ] ], "normalized": [] }, { "id": "PMID-17189191_T18", "type": "Gene_or_gene_product", "text": [ "PHAS-1" ], "offsets": [ [ 850, 856 ] ], "normalized": [] }, { "id": "PMID-17189191_T19", "type": "Gene_or_gene_product", "text": [ "Ddc1" ], "offsets": [ [ 1004, 1008 ] ], "normalized": [] }, { "id": "PMID-17189191_T20", "type": "Gene_or_gene_product", "text": [ "Mec1" ], "offsets": [ [ 1059, 1063 ] ], "normalized": [] } ]

[ { "id": "PMID-17189191_E1", "type": "Activation", "trigger": { "text": [ "activates" ], "offsets": [ [ 21, 30 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189191_T1" } ] }, { "id": "PMID-17189191_E2", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 411, 421 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189191_T7" } ] }, { "id": "PMID-17189191_E3", "type": "Positive_regulation", "trigger": { "text": [ "transduced" ], "offsets": [ [ 488, 498 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189191_T8" } ] }, { "id": "PMID-17189191_E4", "type": "Activation", "trigger": { "text": [ "activates" ], "offsets": [ [ 558, 567 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189191_T9" } ] }, { "id": "PMID-17189191_E5", "type": "Activation", "trigger": { "text": [ "Activated" ], "offsets": [ [ 668, 677 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189191_T10" } ] }, { "id": "PMID-17189191_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 683, 697 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17189191_T10" }, { "role": "Theme", "ref_id": "PMID-17189191_T11" } ] }, { "id": "PMID-17189191_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 683, 697 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17189191_T10" }, { "role": "Theme", "ref_id": "PMID-17189191_T12" } ] }, { "id": "PMID-17189191_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 683, 697 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17189191_T10" }, { "role": "Theme", "ref_id": "PMID-17189191_T13" } ] }, { "id": "PMID-17189191_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 683, 697 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17189191_T10" }, { "role": "Theme", "ref_id": "PMID-17189191_T14" } ] }, { "id": "PMID-17189191_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 683, 697 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17189191_T10" }, { "role": "Theme", "ref_id": "PMID-17189191_T15" } ] }, { "id": "PMID-17189191_E11", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 811, 826 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189191_T17" } ] }, { "id": "PMID-17189191_E12", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 811, 826 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189191_T18" } ] }, { "id": "PMID-17189191_E13", "type": "Positive_regulation", "trigger": { "text": [ "mediates" ], "offsets": [ [ 1017, 1025 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17189191_T19" }, { "role": "Theme", "ref_id": "PMID-17189191_E14" } ] }, { "id": "PMID-17189191_E14", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 1041, 1053 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189191_T20" }, { "role": "Theme", "ref_id": "PMID-17189191_T19" } ] } ]

[]

[]

[ { "id": "PMID-17234339__text", "type": "abstract", "text": [ "Suppression of p53-activated gene, PAG608, attenuates methamphetamine-induced neurotoxicity. \nThe p53-activated gene 608 (PAG608) is a proapoptotic gene activated and regulated by p53 expression in oxidative stress-induced apoptosis of neuronal cells. In this study, we determined the role of PAG608 in methamphetamine-induced neurotoxicity. Treatment of mouse dopaminergic CATH.a cells with 2 mM methamphetamine increased PAG608 expression at 3h followed by increase in phosphorylated p53 expression. Transient transfection of PAG608 antisense cDNA or RNA interference using PAG608 small interfering RNA significantly attenuated the dose-dependent decrease in cell viability of CATH.a cells by methamphetamine (1-4 mM) exposure. In monoaminergic neuronal B65 cells, which contain serotonin rather than dopamine, methamphetamine-induced cell death was also significantly but partially protected by transient transfection of PAG608 antisense cDNA. Furthermore, cell death of PC12 cells produced by methamphetamine (1-5 mM) was almost completely prevented by stable expression of PAG608 antisense cDNA, compared with significant reduction of cell viability in control PC12 cells. Our results showed that suppression of PAG608 using transient and stable transfection with PAG608 antisense cDNA or small interfering RNA attenuates methamphetamine-induced death of various monoaminergic neuronal cells, suggesting that methamphetamine neurotoxicity in monoaminergic cells is related, at least in part, to induction of PAG608 expression.\n" ], "offsets": [ [ 0, 1532 ] ] } ]

[ { "id": "PMID-17234339_T1", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 15, 18 ] ], "normalized": [] }, { "id": "PMID-17234339_T2", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 35, 41 ] ], "normalized": [] }, { "id": "PMID-17234339_T3", "type": "Simple_chemical", "text": [ "methamphetamine" ], "offsets": [ [ 54, 69 ] ], "normalized": [] }, { "id": "PMID-17234339_T4", "type": "Gene_or_gene_product", "text": [ "p53-activated gene 608" ], "offsets": [ [ 98, 120 ] ], "normalized": [] }, { "id": "PMID-17234339_T5", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 122, 128 ] ], "normalized": [] }, { "id": "PMID-17234339_T6", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 180, 183 ] ], "normalized": [] }, { "id": "PMID-17234339_T7", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 293, 299 ] ], "normalized": [] }, { "id": "PMID-17234339_T8", "type": "Simple_chemical", "text": [ "methamphetamine" ], "offsets": [ [ 303, 318 ] ], "normalized": [] }, { "id": "PMID-17234339_T9", "type": "Simple_chemical", "text": [ "methamphetamine" ], "offsets": [ [ 397, 412 ] ], "normalized": [] }, { "id": "PMID-17234339_T10", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 423, 429 ] ], "normalized": [] }, { "id": "PMID-17234339_T11", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 486, 489 ] ], "normalized": [] }, { "id": "PMID-17234339_T12", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 528, 534 ] ], "normalized": [] }, { "id": "PMID-17234339_T13", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 576, 582 ] ], "normalized": [] }, { "id": "PMID-17234339_T14", "type": "Simple_chemical", "text": [ "methamphetamine" ], "offsets": [ [ 695, 710 ] ], "normalized": [] }, { "id": "PMID-17234339_T15", "type": "Simple_chemical", "text": [ "serotonin" ], "offsets": [ [ 781, 790 ] ], "normalized": [] }, { "id": "PMID-17234339_T16", "type": "Simple_chemical", "text": [ "dopamine" ], "offsets": [ [ 803, 811 ] ], "normalized": [] }, { "id": "PMID-17234339_T17", "type": "Simple_chemical", "text": [ "methamphetamine" ], "offsets": [ [ 813, 828 ] ], "normalized": [] }, { "id": "PMID-17234339_T18", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 924, 930 ] ], "normalized": [] }, { "id": "PMID-17234339_T19", "type": "Simple_chemical", "text": [ "methamphetamine" ], "offsets": [ [ 997, 1012 ] ], "normalized": [] }, { "id": "PMID-17234339_T20", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 1078, 1084 ] ], "normalized": [] }, { "id": "PMID-17234339_T21", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 1217, 1223 ] ], "normalized": [] }, { "id": "PMID-17234339_T22", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 1269, 1275 ] ], "normalized": [] }, { "id": "PMID-17234339_T23", "type": "Simple_chemical", "text": [ "methamphetamine" ], "offsets": [ [ 1327, 1342 ] ], "normalized": [] }, { "id": "PMID-17234339_T24", "type": "Simple_chemical", "text": [ "methamphetamine" ], "offsets": [ [ 1414, 1429 ] ], "normalized": [] }, { "id": "PMID-17234339_T25", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 1513, 1519 ] ], "normalized": [] } ]

[ { "id": "PMID-17234339_E1", "type": "Negative_regulation", "trigger": { "text": [ "Suppression" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_T2" } ] }, { "id": "PMID-17234339_E2", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 19, 28 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17234339_T1" }, { "role": "Theme", "ref_id": "PMID-17234339_T2" } ] }, { "id": "PMID-17234339_E3", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 153, 162 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_T4" }, { "role": "Cause", "ref_id": "PMID-17234339_E5" } ] }, { "id": "PMID-17234339_E4", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 167, 176 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_T4" }, { "role": "Cause", "ref_id": "PMID-17234339_E5" } ] }, { "id": "PMID-17234339_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 184, 194 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_T6" } ] }, { "id": "PMID-17234339_E6", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 215, 222 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_E7" } ] }, { "id": "PMID-17234339_E7", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 223, 232 ] ] }, "arguments": [] }, { "id": "PMID-17234339_E8", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 413, 422 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_E9" }, { "role": "Cause", "ref_id": "PMID-17234339_T9" } ] }, { "id": "PMID-17234339_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 430, 440 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_T10" } ] }, { "id": "PMID-17234339_E10", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 459, 467 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_E12" } ] }, { "id": "PMID-17234339_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 471, 485 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_T11" } ] }, { "id": "PMID-17234339_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 490, 500 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_T11" } ] }, { "id": "PMID-17234339_E13", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 829, 836 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17234339_T17" }, { "role": "Theme", "ref_id": "PMID-17234339_E14" } ] }, { "id": "PMID-17234339_E14", "type": "Pathway", "trigger": { "text": [ "cell death" ], "offsets": [ [ 837, 847 ] ] }, "arguments": [] }, { "id": "PMID-17234339_E15", "type": "Negative_regulation", "trigger": { "text": [ "protected" ], "offsets": [ [ 885, 894 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_E14" } ] }, { "id": "PMID-17234339_E16", "type": "Pathway", "trigger": { "text": [ "cell death" ], "offsets": [ [ 960, 970 ] ] }, "arguments": [] }, { "id": "PMID-17234339_E17", "type": "Positive_regulation", "trigger": { "text": [ "produced" ], "offsets": [ [ 985, 993 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_E16" }, { "role": "Cause", "ref_id": "PMID-17234339_T19" } ] }, { "id": "PMID-17234339_E18", "type": "Negative_regulation", "trigger": { "text": [ "prevented" ], "offsets": [ [ 1044, 1053 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_E16" } ] }, { "id": "PMID-17234339_E19", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 1202, 1213 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_T21" } ] }, { "id": "PMID-17234339_E20", "type": "Negative_regulation", "trigger": { "text": [ "attenuates" ], "offsets": [ [ 1316, 1326 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_E22" } ] }, { "id": "PMID-17234339_E21", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1343, 1350 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17234339_T23" }, { "role": "Theme", "ref_id": "PMID-17234339_E22" } ] }, { "id": "PMID-17234339_E22", "type": "Pathway", "trigger": { "text": [ "death" ], "offsets": [ [ 1351, 1356 ] ] }, "arguments": [] }, { "id": "PMID-17234339_E23", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1500, 1509 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_E24" } ] }, { "id": "PMID-17234339_E24", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1520, 1530 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17234339_T25" } ] } ]

[ { "id": "PMID-17234339_1", "entity_ids": [ "PMID-17234339_T4", "PMID-17234339_T5" ] } ]

[]

[ { "id": "PMID-17254967__text", "type": "abstract", "text": [ "p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2. \nThe kinase inhibitor p27Kip1 regulates the G1 cell cycle phase. Here, we present data indicating that the oncogenic kinase Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Src inhibitors increase cellular p27 stability, and Src overexpression accelerates p27 proteolysis. Src-phosphorylated p27 is shown to inhibit cyclin E-Cdk2 poorly in vitro, and Src transfection reduces p27-cyclin E-Cdk2 complexes. Our data indicate that phosphorylation by Src impairs the Cdk2 inhibitory action of p27 and reduces its steady-state binding to cyclin E-Cdk2 to facilitate cyclin E-Cdk2-dependent p27 proteolysis. Furthermore, we find that Src-activated breast cancer lines show reduced p27 and observe a correlation between Src activation and reduced nuclear p27 in 482 primary human breast cancers. Importantly, we report that in tamoxifen-resistant breast cancer cell lines, Src inhibition can increase p27 levels and restore tamoxifen sensitivity. These data provide a new rationale for Src inhibitors in cancer therapy. \n" ], "offsets": [ [ 0, 1122 ] ] } ]

[ { "id": "PMID-17254967_T1", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-17254967_T2", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 23, 26 ] ], "normalized": [] }, { "id": "PMID-17254967_T3", "type": "Complex", "text": [ "cyclin E-Cdk2" ], "offsets": [ [ 51, 64 ] ], "normalized": [] }, { "id": "PMID-17254967_T4", "type": "Gene_or_gene_product", "text": [ "p27Kip1" ], "offsets": [ [ 88, 95 ] ], "normalized": [] }, { "id": "PMID-17254967_T5", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 190, 193 ] ], "normalized": [] }, { "id": "PMID-17254967_T6", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 204, 207 ] ], "normalized": [] }, { "id": "PMID-17254967_T7", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 245, 248 ] ], "normalized": [] }, { "id": "PMID-17254967_T8", "type": "Simple_chemical", "text": [ "tyrosine 74" ], "offsets": [ [ 252, 263 ] ], "normalized": [] }, { "id": "PMID-17254967_T9", "type": "Simple_chemical", "text": [ "tyrosine 88" ], "offsets": [ [ 268, 279 ] ], "normalized": [] }, { "id": "PMID-17254967_T10", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 281, 284 ] ], "normalized": [] }, { "id": "PMID-17254967_T11", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 314, 317 ] ], "normalized": [] }, { "id": "PMID-17254967_T12", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 333, 336 ] ], "normalized": [] }, { "id": "PMID-17254967_T13", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 364, 367 ] ], "normalized": [] }, { "id": "PMID-17254967_T14", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 381, 384 ] ], "normalized": [] }, { "id": "PMID-17254967_T15", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 400, 403 ] ], "normalized": [] }, { "id": "PMID-17254967_T16", "type": "Complex", "text": [ "cyclin E-Cdk2" ], "offsets": [ [ 424, 437 ] ], "normalized": [] }, { "id": "PMID-17254967_T17", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 459, 462 ] ], "normalized": [] }, { "id": "PMID-17254967_T18", "type": "Complex", "text": [ "p27-cyclin E-Cdk2" ], "offsets": [ [ 484, 501 ] ], "normalized": [] }, { "id": "PMID-17254967_T19", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 555, 558 ] ], "normalized": [] }, { "id": "PMID-17254967_T20", "type": "Gene_or_gene_product", "text": [ "Cdk2" ], "offsets": [ [ 571, 575 ] ], "normalized": [] }, { "id": "PMID-17254967_T21", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 597, 600 ] ], "normalized": [] }, { "id": "PMID-17254967_T22", "type": "Complex", "text": [ "cyclin E-Cdk2" ], "offsets": [ [ 641, 654 ] ], "normalized": [] }, { "id": "PMID-17254967_T23", "type": "Complex", "text": [ "cyclin E-Cdk2" ], "offsets": [ [ 669, 682 ] ], "normalized": [] }, { "id": "PMID-17254967_T24", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 693, 696 ] ], "normalized": [] }, { "id": "PMID-17254967_T25", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 736, 739 ] ], "normalized": [] }, { "id": "PMID-17254967_T26", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 783, 786 ] ], "normalized": [] }, { "id": "PMID-17254967_T27", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 821, 824 ] ], "normalized": [] }, { "id": "PMID-17254967_T28", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 848, 855 ] ], "normalized": [] }, { "id": "PMID-17254967_T29", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 856, 859 ] ], "normalized": [] }, { "id": "PMID-17254967_T30", "type": "Simple_chemical", "text": [ "tamoxifen" ], "offsets": [ [ 928, 937 ] ], "normalized": [] }, { "id": "PMID-17254967_T31", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 974, 977 ] ], "normalized": [] }, { "id": "PMID-17254967_T32", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 1002, 1005 ] ], "normalized": [] }, { "id": "PMID-17254967_T33", "type": "Simple_chemical", "text": [ "tamoxifen" ], "offsets": [ [ 1025, 1034 ] ], "normalized": [] }, { "id": "PMID-17254967_T34", "type": "Gene_or_gene_product", "text": [ "Src" ], "offsets": [ [ 1087, 1090 ] ], "normalized": [] } ]

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cycle" ], "offsets": [ [ 113, 123 ] ] }, "arguments": [] }, { "id": "PMID-17254967_E6", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 194, 203 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T6" }, { "role": "Cause", "ref_id": "PMID-17254967_E8" } ] }, { "id": "PMID-17254967_E7", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 194, 203 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T6" }, { "role": "Cause", "ref_id": "PMID-17254967_E9" } ] }, { "id": "PMID-17254967_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 226, 241 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-17254967_T8" }, { "role": "Theme", "ref_id": "PMID-17254967_T7" }, { "role": "Cause", "ref_id": "PMID-17254967_T5" } ] }, { "id": "PMID-17254967_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 226, 241 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-17254967_T9" }, { "role": "Theme", "ref_id": "PMID-17254967_T7" }, { "role": "Cause", "ref_id": "PMID-17254967_T5" } ] }, { "id": "PMID-17254967_E10", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 296, 304 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T11" } ] }, { "id": "PMID-17254967_E11", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 337, 351 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T12" } ] }, { "id": "PMID-17254967_E12", "type": "Positive_regulation", "trigger": { "text": [ "accelerates" ], "offsets": [ [ 352, 363 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_E13" }, { "role": "Cause", "ref_id": "PMID-17254967_E11" } ] }, { "id": "PMID-17254967_E13", "type": "Degradation", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 368, 379 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T13" } ] }, { "id": "PMID-17254967_E14", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 385, 399 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T15" }, { "role": "Cause", "ref_id": "PMID-17254967_T14" } ] }, { "id": "PMID-17254967_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 416, 423 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17254967_T15" }, { "role": "Theme", "ref_id": "PMID-17254967_T16" } ] }, { "id": "PMID-17254967_E16", "type": "Negative_regulation", "trigger": { "text": [ "reduces" ], "offsets": [ [ 476, 483 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17254967_T17" }, { "role": "Theme", "ref_id": "PMID-17254967_T18" } ] }, { "id": "PMID-17254967_E17", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 536, 551 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T21" }, { "role": "Cause", "ref_id": "PMID-17254967_T19" } ] }, { "id": "PMID-17254967_E18", "type": "Negative_regulation", "trigger": { "text": [ "impairs" ], "offsets": [ [ 559, 566 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_E19" }, { "role": "Cause", "ref_id": "PMID-17254967_E17" } ] }, { "id": "PMID-17254967_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 576, 586 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T20" }, { "role": "Cause", "ref_id": "PMID-17254967_T21" } ] }, { "id": "PMID-17254967_E20", "type": "Negative_regulation", "trigger": { "text": [ "reduces" ], "offsets": [ [ 605, 612 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17254967_E17" }, { "role": "Theme", "ref_id": "PMID-17254967_E21" } ] }, { "id": "PMID-17254967_E21", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 630, 637 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T21" }, { "role": "Theme", "ref_id": "PMID-17254967_T22" } ] }, { 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825, 835 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T27" } ] }, { "id": "PMID-17254967_E27", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 840, 847 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T29" } ] }, { "id": "PMID-17254967_E28", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 978, 988 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17254967_T31" } ] }, { "id": "PMID-17254967_E29", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 993, 1001 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17254967_E28" }, { "role": "Theme", "ref_id": "PMID-17254967_T32" } ] } ]

[]

[]

[ { "id": "PMID-17277771__text", "type": "abstract", "text": [ "Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. \nInsulin stimulates protein synthesis and cell growth by activation of the protein kinases Akt (also known as protein kinase B, PKB) and mammalian target of rapamycin (mTOR). It was reported that Akt activates mTOR by phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2). However, in recent studies the physiological requirement of Akt phosphorylation of TSC2 for mTOR activation has been questioned. Here, we identify PRAS40 (proline-rich Akt/PKB substrate 40 kDa) as a novel mTOR binding partner that mediates Akt signals to mTOR. PRAS40 binds the mTOR kinase domain and its interaction with mTOR is induced under conditions that inhibit mTOR signalling, such as nutrient or serum deprivation or mitochondrial metabolic inhibition. Binding of PRAS40 inhibits mTOR activity and suppresses constitutive activation of mTOR in cells lacking TSC2. PRAS40 silencing inactivates insulin-receptor substrate-1 (IRS-1) and Akt, and uncouples the response of mTOR to Akt signals. Furthermore, PRAS40 phosphorylation by Akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mTOR. These findings identify PRAS40 as an important regulator of insulin sensitivity of the Akt-mTOR pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes. \n" ], "offsets": [ [ 0, 1402 ] ] } ]

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[ 179, 195 ] ], "normalized": [] }, { "id": "PMID-17277771_T9", "type": "Gene_or_gene_product", "text": [ "PKB" ], "offsets": [ [ 197, 200 ] ], "normalized": [] }, { "id": "PMID-17277771_T10", "type": "Gene_or_gene_product", "text": [ "mammalian target of rapamycin" ], "offsets": [ [ 206, 235 ] ], "normalized": [] }, { "id": "PMID-17277771_T11", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 237, 241 ] ], "normalized": [] }, { "id": "PMID-17277771_T12", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 265, 268 ] ], "normalized": [] }, { "id": "PMID-17277771_T13", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 279, 283 ] ], "normalized": [] }, { "id": "PMID-17277771_T14", "type": "Gene_or_gene_product", "text": [ "tuberous sclerosis complex 2" ], "offsets": [ [ 321, 349 ] ], "normalized": [] }, { "id": "PMID-17277771_T15", "type": "Gene_or_gene_product", "text": [ "TSC2" ], "offsets": [ [ 351, 355 ] ], "normalized": [] }, { "id": "PMID-17277771_T16", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 418, 421 ] ], "normalized": [] }, { "id": "PMID-17277771_T17", "type": "Gene_or_gene_product", "text": [ "TSC2" ], "offsets": [ [ 441, 445 ] ], "normalized": [] }, { "id": "PMID-17277771_T18", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 450, 454 ] ], "normalized": [] }, { "id": "PMID-17277771_T19", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 505, 511 ] ], "normalized": [] }, { "id": "PMID-17277771_T20", "type": "Gene_or_gene_product", "text": [ "proline-rich Akt/PKB substrate 40 kDa" ], "offsets": [ [ 513, 550 ] ], "normalized": [] }, { "id": "PMID-17277771_T21", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 563, 567 ] ], "normalized": [] }, { "id": "PMID-17277771_T22", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 598, 601 ] ], "normalized": [] }, { "id": "PMID-17277771_T23", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 613, 617 ] ], "normalized": [] }, { "id": "PMID-17277771_T24", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 619, 625 ] ], "normalized": [] }, { "id": "PMID-17277771_T25", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 636, 640 ] ], "normalized": [] }, { "id": "PMID-17277771_T26", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 680, 684 ] ], "normalized": [] }, { "id": "PMID-17277771_T27", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 726, 730 ] ], "normalized": [] }, { "id": "PMID-17277771_T28", "type": "Cellular_component", "text": [ "mitochondrial" ], "offsets": [ [ 784, 797 ] ], "normalized": [] }, { "id": "PMID-17277771_T29", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 831, 837 ] ], "normalized": [] }, { "id": "PMID-17277771_T30", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 847, 851 ] ], "normalized": [] }, { "id": "PMID-17277771_T31", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 903, 907 ] ], "normalized": [] }, { "id": "PMID-17277771_T32", "type": "Gene_or_gene_product", "text": [ "TSC2" ], "offsets": [ [ 925, 929 ] ], "normalized": [] }, { "id": "PMID-17277771_T33", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 931, 937 ] ], "normalized": [] }, { "id": "PMID-17277771_T34", "type": "Gene_or_gene_product", "text": [ "insulin-receptor substrate-1" ], "offsets": [ [ 960, 988 ] ], "normalized": [] }, { "id": "PMID-17277771_T35", "type": "Gene_or_gene_product", "text": [ "IRS-1" ], "offsets": [ [ 990, 995 ] ], "normalized": [] }, { "id": "PMID-17277771_T36", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1001, 1004 ] ], "normalized": [] }, { "id": "PMID-17277771_T37", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1036, 1040 ] ], "normalized": [] }, { "id": "PMID-17277771_T38", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1044, 1047 ] ], "normalized": [] }, { "id": "PMID-17277771_T39", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 1070, 1076 ] ], "normalized": [] }, { "id": "PMID-17277771_T40", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1096, 1099 ] ], "normalized": [] }, { "id": "PMID-17277771_T41", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 1121, 1127 ] ], "normalized": [] }, { "id": "PMID-17277771_T42", "type": "Cellular_component", "text": [ "cytosolic" ], "offsets": [ [ 1131, 1140 ] ], "normalized": [] }, { "id": "PMID-17277771_T43", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 1173, 1180 ] ], "normalized": [] }, { "id": "PMID-17277771_T44", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1194, 1198 ] ], "normalized": [] }, { "id": "PMID-17277771_T45", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 1224, 1230 ] ], "normalized": [] }, { "id": "PMID-17277771_T46", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 1260, 1267 ] ], "normalized": [] }, { "id": "PMID-17277771_T47", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1287, 1290 ] ], "normalized": [] }, { "id": "PMID-17277771_T48", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1291, 1295 ] ], "normalized": [] }, { "id": "PMID-17277771_T49", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 1357, 1364 ] ], "normalized": [] } ]

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], "offsets": [ [ 688, 695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17277771_E16" } ] }, { "id": "PMID-17277771_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 718, 725 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17277771_E19" } ] }, { "id": "PMID-17277771_E19", "type": "Pathway", "trigger": { "text": [ "signalling" ], "offsets": [ [ 731, 741 ] ] }, "arguments": [] }, { "id": "PMID-17277771_E20", "type": "Binding", "trigger": { "text": [ "Binding" ], "offsets": [ [ 820, 827 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17277771_T29" }, { "role": "Theme", "ref_id": "PMID-17277771_T30" } ] }, { "id": "PMID-17277771_E21", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 838, 846 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17277771_E20" }, { "role": "Theme", "ref_id": "PMID-17277771_T30" } ] }, { "id": "PMID-17277771_E22", "type": "Negative_regulation", "trigger": 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"PMID-17277771_T34" } ] }, { "id": "PMID-17277771_E27", "type": "Inactivation", "trigger": { "text": [ "inactivates" ], "offsets": [ [ 948, 959 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17277771_E25" }, { "role": "Theme", "ref_id": "PMID-17277771_T36" } ] }, { "id": "PMID-17277771_E28", "type": "Negative_regulation", "trigger": { "text": [ "uncouples" ], "offsets": [ [ 1010, 1019 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17277771_E29" }, { "role": "Cause", "ref_id": "PMID-17277771_E25" } ] }, { "id": "PMID-17277771_E29", "type": "Regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 1024, 1032 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17277771_T37" }, { "role": "Cause", "ref_id": "PMID-17277771_E30" } ] }, { "id": "PMID-17277771_E30", "type": "Pathway", "trigger": { "text": [ "signals" ], "offsets": [ [ 1048, 1055 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17277771_T38" } ] }, { "id": "PMID-17277771_E31", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1077, 1092 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17277771_T39" }, { "role": "Cause", "ref_id": "PMID-17277771_T40" } ] }, { "id": "PMID-17277771_E32", "type": "Binding", "trigger": { "text": [ "association" ], "offsets": [ [ 1104, 1115 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17277771_T39" }, { "role": "Theme", "ref_id": "PMID-17277771_T41" } ] }, { "id": "PMID-17277771_E33", "type": "Positive_regulation", "trigger": { "text": [ "crucial" ], "offsets": [ [ 1161, 1168 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17277771_E31" }, { "role": "Theme", "ref_id": "PMID-17277771_E35" } ] }, { "id": "PMID-17277771_E34", "type": "Positive_regulation", "trigger": { "text": [ "crucial" ], "offsets": [ [ 1161, 1168 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17277771_E32" }, { "role": "Theme", "ref_id": "PMID-17277771_E35" } ] }, { "id": "PMID-17277771_E35", "type": "Positive_regulation", "trigger": { "text": [ "stimulate" ], "offsets": [ [ 1184, 1193 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17277771_T44" }, { "role": "Cause", "ref_id": "PMID-17277771_T43" } ] }, { "id": "PMID-17277771_E36", "type": "Regulation", "trigger": { "text": [ "regulator" ], "offsets": [ [ 1247, 1256 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17277771_T45" }, { "role": "Theme", "ref_id": "PMID-17277771_E37" } ] }, { "id": "PMID-17277771_E37", "type": "Regulation", "trigger": { "text": [ "sensitivity" ], "offsets": [ [ 1268, 1279 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17277771_E38" }, { "role": "Cause", "ref_id": "PMID-17277771_T46" } ] }, { "id": "PMID-17277771_E38", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1296, 1303 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17277771_T47" }, { "role": "Participant", "ref_id": "PMID-17277771_T48" } ] } ]

[ { "id": "PMID-17277771_1", "entity_ids": [ "PMID-17277771_T3", "PMID-17277771_T4" ] }, { "id": "PMID-17277771_2", "entity_ids": [ "PMID-17277771_T7", "PMID-17277771_T8", "PMID-17277771_T9" ] }, { "id": "PMID-17277771_3", "entity_ids": [ "PMID-17277771_T10", "PMID-17277771_T11" ] }, { "id": "PMID-17277771_4", "entity_ids": [ "PMID-17277771_T14", "PMID-17277771_T15" ] }, { "id": "PMID-17277771_5", "entity_ids": [ "PMID-17277771_T19", "PMID-17277771_T20" ] }, { "id": "PMID-17277771_6", "entity_ids": [ "PMID-17277771_T34", "PMID-17277771_T35" ] } ]

[]

[ { "id": "PMID-1730413__text", "type": "abstract", "text": [ "Parallel pathways of gene regulation: homologous regulators SWI5 and ACE2 differentially control transcription of HO and chitinase. \nTwo independent pathways of transcriptional regulation that show functional homology have been identified in yeast. It has been demonstrated previously that SWI5 encodes a zinc finger DNA-binding protein whose transcription and cellular localization both are cell cycle regulated. We show that ACE2, whose zinc finger region is nearly identical to that of SWI5, shows patterns of cell cycle-regulated transcription and nuclear localization similar to those seen previously for SWI5. Despite their similarities, SWI5 and ACE2 function in separate pathways of transcriptional regulation. SWI5 is a transcriptional activator of the HO endonuclease gene, whereas ACE2 is not. In contrast, ACE2 is a transcriptional activator of the CTS1 gene (which encodes chitinase), whereas SWI5 is not. An additional parallel between the SWI5/HO pathway and the ACE2/CTS1 pathway is that HO and CTS1 both are cell cycle regulated in the same way, and HO and CTS1 both require the SWI4 and SWI6 transcriptional activators. Overproduction of either SWI5 or ACE2 permits transcriptional activation of the target gene from the other pathway, suggesting that the DNA-binding proteins are capable of binding in vivo to promoters that they do not usually activate. Chimeric SWI5/ACE2 protein fusion experiments suggest that promoter specificity resides in a domain distinct from the zinc finger domain.\n" ], "offsets": [ [ 0, 1512 ] ] } ]

[ { "id": "PMID-1730413_T1", "type": "Gene_or_gene_product", "text": [ "SWI5" ], "offsets": [ [ 60, 64 ] ], "normalized": [] }, { "id": "PMID-1730413_T2", "type": "Gene_or_gene_product", "text": [ "ACE2" ], "offsets": [ [ 69, 73 ] ], "normalized": [] }, { "id": "PMID-1730413_T3", "type": "Gene_or_gene_product", "text": [ "HO" ], "offsets": [ [ 114, 116 ] ], "normalized": [] }, { "id": "PMID-1730413_T4", "type": "Gene_or_gene_product", "text": [ "chitinase" ], "offsets": [ [ 121, 130 ] ], "normalized": [] }, { "id": "PMID-1730413_T5", "type": "Gene_or_gene_product", "text": [ "SWI5" ], "offsets": [ [ 290, 294 ] ], "normalized": [] }, { "id": "PMID-1730413_T6", "type": "Simple_chemical", "text": [ "zinc" ], "offsets": [ [ 305, 309 ] ], "normalized": [] }, { "id": "PMID-1730413_T7", "type": "Gene_or_gene_product", "text": [ "ACE2" ], "offsets": [ [ 427, 431 ] ], "normalized": [] }, { "id": "PMID-1730413_T8", "type": "Simple_chemical", "text": [ "zinc" ], "offsets": [ [ 439, 443 ] ], "normalized": [] }, { "id": "PMID-1730413_T9", "type": "Gene_or_gene_product", "text": [ "SWI5" ], "offsets": [ [ 489, 493 ] ], "normalized": [] }, { "id": "PMID-1730413_T10", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 552, 559 ] ], "normalized": [] }, { "id": "PMID-1730413_T11", "type": "Gene_or_gene_product", "text": [ "SWI5" ], "offsets": [ [ 610, 614 ] ], "normalized": [] }, { "id": "PMID-1730413_T12", "type": "Gene_or_gene_product", "text": [ "SWI5" ], "offsets": [ [ 644, 648 ] ], "normalized": [] }, { "id": "PMID-1730413_T13", "type": "Gene_or_gene_product", "text": [ "ACE2" ], "offsets": [ [ 653, 657 ] ], "normalized": [] }, { "id": "PMID-1730413_T14", "type": "Gene_or_gene_product", "text": [ "SWI5" ], "offsets": [ [ 719, 723 ] ], "normalized": [] }, { "id": "PMID-1730413_T15", "type": "Gene_or_gene_product", "text": [ "HO" ], "offsets": [ [ 762, 764 ] ], "normalized": [] }, { "id": "PMID-1730413_T16", "type": "Gene_or_gene_product", "text": [ "ACE2" ], "offsets": [ [ 792, 796 ] ], "normalized": [] }, { "id": "PMID-1730413_T17", "type": "Gene_or_gene_product", "text": [ "ACE2" ], "offsets": [ [ 818, 822 ] ], "normalized": [] }, { "id": "PMID-1730413_T18", "type": "Gene_or_gene_product", "text": [ "CTS1" ], "offsets": [ [ 861, 865 ] ], "normalized": [] }, { "id": "PMID-1730413_T19", "type": "Gene_or_gene_product", "text": [ "chitinase" ], "offsets": [ [ 886, 895 ] ], "normalized": [] }, { "id": "PMID-1730413_T20", "type": "Gene_or_gene_product", "text": [ "SWI5" ], "offsets": [ [ 906, 910 ] ], "normalized": [] }, { "id": "PMID-1730413_T21", "type": "Gene_or_gene_product", "text": [ "SWI5" ], "offsets": [ [ 954, 958 ] ], "normalized": [] }, { "id": "PMID-1730413_T22", "type": "Gene_or_gene_product", "text": [ "HO" ], "offsets": [ [ 959, 961 ] ], "normalized": [] }, { "id": "PMID-1730413_T23", "type": "Gene_or_gene_product", "text": [ "ACE2" ], "offsets": [ [ 978, 982 ] ], "normalized": [] }, { "id": "PMID-1730413_T24", "type": "Gene_or_gene_product", "text": [ "CTS1" ], "offsets": [ [ 983, 987 ] ], "normalized": [] }, { "id": "PMID-1730413_T25", "type": "Gene_or_gene_product", "text": [ "HO" ], "offsets": [ [ 1004, 1006 ] ], "normalized": [] }, { "id": "PMID-1730413_T26", "type": "Gene_or_gene_product", "text": [ "CTS1" ], "offsets": [ [ 1011, 1015 ] ], "normalized": [] }, { "id": "PMID-1730413_T27", "type": "Gene_or_gene_product", "text": [ "HO" ], "offsets": [ [ 1067, 1069 ] ], "normalized": [] }, { "id": "PMID-1730413_T28", "type": "Gene_or_gene_product", "text": [ "CTS1" ], "offsets": [ [ 1074, 1078 ] ], "normalized": [] }, { "id": "PMID-1730413_T29", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 1096, 1100 ] ], "normalized": [] }, { "id": "PMID-1730413_T30", "type": "Gene_or_gene_product", "text": [ "SWI6" ], "offsets": [ [ 1105, 1109 ] ], "normalized": [] }, { "id": "PMID-1730413_T31", "type": "Gene_or_gene_product", "text": [ "SWI5" ], "offsets": [ [ 1163, 1167 ] ], "normalized": [] }, { "id": "PMID-1730413_T32", "type": "Gene_or_gene_product", "text": [ "ACE2" ], "offsets": [ [ 1171, 1175 ] ], "normalized": [] }, { "id": "PMID-1730413_T33", "type": "Gene_or_gene_product", "text": [ "SWI5/ACE2" ], "offsets": [ [ 1383, 1392 ] ], "normalized": [] }, { "id": "PMID-1730413_T34", "type": "Simple_chemical", "text": [ "zinc" ], "offsets": [ [ 1492, 1496 ] ], "normalized": [] } ]

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"ref_id": "PMID-1730413_E9" }, { "role": "Theme", "ref_id": "PMID-1730413_E7" } ] }, { "id": "PMID-1730413_E11", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 403, 412 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1730413_E9" }, { "role": "Theme", "ref_id": "PMID-1730413_E8" } ] }, { "id": "PMID-1730413_E12", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 513, 523 ] ] }, "arguments": [] }, { "id": "PMID-1730413_E13", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 560, 572 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-1730413_T10" }, { "role": "Theme", "ref_id": "PMID-1730413_T7" } ] }, { "id": "PMID-1730413_E14", "type": "Activation", "trigger": { "text": [ "activator" ], "offsets": [ [ 745, 754 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1730413_T15" }, { "role": "Cause", "ref_id": "PMID-1730413_T14" } ] }, { "id": "PMID-1730413_E15", "type": "Activation", "trigger": { "text": [ "activator" ], "offsets": [ [ 745, 754 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1730413_T15" }, { "role": "Cause", "ref_id": "PMID-1730413_T16" } ] }, { "id": "PMID-1730413_E16", "type": "Activation", "trigger": { "text": [ "activator" ], "offsets": [ [ 844, 853 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1730413_T18" }, { "role": "Cause", "ref_id": "PMID-1730413_T17" } ] }, { "id": "PMID-1730413_E17", "type": "Activation", "trigger": { "text": [ "activator" ], "offsets": [ [ 844, 853 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1730413_T18" }, { "role": "Cause", "ref_id": "PMID-1730413_T20" } ] }, { "id": "PMID-1730413_E18", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 962, 969 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-1730413_T21" }, { "role": "Participant", "ref_id": "PMID-1730413_T22" } ] }, { "id": "PMID-1730413_E19", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 988, 995 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-1730413_T23" }, { "role": "Participant", "ref_id": "PMID-1730413_T24" } ] }, { "id": "PMID-1730413_E20", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1025, 1035 ] ] }, "arguments": [] }, { "id": "PMID-1730413_E21", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1036, 1045 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1730413_E20" }, { "role": "Theme", "ref_id": "PMID-1730413_T25" } ] }, { "id": "PMID-1730413_E22", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1036, 1045 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-1730413_E20" }, { "role": "Theme", "ref_id": "PMID-1730413_T26" } ] }, { "id": "PMID-1730413_E23", "type": "Positive_regulation", "trigger": { "text": [ "require" ], "offsets": [ [ 1084, 1091 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1730413_T27" }, { "role": "Cause", "ref_id": "PMID-1730413_T29" } ] }, { "id": "PMID-1730413_E24", "type": "Positive_regulation", "trigger": { "text": [ "require" ], "offsets": [ [ 1084, 1091 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1730413_T28" }, { "role": "Cause", "ref_id": "PMID-1730413_T29" } ] }, { "id": "PMID-1730413_E25", "type": "Positive_regulation", "trigger": { "text": [ "require" ], "offsets": [ [ 1084, 1091 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1730413_T27" }, { "role": "Cause", "ref_id": "PMID-1730413_T30" } ] }, { "id": "PMID-1730413_E26", "type": "Positive_regulation", "trigger": { "text": [ "require" ], "offsets": [ [ 1084, 1091 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1730413_T28" }, { "role": "Cause", "ref_id": "PMID-1730413_T30" } ] }, { "id": "PMID-1730413_E27", "type": "Gene_expression", "trigger": { "text": [ "Overproduction" ], "offsets": [ [ 1138, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1730413_T31" } ] }, { "id": "PMID-1730413_E28", "type": "Gene_expression", "trigger": { "text": [ "Overproduction" ], "offsets": [ [ 1138, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1730413_T32" } ] } ]

[]

[]

[ { "id": "PMID-17332736__text", "type": "abstract", "text": [ "Phosphoinositide 3-kinase is required for high glucose-induced hypertrophy and p21WAF1 expression in LLC-PK1 cells. \nTransforming growth factor-beta (TGF-beta), Smads, and the cyclin-dependent kinase (cdk) inhibitor p21(WAF1) are important in the pathogenesis of diabetic tubular hypertrophy. Phosphoinositide 3 kinase (PI3K)/Akt kinase activity is increased in diabetic glomerular hypertrophy. Thus, we studied the role of PI3K in high glucose (30 mM)-induced p21(WAF1), Smad2/3, and cell cycle-dependent hypertrophy in LLC-PK1 cells. We found that high glucose time-dependently (1-48 h) increased PI3K/Akt kinase activity. LY294002 (a PI3K inhibitor) attenuated high glucose-induced cell cycle-dependent (G(0)/G(1) phase) hypertrophy at 72 h while attenuating high glucose-induced p21(WAF1) gene transcription and protein expression at 36-48 h. LY294002 also attenuated high glucose-induced binding of p21(WAF1) to the cyclin E/cdk2 complex, whereas attenuating high glucose-induced TGF-beta bioactivity, Smad2/3 phosphorylation, and Smad2/3 DNA-binding activity at 36-48 h. We concluded that PI3K is required for high glucose-induced cell cycle-dependent hypertrophy, p21(WAF1) transcription and expression, p21(WAF1) binding to the cyclin E/cdk2 complex, TGF-beta bioactivity, and Smad2/3 activity in LLC-PK1 cells.\n" ], "offsets": [ [ 0, 1320 ] ] } ]

[ { "id": "PMID-17332736_T1", "type": "Gene_or_gene_product", "text": [ "Phosphoinositide 3-kinase" ], "offsets": [ [ 0, 25 ] ], "normalized": [] }, { "id": "PMID-17332736_T2", "type": "Simple_chemical", "text": [ "glucose" ], "offsets": [ [ 47, 54 ] ], "normalized": [] }, { "id": "PMID-17332736_T3", "type": "Gene_or_gene_product", "text": [ "p21WAF1" ], "offsets": [ [ 79, 86 ] ], "normalized": [] }, { "id": "PMID-17332736_T4", "type": "Gene_or_gene_product", "text": [ "Transforming growth factor-beta" ], "offsets": [ [ 117, 148 ] ], "normalized": [] }, { "id": "PMID-17332736_T5", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 150, 158 ] ], "normalized": [] }, { "id": "PMID-17332736_T6", "type": "Gene_or_gene_product", "text": [ "Smads" ], "offsets": [ [ 161, 166 ] ], "normalized": [] }, { "id": "PMID-17332736_T7", "type": "Gene_or_gene_product", "text": [ "cyclin-dependent kinase" ], "offsets": [ [ 176, 199 ] ], "normalized": [] }, { "id": "PMID-17332736_T8", 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[ { "id": "PMID-17346240__text", "type": "abstract", "text": [ "Nutrient-responsive mTOR signalling grows on Sterile ground. \nThe control of cell growth, that is cell size, is largely controlled by mTOR (the mammalian target of rapamycin), a large serine/threonine protein kinase that regulates ribosome biogenesis and protein translation. mTOR activity is regulated both by the availability of growth factors, such as insulin/IGF-1 (insulin-like growth factor 1), and by nutrients, notably the supply of certain key amino acids. The last few years have seen a remarkable increase in our understanding of the canonical, growth factor-regulated pathway for mTOR activation, which is mediated by the class I PI3Ks (phosphoinositide 3-kinases), PKB (protein kinase B), TSC1/2 (the tuberous sclerosis complex) and the small GTPase, Rheb. However, the nutrient-responsive input into mTOR is important in its own right and is also required for maximal activation of mTOR signalling by growth factors. Despite this, the details of the nutrient-responsive signalling pathway(s) controlling mTOR have remained elusive, although recent studies have suggested a role for the class III PI3K hVps34. In this issue of the Biochemical Journal, Findlay et al. demonstrate that the protein kinase MAP4K3 [mitogen-activated protein kinase kinase kinase kinase-3, a Ste20 family protein kinase also known as GLK (germinal centre-like kinase)] is a new component of the nutrient-responsive pathway. MAP4K3 activity is stimulated by administration of amino acids, but not growth factors, and this is insensitive to rapamycin, most likely placing MAP4K3 upstream of mTOR. Indeed, MAP4K3 is required for phosphorylation of known mTOR targets such as S6K1 (S6 kinase 1), and overexpression of MAP4K3 promotes the rapamycin-sensitive phosphorylation of these same targets. Finally, knockdown of MAP4K3 levels causes a decrease in cell size. The results suggest that MAP4K3 is a new component in the nutrient-responsive pathway for mTOR activation and reveal a completely new function for MAP4K3 in promoting cell growth. Given that mTOR activity is frequently deregulated in cancer, there is much interest in new strategies for inhibition of this pathway. In this context, MAP4K3 looks like an attractive drug target since inhibitors of this enzyme should switch off mTOR, thereby inhibiting cell growth and proliferation, and promoting apoptosis.\n" ], "offsets": [ [ 0, 2359 ] ] } ]

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"Gene_or_gene_product", "text": [ "IGF-1" ], "offsets": [ [ 363, 368 ] ], "normalized": [] }, { "id": "PMID-17346240_T9", "type": "Gene_or_gene_product", "text": [ "insulin-like growth factor 1" ], "offsets": [ [ 370, 398 ] ], "normalized": [] }, { "id": "PMID-17346240_T10", "type": "Gene_or_gene_product", "text": [ "growth factor" ], "offsets": [ [ 556, 569 ] ], "normalized": [] }, { "id": "PMID-17346240_T11", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 592, 596 ] ], "normalized": [] }, { "id": "PMID-17346240_T12", "type": "Gene_or_gene_product", "text": [ "class I PI3Ks" ], "offsets": [ [ 634, 647 ] ], "normalized": [] }, { "id": "PMID-17346240_T13", "type": "Gene_or_gene_product", "text": [ "phosphoinositide 3-kinases" ], "offsets": [ [ 649, 675 ] ], "normalized": [] }, { "id": "PMID-17346240_T14", "type": "Gene_or_gene_product", "text": [ "PKB" ], "offsets": [ [ 678, 681 ] ], "normalized": [] }, { "id": "PMID-17346240_T15", "type": "Gene_or_gene_product", "text": [ "protein kinase B" ], "offsets": [ [ 683, 699 ] ], "normalized": [] }, { "id": "PMID-17346240_T16", "type": "Complex", "text": [ "TSC1" ], "offsets": [ [ 702, 706 ] ], "normalized": [] }, { "id": "PMID-17346240_T17", "type": "Complex", "text": [ "tuberous sclerosis complex" ], "offsets": [ [ 714, 740 ] ], "normalized": [] }, { "id": "PMID-17346240_T18", "type": "Gene_or_gene_product", "text": [ "GTPase" ], "offsets": [ [ 756, 762 ] ], "normalized": [] }, { "id": "PMID-17346240_T19", "type": "Gene_or_gene_product", "text": [ "Rheb" ], "offsets": [ [ 764, 768 ] ], "normalized": [] }, { "id": "PMID-17346240_T20", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 814, 818 ] ], "normalized": [] }, { "id": "PMID-17346240_T21", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 896, 900 ] ], "normalized": [] }, { "id": "PMID-17346240_T22", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1018, 1022 ] ], "normalized": [] }, { "id": "PMID-17346240_T23", "type": "Gene_or_gene_product", "text": [ "class III PI3K" ], "offsets": [ [ 1100, 1114 ] ], "normalized": [] }, { "id": "PMID-17346240_T24", "type": "Gene_or_gene_product", "text": [ "hVps34" ], "offsets": [ [ 1115, 1121 ] ], "normalized": [] }, { "id": "PMID-17346240_T25", "type": "Gene_or_gene_product", "text": [ "MAP4K3" ], "offsets": [ [ 1216, 1222 ] ], "normalized": [] }, { "id": "PMID-17346240_T26", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein kinase kinase kinase kinase-3" ], "offsets": [ [ 1224, 1279 ] ], "normalized": [] }, { "id": "PMID-17346240_T27", "type": "Gene_or_gene_product", "text": [ "Ste20" ], "offsets": [ [ 1283, 1288 ] ], "normalized": [] }, { "id": "PMID-17346240_T28", "type": "Gene_or_gene_product", "text": [ "GLK" ], "offsets": [ [ 1325, 1328 ] ], "normalized": [] }, { "id": "PMID-17346240_T29", "type": "Gene_or_gene_product", "text": [ "germinal centre-like kinase" ], "offsets": [ [ 1330, 1357 ] ], "normalized": [] }, { "id": "PMID-17346240_T30", "type": "Gene_or_gene_product", "text": [ "MAP4K3" ], "offsets": [ [ 1415, 1421 ] ], "normalized": [] }, { "id": "PMID-17346240_T31", "type": "Simple_chemical", "text": [ "rapamycin" ], "offsets": [ [ 1530, 1539 ] ], "normalized": [] }, { "id": "PMID-17346240_T32", "type": "Gene_or_gene_product", "text": [ "MAP4K3" ], "offsets": [ [ 1561, 1567 ] ], "normalized": [] }, { "id": "PMID-17346240_T33", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1580, 1584 ] ], "normalized": [] }, { "id": "PMID-17346240_T34", "type": "Gene_or_gene_product", "text": [ "MAP4K3" ], "offsets": [ [ 1594, 1600 ] ], "normalized": [] }, { "id": "PMID-17346240_T35", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1642, 1646 ] ], "normalized": [] }, { "id": "PMID-17346240_T36", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 1663, 1667 ] ], "normalized": [] }, { "id": "PMID-17346240_T37", "type": "Gene_or_gene_product", "text": [ "S6 kinase 1" ], "offsets": [ [ 1669, 1680 ] ], "normalized": [] }, { "id": "PMID-17346240_T38", "type": "Gene_or_gene_product", "text": [ "MAP4K3" ], "offsets": [ [ 1705, 1711 ] ], "normalized": [] }, { "id": "PMID-17346240_T39", "type": "Simple_chemical", "text": [ "rapamycin" ], "offsets": [ [ 1725, 1734 ] ], "normalized": [] }, { "id": "PMID-17346240_T40", "type": "Gene_or_gene_product", "text": [ "MAP4K3" ], "offsets": [ [ 1806, 1812 ] ], "normalized": [] }, { "id": "PMID-17346240_T41", "type": "Gene_or_gene_product", "text": [ "MAP4K3" ], "offsets": [ [ 1877, 1883 ] ], "normalized": [] }, { "id": "PMID-17346240_T42", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1942, 1946 ] ], "normalized": [] }, { "id": "PMID-17346240_T43", "type": "Gene_or_gene_product", "text": [ "MAP4K3" ], "offsets": [ [ 1999, 2005 ] ], "normalized": [] }, { "id": "PMID-17346240_T44", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 2043, 2047 ] ], "normalized": [] }, { "id": "PMID-17346240_T45", "type": "Gene_or_gene_product", "text": [ "MAP4K3" ], "offsets": [ [ 2184, 2190 ] ], "normalized": [] }, { "id": "PMID-17346240_T46", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 2278, 2282 ] ], "normalized": [] } ]

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pathway" ], "offsets": [ [ 570, 587 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17346240_T10" } ] }, { "id": "PMID-17346240_E6", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 597, 607 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_T11" }, { "role": "Cause", "ref_id": "PMID-17346240_E5" } ] }, { "id": "PMID-17346240_E7", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 618, 626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_E6" }, { "role": "Cause", "ref_id": "PMID-17346240_T12" } ] }, { "id": "PMID-17346240_E8", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 618, 626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_E6" }, { "role": "Cause", "ref_id": "PMID-17346240_T14" } ] }, { "id": "PMID-17346240_E9", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 618, 626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_E6" }, { "role": "Cause", "ref_id": "PMID-17346240_T16" } ] }, { "id": "PMID-17346240_E10", "type": "Regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 618, 626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_E6" }, { "role": "Cause", "ref_id": "PMID-17346240_T19" } ] }, { "id": "PMID-17346240_E11", "type": "Positive_regulation", "trigger": { "text": [ "responsive" ], "offsets": [ [ 792, 802 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_E12" } ] }, { "id": "PMID-17346240_E12", "type": "Regulation", "trigger": { "text": [ "input" ], "offsets": [ [ 803, 808 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_T20" } ] }, { "id": "PMID-17346240_E13", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 861, 869 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_E14" }, { "role": "Cause", "ref_id": "PMID-17346240_E12" } ] }, { "id": "PMID-17346240_E14", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 882, 892 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_T21" } ] }, { "id": "PMID-17346240_E15", "type": "Pathway", "trigger": { "text": [ "signalling" ], "offsets": [ [ 901, 911 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17346240_T21" } ] }, { "id": "PMID-17346240_E16", "type": "Regulation", "trigger": { "text": [ "controlling" ], "offsets": [ [ 1006, 1017 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_T22" } ] }, { "id": "PMID-17346240_E17", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1087, 1091 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17346240_T23" }, { "role": "Theme", "ref_id": "PMID-17346240_T22" } ] }, { "id": "PMID-17346240_E18", "type": "Activation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1434, 1444 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_T30" } ] }, { "id": "PMID-17346240_E19", "type": "Activation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1434, 1444 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_T30" } ] }, { "id": "PMID-17346240_E20", "type": "Activation", "trigger": { "text": [ "insensitive" ], "offsets": [ [ 1515, 1526 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17346240_T31" }, { "role": "Theme", "ref_id": "PMID-17346240_T30" } ] }, { "id": "PMID-17346240_E21", "type": "Regulation", "trigger": { "text": [ "upstream" ], "offsets": [ [ 1568, 1576 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17346240_T32" }, { "role": "Theme", "ref_id": "PMID-17346240_T33" } ] }, { "id": "PMID-17346240_E22", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1617, 1632 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17346240_T34" }, { "role": "Theme", "ref_id": "PMID-17346240_T36" } ] }, { "id": "PMID-17346240_E23", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1687, 1701 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_T38" } ] }, { "id": "PMID-17346240_E24", "type": "Positive_regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 1712, 1720 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17346240_E23" }, { "role": "Theme", "ref_id": "PMID-17346240_E26" } ] }, { "id": "PMID-17346240_E25", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 1735, 1744 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17346240_T39" }, { "role": "Theme", "ref_id": "PMID-17346240_E26" } ] }, { "id": "PMID-17346240_E26", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1745, 1760 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_T36" } ] }, { "id": "PMID-17346240_E27", "type": "Pathway", "trigger": { "text": [ "nutrient-responsive pathway" ], "offsets": [ [ 1910, 1937 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17346240_T41" } ] }, { "id": "PMID-17346240_E28", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1947, 1957 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_T42" } ] }, { "id": "PMID-17346240_E29", "type": "Regulation", "trigger": { "text": [ "deregulated" ], "offsets": [ [ 2071, 2082 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_T44" } ] }, { "id": "PMID-17346240_E30", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 2139, 2149 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_E27" } ] }, { "id": "PMID-17346240_E31", "type": "Inactivation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 2234, 2244 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_T45" } ] }, { "id": "PMID-17346240_E32", "type": "Inactivation", "trigger": { "text": [ "switch off" ], "offsets": [ [ 2267, 2277 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17346240_E31" }, { "role": "Theme", "ref_id": "PMID-17346240_T46" } ] }, { "id": "PMID-17346240_E33", "type": "Positive_regulation", "trigger": { "text": [ "promoting" ], "offsets": [ [ 2338, 2347 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17346240_E34" }, { "role": "Cause", "ref_id": "PMID-17346240_E31" } ] }, { "id": "PMID-17346240_E34", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 2348, 2357 ] ] }, "arguments": [] } ]

[ { "id": "PMID-17346240_1", "entity_ids": [ "PMID-17346240_T2", "PMID-17346240_T3" ] }, { "id": "PMID-17346240_2", "entity_ids": [ "PMID-17346240_T8", "PMID-17346240_T9" ] }, { "id": "PMID-17346240_3", "entity_ids": [ "PMID-17346240_T12", "PMID-17346240_T13" ] }, { "id": "PMID-17346240_4", "entity_ids": [ "PMID-17346240_T15", "PMID-17346240_T14" ] }, { "id": "PMID-17346240_5", "entity_ids": [ "PMID-17346240_T16", "PMID-17346240_T17" ] }, { "id": "PMID-17346240_6", "entity_ids": [ "PMID-17346240_T23", "PMID-17346240_T24" ] }, { "id": "PMID-17346240_7", "entity_ids": [ "PMID-17346240_T28", "PMID-17346240_T29", "PMID-17346240_T25", "PMID-17346240_T26" ] }, { "id": "PMID-17346240_8", "entity_ids": [ "PMID-17346240_T36", "PMID-17346240_T37" ] } ]

[]

[ { "id": "PMID-17376031__text", "type": "abstract", "text": [ "Signalling to translation: how signal transduction pathways control the protein synthetic machinery. \nRecent advances in our understanding of both the regulation of components of the translational machinery and the upstream signalling pathways that modulate them have provided important new insights into the mechanisms by which hormones, growth factors, nutrients and cellular energy status control protein synthesis in mammalian cells. The importance of proper control of mRNA translation is strikingly illustrated by the fact that defects in this process or its control are implicated in a number of disease states, such as cancer, tissue hypertrophy and neurodegeneration. Signalling pathways such as those involving mTOR (mammalian target of rapamycin) and mitogen-activated protein kinases modulate the phosphorylation of translation factors, the activities of the protein kinases that act upon them and the association of RNA-binding proteins with specific mRNAs. These effects contribute both to the overall control of protein synthesis (which is linked to cell growth) and to the modulation of the translation or stability of specific mRNAs. However, important questions remain about both the contributions of individual regulatory events to the control of general protein synthesis and the mechanisms by which the translation of specific mRNAs is controlled. \n" ], "offsets": [ [ 0, 1370 ] ] } ]

[ { "id": "PMID-17376031_T1", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 721, 725 ] ], "normalized": [] }, { "id": "PMID-17376031_T2", "type": "Gene_or_gene_product", "text": [ "mammalian target of rapamycin" ], "offsets": [ [ 727, 756 ] ], "normalized": [] } ]

[ { "id": "PMID-17376031_E1", "type": "Pathway", "trigger": { "text": [ "Signalling pathways" ], "offsets": [ [ 677, 696 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17376031_T1" } ] } ]

[ { "id": "PMID-17376031_1", "entity_ids": [ "PMID-17376031_T1", "PMID-17376031_T2" ] } ]

[]

[ { "id": "PMID-17459880__text", "type": "abstract", "text": [ "Mitotic phosphorylation of the anaphase-promoting complex inhibitory subunit Mnd2 is necessary for efficient progression through meiosis i. \nThe yeast anaphase-promoting complex (APC) subunit Mnd2 is necessary for maintaining sister chromatid cohesion in prophase I of meiosis by inhibiting premature ubiquitination and subsequent degradation of substrates by the APC(Ama1) ubiquitin ligase. In a proteomics screen for post-translational modifications on the APC, we discovered that Mnd2 is phosphorylated during mitosis in a cell cycle-dependent manner. We identified and characterized the sites of mitotic Mnd2 phosphorylation during the cell cycle. Collective mutation of Mnd2 phosphorylation sites to alanine had no effect on vegetative growth but a striking effect (>85% reduction) on the percentage of tetrad-forming cells compared with the wild type strain. Similar to the MND2 deletion strain, cells harboring the alanine mutant that did not form spores arrested after premeiotic S phase with a single undivided nucleus and low levels of the APC(Ama1) meiotic substrate, Clb5, relative to wild type cells. In contrast, collective mutation of Mnd2 phosphorylation sites to aspartic acid resulted in partial suppression of the sporulation defect. No differences were observed in the binding between each Mnd2 isoform and the APC in vitro. However, in vivo, we observed a gradient in the abundance of APC-associated Mnd2 in each strain that was proportional to the observed differences in sporulation and Clb5 levels. Taken together, these data suggest that mitotic phosphorylation of Mnd2 is necessary for APC-mediated progression beyond the first meiotic nuclear division.\n" ], "offsets": [ [ 0, 1680 ] ] } ]

[ { "id": "PMID-17459880_T1", "type": "Complex", "text": [ "anaphase-promoting complex" ], "offsets": [ [ 31, 57 ] ], "normalized": [] }, { "id": "PMID-17459880_T2", "type": "Gene_or_gene_product", "text": [ "Mnd2" ], "offsets": [ [ 77, 81 ] ], "normalized": [] }, { "id": "PMID-17459880_T3", "type": "Complex", "text": [ "anaphase-promoting complex" ], "offsets": [ [ 151, 177 ] ], "normalized": [] }, { "id": "PMID-17459880_T4", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 179, 182 ] ], "normalized": [] }, { "id": "PMID-17459880_T5", "type": "Gene_or_gene_product", "text": [ "Mnd2" ], "offsets": [ [ 192, 196 ] ], "normalized": [] }, { "id": "PMID-17459880_T6", "type": "Cellular_component", "text": [ "sister chromatid" ], "offsets": [ [ 226, 242 ] ], "normalized": [] }, { "id": "PMID-17459880_T7", "type": "Complex", "text": [ "APC(Ama1)" ], "offsets": [ [ 364, 373 ] ], "normalized": [] }, { "id": "PMID-17459880_T8", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 374, 383 ] ], "normalized": [] }, { "id": "PMID-17459880_T9", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 459, 462 ] ], "normalized": [] }, { "id": "PMID-17459880_T10", "type": "Gene_or_gene_product", "text": [ "Mnd2" ], "offsets": [ [ 483, 487 ] ], "normalized": [] }, { "id": "PMID-17459880_T11", "type": "Gene_or_gene_product", "text": [ "Mnd2" ], "offsets": [ [ 608, 612 ] ], "normalized": [] }, { "id": "PMID-17459880_T12", "type": "Gene_or_gene_product", "text": [ "Mnd2" ], "offsets": [ [ 675, 679 ] ], "normalized": [] }, { "id": "PMID-17459880_T13", "type": "Simple_chemical", "text": [ "alanine" ], "offsets": [ [ 705, 712 ] ], "normalized": [] }, { "id": "PMID-17459880_T14", "type": "Gene_or_gene_product", "text": [ "MND2" ], "offsets": [ [ 880, 884 ] ], "normalized": [] }, { "id": "PMID-17459880_T15", "type": "Simple_chemical", "text": [ "alanine" ], "offsets": [ [ 922, 929 ] ], "normalized": [] }, { "id": "PMID-17459880_T16", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 1020, 1027 ] ], "normalized": [] }, { "id": "PMID-17459880_T17", "type": "Complex", "text": [ "APC(Ama1)" ], "offsets": [ [ 1050, 1059 ] ], "normalized": [] }, { "id": "PMID-17459880_T18", "type": "Gene_or_gene_product", "text": [ "Clb5" ], "offsets": [ [ 1079, 1083 ] ], "normalized": [] }, { "id": "PMID-17459880_T19", "type": "Gene_or_gene_product", "text": [ "Mnd2" ], "offsets": [ [ 1150, 1154 ] ], "normalized": [] }, { "id": "PMID-17459880_T20", "type": "Simple_chemical", "text": [ "aspartic acid" ], "offsets": [ [ 1180, 1193 ] ], "normalized": [] }, { "id": "PMID-17459880_T21", "type": "Gene_or_gene_product", "text": [ "Mnd2" ], "offsets": [ [ 1310, 1314 ] ], "normalized": [] }, { "id": "PMID-17459880_T22", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 1331, 1334 ] ], "normalized": [] }, { "id": "PMID-17459880_T23", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 1406, 1409 ] ], "normalized": [] }, { "id": "PMID-17459880_T24", "type": "Gene_or_gene_product", "text": [ "Mnd2" ], "offsets": [ [ 1421, 1425 ] ], "normalized": [] }, { "id": "PMID-17459880_T25", "type": "Gene_or_gene_product", "text": [ "Clb5" ], "offsets": [ [ 1510, 1514 ] ], "normalized": [] }, { "id": "PMID-17459880_T26", "type": "Gene_or_gene_product", "text": [ "Mnd2" ], "offsets": [ [ 1590, 1594 ] ], "normalized": [] }, { "id": "PMID-17459880_T27", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 1612, 1615 ] ], "normalized": [] }, { "id": "PMID-17459880_T28", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1662, 1669 ] ], "normalized": [] } ]

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[ { "id": "PMID-17459880_1", "entity_ids": [ "PMID-17459880_T3", "PMID-17459880_T4" ] } ]

[]

[ { "id": "PMID-17461779__text", "type": "abstract", "text": [ "Identification of Protor as a novel Rictor-binding component of mTOR complex-2. \nThe mTOR (mammalian target of rapamycin) protein kinase is an important regulator of cell growth. Two complexes of mTOR have been identified: complex 1, consisting of mTOR-Raptor (regulatory associated protein of mTOR)-mLST8 (termed mTORC1), and complex 2, comprising mTOR-Rictor (rapamycininsensitive companion of mTOR)-mLST8-Sin1 (termed mTORC2). mTORC1 phosphorylates the p70 ribosomal S6K (S6 kinase) at its hydrophobic motif (Thr389), whereas mTORC2 phosphorylates PKB (protein kinase B) at its hydrophobic motif (Ser473). In the present study, we report that widely expressed isoforms of unstudied proteins termed Protor-1 (protein observed with Rictor-1) and Protor-2 interact with Rictor and are components of mTORC2. We demonstrate that immunoprecipitation of Protor-1 or Protor-2 results in the co-immunoprecipitation of other mTORC2 subunits, but not Raptor, a specific component of mTORC1. We show that detergents such as Triton X-100 or n-octylglucoside dissociate mTOR and mLST8 from a complex of Protor-1, Sin1 and Rictor. We also provide evidence that Rictor regulates the expression of Protor-1, and that Protor-1 is not required for the assembly of other mTORC2 subunits into a complex. Protor-1 is a novel Rictor-binding subunit of mTORC2, but further work is required to establish its role. \n" ], "offsets": [ [ 0, 1393 ] ] } ]

[ { "id": "PMID-17461779_T1", "type": "Gene_or_gene_product", "text": [ "Protor" ], "offsets": [ [ 18, 24 ] ], "normalized": [] }, { "id": "PMID-17461779_T2", "type": "Gene_or_gene_product", "text": [ "Rictor" ], "offsets": [ [ 36, 42 ] ], "normalized": [] }, { "id": "PMID-17461779_T3", "type": "Complex", "text": [ "mTOR complex-2" ], "offsets": [ [ 64, 78 ] ], "normalized": [] }, { "id": "PMID-17461779_T4", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 85, 89 ] ], "normalized": [] }, { "id": "PMID-17461779_T5", "type": "Gene_or_gene_product", "text": [ "mammalian target of rapamycin" ], "offsets": [ [ 91, 120 ] ], "normalized": [] }, { "id": "PMID-17461779_T6", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 196, 200 ] ], "normalized": [] }, { "id": "PMID-17461779_T7", "type": "Complex", "text": [ "complex 1" ], "offsets": [ [ 223, 232 ] ], "normalized": [] }, { "id": "PMID-17461779_T8", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 248, 252 ] ], "normalized": [] }, { "id": "PMID-17461779_T9", "type": "Gene_or_gene_product", "text": [ "Raptor" ], "offsets": [ [ 253, 259 ] ], "normalized": [] }, { "id": "PMID-17461779_T10", "type": "Gene_or_gene_product", "text": [ "regulatory associated protein of mTOR" ], "offsets": [ [ 261, 298 ] ], "normalized": [] }, { "id": "PMID-17461779_T11", "type": "Gene_or_gene_product", "text": [ "mLST8" ], "offsets": [ [ 300, 305 ] ], "normalized": [] }, { "id": "PMID-17461779_T12", "type": "Complex", "text": [ "mTORC1" ], "offsets": [ [ 314, 320 ] ], "normalized": [] }, { "id": "PMID-17461779_T13", "type": "Complex", "text": [ "complex 2" ], "offsets": [ [ 327, 336 ] ], "normalized": [] }, { "id": "PMID-17461779_T14", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 349, 353 ] ], "normalized": [] }, { "id": "PMID-17461779_T15", "type": "Gene_or_gene_product", "text": [ "Rictor" ], "offsets": [ [ 354, 360 ] ], "normalized": [] }, { "id": "PMID-17461779_T16", "type": "Gene_or_gene_product", "text": [ "rapamycininsensitive companion of mTOR" ], "offsets": [ [ 362, 400 ] ], "normalized": [] }, { "id": "PMID-17461779_T17", "type": "Gene_or_gene_product", "text": [ "mLST8" ], "offsets": [ [ 402, 407 ] ], "normalized": [] }, { "id": "PMID-17461779_T18", "type": "Gene_or_gene_product", "text": [ "Sin1" ], "offsets": [ [ 408, 412 ] ], "normalized": [] }, { "id": "PMID-17461779_T19", "type": "Complex", "text": [ "mTORC2" ], "offsets": [ [ 421, 427 ] ], "normalized": [] }, { "id": "PMID-17461779_T20", "type": "Complex", "text": [ "mTORC1" ], "offsets": [ [ 430, 436 ] ], "normalized": [] }, { "id": "PMID-17461779_T21", "type": "Gene_or_gene_product", "text": [ "p70 ribosomal S6K" ], "offsets": [ [ 456, 473 ] ], "normalized": [] }, { "id": "PMID-17461779_T22", "type": "Gene_or_gene_product", "text": [ "(S6 kinase" ], "offsets": [ [ 474, 484 ] ], "normalized": [] }, { "id": "PMID-17461779_T23", "type": "Simple_chemical", "text": [ "Thr389" ], "offsets": [ [ 512, 518 ] ], "normalized": [] }, { "id": "PMID-17461779_T24", "type": "Complex", "text": [ "mTORC2" ], "offsets": [ [ 529, 535 ] ], "normalized": [] }, { "id": "PMID-17461779_T25", "type": "Gene_or_gene_product", "text": [ "PKB" ], "offsets": [ [ 551, 554 ] ], "normalized": [] }, { "id": "PMID-17461779_T26", "type": "Gene_or_gene_product", "text": [ "protein kinase B" ], "offsets": [ [ 556, 572 ] ], "normalized": [] }, { "id": "PMID-17461779_T27", "type": "Simple_chemical", "text": [ "(Ser473" ], "offsets": [ [ 599, 606 ] ], "normalized": [] }, { "id": "PMID-17461779_T28", "type": "Gene_or_gene_product", "text": [ "Protor-1" ], "offsets": [ [ 701, 709 ] ], "normalized": [] }, { "id": "PMID-17461779_T29", "type": "Gene_or_gene_product", "text": [ "protein observed with Rictor-1" ], "offsets": [ [ 711, 741 ] ], "normalized": [] }, { "id": "PMID-17461779_T30", "type": "Gene_or_gene_product", "text": [ "Protor-2" ], "offsets": [ [ 747, 755 ] ], "normalized": [] }, { "id": "PMID-17461779_T31", "type": "Gene_or_gene_product", "text": [ "Rictor" ], "offsets": [ [ 770, 776 ] ], "normalized": [] }, { "id": "PMID-17461779_T32", "type": "Complex", "text": [ "mTORC2" ], "offsets": [ [ 799, 805 ] ], "normalized": [] }, { "id": "PMID-17461779_T33", "type": "Gene_or_gene_product", "text": [ "Protor-1" ], "offsets": [ [ 850, 858 ] ], "normalized": [] }, { "id": "PMID-17461779_T34", "type": "Gene_or_gene_product", "text": [ "Protor-2" ], "offsets": [ [ 862, 870 ] ], "normalized": [] }, { "id": "PMID-17461779_T35", "type": "Complex", "text": [ "mTORC2" ], "offsets": [ [ 918, 924 ] ], "normalized": [] }, { "id": "PMID-17461779_T36", "type": "Gene_or_gene_product", "text": [ "Raptor" ], "offsets": [ [ 943, 949 ] ], "normalized": [] }, { "id": "PMID-17461779_T37", "type": "Complex", "text": [ "mTORC1" ], "offsets": [ [ 975, 981 ] ], "normalized": [] }, { "id": "PMID-17461779_T38", "type": "Simple_chemical", "text": [ "Triton X-100" ], "offsets": [ [ 1015, 1027 ] ], "normalized": [] }, { "id": "PMID-17461779_T39", "type": "Simple_chemical", "text": [ "n-octylglucoside" ], "offsets": [ [ 1031, 1047 ] ], "normalized": [] }, { "id": "PMID-17461779_T40", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 1059, 1063 ] ], "normalized": [] }, { "id": "PMID-17461779_T41", "type": "Gene_or_gene_product", "text": [ "mLST8" ], "offsets": [ [ 1068, 1073 ] ], "normalized": [] }, { "id": "PMID-17461779_T42", "type": "Gene_or_gene_product", "text": [ "Protor-1" ], "offsets": [ [ 1092, 1100 ] ], "normalized": [] }, { "id": "PMID-17461779_T43", "type": "Gene_or_gene_product", "text": [ "Sin1" ], "offsets": [ [ 1102, 1106 ] ], "normalized": [] }, { "id": "PMID-17461779_T44", "type": "Gene_or_gene_product", "text": [ "Rictor" ], "offsets": [ [ 1111, 1117 ] ], "normalized": [] }, { "id": "PMID-17461779_T45", "type": "Gene_or_gene_product", "text": [ "Rictor" ], "offsets": [ [ 1149, 1155 ] ], "normalized": [] }, { "id": "PMID-17461779_T46", "type": "Gene_or_gene_product", "text": [ "Protor-1" ], "offsets": [ [ 1184, 1192 ] ], "normalized": [] }, { "id": "PMID-17461779_T47", "type": "Gene_or_gene_product", "text": [ "Protor-1" ], "offsets": [ [ 1203, 1211 ] ], "normalized": [] }, { "id": "PMID-17461779_T48", "type": "Complex", "text": [ "mTORC2" ], "offsets": [ [ 1254, 1260 ] ], "normalized": [] }, { "id": "PMID-17461779_T49", "type": "Gene_or_gene_product", "text": [ "Protor-1" ], "offsets": [ [ 1286, 1294 ] ], "normalized": [] }, { "id": "PMID-17461779_T50", "type": "Gene_or_gene_product", "text": [ "Rictor" ], "offsets": [ [ 1306, 1312 ] ], "normalized": [] }, { "id": "PMID-17461779_T51", "type": "Complex", "text": [ "mTORC2" ], "offsets": [ [ 1332, 1338 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-17471234__text", "type": "abstract", "text": [ "PAC1 is a direct transcription target of E2F-1 in apoptotic signaling. \nE2F-1 controls multiple cellular activities through transcriptional regulation of its target genes. As a mediator of cell death, E2F-1 can eliminate latent neoplastic cells through apoptosis. However, the mechanism by which E2F-1 mediates cancer cell killing is largely unknown. In this paper, we report that phosphatase of activated cells 1 (PAC1) phosphatase is a direct transcription target of E2F-1 in signaling apoptosis. We show that ectopic E2F-1 increases expression of PAC1 at both transcriptional and translational levels in breast cancer cells. E2F-1 physically interacts with the promoter of PAC1, binds to its consensus sequence in the promoter and transactivates the PAC1 promoter. E2F-1 suppresses extracellular signal-regulated kinase (ERK) phosphorylation through PAC1 and causes cancer cell death by apoptosis following treatment with a chemotherapeutic agent N-4-hydroxyphenylretinamide (4-HPR). Furthermore, ectopic PAC1 inhibits ERK phosphorylation and mediates cell killing. Moreover, endogenous E2F-1 upregulates PAC1 and suppresses ERK activity, leading to cell death in response to 4-HPR. These results reveal a crucial role of PAC1 in E2F-1-directed apoptosis. Our study demonstrates that E2F-1 mediates apoptosis through transcriptional regulation of PAC1 and subsequent suppression of the ERK signaling. Our findings establish a functional link between E2F-1 and mitogen-activated protein kinases. The E2F-1-PAC1 cascade in cancer cell killing may provide a molecular basis for cancer therapeutic intervention.\n" ], "offsets": [ [ 0, 1611 ] ] } ]

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"increases" ], "offsets": [ [ 526, 535 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17471234_T9" }, { "role": "Theme", "ref_id": "PMID-17471234_E7" } ] }, { "id": "PMID-17471234_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 536, 546 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_T10" } ] }, { "id": "PMID-17471234_E8", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 563, 578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_T10" } ] }, { "id": "PMID-17471234_E9", "type": "Translation", "trigger": { "text": [ "translational" ], "offsets": [ [ 583, 596 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_T10" } ] }, { "id": "PMID-17471234_E10", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 645, 654 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_T11" }, { "role": "Theme", "ref_id": "PMID-17471234_T12" } ] }, { "id": "PMID-17471234_E11", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 682, 687 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_T12" }, { "role": "Theme", "ref_id": "PMID-17471234_T11" } ] }, { "id": "PMID-17471234_E12", "type": "Positive_regulation", "trigger": { "text": [ "transactivates" ], "offsets": [ [ 734, 748 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_T13" }, { "role": "Cause", "ref_id": "PMID-17471234_T11" } ] }, { "id": "PMID-17471234_E13", "type": "Negative_regulation", "trigger": { "text": [ "suppresses" ], "offsets": [ [ 774, 784 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17471234_T14" }, { "role": "Theme", "ref_id": "PMID-17471234_E14" } ] }, { "id": "PMID-17471234_E14", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 829, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_T15" } ] }, { "id": "PMID-17471234_E15", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 890, 899 ] ] }, "arguments": [] }, { "id": "PMID-17471234_E16", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 1013, 1021 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17471234_T20" }, { "role": "Theme", "ref_id": "PMID-17471234_E17" } ] }, { "id": "PMID-17471234_E17", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1026, 1041 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_T21" } ] }, { "id": "PMID-17471234_E18", "type": "Positive_regulation", "trigger": { "text": [ "upregulates" ], "offsets": [ [ 1096, 1107 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17471234_T22" }, { "role": "Theme", "ref_id": "PMID-17471234_T23" } ] }, { "id": "PMID-17471234_E19", "type": "Negative_regulation", "trigger": { "text": [ "suppresses" ], "offsets": [ [ 1117, 1127 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_T24" }, { "role": "Cause", "ref_id": "PMID-17471234_T22" } ] }, { "id": "PMID-17471234_E20", "type": "Positive_regulation", "trigger": { "text": [ "crucial" ], "offsets": [ [ 1209, 1216 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_T26" } ] }, { "id": "PMID-17471234_E21", "type": "Positive_regulation", "trigger": { "text": [ "directed" ], "offsets": [ [ 1239, 1247 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17471234_T27" }, { "role": "Theme", "ref_id": "PMID-17471234_E22" } ] }, { "id": "PMID-17471234_E22", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1248, 1257 ] ] }, "arguments": [] }, { "id": "PMID-17471234_E23", "type": "Positive_regulation", "trigger": { "text": [ "mediates" ], "offsets": [ [ 1293, 1301 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_E24" }, { "role": "Cause", "ref_id": "PMID-17471234_E25" } ] }, { "id": "PMID-17471234_E24", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1302, 1311 ] ] }, "arguments": [] }, { "id": "PMID-17471234_E25", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1336, 1346 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_T29" }, { "role": "Cause", "ref_id": "PMID-17471234_T28" } ] }, { "id": "PMID-17471234_E26", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 1370, 1381 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17471234_E27" } ] }, { "id": "PMID-17471234_E27", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1393, 1402 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17471234_T30" } ] } ]

[ { "id": "PMID-17471234_1", "entity_ids": [ "PMID-17471234_T6", "PMID-17471234_T7" ] }, { "id": "PMID-17471234_2", "entity_ids": [ "PMID-17471234_T15", "PMID-17471234_T16" ] }, { "id": "PMID-17471234_3", "entity_ids": [ "PMID-17471234_T18", "PMID-17471234_T19" ] } ]

[]

[ { "id": "PMID-17504936__text", "type": "abstract", "text": [ "Ipl1p-dependent phosphorylation of Mad3p is required for the spindle checkpoint response to lack of tension at kinetochores. \nThe spindle checkpoint delays anaphase onset until all chromosomes are correctly attached to microtubules. Ipl1 protein kinase (Aurora B) is required to correct inappropriate kinetochore-microtubule attachments and for the response to lack of tension between sister kinetochores. Here we identify residues in the checkpoint protein Mad3p that are phosphorylated by Ipl1p. When phosphorylation of Mad3p at two sites is prevented, the cell's response to reduced kinetochore tension is dramatically curtailed. Our data provide strong evidence for a distinct checkpoint pathway responding to lack of sister kinetochore tension, in which Ipl1p-dependent phosphorylation of Mad3p is a key step.\n" ], "offsets": [ [ 0, 815 ] ] } ]

[ { "id": "PMID-17504936_T1", "type": "Gene_or_gene_product", "text": [ "Ipl1p" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-17504936_T2", "type": "Gene_or_gene_product", "text": [ "Mad3p" ], "offsets": [ [ 35, 40 ] ], "normalized": [] }, { "id": "PMID-17504936_T3", "type": "Cellular_component", "text": [ "spindle" ], "offsets": [ [ 61, 68 ] ], "normalized": [] }, { "id": "PMID-17504936_T4", "type": "Cellular_component", "text": [ "kinetochores" ], "offsets": [ [ 111, 123 ] ], "normalized": [] }, { "id": "PMID-17504936_T5", "type": "Cellular_component", "text": [ "spindle" ], "offsets": [ [ 130, 137 ] ], "normalized": [] }, { "id": "PMID-17504936_T6", "type": "Cellular_component", "text": [ "chromosomes" ], "offsets": [ [ 181, 192 ] ], "normalized": [] }, { "id": "PMID-17504936_T7", "type": "Cellular_component", "text": [ "microtubules" ], "offsets": [ [ 219, 231 ] ], "normalized": [] }, { "id": "PMID-17504936_T8", "type": "Gene_or_gene_product", "text": [ "Ipl1" ], "offsets": [ [ 233, 237 ] ], "normalized": [] }, { "id": "PMID-17504936_T9", "type": "Gene_or_gene_product", "text": [ "Aurora B" ], "offsets": [ [ 254, 262 ] ], "normalized": [] }, { "id": "PMID-17504936_T10", "type": "Cellular_component", "text": [ "kinetochore" ], "offsets": [ [ 301, 312 ] ], "normalized": [] }, { "id": "PMID-17504936_T11", "type": "Cellular_component", "text": [ "microtubule" ], "offsets": [ [ 313, 324 ] ], "normalized": [] }, { "id": "PMID-17504936_T12", "type": "Cellular_component", "text": [ "kinetochores" ], "offsets": [ [ 392, 404 ] ], "normalized": [] }, { "id": "PMID-17504936_T13", "type": "Gene_or_gene_product", "text": [ "Mad3p" ], "offsets": [ [ 458, 463 ] ], "normalized": [] }, { "id": "PMID-17504936_T14", "type": "Gene_or_gene_product", "text": [ "Ipl1p" ], "offsets": [ [ 491, 496 ] ], "normalized": [] }, { "id": "PMID-17504936_T15", "type": "Gene_or_gene_product", "text": [ "Mad3p" ], "offsets": [ [ 522, 527 ] ], "normalized": [] }, { "id": "PMID-17504936_T16", "type": "Cellular_component", "text": [ "kinetochore" ], "offsets": [ [ 586, 597 ] ], "normalized": [] }, { "id": "PMID-17504936_T17", "type": "Cellular_component", "text": [ "kinetochore" ], "offsets": [ [ 729, 740 ] ], "normalized": [] }, { "id": "PMID-17504936_T18", "type": "Gene_or_gene_product", "text": [ "Ipl1p" ], "offsets": [ [ 759, 764 ] ], "normalized": [] }, { "id": "PMID-17504936_T19", "type": "Gene_or_gene_product", "text": [ "Mad3p" ], "offsets": [ [ 794, 799 ] ], "normalized": [] } ]

[ { "id": "PMID-17504936_E1", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 6, 15 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17504936_E2" }, { "role": "Cause", "ref_id": "PMID-17504936_T1" } ] }, { "id": "PMID-17504936_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 16, 31 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17504936_T2" } ] }, { "id": "PMID-17504936_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 473, 487 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17504936_T13" }, { "role": "Cause", "ref_id": "PMID-17504936_T14" } ] }, { "id": "PMID-17504936_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 503, 518 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17504936_T15" } ] }, { "id": "PMID-17504936_E5", "type": "Negative_regulation", "trigger": { "text": [ "prevented" ], "offsets": [ [ 544, 553 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17504936_E4" } ] }, { "id": "PMID-17504936_E6", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 765, 774 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17504936_T18" }, { "role": "Theme", "ref_id": "PMID-17504936_E7" } ] }, { "id": "PMID-17504936_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 775, 790 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17504936_T19" } ] } ]

[ { "id": "PMID-17504936_1", "entity_ids": [ "PMID-17504936_T8", "PMID-17504936_T9" ] } ]

[]

[ { "id": "PMID-17592775__text", "type": "abstract", "text": [ "Nerve growth factor potentiates p53 DNA binding but inhibits nitric oxide-induced apoptosis in neuronal PC12 cells. \nNGF is recognized for its role in neuronal differentiation and maintenance. Differentiation of PC12 cells by NGF involves p53, a transcription factor that controls growth arrest and apoptosis. We investigated NGF influence over p53 activity during NO-induced apoptosis by sodium nitroprusside in differentiated and mitotic PC12 cells. NGF-differentiation produced increased p53 levels, nuclear localization and sequence-specific DNA binding. Apoptosis in mitotic cells also produced these events but the accompanying activation of caspases 1-10 and mitochondrial depolarization were inhibited during NGF differentiation and could be reversed in p53-silenced cells. Transcriptional regulation of PUMA and survivin expression were not inhibited by NGF, although NO-induced mitochondrial depolarization was dependent upon de novo gene transcription and only occurred in mitotic cells. We conclude that NGF mediates prosurvival signaling by increasing factors such as Bcl-2 and p21(Waf1/Cip1) without altering p53 transcriptional activity to inhibit mitochondrial depolarization, caspase activation and apoptosis.\n" ], "offsets": [ [ 0, 1227 ] ] } ]

[ { "id": "PMID-17592775_T1", "type": "Gene_or_gene_product", "text": [ "Nerve growth factor" ], "offsets": [ [ 0, 19 ] ], "normalized": [] }, { "id": "PMID-17592775_T2", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 32, 35 ] ], "normalized": [] }, { "id": "PMID-17592775_T3", "type": "Simple_chemical", "text": [ "nitric oxide" ], "offsets": [ [ 61, 73 ] ], "normalized": [] }, { "id": "PMID-17592775_T4", "type": "Gene_or_gene_product", "text": [ "NGF" ], "offsets": [ [ 117, 120 ] ], "normalized": [] }, { "id": "PMID-17592775_T5", "type": "Gene_or_gene_product", "text": [ "NGF" ], "offsets": [ [ 226, 229 ] ], "normalized": [] }, { "id": "PMID-17592775_T6", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 239, 242 ] ], "normalized": [] }, { "id": "PMID-17592775_T7", "type": "Gene_or_gene_product", "text": [ "NGF" ], "offsets": [ [ 326, 329 ] ], "normalized": [] }, { "id": "PMID-17592775_T8", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 345, 348 ] ], "normalized": [] }, { "id": "PMID-17592775_T9", "type": "Simple_chemical", "text": [ "NO" ], "offsets": [ [ 365, 367 ] ], "normalized": [] }, { "id": "PMID-17592775_T10", "type": "Simple_chemical", "text": [ "sodium nitroprusside" ], "offsets": [ [ 389, 409 ] ], "normalized": [] }, { "id": "PMID-17592775_T11", "type": "Gene_or_gene_product", "text": [ "NGF" ], "offsets": [ [ 452, 455 ] ], "normalized": [] }, { "id": "PMID-17592775_T12", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 491, 494 ] ], "normalized": [] }, { "id": "PMID-17592775_T13", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 503, 510 ] ], "normalized": [] }, { "id": "PMID-17592775_T14", "type": "Gene_or_gene_product", "text": [ "caspases 1" ], "offsets": [ [ 648, 658 ] ], "normalized": [] }, { "id": "PMID-17592775_T15", "type": "Gene_or_gene_product", "text": [ "10" ], "offsets": [ [ 659, 661 ] ], "normalized": [] }, { "id": "PMID-17592775_T16", "type": "Cellular_component", "text": [ "mitochondrial" ], "offsets": [ [ 666, 679 ] ], "normalized": [] }, { "id": "PMID-17592775_T17", "type": "Gene_or_gene_product", "text": [ "NGF" ], "offsets": [ [ 717, 720 ] ], "normalized": [] }, { "id": "PMID-17592775_T18", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 762, 765 ] ], "normalized": [] }, { "id": "PMID-17592775_T19", "type": "Gene_or_gene_product", "text": [ "PUMA" ], "offsets": [ [ 812, 816 ] ], "normalized": [] }, { "id": "PMID-17592775_T20", "type": "Gene_or_gene_product", "text": [ "survivin" ], "offsets": [ [ 821, 829 ] ], "normalized": [] }, { "id": "PMID-17592775_T21", "type": "Gene_or_gene_product", "text": [ "NGF" ], "offsets": [ [ 863, 866 ] ], "normalized": [] }, { "id": "PMID-17592775_T22", "type": "Simple_chemical", "text": [ "NO" ], "offsets": [ [ 877, 879 ] ], "normalized": [] }, { "id": "PMID-17592775_T23", "type": "Cellular_component", "text": [ "mitochondrial" ], "offsets": [ [ 888, 901 ] ], "normalized": [] }, { "id": "PMID-17592775_T24", "type": "Gene_or_gene_product", "text": [ "NGF" ], "offsets": [ [ 1016, 1019 ] ], "normalized": [] }, { "id": "PMID-17592775_T25", "type": "Gene_or_gene_product", "text": [ "Bcl-2" ], "offsets": [ [ 1081, 1086 ] ], "normalized": [] }, { "id": "PMID-17592775_T26", "type": "Gene_or_gene_product", "text": [ "p21" ], "offsets": [ [ 1091, 1094 ] ], "normalized": [] }, { "id": "PMID-17592775_T27", "type": "Gene_or_gene_product", "text": [ "Waf1" ], "offsets": [ [ 1095, 1099 ] ], "normalized": [] }, { "id": "PMID-17592775_T28", "type": "Gene_or_gene_product", "text": [ "Cip1" ], "offsets": [ [ 1100, 1104 ] ], "normalized": [] }, { "id": "PMID-17592775_T29", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1123, 1126 ] ], "normalized": [] }, { "id": "PMID-17592775_T30", "type": "Cellular_component", "text": [ "mitochondrial" ], "offsets": [ [ 1163, 1176 ] ], "normalized": [] }, { "id": "PMID-17592775_T31", "type": "Gene_or_gene_product", "text": [ "caspase" ], "offsets": [ [ 1193, 1200 ] ], "normalized": [] } ]

[ { "id": "PMID-17592775_E1", "type": "Positive_regulation", "trigger": { "text": [ "potentiates" ], "offsets": [ [ 20, 31 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T1" }, { "role": "Theme", "ref_id": "PMID-17592775_E2" } ] }, { "id": "PMID-17592775_E2", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 40, 47 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_T2" } ] }, { "id": "PMID-17592775_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 52, 60 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T1" }, { "role": "Theme", "ref_id": "PMID-17592775_E5" } ] }, { "id": "PMID-17592775_E4", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 74, 81 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T3" }, { "role": "Theme", "ref_id": "PMID-17592775_E5" } ] }, { "id": "PMID-17592775_E5", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 82, 91 ] ] }, "arguments": [] }, { "id": "PMID-17592775_E6", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 272, 280 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T6" }, { "role": "Theme", "ref_id": "PMID-17592775_E7" } ] }, { "id": "PMID-17592775_E7", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 299, 308 ] ] }, "arguments": [] }, { "id": "PMID-17592775_E8", "type": "Regulation", "trigger": { "text": [ "influence" ], "offsets": [ [ 330, 339 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T7" }, { "role": "Theme", "ref_id": "PMID-17592775_T8" } ] }, { "id": "PMID-17592775_E9", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 368, 375 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T9" }, { "role": "Theme", "ref_id": "PMID-17592775_E10" } ] }, { "id": "PMID-17592775_E10", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 376, 385 ] ] }, "arguments": [] }, { "id": "PMID-17592775_E11", "type": "Positive_regulation", "trigger": { "text": [ "produced" ], "offsets": [ [ 472, 480 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_E14" } ] }, { "id": "PMID-17592775_E12", "type": "Positive_regulation", "trigger": { "text": [ "produced" ], "offsets": [ [ 472, 480 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_E15" } ] }, { "id": "PMID-17592775_E13", "type": "Positive_regulation", "trigger": { "text": [ "produced" ], "offsets": [ [ 472, 480 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_E16" } ] }, { "id": "PMID-17592775_E14", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 481, 490 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_T12" } ] }, { "id": "PMID-17592775_E15", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 511, 523 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-17592775_T13" }, { "role": "Theme", "ref_id": "PMID-17592775_T12" } ] }, { "id": "PMID-17592775_E16", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 550, 557 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_T12" } ] }, { "id": "PMID-17592775_E17", "type": "Pathway", "trigger": { "text": [ "Apoptosis" ], "offsets": [ [ 559, 568 ] ] }, "arguments": [] }, { "id": "PMID-17592775_E18", "type": "Positive_regulation", "trigger": { "text": [ "produced" ], "offsets": [ [ 591, 599 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_E17" }, { "role": "Theme", "ref_id": "PMID-17592775_E14" } ] }, { "id": "PMID-17592775_E19", "type": "Positive_regulation", "trigger": { "text": [ "produced" ], "offsets": [ [ 591, 599 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_E17" }, { "role": "Theme", "ref_id": "PMID-17592775_E15" } ] }, { "id": "PMID-17592775_E20", "type": "Positive_regulation", "trigger": { "text": [ "produced" ], "offsets": [ [ 591, 599 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_E17" }, { "role": "Theme", "ref_id": "PMID-17592775_E16" } ] }, { "id": "PMID-17592775_E21", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 634, 644 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_T14" } ] }, { "id": "PMID-17592775_E22", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 634, 644 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_T15" } ] }, { "id": "PMID-17592775_E23", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 700, 709 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_E21" } ] }, { "id": "PMID-17592775_E24", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 700, 709 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_E22" } ] }, { "id": "PMID-17592775_E25", "type": "Negative_regulation", "trigger": { "text": [ "reversed" ], "offsets": [ [ 750, 758 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_E22" } ] }, { "id": "PMID-17592775_E26", "type": "Negative_regulation", "trigger": { "text": [ "reversed" ], "offsets": [ [ 750, 758 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_E21" } ] }, { "id": "PMID-17592775_E27", "type": "Inactivation", "trigger": { "text": [ "silenced" ], "offsets": [ [ 766, 774 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_T18" } ] }, { "id": "PMID-17592775_E28", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 798, 808 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_E30" } ] }, { "id": "PMID-17592775_E29", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 798, 808 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_E31" } ] }, { "id": "PMID-17592775_E30", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 830, 840 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_T19" } ] }, { "id": "PMID-17592775_E31", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 830, 840 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_T20" } ] }, { "id": "PMID-17592775_E32", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 850, 859 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T21" }, { "role": "Theme", "ref_id": "PMID-17592775_E28" } ] }, { "id": "PMID-17592775_E33", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 850, 859 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T21" }, { "role": "Theme", "ref_id": "PMID-17592775_E29" } ] }, { "id": "PMID-17592775_E34", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 1054, 1064 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T24" }, { "role": "Theme", "ref_id": "PMID-17592775_T25" } ] }, { "id": "PMID-17592775_E35", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 1054, 1064 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T24" }, { "role": "Theme", "ref_id": "PMID-17592775_T26" } ] }, { "id": "PMID-17592775_E36", "type": "Regulation", "trigger": { "text": [ "altering" ], "offsets": [ [ 1114, 1122 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_T29" }, { "role": "Cause", "ref_id": "PMID-17592775_T24" } ] }, { "id": "PMID-17592775_E37", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1155, 1162 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T24" }, { "role": "Theme", "ref_id": "PMID-17592775_E39" } ] }, { "id": "PMID-17592775_E38", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1155, 1162 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17592775_T24" }, { "role": "Theme", "ref_id": "PMID-17592775_E40" } ] }, { "id": "PMID-17592775_E39", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1201, 1211 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17592775_T31" } ] }, { "id": "PMID-17592775_E40", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1216, 1225 ] ] }, "arguments": [] } ]

[ { "id": "PMID-17592775_1", "entity_ids": [ "PMID-17592775_T26", "PMID-17592775_T27", "PMID-17592775_T28" ] } ]

[]

[ { "id": "PMID-17604271__text", "type": "abstract", "text": [ "PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. \nSignaling through the mammalian target of rapamycin complex 1 (mTORC1) is positively regulated by amino acids and insulin. PRAS40 associates with mTORC1 (which contains raptor) but not mTORC2. PRAS40 interacts with raptor, and this requires an intact TOR-signaling (TOS) motif in PRAS40. Like TOS motif-containing proteins such as eIF4E-binding protein 1 (4E-BP1), PRAS40 is a substrate for phosphorylation by mTORC1. Consistent with this, starvation of cells of amino acids or treatment with rapamycin alters the phosphorylation of PRAS40. PRAS40 binds 14-3-3 proteins, and this requires both amino acids and insulin. Binding of PRAS40 to 14-3-3 proteins is inhibited by TSC1/2 (negative regulators of mTORC1) and stimulated by Rheb in a rapamycin-sensitive manner. This confirms that PRAS40 is a target for regulation by mTORC1. Small interfering RNA-mediated knockdown of PRAS40 impairs both the amino acid- and insulin-stimulated phosphorylation of 4E-BP1 and the phosphorylation of S6. However, this has no effect on the phosphorylation of Akt or TSC2 (an Akt substrate). These data place PRAS40 downstream of mTORC1 but upstream of its effectors, such as S6K1 and 4E-BP1. \n" ], "offsets": [ [ 0, 1301 ] ] } ]

[ { "id": "PMID-17604271_T1", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "PMID-17604271_T2", "type": "Complex", "text": [ "mammalian target of rapamycin complex 1" ], "offsets": [ [ 23, 62 ] ], "normalized": [] }, { "id": "PMID-17604271_T3", "type": "Complex", "text": [ "mammalian target of rapamycin complex 1" ], "offsets": [ [ 144, 183 ] ], "normalized": [] }, { "id": "PMID-17604271_T4", "type": "Complex", "text": [ "mTORC1" ], "offsets": [ [ 185, 191 ] ], "normalized": [] }, { "id": "PMID-17604271_T5", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 236, 243 ] ], "normalized": [] }, { "id": "PMID-17604271_T6", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 245, 251 ] ], "normalized": [] }, { "id": "PMID-17604271_T7", "type": "Complex", "text": [ "mTORC1" ], "offsets": [ [ 268, 274 ] ], "normalized": [] }, { "id": "PMID-17604271_T8", "type": "Gene_or_gene_product", "text": [ "raptor" ], "offsets": [ [ 291, 297 ] ], "normalized": [] }, { "id": "PMID-17604271_T9", "type": "Complex", "text": [ "mTORC2" ], "offsets": [ [ 307, 313 ] ], "normalized": [] }, { "id": "PMID-17604271_T10", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 315, 321 ] ], "normalized": [] }, { "id": "PMID-17604271_T11", "type": "Gene_or_gene_product", "text": [ "raptor" ], "offsets": [ [ 337, 343 ] ], "normalized": [] }, { "id": "PMID-17604271_T12", "type": "Gene_or_gene_product", "text": [ "TOR" ], "offsets": [ [ 373, 376 ] ], "normalized": [] }, { "id": "PMID-17604271_T13", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 402, 408 ] ], "normalized": [] }, { "id": "PMID-17604271_T14", "type": "Gene_or_gene_product", "text": [ "eIF4E-binding protein 1" ], "offsets": [ [ 453, 476 ] ], "normalized": [] }, { "id": "PMID-17604271_T15", "type": "Gene_or_gene_product", "text": [ "4E-BP1" ], "offsets": [ [ 478, 484 ] ], "normalized": [] }, { "id": "PMID-17604271_T16", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 487, 493 ] ], "normalized": [] }, { "id": "PMID-17604271_T17", "type": "Complex", "text": [ "mTORC1" ], "offsets": [ [ 532, 538 ] ], "normalized": [] }, { "id": "PMID-17604271_T18", "type": "Simple_chemical", "text": [ "rapamycin" ], "offsets": [ [ 615, 624 ] ], "normalized": [] }, { "id": "PMID-17604271_T19", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 655, 661 ] ], "normalized": [] }, { "id": "PMID-17604271_T20", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 663, 669 ] ], "normalized": [] }, { "id": "PMID-17604271_T21", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 676, 682 ] ], "normalized": [] }, { "id": "PMID-17604271_T22", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 732, 739 ] ], "normalized": [] }, { "id": "PMID-17604271_T23", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 752, 758 ] ], "normalized": [] }, { "id": "PMID-17604271_T24", "type": "Gene_or_gene_product", "text": [ "14-3-3" ], "offsets": [ [ 762, 768 ] ], "normalized": [] }, { "id": "PMID-17604271_T25", "type": "Gene_or_gene_product", "text": [ "TSC1" ], "offsets": [ [ 794, 798 ] ], "normalized": [] }, { "id": "PMID-17604271_T26", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 799, 800 ] ], "normalized": [] }, { "id": "PMID-17604271_T27", "type": "Complex", "text": [ "mTORC1" ], "offsets": [ [ 825, 831 ] ], "normalized": [] }, { "id": "PMID-17604271_T28", "type": "Gene_or_gene_product", "text": [ "Rheb" ], "offsets": [ [ 851, 855 ] ], "normalized": [] }, { "id": "PMID-17604271_T29", "type": "Simple_chemical", "text": [ "rapamycin" ], "offsets": [ [ 861, 870 ] ], "normalized": [] }, { "id": "PMID-17604271_T30", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 908, 914 ] ], "normalized": [] }, { "id": "PMID-17604271_T31", "type": "Complex", "text": [ "mTORC1" ], "offsets": [ [ 945, 951 ] ], "normalized": [] }, { "id": "PMID-17604271_T32", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 997, 1003 ] ], "normalized": [] }, { "id": "PMID-17604271_T33", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 1037, 1044 ] ], "normalized": [] }, { "id": "PMID-17604271_T34", "type": "Gene_or_gene_product", "text": [ "4E-BP1" ], "offsets": [ [ 1075, 1081 ] ], "normalized": [] }, { "id": "PMID-17604271_T35", "type": "Gene_or_gene_product", "text": [ "S6" ], "offsets": [ [ 1109, 1111 ] ], "normalized": [] }, { "id": "PMID-17604271_T36", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1167, 1170 ] ], "normalized": [] }, { "id": "PMID-17604271_T37", "type": "Gene_or_gene_product", "text": [ "TSC2" ], "offsets": [ [ 1174, 1178 ] ], "normalized": [] }, { "id": "PMID-17604271_T38", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1183, 1186 ] ], "normalized": [] }, { "id": "PMID-17604271_T39", "type": "Gene_or_gene_product", "text": [ "PRAS40" ], "offsets": [ [ 1216, 1222 ] ], "normalized": [] }, { "id": "PMID-17604271_T40", "type": "Complex", "text": [ "mTORC1" ], "offsets": [ [ 1237, 1243 ] ], "normalized": [] }, { "id": "PMID-17604271_T41", "type": "Gene_or_gene_product", "text": [ "S6K1" ], "offsets": [ [ 1283, 1287 ] ], "normalized": [] }, { "id": "PMID-17604271_T42", "type": "Gene_or_gene_product", "text": [ "4E-BP1" ], "offsets": [ [ 1292, 1298 ] ], "normalized": [] } ]

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] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T6" }, { "role": "Theme", "ref_id": "PMID-17604271_T7" } ] }, { "id": "PMID-17604271_E6", "type": "Binding", "trigger": { "text": [ "associates" ], "offsets": [ [ 252, 262 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T6" }, { "role": "Theme", "ref_id": "PMID-17604271_T9" } ] }, { "id": "PMID-17604271_E7", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 322, 331 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T10" }, { "role": "Theme", "ref_id": "PMID-17604271_T11" } ] }, { "id": "PMID-17604271_E8", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 354, 362 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_E7" } ] }, { "id": "PMID-17604271_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 513, 528 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17604271_T17" }, { "role": "Theme", "ref_id": "PMID-17604271_T16" } ] }, { "id": "PMID-17604271_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 513, 528 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17604271_T17" }, { "role": "Theme", "ref_id": "PMID-17604271_T14" } ] }, { "id": "PMID-17604271_E11", "type": "Regulation", "trigger": { "text": [ "alters" ], "offsets": [ [ 625, 631 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17604271_T18" }, { "role": "Theme", "ref_id": "PMID-17604271_E12" } ] }, { "id": "PMID-17604271_E12", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 636, 651 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T19" } ] }, { "id": "PMID-17604271_E13", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 670, 675 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T20" }, { "role": "Theme", "ref_id": "PMID-17604271_T21" } ] }, { "id": "PMID-17604271_E14", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 702, 710 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_E13" }, { "role": "Cause", "ref_id": "PMID-17604271_T22" } ] }, { "id": "PMID-17604271_E15", "type": "Binding", "trigger": { "text": [ "Binding" ], "offsets": [ [ 741, 748 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T23" }, { "role": "Theme", "ref_id": "PMID-17604271_T24" } ] }, { "id": "PMID-17604271_E16", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 781, 790 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_E15" }, { "role": "Cause", "ref_id": "PMID-17604271_T26" } ] }, { "id": "PMID-17604271_E17", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 781, 790 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_E15" }, { "role": "Cause", "ref_id": "PMID-17604271_T25" } ] }, { "id": "PMID-17604271_E18", "type": "Negative_regulation", "trigger": { "text": [ "negative regulators" ], "offsets": [ [ 802, 821 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T27" }, { "role": "Cause", "ref_id": "PMID-17604271_T26" } ] }, { "id": "PMID-17604271_E19", "type": "Negative_regulation", "trigger": { "text": [ "negative regulators" ], "offsets": [ [ 802, 821 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T27" }, { "role": "Cause", "ref_id": "PMID-17604271_T25" } ] }, { "id": "PMID-17604271_E20", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 837, 847 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17604271_T28" }, { "role": "Theme", "ref_id": "PMID-17604271_E15" } ] }, { "id": "PMID-17604271_E21", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 871, 880 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_E20" }, { "role": "Cause", "ref_id": "PMID-17604271_T29" } ] }, { "id": "PMID-17604271_E22", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 931, 941 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17604271_T31" }, { "role": "Theme", "ref_id": "PMID-17604271_T30" } ] }, { "id": "PMID-17604271_E23", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 975, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_E24" } ] }, { "id": "PMID-17604271_E24", "type": "Inactivation", "trigger": { "text": [ "knockdown" ], "offsets": [ [ 984, 993 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T32" } ] }, { "id": "PMID-17604271_E25", "type": "Negative_regulation", "trigger": { "text": [ "impairs" ], "offsets": [ [ 1004, 1011 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17604271_E24" }, { "role": "Theme", "ref_id": "PMID-17604271_E28" } ] }, { "id": "PMID-17604271_E26", "type": "Negative_regulation", "trigger": { "text": [ "impairs" ], "offsets": [ [ 1004, 1011 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17604271_E24" }, { "role": "Theme", "ref_id": "PMID-17604271_E29" } ] }, { "id": "PMID-17604271_E27", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1045, 1055 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17604271_T33" }, { "role": "Theme", "ref_id": "PMID-17604271_E28" } ] }, { "id": "PMID-17604271_E28", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1056, 1071 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T34" } ] }, { "id": "PMID-17604271_E29", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1090, 1105 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T35" } ] }, { "id": "PMID-17604271_E30", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1134, 1140 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17604271_E24" }, { "role": "Theme", "ref_id": "PMID-17604271_E33" } ] }, { "id": "PMID-17604271_E31", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1134, 1140 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17604271_E24" }, { "role": "Theme", "ref_id": "PMID-17604271_E32" } ] }, { "id": "PMID-17604271_E32", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1148, 1163 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T37" } ] }, { "id": "PMID-17604271_E33", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1148, 1163 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17604271_T36" } ] } ]

[ { "id": "PMID-17604271_1", "entity_ids": [ "PMID-17604271_T3", "PMID-17604271_T4" ] }, { "id": "PMID-17604271_2", "entity_ids": [ "PMID-17604271_T14", "PMID-17604271_T15" ] } ]

[]

[ { "id": "PMID-17652458__text", "type": "abstract", "text": [ "A Bir1p Sli15p kinetochore passenger complex regulates septin organization during anaphase. \nKinetochore-passenger complexes in metazoans have been proposed to coordinate the segregation of chromosomes in anaphase with the induction of cytokinesis. Passenger protein homologues in the budding yeast Saccharomyces cerevisiae play a critical role early in mitosis, ensuring proper biorientation of kinetochore-microtubule attachments. Our recent work has implicated the passenger protein Bir1p (Survivin) and the inner kinetochore complex centromere binding factor 3 (CBF3) in the regulation of septin dynamics during anaphase. Here, we present data that is consistent with there being multiple passenger protein complexes. Our data show that Bir1p links together a large passenger complex containing Ndc10p, Sli15p (INCENP), and Ipl1p (Aurora B) and that the interaction between Bir1p and Sli15p is specifically involved in regulating septin dynamics during anaphase. Neither conditional alleles nor mutants of BIR1 that disrupt the interaction between Bir1p and Sli15p resulted in mono-attached kinetochores, suggesting that the Bir1p-Sli15p complex functions in anaphase and independently from Sli15p-Ipl1p complexes. We present a model for how discrete passenger complexes coordinate distinct aspects of mitosis.\n" ], "offsets": [ [ 0, 1315 ] ] } ]

[ { "id": "PMID-17652458_T1", "type": "Complex", "text": [ "Bir1p Sli15p" ], "offsets": [ [ 2, 14 ] ], "normalized": [] }, { "id": "PMID-17652458_T2", "type": "Cellular_component", "text": [ "kinetochore" ], "offsets": [ [ 15, 26 ] ], "normalized": [] }, { "id": "PMID-17652458_T3", "type": "Gene_or_gene_product", "text": [ "septin" ], "offsets": [ [ 55, 61 ] ], "normalized": [] }, { "id": "PMID-17652458_T4", "type": "Cellular_component", "text": [ "chromosomes" ], "offsets": [ [ 190, 201 ] ], "normalized": [] }, { "id": "PMID-17652458_T5", "type": "Cellular_component", "text": [ "kinetochore" ], "offsets": [ [ 396, 407 ] ], "normalized": [] }, { "id": "PMID-17652458_T6", "type": "Cellular_component", "text": [ "microtubule" ], "offsets": [ [ 408, 419 ] ], "normalized": [] }, { "id": "PMID-17652458_T7", "type": "Gene_or_gene_product", "text": [ "Bir1p" ], "offsets": [ [ 486, 491 ] ], "normalized": [] }, { "id": "PMID-17652458_T8", "type": "Gene_or_gene_product", "text": [ "Survivin" ], "offsets": [ [ 493, 501 ] ], "normalized": [] }, { "id": "PMID-17652458_T9", "type": "Cellular_component", "text": [ "kinetochore" ], "offsets": [ [ 517, 528 ] ], "normalized": [] }, { "id": "PMID-17652458_T10", "type": "Gene_or_gene_product", "text": [ "centromere binding factor 3" ], "offsets": [ [ 537, 564 ] ], "normalized": [] }, { "id": "PMID-17652458_T11", "type": "Gene_or_gene_product", "text": [ "CBF3" ], "offsets": [ [ 566, 570 ] ], "normalized": [] }, { "id": "PMID-17652458_T12", "type": "Gene_or_gene_product", "text": [ "septin" ], "offsets": [ [ 593, 599 ] ], "normalized": [] }, { "id": "PMID-17652458_T13", "type": "Gene_or_gene_product", "text": [ "Bir1p" ], "offsets": [ [ 741, 746 ] ], "normalized": [] }, { "id": "PMID-17652458_T14", "type": "Gene_or_gene_product", "text": [ "Ndc10p" ], "offsets": [ [ 799, 805 ] ], "normalized": [] }, { "id": "PMID-17652458_T15", "type": "Gene_or_gene_product", "text": [ "Sli15p" ], "offsets": [ [ 807, 813 ] ], "normalized": [] }, { "id": "PMID-17652458_T16", "type": "Gene_or_gene_product", "text": [ "INCENP" ], "offsets": [ [ 815, 821 ] ], "normalized": [] }, { "id": "PMID-17652458_T17", "type": "Gene_or_gene_product", "text": [ "Ipl1p" ], "offsets": [ [ 828, 833 ] ], "normalized": [] }, { "id": "PMID-17652458_T18", "type": "Gene_or_gene_product", "text": [ "Aurora B" ], "offsets": [ [ 835, 843 ] ], "normalized": [] }, { "id": "PMID-17652458_T19", "type": "Gene_or_gene_product", "text": [ "Bir1p" ], "offsets": [ [ 878, 883 ] ], "normalized": [] }, { "id": "PMID-17652458_T20", "type": "Gene_or_gene_product", "text": [ "Sli15p" ], "offsets": [ [ 888, 894 ] ], "normalized": [] }, { "id": "PMID-17652458_T21", "type": "Gene_or_gene_product", "text": [ "septin" ], "offsets": [ [ 934, 940 ] ], "normalized": [] }, { "id": "PMID-17652458_T22", "type": "Gene_or_gene_product", "text": [ "BIR1" ], "offsets": [ [ 1010, 1014 ] ], "normalized": [] }, { "id": "PMID-17652458_T23", "type": "Gene_or_gene_product", "text": [ "Bir1p" ], "offsets": [ [ 1052, 1057 ] ], "normalized": [] }, { "id": "PMID-17652458_T24", "type": "Gene_or_gene_product", "text": [ "Sli15p" ], "offsets": [ [ 1062, 1068 ] ], "normalized": [] }, { "id": "PMID-17652458_T25", "type": "Cellular_component", "text": [ "kinetochores" ], "offsets": [ [ 1095, 1107 ] ], "normalized": [] }, { "id": "PMID-17652458_T26", "type": "Complex", "text": [ "Bir1p-Sli15p" ], "offsets": [ [ 1129, 1141 ] ], "normalized": [] }, { "id": "PMID-17652458_T27", "type": "Complex", "text": [ "Sli15p-Ipl1p" ], "offsets": [ [ 1195, 1207 ] ], "normalized": [] } ]

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[ { "id": "PMID-17652458_1", "entity_ids": [ "PMID-17652458_T7", "PMID-17652458_T8" ] }, { "id": "PMID-17652458_2", "entity_ids": [ "PMID-17652458_T10", "PMID-17652458_T11" ] }, { "id": "PMID-17652458_3", "entity_ids": [ "PMID-17652458_T15", "PMID-17652458_T16" ] }, { "id": "PMID-17652458_4", "entity_ids": [ "PMID-17652458_T17", "PMID-17652458_T18" ] } ]

[]

[ { "id": "PMID-17690098__text", "type": "abstract", "text": [ "Acetylation of lysine 56 of histone H3 catalyzed by RTT109 and regulated by ASF1 is required for replisome integrity. \nIn budding yeast, acetylation of histone H3 lysine 56 (H3-K56) is catalyzed by the Rtt109-Vps75 histone acetyltransferase (HAT) complex, with Rtt109 being the catalytic subunit, and histone chaperone Asf1 is required for this modification. Cells lacking Rtt109 are susceptible to perturbations in DNA replication. However, how Asf1 regulates acetylation of H3-K56 and how loss of H3-K56 acetylation affects DNA replication are unclear. We show that at low concentrations the Rtt109-Vps75 HAT complex acetylates H3-K56 in vitro when H3/H4 is complexed with Asf1, but not H3/H4 tetramers, recapitulating the in vivo requirement of Asf1 for H3-K56 acetylation using recombinant proteins. Moreover, the Rtt109-Vps75 complex interacts with Asf1-H3/H4 but not Asf1. In vivo, the Rtt109-Asf1 interaction is also dependent on the ability of Asf1 to bind H3/H4. Furthermore, the Rtt109 homolog in Schizosaccharomyces pombe (SpRtt109) also displayed an Asf1-dependent H3-K56 HAT activity in vitro. These results indicate that Asf1 regulates H3-K56 acetylation by presenting histones H3 and H4 to Rtt109-Vps575 for acetylation, and this mechanism is likely to be conserved. Finally, we have shown that cells lacking Rtt109 or expressing H3-K56 mutants exhibited significant reduction in the association of three proteins with stalled DNA replication forks and hyper-recombination of replication forks stalled at replication fork barriers of the ribosomal DNA locus compared with wild-type cells. Taken together, these studies provide novel insight into the role of Asf1 in the regulation of H3-K56 acetylation and the function of this modification in DNA replication.\n" ], "offsets": [ [ 0, 1776 ] ] } ]

[ { "id": "PMID-17690098_T1", "type": "Simple_chemical", "text": [ "lysine 56" ], "offsets": [ [ 15, 24 ] ], "normalized": [] }, { "id": "PMID-17690098_T2", "type": "Gene_or_gene_product", "text": [ "histone H3" ], "offsets": [ [ 28, 38 ] ], "normalized": [] }, { "id": "PMID-17690098_T3", "type": "Gene_or_gene_product", "text": [ "RTT109" ], "offsets": [ [ 52, 58 ] ], "normalized": [] }, { "id": "PMID-17690098_T4", "type": "Gene_or_gene_product", "text": [ "ASF1" ], "offsets": [ [ 76, 80 ] ], "normalized": [] }, { "id": "PMID-17690098_T5", "type": "Gene_or_gene_product", "text": [ "histone H3" ], "offsets": [ [ 152, 162 ] ], "normalized": [] }, { "id": "PMID-17690098_T6", "type": "Simple_chemical", "text": [ "lysine 56" ], "offsets": [ [ 163, 172 ] ], "normalized": [] }, { "id": "PMID-17690098_T7", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 174, 176 ] ], "normalized": [] }, { "id": "PMID-17690098_T8", "type": "Simple_chemical", "text": [ "K56" ], "offsets": [ [ 177, 180 ] ], "normalized": [] }, { "id": "PMID-17690098_T9", "type": "Complex", "text": [ "Rtt109-Vps75" ], "offsets": [ [ 202, 214 ] ], "normalized": [] }, { "id": "PMID-17690098_T10", "type": "Gene_or_gene_product", "text": [ "histone acetyltransferase" ], "offsets": [ [ 215, 240 ] ], "normalized": [] }, { "id": "PMID-17690098_T11", "type": "Gene_or_gene_product", "text": [ "HAT" ], "offsets": [ [ 242, 245 ] ], "normalized": [] }, { "id": "PMID-17690098_T12", "type": "Gene_or_gene_product", "text": [ "Rtt109" ], "offsets": [ [ 261, 267 ] ], "normalized": [] }, { "id": "PMID-17690098_T13", "type": "Gene_or_gene_product", "text": [ "histone" ], "offsets": [ [ 301, 308 ] ], "normalized": [] }, { "id": "PMID-17690098_T14", "type": "Gene_or_gene_product", "text": [ "Asf1" ], "offsets": [ [ 319, 323 ] ], "normalized": [] }, { "id": "PMID-17690098_T15", "type": "Gene_or_gene_product", "text": [ "Rtt109" ], "offsets": [ [ 373, 379 ] ], "normalized": [] }, { "id": "PMID-17690098_T16", "type": "Gene_or_gene_product", "text": [ "Asf1" ], "offsets": [ [ 446, 450 ] ], "normalized": [] }, { "id": "PMID-17690098_T17", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 476, 478 ] ], "normalized": [] }, { "id": "PMID-17690098_T18", "type": "Simple_chemical", "text": [ "K56" ], "offsets": [ [ 479, 482 ] ], "normalized": [] }, { "id": "PMID-17690098_T19", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 499, 501 ] ], "normalized": [] }, { "id": "PMID-17690098_T20", "type": "Simple_chemical", "text": [ "K56" ], "offsets": [ [ 502, 505 ] ], "normalized": [] }, { "id": "PMID-17690098_T21", "type": "Complex", "text": [ "Rtt109-Vps75" ], "offsets": [ [ 594, 606 ] ], "normalized": [] }, { "id": "PMID-17690098_T22", "type": "Gene_or_gene_product", "text": [ "HAT" ], "offsets": [ [ 607, 610 ] ], "normalized": [] }, { "id": "PMID-17690098_T23", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 630, 632 ] ], "normalized": [] }, { "id": "PMID-17690098_T24", "type": "Simple_chemical", "text": [ "K56" ], "offsets": [ [ 633, 636 ] ], "normalized": [] }, { "id": "PMID-17690098_T25", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 651, 653 ] ], "normalized": [] }, { "id": "PMID-17690098_T26", "type": "Gene_or_gene_product", "text": [ "H4" ], "offsets": [ [ 654, 656 ] ], "normalized": [] }, { "id": "PMID-17690098_T27", "type": "Gene_or_gene_product", "text": [ "Asf1" ], "offsets": [ [ 675, 679 ] ], "normalized": [] }, { "id": "PMID-17690098_T28", "type": "Complex", "text": [ "H3/H4" ], "offsets": [ [ 689, 694 ] ], "normalized": [] }, { "id": "PMID-17690098_T29", "type": "Gene_or_gene_product", "text": [ "Asf1" ], "offsets": [ [ 748, 752 ] ], "normalized": [] }, { "id": "PMID-17690098_T30", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 757, 759 ] ], "normalized": [] }, { "id": "PMID-17690098_T31", "type": "Simple_chemical", "text": [ "K56" ], "offsets": [ [ 760, 763 ] ], "normalized": [] }, { "id": "PMID-17690098_T32", "type": "Complex", "text": [ "Rtt109-Vps75" ], "offsets": [ [ 818, 830 ] ], "normalized": [] }, { "id": "PMID-17690098_T33", "type": "Complex", "text": [ "Asf1-H3" ], "offsets": [ [ 854, 861 ] ], "normalized": [] }, { "id": "PMID-17690098_T34", "type": "Complex", "text": [ "H4" ], "offsets": [ [ 862, 864 ] ], "normalized": [] }, { "id": "PMID-17690098_T35", "type": "Gene_or_gene_product", "text": [ "Asf1" ], "offsets": [ [ 873, 877 ] ], "normalized": [] }, { "id": "PMID-17690098_T36", "type": "Complex", "text": [ "Rtt109-Asf1" ], "offsets": [ [ 892, 903 ] ], "normalized": [] }, { "id": "PMID-17690098_T37", "type": "Gene_or_gene_product", "text": [ "Asf1" ], "offsets": [ [ 952, 956 ] ], "normalized": [] }, { "id": "PMID-17690098_T38", "type": "Gene_or_gene_product", "text": [ "H3/H4" ], "offsets": [ [ 965, 970 ] ], "normalized": [] }, { "id": "PMID-17690098_T39", "type": "Gene_or_gene_product", "text": [ "Rtt109" ], "offsets": [ [ 989, 995 ] ], "normalized": [] }, { "id": "PMID-17690098_T40", "type": "Gene_or_gene_product", "text": [ "SpRtt109" ], "offsets": [ [ 1034, 1042 ] ], "normalized": [] }, { "id": "PMID-17690098_T41", "type": "Gene_or_gene_product", "text": [ "Asf1" ], "offsets": [ [ 1062, 1066 ] ], "normalized": [] }, { "id": "PMID-17690098_T42", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 1077, 1079 ] ], "normalized": [] }, { "id": "PMID-17690098_T43", "type": "Simple_chemical", "text": [ "K56" ], "offsets": [ [ 1080, 1083 ] ], "normalized": [] }, { "id": "PMID-17690098_T44", "type": "Gene_or_gene_product", "text": [ "HAT" ], "offsets": [ [ 1084, 1087 ] ], "normalized": [] }, { "id": "PMID-17690098_T45", "type": "Gene_or_gene_product", "text": [ "Asf1" ], "offsets": [ [ 1135, 1139 ] ], "normalized": [] }, { "id": "PMID-17690098_T46", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 1150, 1152 ] ], "normalized": [] }, { "id": "PMID-17690098_T47", "type": "Simple_chemical", "text": [ "K56" ], "offsets": [ [ 1153, 1156 ] ], "normalized": [] }, { "id": "PMID-17690098_T48", "type": "Gene_or_gene_product", "text": [ "histones H3" ], "offsets": [ [ 1183, 1194 ] ], "normalized": [] }, { "id": "PMID-17690098_T49", "type": "Gene_or_gene_product", "text": [ "H4" ], "offsets": [ [ 1199, 1201 ] ], "normalized": [] }, { "id": "PMID-17690098_T50", "type": "Complex", "text": [ "Rtt109-Vps575" ], "offsets": [ [ 1205, 1218 ] ], "normalized": [] }, { "id": "PMID-17690098_T51", "type": "Gene_or_gene_product", "text": [ "Rtt109" ], "offsets": [ [ 1324, 1330 ] ], "normalized": [] }, { "id": "PMID-17690098_T52", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 1345, 1347 ] ], "normalized": [] }, { "id": "PMID-17690098_T53", "type": "Simple_chemical", "text": [ "K56" ], "offsets": [ [ 1348, 1351 ] ], "normalized": [] }, { "id": "PMID-17690098_T54", "type": "Cellular_component", "text": [ "ribosomal" ], "offsets": [ [ 1553, 1562 ] ], "normalized": [] }, { "id": "PMID-17690098_T55", "type": "Gene_or_gene_product", "text": [ "Asf1" ], "offsets": [ [ 1673, 1677 ] ], "normalized": [] }, { "id": "PMID-17690098_T56", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 1699, 1701 ] ], "normalized": [] }, { "id": "PMID-17690098_T57", "type": "Simple_chemical", "text": [ "K56" ], "offsets": [ [ 1702, 1705 ] ], "normalized": [] } ]

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"type": "Positive_regulation", "trigger": { "text": [ "catalyzed" ], "offsets": [ [ 185, 194 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_E4" }, { "role": "Cause", "ref_id": "PMID-17690098_T9" } ] }, { "id": "PMID-17690098_E6", "type": "Positive_regulation", "trigger": { "text": [ "catalyzed" ], "offsets": [ [ 185, 194 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_E4" }, { "role": "Cause", "ref_id": "PMID-17690098_T12" } ] }, { "id": "PMID-17690098_E7", "type": "Positive_regulation", "trigger": { "text": [ "catalyzed" ], "offsets": [ [ 185, 194 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_E4" }, { "role": "Cause", "ref_id": "PMID-17690098_T14" } ] }, { "id": "PMID-17690098_E8", "type": "Inactivation", "trigger": { "text": [ "lacking" ], "offsets": [ [ 365, 372 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T15" } ] }, { "id": "PMID-17690098_E9", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 451, 460 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_E10" }, { "role": "Cause", "ref_id": "PMID-17690098_T16" } ] }, { "id": "PMID-17690098_E10", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 461, 472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T17" }, { "role": "Site", "ref_id": "PMID-17690098_T18" } ] }, { "id": "PMID-17690098_E11", "type": "Negative_regulation", "trigger": { "text": [ "loss" ], "offsets": [ [ 491, 495 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_E12" } ] }, { "id": "PMID-17690098_E12", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 506, 517 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T19" }, { "role": "Site", "ref_id": "PMID-17690098_T20" } ] }, { "id": "PMID-17690098_E13", "type": "Acetylation", "trigger": { "text": [ "acetylates" ], "offsets": [ [ 619, 629 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T23" }, { "role": "Site", "ref_id": "PMID-17690098_T24" }, { "role": "Cause", "ref_id": "PMID-17690098_T22" } ] }, { "id": "PMID-17690098_E14", "type": "Acetylation", "trigger": { "text": [ "acetylates" ], "offsets": [ [ 619, 629 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T23" }, { "role": "Site", "ref_id": "PMID-17690098_T24" }, { "role": "Cause", "ref_id": "PMID-17690098_T21" } ] }, { "id": "PMID-17690098_E15", "type": "Binding", "trigger": { "text": [ "complexed" ], "offsets": [ [ 660, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T25" }, { "role": "Theme", "ref_id": "PMID-17690098_T27" } ] }, { "id": "PMID-17690098_E16", "type": "Binding", "trigger": { "text": [ "complexed" ], "offsets": [ [ 660, 669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T26" }, { "role": "Theme", "ref_id": "PMID-17690098_T27" } ] }, { "id": "PMID-17690098_E17", "type": "Binding", "trigger": { "text": [ "complexed" 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"Theme", "ref_id": "PMID-17690098_T38" }, { "role": "Theme", "ref_id": "PMID-17690098_T37" } ] }, { "id": "PMID-17690098_E26", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1067, 1076 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17690098_T41" }, { "role": "Theme", "ref_id": "PMID-17690098_T42" } ] }, { "id": "PMID-17690098_E27", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 1140, 1149 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17690098_T45" }, { "role": "Theme", "ref_id": "PMID-17690098_E28" } ] }, { "id": "PMID-17690098_E28", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1157, 1168 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T46" }, { "role": "Site", "ref_id": "PMID-17690098_T47" } ] }, { "id": "PMID-17690098_E29", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1223, 1234 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T46" } ] }, { "id": "PMID-17690098_E30", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 1334, 1344 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T52" } ] }, { "id": "PMID-17690098_E31", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1665, 1669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T55" } ] }, { "id": "PMID-17690098_E32", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1685, 1695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_E33" }, { "role": "Cause", "ref_id": "PMID-17690098_E31" } ] }, { "id": "PMID-17690098_E33", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1706, 1717 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690098_T56" } ] } ]

[ { "id": "PMID-17690098_1", "entity_ids": [ "PMID-17690098_T5", "PMID-17690098_T7" ] }, { "id": "PMID-17690098_2", "entity_ids": [ "PMID-17690098_T6", "PMID-17690098_T8" ] }, { "id": "PMID-17690098_3", "entity_ids": [ "PMID-17690098_T10", "PMID-17690098_T11" ] } ]

[]

[ { "id": "PMID-17693255__text", "type": "abstract", "text": [ "IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. \nTNFalpha has recently emerged as a regulator linking inflammation to cancer pathogenesis, but the detailed cellular and molecular mechanisms underlying this link remain to be elucidated. The tuberous sclerosis 1 (TSC1)/TSC2 tumor suppressor complex serves as a repressor of the mTOR pathway, and disruption of TSC1/TSC2 complex function may contribute to tumorigenesis. Here we show that IKKbeta, a major downstream kinase in the TNFalpha signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKbeta-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKbeta is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. Our findings identify a pathway that is critical for inflammation-mediated tumor angiogenesis and may provide a target for clinical intervention in human cancer. \n" ], "offsets": [ [ 0, 1157 ] ] } ]

[ { "id": "PMID-17693255_T1", "type": "Gene_or_gene_product", "text": [ "IKK beta" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-17693255_T2", "type": "Gene_or_gene_product", "text": [ "TSC1" ], "offsets": [ [ 24, 28 ] ], "normalized": [] }, { "id": "PMID-17693255_T3", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 79, 83 ] ], "normalized": [] }, { "id": "PMID-17693255_T4", "type": "Gene_or_gene_product", "text": [ "TNFalpha" ], "offsets": [ [ 94, 102 ] ], "normalized": [] }, { "id": "PMID-17693255_T5", "type": "Complex", "text": [ "tuberous sclerosis 1 (TSC1)/TSC2" ], "offsets": [ [ 285, 317 ] ], "normalized": [] }, { "id": "PMID-17693255_T6", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 372, 376 ] ], "normalized": [] }, { "id": "PMID-17693255_T7", "type": "Complex", "text": [ "TSC1/TSC2" ], "offsets": [ [ 404, 413 ] ], "normalized": [] }, { "id": "PMID-17693255_T8", "type": "Gene_or_gene_product", "text": [ "IKKbeta" ], "offsets": [ [ 482, 489 ] ], "normalized": [] }, { "id": "PMID-17693255_T9", "type": "Gene_or_gene_product", "text": [ "TNFalpha" ], "offsets": [ [ 524, 532 ] ], "normalized": [] }, { "id": "PMID-17693255_T10", "type": "Gene_or_gene_product", "text": [ "TSC1" ], "offsets": [ [ 597, 601 ] ], "normalized": [] }, { "id": "PMID-17693255_T11", "type": "Simple_chemical", "text": [ "Ser487" ], "offsets": [ [ 605, 611 ] ], "normalized": [] }, { "id": "PMID-17693255_T12", "type": "Simple_chemical", "text": [ "Ser511" ], "offsets": [ [ 616, 622 ] ], "normalized": [] }, { "id": "PMID-17693255_T13", "type": "Gene_or_gene_product", "text": [ "TSC1" ], "offsets": [ [ 652, 656 ] ], "normalized": [] }, { "id": "PMID-17693255_T14", "type": "Gene_or_gene_product", "text": [ "IKKbeta" ], "offsets": [ [ 662, 669 ] ], "normalized": [] }, { "id": "PMID-17693255_T15", "type": "Gene_or_gene_product", "text": [ "TSC1" ], "offsets": [ [ 679, 683 ] ], "normalized": [] }, { "id": "PMID-17693255_T16", "type": "Gene_or_gene_product", "text": [ "mTOR" ], "offsets": [ [ 710, 714 ] ], "normalized": [] }, { "id": "PMID-17693255_T17", "type": "Gene_or_gene_product", "text": [ "IKKbeta" ], "offsets": [ [ 826, 833 ] ], "normalized": [] }, { "id": "PMID-17693255_T18", "type": "Gene_or_gene_product", "text": [ "TSC1" ], "offsets": [ [ 853, 857 ] ], "normalized": [] }, { "id": "PMID-17693255_T19", "type": "Simple_chemical", "text": [ "Ser511" ], "offsets": [ [ 858, 864 ] ], "normalized": [] }, { "id": "PMID-17693255_T20", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 885, 889 ] ], "normalized": [] } ]

[ { "id": "PMID-17693255_E1", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 9, 20 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17693255_T1" }, { "role": "Theme", "ref_id": "PMID-17693255_T2" } ] }, { "id": "PMID-17693255_E2", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 84, 91 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17693255_T3" } ] }, { "id": "PMID-17693255_E3", "type": "Negative_regulation", "trigger": { "text": [ "repressor" ], "offsets": [ [ 355, 364 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17693255_T5" }, { "role": "Theme", "ref_id": "PMID-17693255_E4" } ] }, { "id": "PMID-17693255_E4", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 377, 384 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17693255_T6" } ] }, { "id": "PMID-17693255_E5", "type": "Dissociation", "trigger": { "text": [ "disruption" ], "offsets": [ [ 390, 400 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17693255_T7" } ] }, { "id": "PMID-17693255_E6", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 533, 550 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17693255_T9" } ] }, { "id": "PMID-17693255_E7", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 563, 572 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17693255_T8" }, { "role": "Theme", "ref_id": "PMID-17693255_T10" } ] }, { "id": "PMID-17693255_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 582, 596 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-17693255_T11" }, { "role": "Theme", "ref_id": "PMID-17693255_T10" }, { "role": "Cause", "ref_id": "PMID-17693255_T8" } ] }, { "id": "PMID-17693255_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 582, 596 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-17693255_T12" }, { "role": "Theme", "ref_id": "PMID-17693255_T10" }, { "role": "Cause", "ref_id": "PMID-17693255_T8" } ] }, { "id": "PMID-17693255_E10", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 637, 648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17693255_T13" }, { "role": "Cause", "ref_id": "PMID-17693255_E7" } ] }, { "id": "PMID-17693255_E11", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 637, 648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17693255_T13" }, { "role": "Cause", "ref_id": "PMID-17693255_E8" } ] }, { "id": "PMID-17693255_E12", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 637, 648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17693255_T13" }, { "role": "Cause", "ref_id": "PMID-17693255_E9" } ] }, { "id": "PMID-17693255_E13", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 670, 678 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17693255_T14" }, { "role": "Theme", "ref_id": "PMID-17693255_E14" } ] }, { "id": "PMID-17693255_E14", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 684, 695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17693255_T15" } ] }, { "id": "PMID-17693255_E15", "type": "Positive_regulation", "trigger": { "text": [ "activates" ], "offsets": [ [ 696, 705 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17693255_E14" }, { "role": "Theme", "ref_id": "PMID-17693255_E16" } ] }, { "id": "PMID-17693255_E16", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 715, 722 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-17693255_T16" } ] }, { "id": "PMID-17693255_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 802, 812 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17693255_T17" } ] }, { "id": "PMID-17693255_E18", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 816, 825 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17693255_T17" } ] }, { "id": "PMID-17693255_E19", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 837, 847 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17693255_E17" }, { "role": "Theme", "ref_id": "PMID-17693255_E21" } ] }, { "id": "PMID-17693255_E20", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 837, 847 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-17693255_E17" }, { "role": "Theme", "ref_id": "PMID-17693255_E22" } ] }, { "id": "PMID-17693255_E21", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 865, 880 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-17693255_T19" }, { "role": "Theme", "ref_id": "PMID-17693255_T18" } ] }, { "id": "PMID-17693255_E22", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 890, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17693255_T20" } ] } ]

[]

[]

[ { "id": "PMID-17898805__text", "type": "abstract", "text": [ "Forkhead proteins control the outcome of transcription factor binding by antiactivation. \nTranscription factors with identical DNA-binding specificity often activate different genes in vivo. Yeast Ace2 and Swi5 are such activators, with targets we classify as Swi5-only, Ace2-only, or both. We define two unique regulatory modes. Ace2 and Swi5 both bind in vitro to Swi5-only genes such as HO, but only Swi5 binds and activates in vivo. In contrast, Ace2 and Swi5 both bind in vivo to Ace2-only genes, such as CTS1, but promoter-bound Swi5 fails to activate. We show that activation by Swi5 is prevented by the binding of the Forkhead factors Fkh1 and Fkh2, which recruit the Rpd3(Large) histone deacetylase complex to the CTS1 promoter. Global analysis shows that all Ace2-only genes are bound by both Ace2 and Swi5, and also by Fkh1/2. Genes normally activated by either Ace2 or Swi5 can be converted to Ace2-only genes by the insertion of Fkh-binding sites. Thus Fkh proteins, which function initially to activate SWI5 and ACE2, subsequently function as Swi5-specific antiactivators.\n" ], "offsets": [ [ 0, 1087 ] ] } ]

[ { "id": "PMID-17898805_T1", "type": "Gene_or_gene_product", "text": [ "Forkhead" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-17898805_T2", "type": "Gene_or_gene_product", "text": [ "Ace2" ], "offsets": [ [ 197, 201 ] ], "normalized": [] }, { "id": "PMID-17898805_T3", "type": "Gene_or_gene_product", "text": [ "Swi5" ], "offsets": [ [ 206, 210 ] ], "normalized": [] }, { "id": "PMID-17898805_T4", "type": "Gene_or_gene_product", "text": [ "Swi5" ], "offsets": [ [ 260, 264 ] ], "normalized": [] }, { "id": "PMID-17898805_T5", "type": "Gene_or_gene_product", "text": [ "Ace2" ], "offsets": [ [ 271, 275 ] ], "normalized": [] }, { "id": "PMID-17898805_T6", "type": "Gene_or_gene_product", "text": [ "Ace2" ], "offsets": [ [ 330, 334 ] ], "normalized": [] }, { "id": "PMID-17898805_T7", "type": "Gene_or_gene_product", "text": [ "Swi5" ], "offsets": [ [ 339, 343 ] ], "normalized": [] }, { "id": "PMID-17898805_T8", "type": "Gene_or_gene_product", "text": [ "Swi5" ], "offsets": [ [ 366, 370 ] ], "normalized": [] }, { "id": "PMID-17898805_T9", "type": "Gene_or_gene_product", "text": [ "HO" ], "offsets": [ [ 390, 392 ] ], "normalized": [] }, { "id": "PMID-17898805_T10", "type": "Gene_or_gene_product", "text": [ "Swi5" ], "offsets": [ [ 403, 407 ] ], "normalized": [] }, { "id": "PMID-17898805_T11", "type": "Gene_or_gene_product", "text": [ "Ace2" ], "offsets": [ [ 450, 454 ] ], "normalized": [] }, { "id": "PMID-17898805_T12", "type": "Gene_or_gene_product", "text": [ "Swi5" ], "offsets": [ [ 459, 463 ] ], "normalized": [] }, { "id": "PMID-17898805_T13", "type": "Gene_or_gene_product", "text": [ "Ace2" ], "offsets": [ [ 485, 489 ] ], "normalized": [] }, { "id": "PMID-17898805_T14", "type": "Gene_or_gene_product", "text": [ "CTS1" ], "offsets": [ [ 510, 514 ] ], "normalized": [] }, { "id": "PMID-17898805_T15", "type": "Gene_or_gene_product", "text": [ "Swi5" ], "offsets": [ [ 535, 539 ] ], "normalized": [] }, { "id": "PMID-17898805_T16", "type": "Gene_or_gene_product", "text": [ "Swi5" ], "offsets": [ [ 586, 590 ] ], "normalized": [] }, { "id": "PMID-17898805_T17", "type": "Gene_or_gene_product", "text": [ "Forkhead" ], "offsets": [ [ 626, 634 ] ], "normalized": [] }, { "id": "PMID-17898805_T18", "type": "Gene_or_gene_product", "text": [ "Fkh1" ], "offsets": [ [ 643, 647 ] ], "normalized": [] }, { "id": "PMID-17898805_T19", "type": "Gene_or_gene_product", "text": [ "Fkh2" ], "offsets": [ [ 652, 656 ] ], "normalized": [] }, { "id": "PMID-17898805_T20", "type": "Complex", "text": [ "Rpd3" ], "offsets": [ [ 676, 680 ] ], "normalized": [] }, { "id": "PMID-17898805_T21", "type": "Gene_or_gene_product", "text": [ "histone deacetylase" ], "offsets": [ [ 688, 707 ] ], "normalized": [] }, { "id": "PMID-17898805_T22", "type": "Gene_or_gene_product", "text": [ "CTS1" ], "offsets": [ [ 723, 727 ] ], "normalized": [] }, { "id": "PMID-17898805_T23", "type": "Gene_or_gene_product", "text": [ "Ace2" ], "offsets": [ [ 769, 773 ] ], "normalized": [] }, { "id": "PMID-17898805_T24", "type": "Gene_or_gene_product", "text": [ "Ace2" ], "offsets": [ [ 803, 807 ] ], "normalized": [] }, { "id": "PMID-17898805_T25", "type": "Gene_or_gene_product", "text": [ "Swi5" ], "offsets": [ [ 812, 816 ] ], "normalized": [] }, { "id": "PMID-17898805_T26", "type": "Gene_or_gene_product", "text": [ "Fkh1" ], "offsets": [ [ 830, 834 ] ], "normalized": [] }, { "id": "PMID-17898805_T27", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 835, 836 ] ], "normalized": [] }, { "id": "PMID-17898805_T28", "type": "Gene_or_gene_product", "text": [ "Ace2" ], "offsets": [ [ 873, 877 ] ], "normalized": [] }, { "id": "PMID-17898805_T29", "type": "Gene_or_gene_product", "text": [ "Swi5" ], "offsets": [ [ 881, 885 ] ], "normalized": [] }, { "id": "PMID-17898805_T30", "type": "Gene_or_gene_product", "text": [ "Ace2" ], "offsets": [ [ 906, 910 ] ], "normalized": [] }, { "id": "PMID-17898805_T31", "type": "Gene_or_gene_product", "text": [ "Fkh" ], "offsets": [ [ 942, 945 ] ], "normalized": [] }, { "id": "PMID-17898805_T32", "type": "Gene_or_gene_product", "text": [ "Fkh" ], "offsets": [ [ 966, 969 ] ], "normalized": [] }, { "id": "PMID-17898805_T33", "type": "Gene_or_gene_product", "text": [ "SWI5" ], "offsets": [ [ 1017, 1021 ] ], "normalized": [] }, { "id": "PMID-17898805_T34", "type": "Gene_or_gene_product", "text": [ "ACE2" ], "offsets": [ [ 1026, 1030 ] ], "normalized": [] }, { "id": "PMID-17898805_T35", "type": "Gene_or_gene_product", "text": [ "Swi5" ], "offsets": [ [ 1057, 1061 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "PMID-18046414__text", "type": "abstract", "text": [ "mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. \nTranscriptional complexes that contain peroxisome-proliferator-activated receptor coactivator (PGC)-1alpha control mitochondrial oxidative function to maintain energy homeostasis in response to nutrient and hormonal signals. An important component in the energy and nutrient pathways is mammalian target of rapamycin (mTOR), a kinase that regulates cell growth, size and survival. However, it is unknown whether and how mTOR controls mitochondrial oxidative activities. Here we show that mTOR is necessary for the maintenance of mitochondrial oxidative function. In skeletal muscle tissues and cells, the mTOR inhibitor rapamycin decreased the gene expression of the mitochondrial transcriptional regulators PGC-1alpha, oestrogen-related receptor alpha and nuclear respiratory factors, resulting in a decrease in mitochondrial gene expression and oxygen consumption. Using computational genomics, we identified the transcription factor yin-yang 1 (YY1) as a common target of mTOR and PGC-1alpha. Knockdown of YY1 caused a significant decrease in mitochondrial gene expression and in respiration, and YY1 was required for rapamycin-dependent repression of those genes. Moreover, mTOR and raptor interacted with YY1, and inhibition of mTOR resulted in a failure of YY1 to interact with and be coactivated by PGC-1alpha. We have therefore identified a mechanism by which a nutrient sensor (mTOR) balances energy metabolism by means of the transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer. \n" ], "offsets": [ [ 0, 1733 ] ] } ]

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[ { "id": "PMID-18046414_1", "entity_ids": [ "PMID-18046414_T6", "PMID-18046414_T7" ] }, { "id": "PMID-18046414_2", "entity_ids": [ "PMID-18046414_T20", "PMID-18046414_T21" ] } ]

[]

[ { "id": "PMID-18088386__text", "type": "abstract", "text": [ "The functions and possible significance of Kremen as the gatekeeper of Wnt signalling in development and pathology. \nKremen (Krm) was originally discovered as a novel transmembrane protein containing the kringle domain. Both Krm1 (the first identified Krm) and its relative Krm2 were later identified to be the high-affinity receptors for Dickkopf (Dkk), the inhibitor of Wnt/beta-catenin signalling. The formation of a ternary complex composed of Krm, Dkk, and Lrp5/6 (the coreceptor of Wnt) inhibits Wnt/beta-catenin signalling. In Xenopus gastrula embryos, Wnt/beta-catenin signalling regulates anterior-posterior patterning, with low-signalling in anterior regions. Inhibition of Krm1/2 induces embryonic head defects. Together with anterior localization of Krms and Dkks, the inhibition of Wnt signalling by Dkk-Krm action seems to allow anterior embryonic development. During mammalian development, krm1 mRNA expression is low in the early stages, but gradually and continuously increases with developmental progression and differentiation. In contrast with the wide, strong expression of krm1 mRNA in mature tissues, expression of krm1 is diminished in a variety of human tumor cells. Since stem cells and undifferentiated cells rely on Wnt/beta-catenin signalling for maintenance in a low differentiation state, the physiological shutdown of Wnt/beta-catenin signalling by Dkk-Krm is likely to set cells on a divergent path toward differentiation. In tumour cells, a deficit of Krm may increase the susceptibility to tumourigenic transformation. Both positive and negative regulation of Wnt/beta-catenin signalling definitively contributes to diverse developmental and physiological processes, including cell-fate determination, tissue patterning and stem cell regulation. Krm is quite significant in these processes as the gatekeeper of the Wnt/beta-catenin signalling pathway.\n" ], "offsets": [ [ 0, 1887 ] ] } ]

[ { "id": "PMID-18088386_T1", "type": "Gene_or_gene_product", "text": [ "Kremen" ], "offsets": [ [ 43, 49 ] ], "normalized": [] }, { "id": "PMID-18088386_T2", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 71, 74 ] ], "normalized": [] }, { "id": "PMID-18088386_T3", "type": "Gene_or_gene_product", "text": [ "Kremen" ], "offsets": [ [ 117, 123 ] ], "normalized": [] }, { "id": "PMID-18088386_T4", "type": "Gene_or_gene_product", "text": [ "Krm" ], "offsets": [ [ 125, 128 ] ], "normalized": [] }, { "id": "PMID-18088386_T5", "type": "Gene_or_gene_product", "text": [ "Krm1" ], "offsets": [ [ 225, 229 ] ], "normalized": [] }, { "id": "PMID-18088386_T6", "type": "Gene_or_gene_product", "text": [ "Krm" ], "offsets": [ [ 252, 255 ] ], "normalized": [] }, { "id": "PMID-18088386_T7", "type": "Gene_or_gene_product", "text": [ "Krm2" ], "offsets": [ [ 274, 278 ] ], "normalized": [] }, { "id": "PMID-18088386_T8", "type": "Gene_or_gene_product", "text": [ "Dickkopf" ], "offsets": [ [ 339, 347 ] ], "normalized": [] }, { "id": "PMID-18088386_T9", "type": "Gene_or_gene_product", "text": [ "Dkk" ], "offsets": [ [ 349, 352 ] ], "normalized": [] }, { "id": "PMID-18088386_T10", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 372, 375 ] ], "normalized": [] }, { "id": "PMID-18088386_T11", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 376, 388 ] ], "normalized": [] }, { "id": "PMID-18088386_T12", "type": "Gene_or_gene_product", "text": [ "Krm" ], "offsets": [ [ 448, 451 ] ], "normalized": [] }, { "id": "PMID-18088386_T13", "type": "Gene_or_gene_product", "text": [ "Dkk" ], "offsets": [ [ 453, 456 ] ], "normalized": [] }, { "id": "PMID-18088386_T14", "type": "Gene_or_gene_product", "text": [ "Lrp5/6" ], "offsets": [ [ 462, 468 ] ], "normalized": [] }, { "id": "PMID-18088386_T15", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 488, 491 ] ], "normalized": [] }, { "id": "PMID-18088386_T16", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 502, 505 ] ], "normalized": [] }, { "id": "PMID-18088386_T17", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 506, 518 ] ], "normalized": [] }, { "id": "PMID-18088386_T18", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 560, 563 ] ], "normalized": [] }, { "id": "PMID-18088386_T19", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 564, 576 ] ], "normalized": [] }, { "id": "PMID-18088386_T20", "type": "Gene_or_gene_product", "text": [ "Krm1" ], "offsets": [ [ 684, 688 ] ], "normalized": [] }, { "id": "PMID-18088386_T21", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 689, 690 ] ], "normalized": [] }, { "id": "PMID-18088386_T22", "type": "Gene_or_gene_product", "text": [ "Krms" ], "offsets": [ [ 762, 766 ] ], "normalized": [] }, { "id": "PMID-18088386_T23", "type": "Gene_or_gene_product", "text": [ "Dkks" ], "offsets": [ [ 771, 775 ] ], "normalized": [] }, { "id": "PMID-18088386_T24", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 795, 798 ] ], "normalized": [] }, { "id": "PMID-18088386_T25", "type": "Gene_or_gene_product", "text": [ "Dkk" ], "offsets": [ [ 813, 816 ] ], "normalized": [] }, { "id": "PMID-18088386_T26", "type": "Gene_or_gene_product", "text": [ "Krm" ], "offsets": [ [ 817, 820 ] ], "normalized": [] }, { "id": "PMID-18088386_T27", "type": "Gene_or_gene_product", "text": [ "krm1" ], "offsets": [ [ 905, 909 ] ], "normalized": [] }, { "id": "PMID-18088386_T28", "type": "Gene_or_gene_product", "text": [ "krm1" ], "offsets": [ [ 1095, 1099 ] ], "normalized": [] }, { "id": "PMID-18088386_T29", "type": "Gene_or_gene_product", "text": [ "krm1" ], "offsets": [ [ 1138, 1142 ] ], "normalized": [] }, { "id": "PMID-18088386_T30", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 1244, 1247 ] ], "normalized": [] }, { "id": "PMID-18088386_T31", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1248, 1260 ] ], "normalized": [] }, { "id": "PMID-18088386_T32", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 1350, 1353 ] ], "normalized": [] }, { "id": "PMID-18088386_T33", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1354, 1366 ] ], "normalized": [] }, { "id": "PMID-18088386_T34", "type": "Gene_or_gene_product", "text": [ "Dkk" ], "offsets": [ [ 1381, 1384 ] ], "normalized": [] }, { "id": "PMID-18088386_T35", "type": "Gene_or_gene_product", "text": [ "Krm" ], "offsets": [ [ 1385, 1388 ] ], "normalized": [] }, { "id": "PMID-18088386_T36", "type": "Gene_or_gene_product", "text": [ "Krm" ], "offsets": [ [ 1486, 1489 ] ], "normalized": [] }, { "id": "PMID-18088386_T37", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 1595, 1598 ] ], "normalized": [] }, { "id": "PMID-18088386_T38", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1599, 1611 ] ], "normalized": [] }, { "id": "PMID-18088386_T39", "type": "Gene_or_gene_product", "text": [ "Krm" ], "offsets": [ [ 1781, 1784 ] ], "normalized": [] }, { "id": "PMID-18088386_T40", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 1850, 1853 ] ], "normalized": [] }, { "id": "PMID-18088386_T41", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1854, 1866 ] ], "normalized": [] } ]

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regulation" ], "offsets": [ [ 1572, 1591 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18088386_E28" } ] }, { "id": "PMID-18088386_E28", "type": "Pathway", "trigger": { "text": [ "signalling" ], "offsets": [ [ 1612, 1622 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-18088386_T37" }, { "role": "Participant", "ref_id": "PMID-18088386_T38" } ] }, { "id": "PMID-18088386_E29", "type": "Regulation", "trigger": { "text": [ "gatekeeper" ], "offsets": [ [ 1832, 1842 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18088386_E30" }, { "role": "Cause", "ref_id": "PMID-18088386_T39" } ] }, { "id": "PMID-18088386_E30", "type": "Pathway", "trigger": { "text": [ "signalling pathway" ], "offsets": [ [ 1867, 1885 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-18088386_T40" }, { "role": "Participant", "ref_id": "PMID-18088386_T41" } ] } ]

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[]

[ { "id": "PMID-18092340__text", "type": "abstract", "text": [ "Differential effects of chemotherapeutic drugs versus the MDM-2 antagonist nutlin-3 on cell cycle progression and induction of apoptosis in SKW6.4 lymphoblastoid B-cells. \nWe have compared the cytotoxic/cytostatic responses of the SKW6.4 lymphoblastoid B-cells to the alkylating agent chlorambucil, the purine analog fludarabine, the non-genotoxic activator of the p53 pathway, Nutlin-3, used alone or in association with the death-inducing ligand recombinant TRAIL. Exposure to chlorambucil, fludarabine, and Nutlin-3 induced p53 accumulation and variably affected cell cycle progression in SKW6.4 lymphoblastoid cells. In particular, chlorambucil induced cell cycle accumulation at the G2/M checkpoint; Nutlin-3 induced early cell cycle arrest at the G1/S checkpoint, while fludarabine showed an intermediate behavior. On the other hand, recombinant TRAIL alone did not affect cell cycle progression but induced a rapid increase of apoptosis. Analysis of the gene expression profile of the p53-transcriptional targets showed distinct features between chlorambucil, Nutlin-3 and fludarabine, which likely account for their differential effect on cell cycle in SKW6.4 cells. In particular, chlorambucil upregulated the steady-state mRNA expression of SFN/14-3-3sigma, a gene involved in G2/M cell cycle arrest. Of note, all agonists upregulated TRAIL-R2 expression in SKW6.4 cells both at the mRNA and protein levels. Consistently, pretreatment with chlorambucil, fludarabine and Nutlin-3 enhanced SKW6.4 sensitivity to TRAIL-mediated apoptosis.\n" ], "offsets": [ [ 0, 1546 ] ] } ]

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"effect" ], "offsets": [ [ 1137, 1143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18092340_E28" }, { "role": "Cause", "ref_id": "PMID-18092340_T18" } ] }, { "id": "PMID-18092340_E26", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1137, 1143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18092340_E28" }, { "role": "Cause", "ref_id": "PMID-18092340_T19" } ] }, { "id": "PMID-18092340_E27", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1137, 1143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18092340_E28" }, { "role": "Cause", "ref_id": "PMID-18092340_T20" } ] }, { "id": "PMID-18092340_E28", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1147, 1157 ] ] }, "arguments": [] }, { "id": "PMID-18092340_E29", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 1203, 1214 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18092340_T21" }, { "role": 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"role": "Theme", "ref_id": "PMID-18092340_E41" }, { "role": "Cause", "ref_id": "PMID-18092340_T26" } ] }, { "id": "PMID-18092340_E39", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1489, 1497 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18092340_E41" }, { "role": "Cause", "ref_id": "PMID-18092340_T27" } ] }, { "id": "PMID-18092340_E40", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1526, 1534 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18092340_T28" }, { "role": "Theme", "ref_id": "PMID-18092340_E41" } ] }, { "id": "PMID-18092340_E41", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1535, 1544 ] ] }, "arguments": [] } ]

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[]

[ { "id": "PMID-18198340__text", "type": "abstract", "text": [ "Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. \nHypoxia induces rapid and dramatic changes in cellular metabolism, in part through inhibition of target of rapamycin (TOR) kinase complex 1 (TORC1) activity. Genetic studies have shown the tuberous sclerosis tumor suppressors TSC1/2 and the REDD1 protein to be essential for hypoxia regulation of TORC1 activity in Drosophila and in mammalian cells. The molecular mechanism and physiologic significance of this effect of hypoxia remain unknown. Here, we demonstrate that hypoxia and REDD1 suppress mammalian TORC1 (mTORC1) activity by releasing TSC2 from its growth factor-induced association with inhibitory 14-3-3 proteins. Endogenous REDD1 is required for both dissociation of endogenous TSC2/14-3-3 and inhibition of mTORC1 in response to hypoxia. REDD1 mutants that fail to bind 14-3-3 are defective in eliciting TSC2/14-3-3 dissociation and mTORC1 inhibition, while TSC2 mutants that do not bind 14-3-3 are inactive in hypoxia signaling to mTORC1. In vitro, loss of REDD1 signaling promotes proliferation and anchorage-independent growth under hypoxia through mTORC1 dysregulation. In vivo, REDD1 loss elicits tumorigenesis in a mouse model, and down-regulation of REDD1 is observed in a subset of human cancers. Together, these findings define a molecular mechanism of signal integration by TSC1/2 that provides insight into the ability of REDD1 to function in a hypoxia-dependent tumor suppressor pathway. \n" ], "offsets": [ [ 0, 1519 ] ] } ]

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[]

[ { "id": "PMID-18242749__text", "type": "abstract", "text": [ "Specific induction of PAG608 in cranial and spinal motor neurons of L-DOPA-treated parkinsonian rats. \nWe identified p53-activated gene 608 (PAG608) as a specifically induced gene in striatal tissue of L-DOPA (100mg/kg)-injected hemi-parkinsonian rats using differential display assay. In the present study, we further examined morphological distribution of PAG608 in the central nervous system of L-DOPA-treated hemi-parkinsonian rats. PAG608 expression was markedly induced in fibers and neuronal cells of the lateral globus pallidus and reticular thalamic nucleus adjacent to internal capsule, specifically in the parkinsonian side of L-DOPA-treated models. The protein was also constitutively expressed in motor neurons specifically in either side of the pontine nucleus and motor nuclei of trigeminal and facial nerves. Furthermore, L-DOPA-induced PAG608 expression on motor neurons in the contralateral side of the ventral horn of the spinal cord and the lateral corticospinal tract without cell loss. The specific induction of PAG608 6-48h after L-DOPA injection in the extrapyramidal tracts, pyramidal tracts and corresponding lower motor neurons of the spinal cords suggests its involvement in molecular events in stimulated motor neurons. Taken together with the constitutive expression of PAG608 in the motor nuclei of cranial nerves, PAG608 may be a useful marker of stressed or activated lower motor neurons.\n" ], "offsets": [ [ 0, 1422 ] ] } ]

[ { "id": "PMID-18242749_T1", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 22, 28 ] ], "normalized": [] }, { "id": "PMID-18242749_T2", "type": "Simple_chemical", "text": [ "L-DOPA" ], "offsets": [ [ 68, 74 ] ], "normalized": [] }, { "id": "PMID-18242749_T3", "type": "Gene_or_gene_product", "text": [ "p53-activated gene 608" ], "offsets": [ [ 117, 139 ] ], "normalized": [] }, { "id": "PMID-18242749_T4", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 141, 147 ] ], "normalized": [] }, { "id": "PMID-18242749_T5", "type": "Simple_chemical", "text": [ "L-DOPA" ], "offsets": [ [ 202, 208 ] ], "normalized": [] }, { "id": "PMID-18242749_T6", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 358, 364 ] ], "normalized": [] }, { "id": "PMID-18242749_T7", "type": "Simple_chemical", "text": [ "L-DOPA" ], "offsets": [ [ 398, 404 ] ], "normalized": [] }, { "id": "PMID-18242749_T8", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 437, 443 ] ], "normalized": [] }, { "id": "PMID-18242749_T9", "type": "Simple_chemical", "text": [ "L-DOPA" ], "offsets": [ [ 638, 644 ] ], "normalized": [] }, { "id": "PMID-18242749_T10", "type": "Simple_chemical", "text": [ "L-DOPA" ], "offsets": [ [ 838, 844 ] ], "normalized": [] }, { "id": "PMID-18242749_T11", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 853, 859 ] ], "normalized": [] }, { "id": "PMID-18242749_T12", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 1034, 1040 ] ], "normalized": [] }, { "id": "PMID-18242749_T13", "type": "Simple_chemical", "text": [ "L-DOPA" ], "offsets": [ [ 1053, 1059 ] ], "normalized": [] }, { "id": "PMID-18242749_T14", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 1300, 1306 ] ], "normalized": [] }, { "id": "PMID-18242749_T15", "type": "Gene_or_gene_product", "text": [ "PAG608" ], "offsets": [ [ 1346, 1352 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-18310316__text", "type": "abstract", "text": [ "Small molecular weight variants of p53 are expressed in human melanoma cells and are induced by the DNA-damaging agent cisplatin. \nPURPOSE: Metastatic melanoma is largely unresponsive to DNA-damaging chemotherapy agents, although WTp53 is frequently detected. Several isoforms of p53 have been discovered, some of which inhibit p53 function. We therefore examined whether p53 isoforms were present in melanoma and whether they may contribute to aberrant p53 function in melanoma. EXPERIMENTAL DESIGN: We studied the expression and subcellular localization of p53 and its isoforms in a panel of human melanoma cell lines using Western blot, two-dimensional electrophoresis, and reverse transcription-PCR. We also characterized the relationship between the expression of p53, p53 isoforms, and p53 target genes following treatment with the DNA-damaging agent cisplatin. RESULTS: We report that p53beta and Delta40p53 were expressed in the majority of melanoma cell lines at the mRNA level, but were absent or expressed at low levels in fibroblasts and melanocytes, suggesting that their expression may play a role in melanoma development. Analysis by two-dimensional gel electrophoresis revealed that p53beta was expressed at the protein level in melanoma cells. Both p53 and the small molecular weight forms of p53 were aberrantly expressed between the nuclear and cytosolic fractions of melanoma cell lines, compared with normal fibroblasts. Treatment with cisplatin had differential effects on WTp53 and the small molecular weight form of p53 that were cell line dependent. Delta40p53 was shown to inhibit, whereas p53beta was shown to enhance, p53-dependent transcription of p21 and PUMA. CONCLUSIONS: p53beta and Delta40p53 are expressed in melanoma and this may have important implications for understanding resistance of melanoma to DNA-damaging chemotherapy.\n" ], "offsets": [ [ 0, 1865 ] ] } ]

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[]

[]

[ { "id": "PMID-18391023__text", "type": "abstract", "text": [ "PTEN represses RNA polymerase III-dependent transcription by targeting the TFIIIB complex. \nPTEN, a tumor suppressor whose function is frequently lost in human cancers, possesses a lipid phosphatase activity that represses phosphatidylinositol 3-kinase (PI3K) signaling, controlling cell growth, proliferation, and survival. The potential for PTEN to regulate the synthesis of RNA polymerase (Pol) III transcription products, including tRNAs and 5S rRNAs, was evaluated. The expression of PTEN in PTEN-deficient cells repressed RNA Pol III transcription, whereas decreased PTEN expression enhanced transcription. Transcription repression by PTEN was uncoupled from PTEN-mediated effects on the cell cycle and was independent of p53. PTEN acts through its lipid phosphatase activity, inhibiting the PI3K/Akt/mTOR/S6K pathway to decrease transcription. PTEN, through the inactivation of mTOR, targets the TFIIIB complex, disrupting the association between TATA-binding protein and Brf1. Kinetic analysis revealed that PTEN initially induces a decrease in the serine phosphorylation of Brf1, leading to a selective reduction in the occupancy of all TFIIIB subunits on tRNA(Leu) genes, whereas prolonged PTEN expression results in the enhanced serine phosphorylation of Bdp1. Together, these results demonstrate a new class of genes regulated by PTEN through its ability to repress the activation of PI3K/Akt/mTOR/S6K signaling. \n" ], "offsets": [ [ 0, 1426 ] ] } ]

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"Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 540, 553 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_T11" } ] }, { "id": "PMID-18391023_E11", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 563, 572 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_E12" } ] }, { "id": "PMID-18391023_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 578, 588 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_T12" } ] }, { "id": "PMID-18391023_E13", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 589, 597 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_E14" }, { "role": "Cause", "ref_id": "PMID-18391023_E11" } ] }, { "id": "PMID-18391023_E14", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 598, 611 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_T11" } ] }, { "id": "PMID-18391023_E15", "type": "Transcription", "trigger": { "text": [ "Transcription" ], "offsets": [ [ 613, 626 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_T11" } ] }, { "id": "PMID-18391023_E16", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 627, 637 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18391023_T13" }, { "role": "Theme", "ref_id": "PMID-18391023_E15" } ] }, { "id": "PMID-18391023_E17", "type": "Regulation", "trigger": { "text": [ "uncoupled" ], "offsets": [ [ 650, 659 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_E16" }, { "role": "Cause", "ref_id": "PMID-18391023_E19" } ] }, { "id": "PMID-18391023_E18", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 670, 678 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18391023_T14" }, { "role": "Theme", "ref_id": "PMID-18391023_E19" } ] }, { "id": "PMID-18391023_E19", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 679, 686 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_E20" } ] }, { "id": "PMID-18391023_E20", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 694, 704 ] ] }, "arguments": [] }, { "id": "PMID-18391023_E21", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 713, 724 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18391023_T15" }, { "role": "Theme", "ref_id": "PMID-18391023_E16" } ] }, { "id": "PMID-18391023_E22", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 783, 793 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_E23" }, { "role": "Cause", "ref_id": "PMID-18391023_T16" } ] }, { "id": "PMID-18391023_E23", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 816, 823 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-18391023_T17" }, { "role": "Participant", "ref_id": "PMID-18391023_T18" }, { "role": "Participant", "ref_id": "PMID-18391023_T19" }, { "role": "Participant", "ref_id": "PMID-18391023_T20" } ] }, { "id": "PMID-18391023_E24", "type": "Inactivation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 869, 881 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_T22" }, { "role": "Cause", "ref_id": "PMID-18391023_T21" } ] }, { "id": "PMID-18391023_E25", "type": "Regulation", "trigger": { "text": [ "targets" ], "offsets": [ [ 891, 898 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18391023_E24" }, { "role": "Theme", "ref_id": "PMID-18391023_T23" } ] }, { "id": "PMID-18391023_E26", "type": "Negative_regulation", "trigger": { "text": [ "disrupting" ], "offsets": [ [ 919, 929 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_E27" }, { "role": "Cause", "ref_id": "PMID-18391023_T21" } ] }, { "id": "PMID-18391023_E27", "type": "Binding", "trigger": { "text": [ "association" ], "offsets": [ [ 934, 945 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_T24" }, { "role": "Theme", "ref_id": "PMID-18391023_T25" } ] }, { "id": "PMID-18391023_E28", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 1031, 1038 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_E29" }, { "role": "Cause", "ref_id": "PMID-18391023_T26" } ] }, { "id": "PMID-18391023_E29", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1041, 1049 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_E30" } ] }, { "id": "PMID-18391023_E30", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1064, 1079 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-18391023_T27" }, { "role": "Theme", "ref_id": "PMID-18391023_T28" } ] }, { "id": "PMID-18391023_E31", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1205, 1215 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_T30" } ] }, { "id": "PMID-18391023_E32", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1231, 1239 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18391023_E31" }, { "role": "Theme", "ref_id": "PMID-18391023_E33" } ] }, { "id": "PMID-18391023_E33", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1247, 1262 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-18391023_T31" }, { "role": "Theme", "ref_id": "PMID-18391023_T32" } ] }, { "id": "PMID-18391023_E34", "type": "Negative_regulation", "trigger": { "text": [ "repress" ], "offsets": [ [ 1370, 1377 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_E35" }, { "role": "Cause", "ref_id": "PMID-18391023_T33" } ] }, { "id": "PMID-18391023_E35", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1382, 1392 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18391023_E36" } ] }, { "id": "PMID-18391023_E36", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1414, 1423 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-18391023_T34" }, { "role": "Participant", "ref_id": "PMID-18391023_T35" }, { "role": "Participant", "ref_id": "PMID-18391023_T36" }, { "role": "Participant", "ref_id": "PMID-18391023_T37" } ] } ]

[ { "id": "PMID-18391023_1", "entity_ids": [ "PMID-18391023_T5", "PMID-18391023_T6" ] } ]

[]

[ { "id": "PMID-18409048__text", "type": "abstract", "text": [ "Inhibitory effect of citral on NO production by suppression of iNOS expression and NF-kappa B activation in RAW264.7 cells. \nCitral is a major compound of lemongrass (Cymbopogon citratus L.) that has many pharmacological activities such as anti-fungal and anti-bacterial effects. In this study, we investigated the anti-inflammatory effect of citral and defined its mechanism of action in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Citral (3-12 microg/mL) significantly inhibited LPS-induced nitric oxide (NO) production in a concentration-dependent manner (IC50: 6.5 microg/mL). Furthermore, it was found that citral effectively inhibited the transcriptional activity and expression of iNOS, and potently suppressed the DNA binding activity and nuclear translocation of NF-kappa B as well as I kappa B phosphorylation in a concentration dependent manner. These results suggest that citral is anti-inflammatory, and its effects may be due to the inhibition of NO production through the suppression of NF-kappa B activation.\n" ], "offsets": [ [ 0, 1034 ] ] } ]

[ { "id": "PMID-18409048_T1", "type": "Simple_chemical", "text": [ "citral" ], "offsets": [ [ 21, 27 ] ], "normalized": [] }, { "id": "PMID-18409048_T2", "type": "Simple_chemical", "text": [ "NO" ], "offsets": [ [ 31, 33 ] ], "normalized": [] }, { "id": "PMID-18409048_T3", "type": "Gene_or_gene_product", "text": [ "iNOS" ], "offsets": [ [ 63, 67 ] ], "normalized": [] }, { "id": "PMID-18409048_T4", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 83, 93 ] ], "normalized": [] }, { "id": "PMID-18409048_T5", "type": "Simple_chemical", "text": [ "Citral" ], "offsets": [ [ 125, 131 ] ], "normalized": [] }, { "id": "PMID-18409048_T6", "type": "Simple_chemical", "text": [ "citral" ], "offsets": [ [ 343, 349 ] ], "normalized": [] }, { "id": "PMID-18409048_T7", "type": "Simple_chemical", "text": [ "lipopolysaccharide" ], "offsets": [ [ 389, 407 ] ], "normalized": [] }, { "id": "PMID-18409048_T8", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 409, 412 ] ], "normalized": [] }, { "id": "PMID-18409048_T9", "type": "Simple_chemical", "text": [ "Citral" ], "offsets": [ [ 442, 448 ] ], "normalized": [] }, { "id": "PMID-18409048_T10", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 490, 493 ] ], "normalized": [] }, { "id": "PMID-18409048_T11", "type": "Simple_chemical", "text": [ "nitric oxide" ], "offsets": [ [ 502, 514 ] ], "normalized": [] }, { "id": "PMID-18409048_T12", "type": "Simple_chemical", "text": [ "NO" ], "offsets": [ [ 516, 518 ] ], "normalized": [] }, { "id": "PMID-18409048_T13", "type": "Simple_chemical", "text": [ "citral" ], "offsets": [ [ 621, 627 ] ], "normalized": [] }, { "id": "PMID-18409048_T14", "type": "Gene_or_gene_product", "text": [ "iNOS" ], "offsets": [ [ 697, 701 ] ], "normalized": [] }, { "id": "PMID-18409048_T15", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 756, 763 ] ], "normalized": [] }, { "id": "PMID-18409048_T16", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 781, 791 ] ], "normalized": [] }, { "id": "PMID-18409048_T17", "type": "Gene_or_gene_product", "text": [ "I kappa B" ], "offsets": [ [ 803, 812 ] ], "normalized": [] }, { "id": "PMID-18409048_T18", "type": "Simple_chemical", "text": [ "citral" ], "offsets": [ [ 893, 899 ] ], "normalized": [] }, { "id": "PMID-18409048_T19", "type": "Simple_chemical", "text": [ "NO" ], "offsets": [ [ 970, 972 ] ], "normalized": [] }, { "id": "PMID-18409048_T20", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 1011, 1021 ] ], "normalized": [] } ]

[ { "id": "PMID-18409048_E1", "type": "Negative_regulation", "trigger": { "text": [ "Inhibitory" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18409048_E2" } ] }, { "id": "PMID-18409048_E2", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 11, 17 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18409048_T1" }, { "role": "Theme", "ref_id": "PMID-18409048_E3" } ] }, { "id": "PMID-18409048_E3", "type": "Conversion", "trigger": { "text": [ "production" ], "offsets": [ [ 34, 44 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-18409048_T2" } ] }, { "id": "PMID-18409048_E4", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 48, 59 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18409048_E2" }, { "role": "Theme", "ref_id": "PMID-18409048_E6" } ] }, { "id": "PMID-18409048_E5", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 48, 59 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18409048_E2" }, { "role": "Theme", "ref_id": "PMID-18409048_E7" } ] }, { "id": "PMID-18409048_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 68, 78 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18409048_T3" } ] }, { "id": "PMID-18409048_E7", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 94, 104 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18409048_T4" } ] }, { "id": "PMID-18409048_E8", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 480, 489 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18409048_T9" }, { "role": "Theme", "ref_id": "PMID-18409048_E10" } ] }, { "id": "PMID-18409048_E9", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 494, 501 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18409048_T10" }, { "role": "Theme", "ref_id": "PMID-18409048_E10" } ] }, { "id": "PMID-18409048_E10", "type": "Conversion", "trigger": { "text": [ "production" ], "offsets": [ [ 520, 530 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-18409048_T11" } ] }, { "id": "PMID-18409048_E11", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 640, 649 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18409048_T13" }, { "role": "Theme", "ref_id": "PMID-18409048_E12" } ] }, { "id": "PMID-18409048_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 683, 693 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18409048_T14" } ] }, { "id": "PMID-18409048_E13", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 716, 726 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18409048_T13" }, { "role": "Theme", "ref_id": "PMID-18409048_E16" } ] }, { "id": "PMID-18409048_E14", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 716, 726 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18409048_T13" }, { "role": "Theme", "ref_id": "PMID-18409048_E17" } ] }, { "id": "PMID-18409048_E15", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 716, 726 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18409048_T13" }, { "role": "Theme", "ref_id": "PMID-18409048_E18" } ] }, { "id": "PMID-18409048_E16", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 735, 742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18409048_T16" } ] }, { "id": "PMID-18409048_E17", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 764, 777 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-18409048_T15" }, { "role": "Theme", "ref_id": "PMID-18409048_T16" } ] }, { "id": "PMID-18409048_E18", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 813, 828 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18409048_T17" } ] }, { "id": "PMID-18409048_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 956, 966 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18409048_E20" } ] }, { "id": "PMID-18409048_E20", "type": "Conversion", "trigger": { "text": [ "production" ], "offsets": [ [ 973, 983 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-18409048_T19" } ] }, { "id": "PMID-18409048_E21", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 996, 1007 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18409048_E22" }, { "role": "Cause", "ref_id": "PMID-18409048_E19" } ] }, { "id": "PMID-18409048_E22", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1022, 1032 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18409048_T20" } ] } ]

[ { "id": "PMID-18409048_1", "entity_ids": [ "PMID-18409048_T7", "PMID-18409048_T8" ] }, { "id": "PMID-18409048_2", "entity_ids": [ "PMID-18409048_T11", "PMID-18409048_T12" ] } ]

[]

[ { "id": "PMID-18552837__text", "type": "abstract", "text": [ "Positive feedback sharpens the anaphase switch. \nAt the onset of anaphase, sister-chromatid cohesion is dissolved abruptly and irreversibly, ensuring that all chromosome pairs disjoin almost simultaneously. The regulatory mechanisms that generate this switch-like behaviour are unclear. Anaphase is initiated when a ubiquitin ligase, the anaphase-promoting complex (APC), triggers the destruction of securin, thereby allowing separase, a protease, to disrupt sister-chromatid cohesion. Here we demonstrate that the cyclin-dependent kinase 1 (Cdk1)-dependent phosphorylation of securin near its destruction-box motif inhibits securin ubiquitination by the APC. The phosphatase Cdc14 reverses securin phosphorylation, thereby increasing the rate of securin ubiquitination. Because separase is known to activate Cdc14 (refs 5 and 6), our results support the existence of a positive feedback loop that increases the abruptness of anaphase. Consistent with this model, we show that mutations that disrupt securin phosphoregulation decrease the synchrony of chromosome segregation. Our results also suggest that coupling securin degradation with changes in Cdk1 and Cdc14 activities helps coordinate the initiation of sister-chromatid separation with changes in spindle dynamics.\n" ], "offsets": [ [ 0, 1274 ] ] } ]

[ { "id": "PMID-18552837_T1", "type": "Cellular_component", "text": [ "sister-chromatid" ], "offsets": [ [ 75, 91 ] ], "normalized": [] }, { "id": "PMID-18552837_T2", "type": "Cellular_component", "text": [ "chromosome" ], "offsets": [ [ 159, 169 ] ], "normalized": [] }, { "id": "PMID-18552837_T3", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 316, 325 ] ], "normalized": [] }, { "id": "PMID-18552837_T4", "type": "Complex", "text": [ "anaphase-promoting complex" ], "offsets": [ [ 338, 364 ] ], "normalized": [] }, { "id": "PMID-18552837_T5", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 366, 369 ] ], "normalized": [] }, { "id": "PMID-18552837_T6", "type": "Gene_or_gene_product", "text": [ "securin" ], "offsets": [ [ 400, 407 ] ], "normalized": [] }, { "id": "PMID-18552837_T7", "type": "Gene_or_gene_product", "text": [ "separase" ], "offsets": [ [ 426, 434 ] ], "normalized": [] }, { "id": "PMID-18552837_T8", "type": "Cellular_component", "text": [ "sister-chromatid" ], "offsets": [ [ 459, 475 ] ], "normalized": [] }, { "id": "PMID-18552837_T9", "type": "Gene_or_gene_product", "text": [ "cyclin-dependent kinase 1" ], "offsets": [ [ 515, 540 ] ], "normalized": [] }, { "id": "PMID-18552837_T10", "type": "Gene_or_gene_product", "text": [ "Cdk1" ], "offsets": [ [ 542, 546 ] ], "normalized": [] }, { "id": "PMID-18552837_T11", "type": "Gene_or_gene_product", "text": [ "securin" ], "offsets": [ [ 577, 584 ] ], "normalized": [] }, { "id": "PMID-18552837_T12", "type": "Gene_or_gene_product", "text": [ "securin" ], "offsets": [ [ 625, 632 ] ], "normalized": [] }, { "id": "PMID-18552837_T13", "type": "Complex", "text": [ "APC" ], "offsets": [ [ 655, 658 ] ], "normalized": [] }, { "id": "PMID-18552837_T14", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 676, 681 ] ], "normalized": [] }, { "id": "PMID-18552837_T15", "type": "Gene_or_gene_product", "text": [ "securin" ], "offsets": [ [ 691, 698 ] ], "normalized": [] }, { "id": "PMID-18552837_T16", "type": "Gene_or_gene_product", "text": [ "securin" ], "offsets": [ [ 747, 754 ] ], "normalized": [] }, { "id": "PMID-18552837_T17", "type": "Gene_or_gene_product", "text": [ "separase" ], "offsets": [ [ 779, 787 ] ], "normalized": [] }, { "id": "PMID-18552837_T18", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 809, 814 ] ], "normalized": [] }, { "id": "PMID-18552837_T19", "type": "Gene_or_gene_product", "text": [ "securin" ], "offsets": [ [ 1000, 1007 ] ], "normalized": [] }, { "id": "PMID-18552837_T20", "type": "Cellular_component", "text": [ "chromosome" ], "offsets": [ [ 1052, 1062 ] ], "normalized": [] }, { "id": "PMID-18552837_T21", "type": "Gene_or_gene_product", "text": [ "securin" ], "offsets": [ [ 1115, 1122 ] ], "normalized": [] }, { "id": "PMID-18552837_T22", "type": "Gene_or_gene_product", "text": [ "Cdk1" ], "offsets": [ [ 1151, 1155 ] ], "normalized": [] }, { "id": "PMID-18552837_T23", "type": "Gene_or_gene_product", "text": [ "Cdc14" ], "offsets": [ [ 1160, 1165 ] ], "normalized": [] }, { "id": "PMID-18552837_T24", "type": "Cellular_component", "text": [ "sister-chromatid" ], "offsets": [ [ 1212, 1228 ] ], "normalized": [] }, { "id": "PMID-18552837_T25", "type": "Cellular_component", "text": [ "spindle" ], "offsets": [ [ 1256, 1263 ] ], "normalized": [] } ]

[ { "id": "PMID-18552837_E1", "type": "Binding", "trigger": { "text": [ "ligase" ], "offsets": [ [ 326, 332 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_T3" }, { "role": "Theme", "ref_id": "PMID-18552837_T5" } ] }, { "id": "PMID-18552837_E2", "type": "Positive_regulation", "trigger": { "text": [ "triggers" ], "offsets": [ [ 372, 380 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_E3" }, { "role": "Cause", "ref_id": "PMID-18552837_T5" } ] }, { "id": "PMID-18552837_E3", "type": "Degradation", "trigger": { "text": [ "destruction" ], "offsets": [ [ 385, 396 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_T6" } ] }, { "id": "PMID-18552837_E4", "type": "Positive_regulation", "trigger": { "text": [ "allowing" ], "offsets": [ [ 417, 425 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18552837_E2" }, { "role": "Theme", "ref_id": "PMID-18552837_E5" } ] }, { "id": "PMID-18552837_E5", "type": "Negative_regulation", "trigger": { "text": [ "disrupt" ], "offsets": [ [ 451, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_T8" }, { "role": "Cause", "ref_id": "PMID-18552837_T7" } ] }, { "id": "PMID-18552837_E6", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 548, 557 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_E7" }, { "role": "Cause", "ref_id": "PMID-18552837_T9" } ] }, { "id": "PMID-18552837_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 558, 573 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_T11" } ] }, { "id": "PMID-18552837_E8", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 616, 624 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18552837_E7" }, { "role": "Theme", "ref_id": "PMID-18552837_E9" } ] }, { "id": "PMID-18552837_E9", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 633, 647 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_T12" }, { "role": "Cause", "ref_id": "PMID-18552837_T13" } ] }, { "id": "PMID-18552837_E10", "type": "Negative_regulation", "trigger": { "text": [ "reverses" ], "offsets": [ [ 682, 690 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18552837_T14" }, { "role": "Theme", "ref_id": "PMID-18552837_E11" } ] }, { "id": "PMID-18552837_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 699, 714 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_T15" } ] }, { "id": "PMID-18552837_E12", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 724, 734 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_E13" }, { "role": "Cause", "ref_id": "PMID-18552837_E10" } ] }, { "id": "PMID-18552837_E13", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 755, 769 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_T16" } ] }, { "id": "PMID-18552837_E14", "type": "Activation", "trigger": { "text": [ "activate" ], "offsets": [ [ 800, 808 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18552837_T17" }, { "role": "Theme", "ref_id": "PMID-18552837_T18" } ] }, { "id": "PMID-18552837_E15", "type": "Negative_regulation", "trigger": { "text": [ "disrupt" ], "offsets": [ [ 992, 999 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_E16" } ] }, { "id": "PMID-18552837_E16", "type": "Regulation", "trigger": { "text": [ "phosphoregulation" ], "offsets": [ [ 1008, 1025 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_T19" } ] }, { "id": "PMID-18552837_E17", "type": "Regulation", "trigger": { "text": [ "coupling" ], "offsets": [ [ 1106, 1114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_E19" }, { "role": "Cause", "ref_id": "PMID-18552837_E20" } ] }, { "id": "PMID-18552837_E18", "type": "Regulation", "trigger": { "text": [ "coupling" ], "offsets": [ [ 1106, 1114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_E19" }, { "role": "Cause", "ref_id": "PMID-18552837_E21" } ] }, { "id": "PMID-18552837_E19", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1123, 1134 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_T21" } ] }, { "id": "PMID-18552837_E20", "type": "Positive_regulation", "trigger": { "text": [ "changes" ], "offsets": [ [ 1140, 1147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_T22" } ] }, { "id": "PMID-18552837_E21", "type": "Positive_regulation", "trigger": { "text": [ "changes" ], "offsets": [ [ 1140, 1147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18552837_T23" } ] } ]

[ { "id": "PMID-18552837_1", "entity_ids": [ "PMID-18552837_T4", "PMID-18552837_T5" ] }, { "id": "PMID-18552837_2", "entity_ids": [ "PMID-18552837_T9", "PMID-18552837_T10" ] } ]

[]

[ { "id": "PMID-18689862__text", "type": "abstract", "text": [ "Promyelocytic leukemia (PML) gene expression is a prognostic factor in ampullary cancer patients. \nBACKGROUND: Promyelocytic leukemia (PML) tumor suppressor gene plays a key role in acute PML pathogenesis but its involvement in pathogenesis and prognosis of solid cancers has not been defined yet. PATIENTS AND METHODS: In all, 62 ampullary adenocarcinoma patients who underwent curative surgery between 1996 and 2005 were included. Expression analysis of PML was carried out by immunohistochemical staining and correlated with disease-free survival (DFS) and overall survival (OS). RESULTS: In 24 tumor specimens (38.7%), PML was classified as absent, in 16 (25.8%) as focally expressed and in 22 (35.5%) as diffusely expressed. By univariate analysis, DFS was significantly influenced by pathological T stage (P=0.03), lymph nodal involvement (P=0.002), and PML expression (P=0.001). DFS in patients without PML expression was 28.0 months versus 45.1 and 75.5 for patients with focal and diffuse expression, respectively. OS in the group of patients without PML expression, with focal expression, and with diffuse expression was 40, 48, and 77 months, respectively (P=0.002). By a multivariate analysis, PML expression was the strongest prognostic factor for DFS (P=0.003) and the only statically significant prognostic factor for OS (P=0.009). CONCLUSIONS: Our preliminary data suggest PML as a novel prognostic tool for ampullary cancer patients.\n" ], "offsets": [ [ 0, 1451 ] ] } ]

[ { "id": "PMID-18689862_T1", "type": "Gene_or_gene_product", "text": [ "Promyelocytic leukemia" ], "offsets": [ [ 0, 22 ] ], "normalized": [] }, { "id": "PMID-18689862_T2", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 24, 27 ] ], "normalized": [] }, { "id": "PMID-18689862_T3", "type": "Gene_or_gene_product", "text": [ "Promyelocytic leukemia" ], "offsets": [ [ 111, 133 ] ], "normalized": [] }, { "id": "PMID-18689862_T4", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 135, 138 ] ], "normalized": [] }, { "id": "PMID-18689862_T5", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 456, 459 ] ], "normalized": [] }, { "id": "PMID-18689862_T6", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 623, 626 ] ], "normalized": [] }, { "id": "PMID-18689862_T7", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 860, 863 ] ], "normalized": [] }, { "id": "PMID-18689862_T8", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 910, 913 ] ], "normalized": [] }, { "id": "PMID-18689862_T9", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 1060, 1063 ] ], "normalized": [] }, { "id": "PMID-18689862_T10", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 1206, 1209 ] ], "normalized": [] }, { "id": "PMID-18689862_T11", "type": "Gene_or_gene_product", "text": [ "PML" ], "offsets": [ [ 1389, 1392 ] ], "normalized": [] } ]

[ { "id": "PMID-18689862_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 34, 44 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T1" } ] }, { "id": "PMID-18689862_E2", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 433, 443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T5" } ] }, { "id": "PMID-18689862_E3", "type": "Gene_expression", "trigger": { "text": [ "absent" ], "offsets": [ [ 645, 651 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T6" } ] }, { "id": "PMID-18689862_E4", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 678, 687 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T6" } ] }, { "id": "PMID-18689862_E5", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 719, 728 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T6" } ] }, { "id": "PMID-18689862_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 864, 874 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T7" } ] }, { "id": "PMID-18689862_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 914, 924 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T8" } ] }, { "id": "PMID-18689862_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 998, 1008 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T8" } ] }, { "id": "PMID-18689862_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1064, 1074 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T9" } ] }, { "id": "PMID-18689862_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1087, 1097 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T9" } ] }, { "id": "PMID-18689862_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1116, 1126 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T9" } ] }, { "id": "PMID-18689862_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1210, 1220 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18689862_T10" } ] } ]

[ { "id": "PMID-18689862_1", "entity_ids": [ "PMID-18689862_T1", "PMID-18689862_T2" ] }, { "id": "PMID-18689862_2", "entity_ids": [ "PMID-18689862_T3", "PMID-18689862_T4" ] } ]

[]

[ { "id": "PMID-18710949__text", "type": "abstract", "text": [ "Phosphorylation of p27Kip1 regulates assembly and activation of cyclin D1-Cdk4. \np27 mediates Cdk2 inhibition and is also found in cyclin D1-Cdk4 complexes. The present data support a role for p27 in the assembly of D-type cyclin-Cdk complexes and indicate that both cyclin D1-Cdk4-p27 assembly and kinase activation are regulated by p27 phosphorylation. Prior work showed that p27 can be phosphorylated by protein kinase B/Akt (PKB/Akt) at T157 and T198. Here we show that PKB activation and the appearance of p27pT157 and p27pT198 precede p27-cyclin D1-Cdk4 assembly in early G(1). PI3K/PKB inhibition rapidly reduced p27pT157 and p27pT198 and dissociated cellular p27-cyclin D1-Cdk4. Mutant p27 allele products lacking phosphorylation at T157 and T198 bound poorly to cellular cyclin D1 and Cdk4. Cellular p27pT157 and p27pT198 coprecipitated with Cdk4 but were not detected in Cdk2 complexes. The addition of p27 to recombinant cyclin D1 and Cdk4 led to cyclin D1-Cdk4-p27 complex formation in vitro. p27 phosphorylation by PKB increased p27-cyclin D1-Cdk4 assembly in vitro but yielded inactive Cdk4. In contrast, Src pretreatment of p27 did not affect p27-cyclin D1-Cdk4 complex formation. However, Src treatment led to tyrosine phosphorylation of p27 and catalytic activation of assembled cyclin D1-Cdk4-p27 complexes. Thus, while PKB-dependent p27 phosphorylation appears to increase cyclin D1-Cdk4-p27 assembly or stabilize these complexes in vitro, cyclin D1-Cdk4-p27 activation requires the tyrosine phosphorylation of p27. Constitutive activation of PKB and Abl or Src family kinases in cancers would drive p27 phosphorylation, increase cyclin D1-Cdk4 assembly and activation, and reduce the cyclin E-Cdk2 inhibitory function of p27. Combined therapy with both Src and PI3K/PKB inhibitors may reverse this process. \n" ], "offsets": [ [ 0, 1828 ] ] } ]

[ { "id": "PMID-18710949_T1", "type": "Gene_or_gene_product", "text": [ "p27Kip1" ], "offsets": [ [ 19, 26 ] ], "normalized": [] }, { "id": "PMID-18710949_T2", "type": "Complex", "text": [ "cyclin D1-Cdk4" ], "offsets": [ [ 64, 78 ] ], "normalized": [] }, { "id": "PMID-18710949_T3", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 81, 84 ] ], "normalized": [] }, { "id": "PMID-18710949_T4", "type": "Gene_or_gene_product", "text": [ "Cdk2" ], "offsets": [ [ 94, 98 ] ], "normalized": [] }, { "id": "PMID-18710949_T5", "type": "Complex", "text": [ "cyclin D1-Cdk4" ], "offsets": [ [ 131, 145 ] ], "normalized": [] }, { "id": "PMID-18710949_T6", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 193, 196 ] ], "normalized": [] }, { "id": "PMID-18710949_T7", "type": "Complex", "text": [ "D-type cyclin-Cdk" ], "offsets": [ [ 216, 233 ] ], "normalized": [] }, { "id": "PMID-18710949_T8", "type": "Complex", "text": [ "cyclin D1-Cdk4-p27" ], "offsets": [ [ 267, 285 ] ], "normalized": [] }, { "id": "PMID-18710949_T9", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 334, 337 ] ], "normalized": [] }, { "id": "PMID-18710949_T10", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 378, 381 ] ], "normalized": [] }, { "id": "PMID-18710949_T11", "type": "Gene_or_gene_product", "text": [ "protein kinase B" ], "offsets": [ [ 407, 423 ] ], "normalized": [] }, { "id": "PMID-18710949_T12", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 424, 427 ] ], "normalized": [] }, { "id": "PMID-18710949_T13", "type": "Gene_or_gene_product", "text": [ "PKB" ], "offsets": [ [ 429, 432 ] ], "normalized": [] }, { "id": "PMID-18710949_T14", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 433, 436 ] ], "normalized": [] }, { "id": "PMID-18710949_T15", "type": "Simple_chemical", "text": [ "T157" ], "offsets": [ [ 441, 445 ] ], "normalized": [] }, { "id": "PMID-18710949_T16", "type": "Simple_chemical", "text": [ "T198" ], "offsets": [ [ 450, 454 ] ], "normalized": [] }, { "id": "PMID-18710949_T17", "type": "Gene_or_gene_product", "text": [ "PKB" ], "offsets": [ [ 474, 477 ] ], "normalized": [] }, { "id": "PMID-18710949_T18", "type": "Gene_or_gene_product", "text": [ "p27pT157" ], "offsets": [ [ 511, 519 ] ], "normalized": [] }, { "id": "PMID-18710949_T19", "type": "Gene_or_gene_product", "text": [ "p27pT198" ], "offsets": [ [ 524, 532 ] ], "normalized": [] }, { "id": "PMID-18710949_T20", "type": "Complex", "text": [ "p27-cyclin D1-Cdk4" ], "offsets": [ [ 541, 559 ] ], "normalized": [] }, { "id": "PMID-18710949_T21", "type": "Gene_or_gene_product", "text": [ "PI3K" ], "offsets": [ [ 584, 588 ] ], "normalized": [] }, { "id": "PMID-18710949_T22", "type": "Gene_or_gene_product", "text": [ "PKB" ], "offsets": [ [ 589, 592 ] ], "normalized": [] }, { "id": "PMID-18710949_T23", "type": "Gene_or_gene_product", "text": [ "p27pT157" ], "offsets": [ [ 620, 628 ] ], "normalized": [] }, { "id": "PMID-18710949_T24", "type": "Gene_or_gene_product", "text": [ "p27pT198" ], "offsets": [ [ 633, 641 ] ], "normalized": [] }, { "id": "PMID-18710949_T25", "type": "Complex", "text": [ "p27-cyclin D1-Cdk4" ], "offsets": [ [ 667, 685 ] ], "normalized": [] }, { "id": "PMID-18710949_T26", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 694, 697 ] ], "normalized": [] }, { "id": "PMID-18710949_T27", "type": "Simple_chemical", "text": [ "T157" ], "offsets": [ [ 741, 745 ] ], "normalized": [] }, { "id": "PMID-18710949_T28", "type": "Simple_chemical", "text": [ "T198" ], "offsets": [ [ 750, 754 ] ], "normalized": [] }, { "id": "PMID-18710949_T29", "type": "Gene_or_gene_product", "text": [ "cyclin D1" ], "offsets": [ [ 780, 789 ] ], "normalized": [] }, { "id": "PMID-18710949_T30", "type": "Gene_or_gene_product", "text": [ "Cdk4" ], "offsets": [ [ 794, 798 ] ], "normalized": [] }, { "id": "PMID-18710949_T31", "type": "Gene_or_gene_product", "text": [ "p27pT157" ], "offsets": [ [ 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1699 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18710949_E53" }, { "role": "Theme", "ref_id": "PMID-18710949_E69" } ] }, { "id": "PMID-18710949_E67", "type": "Negative_regulation", "trigger": { "text": [ "reduce" ], "offsets": [ [ 1693, 1699 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18710949_E51" }, { "role": "Theme", "ref_id": "PMID-18710949_E69" } ] }, { "id": "PMID-18710949_E68", "type": "Negative_regulation", "trigger": { "text": [ "reduce" ], "offsets": [ [ 1693, 1699 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18710949_E52" }, { "role": "Theme", "ref_id": "PMID-18710949_E69" } ] }, { "id": "PMID-18710949_E69", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory function" ], "offsets": [ [ 1718, 1737 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18710949_T62" }, { "role": "Theme", "ref_id": "PMID-18710949_T61" } ] }, { "id": "PMID-18710949_E70", "type": "Negative_regulation", "trigger": { "text": [ "reverse" ], 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[ { "id": "PMID-18710949_1", "entity_ids": [ "PMID-18710949_T11", "PMID-18710949_T12", "PMID-18710949_T13", "PMID-18710949_T14" ] } ]

[]

[ { "id": "PMID-18929644__text", "type": "abstract", "text": [ "Stably overexpressed human Frizzled-2 signals through the beta-catenin pathway and does not activate Ca2+-mobilization in Human Embryonic Kidney 293 cells. \nSignal transduction via the Frizzled family of seven-transmembrane receptors controls important developmental processes. Aberrant signaling caused by altered Frizzled receptor activity or by mutations in downstream signaling components has been implicated in several adult pathologies. A diverse array of intracellular signaling pathways has been suggested to transduce the signals exerted in cells when secreted ligands of the Wnt family bind to Frizzled receptors. Studies with a chimeric receptor composed of Frizzled-2 and the beta2-adrenergic receptor have suggested that the binding of Wnt-5a to Frizzled-2 results in the activation of G proteins of the Galpha(i) family, the mobilization of calcium from intracellular stores and the induction of gene transcription through nuclear factor of activated T cells. In this report, we demonstrate by using beta-lactamase reporter gene technology that full-length, wild-type human Frizzled-2 does not couple to calcium-mediated signaling in HEK293 cells following stimulation with purified recombinant mouse Wnt-5a. In contrast, when stimulated with recombinant mouse Wnt-3a, Frizzled-2 activates the canonical Wnt/Frizzled signaling pathway, involving the transcriptional modulator beta-catenin. Our report underlines the importance of using cell lines stably overexpressing wild-type Frizzled receptors and the use of purified ligands when studying receptor pharmacology. This approach has allowed us to measure the half-maximal concentration for activation of human Frizzled-2 (1.5+/-0.4 nM; avg.+/-SD) and human Frizzled-1 (1.3+/-0.5 nM) following stimulation by Wnt-3a. Our results suggest that there is receptor redundancy with regard to Wnt-3a reception. In addition, we introduce beta-lactamase reporter gene technology as an alternative to luciferase-based reporters to measure Frizzled receptor modulation for the discovery of Frizzled receptor-interacting drugs.\n" ], "offsets": [ [ 0, 2081 ] ] } ]

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"arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T3" } ] }, { "id": "PMID-18929644_E6", "type": "Pathway", "trigger": { "text": [ "Signal transduction" ], "offsets": [ [ 157, 176 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-18929644_T4" } ] }, { "id": "PMID-18929644_E7", "type": "Regulation", "trigger": { "text": [ "altered" ], "offsets": [ [ 307, 314 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T5" } ] }, { "id": "PMID-18929644_E8", "type": "Transport", "trigger": { "text": [ "secreted" ], "offsets": [ [ 561, 569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T7" } ] }, { "id": "PMID-18929644_E9", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 596, 600 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T7" }, { "role": "Theme", "ref_id": "PMID-18929644_T8" } ] }, { "id": "PMID-18929644_E10", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 738, 745 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T11" }, { "role": "Theme", "ref_id": "PMID-18929644_T12" } ] }, { "id": "PMID-18929644_E11", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 770, 777 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18929644_E10" }, { "role": "Theme", "ref_id": "PMID-18929644_E13" } ] }, { "id": "PMID-18929644_E12", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 770, 777 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18929644_E10" }, { "role": "Theme", "ref_id": "PMID-18929644_E14" } ] }, { "id": "PMID-18929644_E13", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 785, 795 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T13" } ] }, { "id": "PMID-18929644_E14", "type": "Transport", "trigger": { "text": [ "mobilization" ], "offsets": [ [ 839, 851 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T15" }, { "role": "FromLoc", "ref_id": "PMID-18929644_T16" } ] }, { "id": "PMID-18929644_E15", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1241, 1251 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18929644_T22" }, { "role": "Theme", "ref_id": "PMID-18929644_T23" } ] }, { "id": "PMID-18929644_E16", "type": "Positive_regulation", "trigger": { "text": [ "activates" ], "offsets": [ [ 1294, 1303 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_E17" }, { "role": "Cause", "ref_id": "PMID-18929644_T23" } ] }, { "id": "PMID-18929644_E17", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 1331, 1348 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-18929644_T24" }, { "role": "Participant", "ref_id": "PMID-18929644_T25" } ] }, { "id": "PMID-18929644_E18", "type": "Gene_expression", "trigger": { "text": [ "overexpressing" ], "offsets": [ [ 1468, 1482 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T27" } ] }, { "id": "PMID-18929644_E19", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1656, 1666 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T28" } ] }, { "id": "PMID-18929644_E20", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1656, 1666 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T29" } ] }, { "id": "PMID-18929644_E21", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 1759, 1770 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18929644_T30" }, { "role": "Theme", "ref_id": "PMID-18929644_T28" } ] }, { "id": "PMID-18929644_E22", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 1759, 1770 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18929644_T30" }, { "role": "Theme", "ref_id": "PMID-18929644_T29" } ] }, { "id": "PMID-18929644_E23", "type": "Regulation", "trigger": { "text": [ "modulation" ], "offsets": [ [ 2012, 2022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T34" } ] }, { "id": "PMID-18929644_E24", "type": "Binding", "trigger": { "text": [ "interacting" ], "offsets": [ [ 2062, 2073 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18929644_T35" } ] } ]

[]

[]

[ { "id": "PMID-18931363__text", "type": "abstract", "text": [ "Porin-incorporated liposome induces Toll-like receptors 2- and 6-dependent maturation and type 1 response of dendritic cell. \nPorin of Shigella dysenteriae was incorporated in liposome (PIL) and presented to mouse splenic dendritic cells (DC). PIL up-regulated Toll-like receptor (TLR) 2 and TLR6 on DC, showing that co-expression of the two TLRs is involved in recognition of porin. Detection of myeloid differentiating factor 88 (MyD88)-TLR2 complex confirmed interaction between the two for triggering the downstream signaling, which ultimately led to TLR2-dependent nuclear translocation of nuclear factor-kappa B. PIL-induced expression of MHC class II (I-Ab), CD40 and CD80 showed maturation of DC, whereas up-regulation of intercellular adhesion molecule-1 and CCR7 implicated the capacity of splenic DC to migrate. Induction of messenger ribonucleic acid for the chemokines, macrophage-inflammatory protein (MIP)-1alpha, MIP-1beta and regulated upon activation, normal T cell expressed and secreted indicated a strong bias of PIL for type 1 polarization that was supported by the intracellular expression and release of tumor necrosis factor (TNF)-alpha and IL-12. Along with CD40 and CD80 expression, release of the cytokines of CD11c+ JAWS II cells was inhibited by TLR2 or simultaneous TLR2 and 6 knockdown showing that recognition of PIL by the two TLRs is essential for DC activation and type 1 polarization. The signaling pathway initiated upon recognition of PIL by the TLRs was MyD88 dependent as confirmed by inhibition of IL-6, TNF-alpha and IL-12 release of MyD88-knockdown JAWS II cells. The maturation and polarization of DC induced T(h)1 phenotype, as evident from proliferation, activation and IFN-gamma release of allogeneic CD4+ T cells in response to PIL-stimulated DC, thereby suggesting that the adjuvant activity of PIL can successfully bridge the innate and adaptive immunity.\n" ], "offsets": [ [ 0, 1907 ] ] } ]

[ { "id": "PMID-18931363_T1", "type": "Gene_or_gene_product", "text": [ "Porin" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-18931363_T2", "type": "Gene_or_gene_product", "text": [ "Toll-like receptors 2" ], "offsets": [ [ 36, 57 ] ], "normalized": [] }, { "id": "PMID-18931363_T3", "type": "Gene_or_gene_product", "text": [ "6" ], "offsets": [ [ 63, 64 ] ], "normalized": [] }, { "id": "PMID-18931363_T4", "type": "Gene_or_gene_product", "text": [ "Porin" ], "offsets": [ [ 126, 131 ] ], "normalized": [] }, { "id": "PMID-18931363_T5", "type": "Gene_or_gene_product", "text": [ "PIL" ], "offsets": [ [ 186, 189 ] ], "normalized": [] }, { "id": "PMID-18931363_T6", "type": "Gene_or_gene_product", "text": [ "PIL" ], "offsets": [ [ 244, 247 ] ], "normalized": [] }, { "id": "PMID-18931363_T7", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor (TLR) 2" ], "offsets": [ [ 261, 287 ] ], "normalized": [] }, { "id": "PMID-18931363_T8", "type": "Gene_or_gene_product", "text": [ "TLR6" ], "offsets": [ [ 292, 296 ] ], "normalized": [] }, { "id": "PMID-18931363_T9", "type": "Gene_or_gene_product", "text": [ "TLRs" ], "offsets": [ [ 342, 346 ] ], "normalized": [] }, { "id": "PMID-18931363_T10", "type": "Gene_or_gene_product", "text": [ "porin" ], "offsets": [ [ 377, 382 ] ], "normalized": [] }, { "id": "PMID-18931363_T11", "type": "Complex", "text": [ "myeloid differentiating factor 88 (MyD88)-TLR2" ], "offsets": [ [ 397, 443 ] ], "normalized": [] }, { "id": "PMID-18931363_T12", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 555, 559 ] ], "normalized": [] }, { "id": "PMID-18931363_T13", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 570, 577 ] ], "normalized": [] }, { "id": "PMID-18931363_T14", "type": "Complex", "text": [ "nuclear factor-kappa B" ], "offsets": [ [ 595, 617 ] ], "normalized": [] }, { "id": "PMID-18931363_T15", "type": "Gene_or_gene_product", "text": [ "PIL" ], "offsets": [ [ 619, 622 ] ], "normalized": [] }, { "id": "PMID-18931363_T16", "type": "Complex", "text": [ "MHC class II" ], "offsets": [ [ 645, 657 ] ], "normalized": [] }, { "id": "PMID-18931363_T17", "type": "Gene_or_gene_product", "text": [ "CD40" ], "offsets": [ [ 666, 670 ] ], "normalized": [] }, { "id": "PMID-18931363_T18", "type": "Gene_or_gene_product", "text": [ "CD80" ], "offsets": [ [ 675, 679 ] ], "normalized": [] }, { "id": "PMID-18931363_T19", "type": "Gene_or_gene_product", "text": [ "intercellular adhesion molecule-1" ], "offsets": [ [ 730, 763 ] ], "normalized": [] }, { "id": "PMID-18931363_T20", "type": "Gene_or_gene_product", "text": [ "CCR7" ], "offsets": [ [ 768, 772 ] ], "normalized": [] }, { "id": "PMID-18931363_T21", "type": "Gene_or_gene_product", "text": [ "macrophage-inflammatory protein (MIP)-1alpha" ], "offsets": [ [ 883, 927 ] ], "normalized": [] }, { "id": "PMID-18931363_T22", "type": "Gene_or_gene_product", "text": [ "MIP-1beta" ], "offsets": [ [ 929, 938 ] ], "normalized": [] }, { "id": "PMID-18931363_T23", "type": "Gene_or_gene_product", "text": [ "regulated upon activation, normal T cell expressed and secreted" ], "offsets": [ [ 943, 1006 ] ], "normalized": [] }, { "id": "PMID-18931363_T24", "type": "Gene_or_gene_product", "text": [ "PIL" ], "offsets": [ [ 1034, 1037 ] ], "normalized": [] }, { "id": "PMID-18931363_T25", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 1088, 1101 ] ], "normalized": [] }, { "id": "PMID-18931363_T26", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor (TNF)-alpha" ], "offsets": [ [ 1128, 1161 ] ], "normalized": [] }, { "id": "PMID-18931363_T27", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 1166, 1171 ] ], "normalized": [] }, { "id": "PMID-18931363_T28", "type": "Gene_or_gene_product", "text": [ "CD40" ], "offsets": [ [ 1184, 1188 ] ], "normalized": [] }, { "id": "PMID-18931363_T29", "type": "Gene_or_gene_product", "text": [ "CD80" ], "offsets": [ [ 1193, 1197 ] ], "normalized": [] }, { "id": "PMID-18931363_T30", "type": "Gene_or_gene_product", "text": [ "CD11c" ], "offsets": [ [ 1238, 1243 ] ], "normalized": [] }, { "id": "PMID-18931363_T31", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1276, 1280 ] ], "normalized": [] }, { "id": "PMID-18931363_T32", "type": "Gene_or_gene_product", "text": [ "TLR2" ], "offsets": [ [ 1297, 1301 ] ], "normalized": [] }, { "id": "PMID-18931363_T33", "type": "Gene_or_gene_product", "text": [ "6" ], "offsets": [ [ 1306, 1307 ] ], "normalized": [] }, { "id": "PMID-18931363_T34", "type": "Gene_or_gene_product", "text": [ "PIL" ], "offsets": [ [ 1346, 1349 ] ], "normalized": [] }, { "id": "PMID-18931363_T35", "type": "Gene_or_gene_product", "text": [ "TLRs" ], "offsets": [ [ 1361, 1365 ] ], "normalized": [] }, { "id": "PMID-18931363_T36", "type": "Gene_or_gene_product", "text": [ "PIL" ], "offsets": [ [ 1474, 1477 ] ], "normalized": [] }, { "id": "PMID-18931363_T37", "type": "Gene_or_gene_product", "text": [ "TLRs" ], "offsets": [ [ 1485, 1489 ] ], "normalized": [] }, { "id": "PMID-18931363_T38", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1494, 1499 ] ], "normalized": [] }, { "id": "PMID-18931363_T39", "type": "Gene_or_gene_product", "text": [ "IL-6" ], "offsets": [ [ 1540, 1544 ] ], "normalized": [] }, { "id": "PMID-18931363_T40", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 1546, 1555 ] ], "normalized": [] }, { "id": "PMID-18931363_T41", "type": "Gene_or_gene_product", "text": [ "IL-12" ], "offsets": [ [ 1560, 1565 ] ], "normalized": [] }, { "id": "PMID-18931363_T42", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1577, 1582 ] ], "normalized": [] }, { "id": "PMID-18931363_T43", "type": "Gene_or_gene_product", "text": [ "IFN-gamma" ], "offsets": [ [ 1717, 1726 ] ], "normalized": [] }, { "id": "PMID-18931363_T44", "type": "Gene_or_gene_product", "text": [ "CD4" ], "offsets": [ [ 1749, 1752 ] ], "normalized": [] }, { "id": "PMID-18931363_T45", "type": "Gene_or_gene_product", "text": [ "PIL" ], "offsets": [ [ 1777, 1780 ] ], "normalized": [] }, { "id": "PMID-18931363_T46", "type": "Gene_or_gene_product", "text": [ "PIL" ], "offsets": [ [ 1845, 1848 ] ], "normalized": [] } ]

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"arguments": [ { "role": "ToLoc", "ref_id": "PMID-18931363_T13" }, { "role": "Theme", "ref_id": "PMID-18931363_T14" } ] }, { "id": "PMID-18931363_E10", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 623, 630 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18931363_T15" }, { "role": "Theme", "ref_id": "PMID-18931363_E12" } ] }, { "id": "PMID-18931363_E11", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 623, 630 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-18931363_T15" }, { "role": "Theme", "ref_id": "PMID-18931363_E13" } ] }, { "id": "PMID-18931363_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 631, 641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T17" } ] }, { "id": "PMID-18931363_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 631, 641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T18" } ] }, { "id": "PMID-18931363_E14", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 713, 726 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T19" } ] }, { "id": "PMID-18931363_E15", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 713, 726 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T20" } ] }, { "id": "PMID-18931363_E16", "type": "Positive_regulation", "trigger": { "text": [ "Induction" ], "offsets": [ [ 823, 832 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T21" } ] }, { "id": "PMID-18931363_E17", "type": "Positive_regulation", "trigger": { "text": [ "Induction" ], "offsets": [ [ 823, 832 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T22" } ] }, { "id": "PMID-18931363_E18", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1102, 1112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T26" } ] }, { "id": "PMID-18931363_E19", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1102, 1112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T27" } ] }, { "id": "PMID-18931363_E20", "type": "Dissociation", "trigger": { "text": [ "release" ], "offsets": [ [ 1117, 1124 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-18931363_T26" } ] }, { "id": "PMID-18931363_E21", "type": "Dissociation", "trigger": { "text": [ "release" ], "offsets": [ [ 1117, 1124 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-18931363_T27" } ] }, { "id": "PMID-18931363_E22", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1198, 1208 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T28" } ] }, { "id": "PMID-18931363_E23", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1198, 1208 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T29" } ] }, { "id": "PMID-18931363_E24", "type": "Inactivation", "trigger": { "text": [ "knockdown" ], "offsets": [ [ 1308, 1317 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T32" } ] }, { "id": "PMID-18931363_E25", "type": "Inactivation", "trigger": { "text": [ "knockdown" ], "offsets": [ [ 1308, 1317 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T33" } ] }, { "id": "PMID-18931363_E26", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1526, 1536 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T39" } ] }, { "id": "PMID-18931363_E27", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1526, 1536 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T40" } ] }, { "id": "PMID-18931363_E28", "type": "Dissociation", "trigger": { "text": [ "release" ], "offsets": [ [ 1566, 1573 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-18931363_T41" } ] }, { "id": "PMID-18931363_E29", "type": "Inactivation", "trigger": { "text": [ "knockdown" ], "offsets": [ [ 1583, 1592 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18931363_T42" } ] }, { "id": "PMID-18931363_E30", "type": "Dissociation", "trigger": { "text": [ "release" ], "offsets": [ [ 1727, 1734 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-18931363_T43" } ] } ]

[]

[]

[ { "id": "PMID-19028555__text", "type": "abstract", "text": [ "TCDD induces cell migration via NFATc1/ATX-signaling in MCF-7 cells. \nBreast cancer is characterized, among others, by the concurrence of lipophilic xenobiotica such as 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) with hypoxic tissue conditions. This condition activates the transcription factors hypoxia inducible factor-1alpha (HIF-1alpha) and aryl hydrocarbon receptor (AhR) that are known to promote tumor progression. An interrelation between these transcription factors and nuclear factor of activated T-cells (NFAT) was implied by gene array analysis. In the present study, the interplay of the three transcription factors was studied and correlated with the migration of MCF-7 cells in response to TCDD and/or hypoxia. An AhR-activation by 10nM TCDD and HIF-1alpha activation by 5% oxygen induced activation of NFATc1. The effects were inhibited by cyclosporine A (CsA), suggesting that the activation of NFAT by AhR or HIF-1alpha signaling is calcineurin-dependent. The expression/activity of the NFAT target gene autotaxin (ATX) was increased. ATX is known to stimulate migration of tumor cells. The hydrolysis product of ATX, lysophosphatidic acid (LPA), increased the migration of MCF-7 cells under normoxia but not under hypoxia. This effect correlated with increased migration observed after TCDD treatment. Hypoxia did not promote migration of MCF-7 cells, suggesting that ATX down-stream signaling was inhibited by hypoxia. In conclusion, the TCDD-mediated activation of NFATc1 is suggested to promote cell migration via ATX/LPA-signaling.\n" ], "offsets": [ [ 0, 1557 ] ] } ]

[ { "id": "PMID-19028555_T1", "type": "Simple_chemical", "text": [ "TCDD" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-19028555_T2", "type": "Gene_or_gene_product", "text": [ "NFATc1" ], "offsets": [ [ 32, 38 ] ], "normalized": [] }, { "id": "PMID-19028555_T3", "type": "Gene_or_gene_product", "text": [ "ATX" ], "offsets": [ [ 39, 42 ] ], "normalized": [] }, { "id": "PMID-19028555_T4", "type": "Simple_chemical", "text": [ "2,3,7,8-tetrachlorodibenzo-para-dioxin" ], "offsets": [ [ 169, 207 ] ], "normalized": [] }, { "id": "PMID-19028555_T5", "type": "Simple_chemical", "text": [ "TCDD" ], "offsets": [ [ 209, 213 ] ], "normalized": [] }, { "id": "PMID-19028555_T6", "type": "Gene_or_gene_product", "text": [ "hypoxia inducible factor-1alpha" ], "offsets": [ [ 298, 329 ] ], "normalized": [] }, { "id": "PMID-19028555_T7", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 331, 341 ] ], "normalized": [] }, { "id": "PMID-19028555_T8", "type": "Gene_or_gene_product", "text": [ "aryl hydrocarbon receptor" ], "offsets": [ [ 347, 372 ] ], "normalized": [] }, { "id": "PMID-19028555_T9", "type": "Gene_or_gene_product", "text": [ "AhR" ], "offsets": [ [ 374, 377 ] ], "normalized": [] }, { "id": "PMID-19028555_T10", "type": "Gene_or_gene_product", "text": [ "nuclear factor of activated T-cells" ], "offsets": [ [ 481, 516 ] ], "normalized": [] }, { "id": "PMID-19028555_T11", "type": "Gene_or_gene_product", "text": [ "NFAT" ], "offsets": [ [ 518, 522 ] ], "normalized": [] }, { "id": "PMID-19028555_T12", "type": "Simple_chemical", "text": [ "TCDD" ], "offsets": [ [ 707, 711 ] ], "normalized": [] }, { "id": "PMID-19028555_T13", "type": "Gene_or_gene_product", "text": [ "AhR" ], "offsets": [ [ 731, 734 ] ], "normalized": [] }, { "id": "PMID-19028555_T14", "type": "Simple_chemical", "text": [ "TCDD" ], "offsets": [ [ 754, 758 ] ], "normalized": [] }, { "id": "PMID-19028555_T15", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 763, 773 ] ], "normalized": [] }, { "id": "PMID-19028555_T16", "type": "Simple_chemical", "text": [ "oxygen" ], "offsets": [ [ 791, 797 ] ], "normalized": [] }, { "id": "PMID-19028555_T17", "type": "Gene_or_gene_product", "text": [ "NFATc1" ], "offsets": [ [ 820, 826 ] ], "normalized": [] }, { "id": "PMID-19028555_T18", "type": "Simple_chemical", "text": [ "cyclosporine A" ], "offsets": [ [ 858, 872 ] ], "normalized": [] }, { "id": "PMID-19028555_T19", "type": "Simple_chemical", "text": [ "CsA" ], "offsets": [ [ 874, 877 ] ], "normalized": [] }, { "id": "PMID-19028555_T20", "type": "Gene_or_gene_product", "text": [ "NFAT" ], "offsets": [ [ 914, 918 ] ], "normalized": [] }, { "id": "PMID-19028555_T21", "type": "Gene_or_gene_product", "text": [ "AhR" ], "offsets": [ [ 922, 925 ] ], "normalized": [] }, { "id": "PMID-19028555_T22", "type": "Gene_or_gene_product", "text": [ "HIF-1alpha" ], "offsets": [ [ 929, 939 ] ], "normalized": [] }, { "id": "PMID-19028555_T23", "type": "Complex", "text": [ "calcineurin" ], "offsets": [ [ 953, 964 ] ], "normalized": [] }, { "id": "PMID-19028555_T24", "type": "Gene_or_gene_product", "text": [ "NFAT" ], "offsets": [ [ 1007, 1011 ] ], "normalized": [] }, { "id": "PMID-19028555_T25", "type": "Gene_or_gene_product", "text": [ "autotaxin" ], "offsets": [ [ 1024, 1033 ] ], "normalized": [] }, { "id": "PMID-19028555_T26", "type": "Gene_or_gene_product", "text": [ "ATX" ], "offsets": [ [ 1035, 1038 ] ], "normalized": [] }, { "id": "PMID-19028555_T27", "type": "Gene_or_gene_product", "text": [ "ATX" ], "offsets": [ [ 1055, 1058 ] ], "normalized": [] }, { "id": "PMID-19028555_T28", "type": "Gene_or_gene_product", "text": [ "ATX" ], "offsets": [ [ 1133, 1136 ] ], "normalized": [] }, { "id": "PMID-19028555_T29", "type": "Simple_chemical", "text": [ "lysophosphatidic acid" ], "offsets": [ [ 1138, 1159 ] ], "normalized": [] }, { "id": "PMID-19028555_T30", "type": "Simple_chemical", "text": [ "LPA" ], "offsets": [ [ 1161, 1164 ] ], "normalized": [] }, { "id": "PMID-19028555_T31", "type": "Simple_chemical", "text": [ "TCDD" ], "offsets": [ [ 1307, 1311 ] ], "normalized": [] }, { "id": "PMID-19028555_T32", "type": "Gene_or_gene_product", "text": [ "ATX" ], "offsets": [ [ 1389, 1392 ] ], "normalized": [] }, { "id": "PMID-19028555_T33", "type": "Simple_chemical", "text": [ "TCDD" ], "offsets": [ [ 1460, 1464 ] ], "normalized": [] }, { "id": "PMID-19028555_T34", "type": "Gene_or_gene_product", "text": [ "NFATc1" ], "offsets": [ [ 1488, 1494 ] ], "normalized": [] }, { "id": "PMID-19028555_T35", "type": "Gene_or_gene_product", "text": [ "ATX" ], "offsets": [ [ 1538, 1541 ] ], "normalized": [] }, { "id": "PMID-19028555_T36", "type": "Simple_chemical", "text": [ "LPA" ], "offsets": [ [ 1542, 1545 ] ], "normalized": [] } ]

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"arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_T13" }, { "role": "Cause", "ref_id": "PMID-19028555_T14" } ] }, { "id": "PMID-19028555_E6", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 774, 784 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_T15" }, { "role": "Cause", "ref_id": "PMID-19028555_T16" } ] }, { "id": "PMID-19028555_E7", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 798, 805 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_E9" }, { "role": "Cause", "ref_id": "PMID-19028555_E6" } ] }, { "id": "PMID-19028555_E8", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 798, 805 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_E9" }, { "role": "Cause", "ref_id": "PMID-19028555_E5" } ] }, { "id": "PMID-19028555_E9", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 806, 816 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_T17" } ] }, { "id": "PMID-19028555_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 845, 854 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_E9" }, { "role": "Cause", "ref_id": "PMID-19028555_T18" } ] }, { "id": "PMID-19028555_E11", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 900, 910 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_T20" }, { "role": "Cause", "ref_id": "PMID-19028555_E13" } ] }, { "id": "PMID-19028555_E12", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 900, 910 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_T20" }, { "role": "Cause", "ref_id": "PMID-19028555_E14" } ] }, { "id": "PMID-19028555_E13", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 940, 949 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19028555_T22" } ] }, { "id": "PMID-19028555_E14", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 940, 949 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19028555_T21" } ] }, { "id": "PMID-19028555_E15", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 965, 974 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19028555_T23" }, { "role": "Theme", "ref_id": "PMID-19028555_E11" } ] }, { "id": "PMID-19028555_E16", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 965, 974 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19028555_T23" }, { "role": "Theme", "ref_id": "PMID-19028555_E12" } ] }, { "id": "PMID-19028555_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 980, 990 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_T25" } ] }, { "id": "PMID-19028555_E18", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1044, 1053 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_E17" } ] }, { "id": "PMID-19028555_E19", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1044, 1053 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_T25" } ] }, { "id": "PMID-19028555_E20", "type": "Conversion", "trigger": { "text": [ "hydrolysis" ], "offsets": [ [ 1111, 1121 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_T28" }, { "role": "Product", "ref_id": "PMID-19028555_T29" } ] }, { "id": "PMID-19028555_E21", "type": "Pathway", "trigger": { "text": [ "down-stream signaling" ], "offsets": [ [ 1393, 1414 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19028555_T32" } ] }, { "id": "PMID-19028555_E22", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1419, 1428 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_E21" } ] }, { "id": "PMID-19028555_E23", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1465, 1473 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19028555_T33" }, { "role": "Theme", "ref_id": "PMID-19028555_E24" } ] }, { "id": "PMID-19028555_E24", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1474, 1484 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19028555_T34" } ] }, { "id": "PMID-19028555_E25", "type": "Positive_regulation", "trigger": { "text": [ "promote" ], "offsets": [ [ 1511, 1518 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19028555_E24" }, { "role": "Theme", "ref_id": "PMID-19028555_E26" } ] }, { "id": "PMID-19028555_E26", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1546, 1555 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19028555_T35" }, { "role": "Participant", "ref_id": "PMID-19028555_T36" } ] } ]

[ { "id": "PMID-19028555_1", "entity_ids": [ "PMID-19028555_T4", "PMID-19028555_T5" ] }, { "id": "PMID-19028555_2", "entity_ids": [ "PMID-19028555_T6", "PMID-19028555_T7" ] }, { "id": "PMID-19028555_3", "entity_ids": [ "PMID-19028555_T8", "PMID-19028555_T9" ] }, { "id": "PMID-19028555_4", "entity_ids": [ "PMID-19028555_T10", "PMID-19028555_T11" ] }, { "id": "PMID-19028555_5", "entity_ids": [ "PMID-19028555_T18", "PMID-19028555_T19" ] }, { "id": "PMID-19028555_6", "entity_ids": [ "PMID-19028555_T25", "PMID-19028555_T26" ] }, { "id": "PMID-19028555_7", "entity_ids": [ "PMID-19028555_T29", "PMID-19028555_T30" ] } ]

[]

[ { "id": "PMID-19121660__text", "type": "abstract", "text": [ "The adaptor protein MyD88 is essential for E coli-induced preterm delivery in mice. \nOBJECTIVE: We used a mouse model of infection-induced preterm delivery to examine the roles of 2 adaptor proteins with central functions in Toll-like receptor signaling: MyD88 (myeloid differentiation primary-response gene 88) and TRIF (Toll/IL-1 receptor (TIR)-domain-containing adaptor protein-inducing IFN-beta). STUDY DESIGN: Mice deficient (KO) for MyD88, TRIF, both (DKO) or neither (WT) were inoculated into the uterus with killed Escherichia coli. Delivery outcomes, fetal status, serum progesterone, and nuclear translocation of the transcription factor nuclear factor kappa B (NFkappaB) were determined. RESULTS: Preterm birth (delivery in less than 48 hours) occurred in WT and TRIF-KO animals in a dose-dependent fashion, reaching 100% with 5-10 x 10(9) bacteria, while MyD88-KO and DKO animals were completely protected from delivery. Intrauterine fetal survival, maintenance of circulating progesterone levels, and nuclear translocation of NFkappaB were also dependent upon MyD88 but not TRIF. In contrast, induction of uterine interleukin (IL)-1beta and tumor necrosis factor alpha (TNF-alpha) depends upon actions of both MyD88 and TRIF. CONCLUSION: E coli-induced preterm delivery in the mouse is completely dependent upon MyD88 but not TRIF.\n" ], "offsets": [ [ 0, 1345 ] ] } ]

[ { "id": "PMID-19121660_T1", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 20, 25 ] ], "normalized": [] }, { "id": "PMID-19121660_T2", "type": "Gene_or_gene_product", "text": [ "Toll-like receptor" ], "offsets": [ [ 225, 243 ] ], "normalized": [] }, { "id": "PMID-19121660_T3", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 255, 260 ] ], "normalized": [] }, { "id": "PMID-19121660_T4", "type": "Gene_or_gene_product", "text": [ "myeloid differentiation primary-response gene 88" ], "offsets": [ [ 262, 310 ] ], "normalized": [] }, { "id": "PMID-19121660_T5", "type": "Gene_or_gene_product", "text": [ "TRIF" ], "offsets": [ [ 316, 320 ] ], "normalized": [] }, { "id": "PMID-19121660_T6", "type": "Gene_or_gene_product", "text": [ "Toll/IL-1 receptor (TIR)-domain-containing adaptor protein-inducing IFN-beta" ], "offsets": [ [ 322, 398 ] ], "normalized": [] }, { "id": "PMID-19121660_T7", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 439, 444 ] ], "normalized": [] }, { "id": "PMID-19121660_T8", "type": "Gene_or_gene_product", "text": [ "TRIF" ], "offsets": [ [ 446, 450 ] ], "normalized": [] }, { "id": "PMID-19121660_T9", "type": "Simple_chemical", "text": [ "progesterone" ], "offsets": [ [ 580, 592 ] ], "normalized": [] }, { "id": "PMID-19121660_T10", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 598, 605 ] ], "normalized": [] }, { "id": "PMID-19121660_T11", "type": "Gene_or_gene_product", "text": [ "transcription factor nuclear factor kappa B" ], "offsets": [ [ 627, 670 ] ], "normalized": [] }, { "id": "PMID-19121660_T12", "type": "Gene_or_gene_product", "text": [ "NFkappaB" ], "offsets": [ [ 672, 680 ] ], "normalized": [] }, { "id": "PMID-19121660_T13", "type": "Gene_or_gene_product", "text": [ "TRIF" ], "offsets": [ [ 774, 778 ] ], "normalized": [] }, { "id": "PMID-19121660_T14", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 867, 872 ] ], "normalized": [] }, { "id": "PMID-19121660_T15", "type": "Simple_chemical", "text": [ "progesterone" ], "offsets": [ [ 989, 1001 ] ], "normalized": [] }, { "id": "PMID-19121660_T16", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1014, 1021 ] ], "normalized": [] }, { "id": "PMID-19121660_T17", "type": "Gene_or_gene_product", "text": [ "NFkappaB" ], "offsets": [ [ 1039, 1047 ] ], "normalized": [] }, { "id": "PMID-19121660_T18", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1073, 1078 ] ], "normalized": [] }, { "id": "PMID-19121660_T19", "type": "Gene_or_gene_product", "text": [ "TRIF" ], "offsets": [ [ 1087, 1091 ] ], "normalized": [] }, { "id": "PMID-19121660_T20", "type": "Gene_or_gene_product", "text": [ "uterine interleukin (IL)-1beta" ], "offsets": [ [ 1119, 1149 ] ], "normalized": [] }, { "id": "PMID-19121660_T21", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 1154, 1181 ] ], "normalized": [] }, { "id": "PMID-19121660_T22", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 1183, 1192 ] ], "normalized": [] }, { "id": "PMID-19121660_T23", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1223, 1228 ] ], "normalized": [] }, { "id": "PMID-19121660_T24", "type": "Gene_or_gene_product", "text": [ "TRIF" ], "offsets": [ [ 1233, 1237 ] ], "normalized": [] }, { "id": "PMID-19121660_T25", "type": "Gene_or_gene_product", "text": [ "MyD88" ], "offsets": [ [ 1325, 1330 ] ], "normalized": [] }, { "id": "PMID-19121660_T26", "type": "Gene_or_gene_product", "text": [ "TRIF" ], "offsets": [ [ 1339, 1343 ] ], "normalized": [] } ]

[ { "id": "PMID-19121660_E1", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 244, 253 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19121660_T2" }, { "role": "Participant", "ref_id": "PMID-19121660_T3" }, { "role": "Participant", "ref_id": "PMID-19121660_T5" } ] }, { "id": "PMID-19121660_E2", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 606, 619 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-19121660_T10" }, { "role": "Theme", "ref_id": "PMID-19121660_T12" } ] }, { "id": "PMID-19121660_E3", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 1022, 1035 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-19121660_T16" }, { "role": "Theme", "ref_id": "PMID-19121660_T17" } ] }, { "id": "PMID-19121660_E4", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1058, 1067 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19121660_E3" }, { "role": "Cause", "ref_id": "PMID-19121660_T18" } ] }, { "id": "PMID-19121660_E5", "type": "Regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1058, 1067 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19121660_T19" }, { "role": "Theme", "ref_id": "PMID-19121660_E3" } ] }, { "id": "PMID-19121660_E6", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1106, 1115 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19121660_T20" } ] }, { "id": "PMID-19121660_E7", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1106, 1115 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19121660_T21" } ] }, { "id": "PMID-19121660_E8", "type": "Positive_regulation", "trigger": { "text": [ "depends" ], "offsets": [ [ 1194, 1201 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19121660_T23" }, { "role": "Theme", "ref_id": "PMID-19121660_E6" } ] }, { "id": "PMID-19121660_E9", "type": "Positive_regulation", "trigger": { "text": [ "depends" ], "offsets": [ [ 1194, 1201 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19121660_T24" }, { "role": "Theme", "ref_id": "PMID-19121660_E6" } ] }, { "id": "PMID-19121660_E10", "type": "Positive_regulation", "trigger": { "text": [ "depends" ], "offsets": [ [ 1194, 1201 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19121660_T24" }, { "role": "Theme", "ref_id": "PMID-19121660_E7" } ] }, { "id": "PMID-19121660_E11", "type": "Positive_regulation", "trigger": { "text": [ "depends" ], "offsets": [ [ 1194, 1201 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19121660_T23" }, { "role": "Theme", "ref_id": "PMID-19121660_E7" } ] } ]

[ { "id": "PMID-19121660_1", "entity_ids": [ "PMID-19121660_T3", "PMID-19121660_T4" ] }, { "id": "PMID-19121660_2", "entity_ids": [ "PMID-19121660_T5", "PMID-19121660_T6" ] }, { "id": "PMID-19121660_3", "entity_ids": [ "PMID-19121660_T11", "PMID-19121660_T12" ] }, { "id": "PMID-19121660_4", "entity_ids": [ "PMID-19121660_T21", "PMID-19121660_T22" ] } ]

[]

[ { "id": "PMID-19125156__text", "type": "abstract", "text": [ "Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. \nThe pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By screening a diverse synthetic chemical library, we have discovered two new classes of small molecules that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/beta-catenin pathway activity. With these small molecules, we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/beta-catenin pathway response in vivo, and we establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.\n" ], "offsets": [ [ 0, 1222 ] ] } ]

[ { "id": "PMID-19125156_T1", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 38, 41 ] ], "normalized": [] }, { "id": "PMID-19125156_T2", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 134, 137 ] ], "normalized": [] }, { "id": "PMID-19125156_T3", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 260, 263 ] ], "normalized": [] }, { "id": "PMID-19125156_T4", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 411, 414 ] ], "normalized": [] }, { "id": "PMID-19125156_T5", "type": "Gene_or_gene_product", "text": [ "Porcupine" ], "offsets": [ [ 477, 486 ] ], "normalized": [] }, { "id": "PMID-19125156_T6", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 490, 498 ] ], "normalized": [] }, { "id": "PMID-19125156_T7", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 560, 563 ] ], "normalized": [] }, { "id": "PMID-19125156_T8", "type": "Gene_or_gene_product", "text": [ "Axin" ], "offsets": [ [ 609, 613 ] ], "normalized": [] }, { "id": "PMID-19125156_T9", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 649, 652 ] ], "normalized": [] }, { "id": "PMID-19125156_T10", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 653, 665 ] ], "normalized": [] }, { "id": "PMID-19125156_T11", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 766, 769 ] ], "normalized": [] }, { "id": "PMID-19125156_T12", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 876, 879 ] ], "normalized": [] }, { "id": "PMID-19125156_T13", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 880, 892 ] ], "normalized": [] }, { "id": "PMID-19125156_T14", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 1096, 1099 ] ], "normalized": [] } ]

[ { "id": "PMID-19125156_E1", "type": "Transport", "trigger": { "text": [ "secreted" ], "offsets": [ [ 125, 133 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19125156_T2" } ] }, { "id": "PMID-19125156_E2", "type": "Negative_regulation", "trigger": { "text": [ "disrupt" ], "offsets": [ [ 403, 410 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19125156_E3" } ] }, { "id": "PMID-19125156_E3", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 415, 422 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19125156_T4" } ] }, { "id": "PMID-19125156_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 452, 460 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19125156_T5" } ] }, { "id": "PMID-19125156_E5", "type": "Localization", "trigger": { "text": [ "bound" ], "offsets": [ [ 499, 504 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19125156_T5" }, { "role": "AtLoc", "ref_id": "PMID-19125156_T6" } ] }, { "id": "PMID-19125156_E6", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 529, 538 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19125156_T5" }, { "role": "Theme", "ref_id": "PMID-19125156_E7" } ] }, { "id": "PMID-19125156_E7", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 546, 556 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19125156_T7" } ] }, { "id": "PMID-19125156_E8", "type": "Negative_regulation", "trigger": { "text": [ "abrogates" ], "offsets": [ [ 584, 593 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19125156_E9" } ] }, { "id": "PMID-19125156_E9", "type": "Degradation", "trigger": { "text": [ "destruction" ], "offsets": [ [ 594, 605 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19125156_T8" } ] }, { "id": "PMID-19125156_E10", "type": "Negative_regulation", "trigger": { "text": [ "suppressors" ], "offsets": [ [ 634, 645 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19125156_E11" }, { "role": "Cause", "ref_id": "PMID-19125156_T8" } ] }, { "id": "PMID-19125156_E11", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 666, 673 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19125156_T9" }, { "role": "Participant", "ref_id": "PMID-19125156_T10" } ] }, { "id": "PMID-19125156_E12", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 770, 777 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19125156_T11" } ] }, { "id": "PMID-19125156_E13", "type": "Negative_regulation", "trigger": { "text": [ "reversible" ], "offsets": [ [ 850, 860 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19125156_E14" } ] }, { "id": "PMID-19125156_E14", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 861, 872 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19125156_E15" } ] }, { "id": "PMID-19125156_E15", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 893, 900 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19125156_T12" }, { "role": "Participant", "ref_id": "PMID-19125156_T13" } ] } ]

[]

[]

[ { "id": "PMID-19166851__text", "type": "abstract", "text": [ "Kaiso is a bimodal modulator for Wnt/beta-catenin signaling. \nThe Wnt family of secreted ligands plays critical roles during embryonic development and tumorigenesis. Here we show that Kaiso, a dual specific DNA-binding protein, functions as a bimodal regulator of canonical Wnt signaling. Loss-of-function analysis of Kaiso abrogated Wnt-mediated reporter activity and axis duplication, whereas gain-of-function analysis of Kaiso dose-dependently resulted in synergistic and suppressive effects. Our analyses further suggest Kaiso can regulate TCF/LEF1-activity for these effects via modulating HDAC1 and beta-catenin-complex formation. Our studies together provide insights into why Kaiso null mice display resistance to intestinal tumors when crossed onto an Apc(Min/+) background.\n" ], "offsets": [ [ 0, 784 ] ] } ]

[ { "id": "PMID-19166851_T1", "type": "Gene_or_gene_product", "text": [ "Kaiso" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-19166851_T2", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 33, 36 ] ], "normalized": [] }, { "id": "PMID-19166851_T3", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 37, 49 ] ], "normalized": [] }, { "id": "PMID-19166851_T4", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 66, 69 ] ], "normalized": [] }, { "id": "PMID-19166851_T5", "type": "Gene_or_gene_product", "text": [ "Kaiso" ], "offsets": [ [ 184, 189 ] ], "normalized": [] }, { "id": "PMID-19166851_T6", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 274, 277 ] ], "normalized": [] }, { "id": "PMID-19166851_T7", "type": "Gene_or_gene_product", "text": [ "Kaiso" ], "offsets": [ [ 318, 323 ] ], "normalized": [] }, { "id": "PMID-19166851_T8", "type": "Gene_or_gene_product", "text": [ "Wnt" ], "offsets": [ [ 334, 337 ] ], "normalized": [] }, { "id": "PMID-19166851_T9", "type": "Gene_or_gene_product", "text": [ "Kaiso" ], "offsets": [ [ 424, 429 ] ], "normalized": [] }, { "id": "PMID-19166851_T10", "type": "Gene_or_gene_product", "text": [ "Kaiso" ], "offsets": [ [ 525, 530 ] ], "normalized": [] }, { "id": "PMID-19166851_T11", "type": "Gene_or_gene_product", "text": [ "TCF/LEF1" ], "offsets": [ [ 544, 552 ] ], "normalized": [] }, { "id": "PMID-19166851_T12", "type": "Gene_or_gene_product", "text": [ "HDAC1" ], "offsets": [ [ 595, 600 ] ], "normalized": [] }, { "id": "PMID-19166851_T13", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 605, 617 ] ], "normalized": [] }, { "id": "PMID-19166851_T14", "type": "Gene_or_gene_product", "text": [ "Kaiso" ], "offsets": [ [ 684, 689 ] ], "normalized": [] }, { "id": "PMID-19166851_T15", "type": "Gene_or_gene_product", "text": [ "Apc" ], "offsets": [ [ 761, 764 ] ], "normalized": [] } ]

[ { "id": "PMID-19166851_E1", "type": "Regulation", "trigger": { "text": [ "modulator" ], "offsets": [ [ 19, 28 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19166851_T1" }, { "role": "Theme", "ref_id": "PMID-19166851_E2" } ] }, { "id": "PMID-19166851_E2", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 50, 59 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19166851_T2" }, { "role": "Participant", "ref_id": "PMID-19166851_T3" } ] }, { "id": "PMID-19166851_E3", "type": "Transport", "trigger": { "text": [ "secreted" ], "offsets": [ [ 80, 88 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19166851_T4" } ] }, { "id": "PMID-19166851_E4", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 211, 218 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19166851_T5" } ] }, { "id": "PMID-19166851_E5", "type": "Regulation", "trigger": { "text": [ "regulator" ], "offsets": [ [ 251, 260 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19166851_E6" }, { "role": "Cause", "ref_id": "PMID-19166851_T5" } ] }, { "id": "PMID-19166851_E6", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 278, 287 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19166851_T6" } ] }, { "id": "PMID-19166851_E7", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 535, 543 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19166851_T11" }, { "role": "Cause", "ref_id": "PMID-19166851_E8" } ] }, { "id": "PMID-19166851_E8", "type": "Regulation", "trigger": { "text": [ "modulating" ], "offsets": [ [ 584, 594 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19166851_T10" }, { "role": "Theme", "ref_id": "PMID-19166851_E9" } ] }, { "id": "PMID-19166851_E9", "type": "Binding", "trigger": { "text": [ "complex formation" ], "offsets": [ [ 618, 635 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19166851_T12" }, { "role": "Theme", "ref_id": "PMID-19166851_T13" } ] } ]

[]

[]

[ { "id": "PMID-19168128__text", "type": "abstract", "text": [ "Licochalcone A significantly suppresses LPS signaling pathway through the inhibition of NF-kappaB p65 phosphorylation at serine 276. \nLicorice root, Glycyrrhiza inflata, has been used as a traditional medicine for the treatment of bronchial asthma and inflammation; however, the mechanism of its anti-inflammatory activity has not been clarified. Here, we investigated the effect of Licochalcone A, a major component of G. inflata, on the LPS signaling pathway. We found that Licochalcone A remarkably inhibited LPS-induced NO production, and TNFalpha expression and MCP-1 expression in both RAW264.7 cells and primary macrophages. Furthermore, when injected with Licochalcone A prior to injection of LPS, the serum level of TNFalpha and MCP-1 in C57BL/6 mice was clearly decreased, indicating that Licochalcone A has a potent anti-inflammatory effect both in vitro and in vivo. Strikingly, Licochalcone A significantly inhibited LPS-induced NF-kappaB transcriptional activation; however, it had no effect on not only the phosphorylation and degradation of IkappaBalpha but also nuclear translocation and DNA binding activity of NF-kappaB p65. Interestingly, Licochalcone A markedly inhibited the phosphorylation of p65 at serine 276. As a result, it reduced NF-kappaB transactivation by preventing the interaction of p65 with p300. Taken together, Licochalcone A might contribute to the potent anti-inflammatory effect of G. inflata through the unique mechanism of NF-kappaB inhibition.\n" ], "offsets": [ [ 0, 1488 ] ] } ]

[ { "id": "PMID-19168128_T1", "type": "Simple_chemical", "text": [ "Licochalcone A" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "PMID-19168128_T2", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 40, 43 ] ], "normalized": [] }, { "id": "PMID-19168128_T3", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 88, 97 ] ], "normalized": [] }, { "id": "PMID-19168128_T4", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 98, 101 ] ], "normalized": [] }, { "id": "PMID-19168128_T5", "type": "Simple_chemical", "text": [ "serine 276" ], "offsets": [ [ 121, 131 ] ], "normalized": [] }, { "id": "PMID-19168128_T6", "type": "Simple_chemical", "text": [ "Licochalcone A" ], "offsets": [ [ 383, 397 ] ], "normalized": [] }, { "id": "PMID-19168128_T7", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 439, 442 ] ], "normalized": [] }, { "id": "PMID-19168128_T8", "type": "Simple_chemical", "text": [ "Licochalcone A" ], "offsets": [ [ 476, 490 ] ], "normalized": [] }, { "id": "PMID-19168128_T9", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 512, 515 ] ], "normalized": [] }, { "id": "PMID-19168128_T10", "type": "Simple_chemical", "text": [ "NO" ], "offsets": [ [ 524, 526 ] ], "normalized": [] }, { "id": "PMID-19168128_T11", "type": "Gene_or_gene_product", "text": [ "TNFalpha" ], "offsets": [ [ 543, 551 ] ], "normalized": [] }, { "id": "PMID-19168128_T12", "type": "Gene_or_gene_product", "text": [ "MCP-1" ], "offsets": [ [ 567, 572 ] ], "normalized": [] }, { "id": "PMID-19168128_T13", "type": "Simple_chemical", "text": [ "Licochalcone A" ], "offsets": [ [ 664, 678 ] ], "normalized": [] }, { "id": "PMID-19168128_T14", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 701, 704 ] ], "normalized": [] }, { "id": "PMID-19168128_T15", "type": "Gene_or_gene_product", "text": [ "TNFalpha" ], "offsets": [ [ 725, 733 ] ], "normalized": [] }, { "id": "PMID-19168128_T16", "type": "Gene_or_gene_product", "text": [ "MCP-1" ], "offsets": [ [ 738, 743 ] ], "normalized": [] }, { "id": "PMID-19168128_T17", "type": "Simple_chemical", "text": [ "Licochalcone A" ], "offsets": [ [ 799, 813 ] ], "normalized": [] }, { "id": "PMID-19168128_T18", "type": "Simple_chemical", "text": [ "Licochalcone A" ], "offsets": [ [ 891, 905 ] ], "normalized": [] }, { "id": "PMID-19168128_T19", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 930, 933 ] ], "normalized": [] }, { "id": "PMID-19168128_T20", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 942, 951 ] ], "normalized": [] }, { "id": "PMID-19168128_T21", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 1057, 1069 ] ], "normalized": [] }, { "id": "PMID-19168128_T22", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1079, 1086 ] ], "normalized": [] }, { "id": "PMID-19168128_T23", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1129, 1138 ] ], "normalized": [] }, { "id": "PMID-19168128_T24", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1139, 1142 ] ], "normalized": [] }, { "id": "PMID-19168128_T25", "type": "Simple_chemical", "text": [ "Licochalcone A" ], "offsets": [ [ 1159, 1173 ] ], "normalized": [] }, { "id": "PMID-19168128_T26", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1216, 1219 ] ], "normalized": [] }, { "id": "PMID-19168128_T27", "type": "Simple_chemical", "text": [ "serine 276" ], "offsets": [ [ 1223, 1233 ] ], "normalized": [] }, { "id": "PMID-19168128_T28", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1259, 1268 ] ], "normalized": [] }, { "id": "PMID-19168128_T29", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1318, 1321 ] ], "normalized": [] }, { "id": "PMID-19168128_T30", "type": "Gene_or_gene_product", "text": [ "p300" ], "offsets": [ [ 1327, 1331 ] ], "normalized": [] }, { "id": "PMID-19168128_T31", "type": "Simple_chemical", "text": [ "Licochalcone A" ], "offsets": [ [ 1349, 1363 ] ], "normalized": [] }, { "id": "PMID-19168128_T32", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1466, 1475 ] ], "normalized": [] } ]

[ { "id": "PMID-19168128_E1", "type": "Negative_regulation", "trigger": { "text": [ "suppresses" ], "offsets": [ [ 29, 39 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_E3" }, { "role": "Cause", "ref_id": "PMID-19168128_E4" } ] }, { "id": "PMID-19168128_E2", "type": "Negative_regulation", "trigger": { "text": [ "suppresses" ], "offsets": [ [ 29, 39 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_E3" }, { "role": "Cause", "ref_id": "PMID-19168128_E5" } ] }, { "id": "PMID-19168128_E3", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 44, 61 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19168128_T2" } ] }, { "id": "PMID-19168128_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 74, 84 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T1" }, { "role": "Theme", "ref_id": "PMID-19168128_E6" } ] }, { "id": "PMID-19168128_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 74, 84 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T1" }, { "role": "Theme", "ref_id": "PMID-19168128_E7" } ] }, { "id": "PMID-19168128_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 102, 117 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-19168128_T5" }, { "role": "Theme", "ref_id": "PMID-19168128_T3" } ] }, { "id": "PMID-19168128_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 102, 117 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-19168128_T5" }, { "role": "Theme", "ref_id": "PMID-19168128_T4" } ] }, { "id": "PMID-19168128_E8", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 373, 379 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_T6" } ] }, { "id": "PMID-19168128_E9", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 443, 460 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19168128_T7" } ] }, { "id": "PMID-19168128_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 502, 511 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T8" }, { "role": "Theme", "ref_id": "PMID-19168128_T10" } ] }, { "id": "PMID-19168128_E11", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 502, 511 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T8" }, { "role": "Theme", "ref_id": "PMID-19168128_E14" } ] }, { "id": "PMID-19168128_E12", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 502, 511 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T8" }, { "role": "Theme", "ref_id": "PMID-19168128_E15" } ] }, { "id": "PMID-19168128_E13", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 516, 523 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T9" }, { "role": "Theme", "ref_id": "PMID-19168128_T10" } ] }, { "id": "PMID-19168128_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 552, 562 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_T11" } ] }, { "id": "PMID-19168128_E15", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 573, 583 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_T12" } ] }, { "id": "PMID-19168128_E16", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 772, 781 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T13" }, { "role": "Theme", "ref_id": "PMID-19168128_T15" } ] }, { "id": "PMID-19168128_E17", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 772, 781 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T13" }, { "role": "Theme", "ref_id": "PMID-19168128_T16" } ] }, { "id": "PMID-19168128_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 920, 929 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_E20" }, { "role": "Cause", "ref_id": "PMID-19168128_T18" } ] }, { "id": "PMID-19168128_E19", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 934, 941 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T19" }, { "role": "Theme", "ref_id": "PMID-19168128_E20" } ] }, { "id": "PMID-19168128_E20", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 968, 978 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_T20" } ] }, { "id": "PMID-19168128_E21", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 999, 1005 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T18" }, { "role": "Theme", "ref_id": "PMID-19168128_E25" } ] }, { "id": "PMID-19168128_E22", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 999, 1005 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T18" }, { "role": "Theme", "ref_id": "PMID-19168128_E26" } ] }, { "id": "PMID-19168128_E23", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 999, 1005 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T18" }, { "role": "Theme", "ref_id": "PMID-19168128_E28" } ] }, { "id": "PMID-19168128_E24", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 999, 1005 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T18" }, { "role": "Theme", "ref_id": "PMID-19168128_E27" } ] }, { "id": "PMID-19168128_E25", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1022, 1037 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_T21" } ] }, { "id": "PMID-19168128_E26", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1042, 1053 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_T21" } ] }, { "id": "PMID-19168128_E27", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 1087, 1100 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-19168128_T22" }, { "role": "Theme", "ref_id": "PMID-19168128_T23" } ] }, { "id": "PMID-19168128_E28", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 1087, 1100 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-19168128_T22" }, { "role": "Theme", "ref_id": "PMID-19168128_T24" } ] }, { "id": "PMID-19168128_E29", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1183, 1192 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19168128_T25" }, { "role": "Theme", "ref_id": "PMID-19168128_E30" } ] }, { "id": "PMID-19168128_E30", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1197, 1212 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_T26" }, { "role": "Site", "ref_id": "PMID-19168128_T27" } ] }, { "id": "PMID-19168128_E31", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1251, 1258 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_E32" } ] }, { "id": "PMID-19168128_E32", "type": "Positive_regulation", "trigger": { "text": [ "transactivation" ], "offsets": [ [ 1269, 1284 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_T28" } ] }, { "id": "PMID-19168128_E33", "type": "Negative_regulation", "trigger": { "text": [ "preventing" ], "offsets": [ [ 1288, 1298 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_E34" }, { "role": "Cause", "ref_id": "PMID-19168128_T25" } ] }, { "id": "PMID-19168128_E34", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1303, 1314 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_T29" }, { "role": "Theme", "ref_id": "PMID-19168128_T30" } ] }, { "id": "PMID-19168128_E35", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1476, 1486 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19168128_T32" } ] } ]

[]

[]

[ { "id": "PMID-19285061__text", "type": "abstract", "text": [ "SDF-1alpha up-regulates interleukin-6 through CXCR4, PI3K/Akt, ERK, and NF-kappaB-dependent pathway in microglia. \nStromal cell-derived factor-1 (SDF-1), also known as CXCL12, and its receptor CXC chemokine receptor 4 (CXCR4) express in various kinds of cells in central nervous system. The SDF-1/CXCR4 signaling pathway is regulated by diverse biological effects. SDF-1 is up-regulated in the ischemic penumbra following stroke and has been known to be associated with the homing of bone marrow cells to injury. However, the effect of SDF-1alpha/CXCR4 on cytokine production in microglia is mostly unknown. Here, we demonstrated that SDF-1alpha enhanced IL-6 production in both primary cultured microglia and BV-2 microglia. We further investigated the signaling pathway involved in IL-6 production stimulated by SDF-1alpha in microglia. SDF-1alpha increased IL-6 production in both protein and mRNA levels. These effects were attenuated by ERK, phosphatidylinositol 3-kinase (PI3K), NF-kappaB inhibitors, and IkappaB protease inhibitor. Stimulation of microglia with SDF-1alpha also increased Akt and ERK1/2 phosphorylation. In addition, SDF-1alpha treatment also increased IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation at Ser(276), translocation of p65 and p50 from cytosol to nucleus and kappaB-luciferase activity. Moreover, SDF-1alpha-mediated increase of kappaB-luciferase activity was inhibited by pre-transfection of DN-p85, DN-Akt or DN-ERK2. Increase of IKK alpha/beta phosphorylation and binding of p65 and p50 to the NF-kappaB element were both antagonized by PI3K and ERK inhibitors. Our results demonstrate a mechanism linking SDF-1alpha and IL-6, and provide additional support for the notion that SDF-1alpha plays a regulatory role in microglia activation.\n" ], "offsets": [ [ 0, 1864 ] ] } ]

[ { "id": "PMID-19285061_T1", "type": "Gene_or_gene_product", "text": [ "SDF-1alpha" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "PMID-19285061_T2", "type": "Gene_or_gene_product", "text": [ "interleukin-6" ], "offsets": [ [ 24, 37 ] ], "normalized": [] }, { "id": "PMID-19285061_T3", "type": "Gene_or_gene_product", "text": [ "CXCR4" ], "offsets": [ [ 46, 51 ] ], "normalized": [] }, { "id": "PMID-19285061_T4", "type": "Gene_or_gene_product", "text": [ "PI3K" ], "offsets": [ [ 53, 57 ] ], "normalized": [] }, { "id": "PMID-19285061_T5", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 58, 61 ] ], "normalized": [] }, { "id": "PMID-19285061_T6", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 63, 66 ] ], "normalized": [] }, { "id": "PMID-19285061_T7", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 72, 81 ] ], "normalized": [] }, { "id": "PMID-19285061_T8", "type": "Gene_or_gene_product", "text": [ "Stromal cell-derived factor-1" ], "offsets": [ [ 115, 144 ] ], "normalized": [] }, { "id": "PMID-19285061_T9", "type": "Gene_or_gene_product", "text": [ "SDF-1" ], "offsets": [ [ 146, 151 ] ], "normalized": [] }, { "id": "PMID-19285061_T10", "type": "Gene_or_gene_product", "text": [ "CXCL12" ], "offsets": [ [ 168, 174 ] ], "normalized": [] }, { "id": "PMID-19285061_T11", "type": "Gene_or_gene_product", "text": [ "receptor CXC chemokine receptor 4" ], "offsets": [ [ 184, 217 ] ], "normalized": [] }, { "id": "PMID-19285061_T12", "type": "Gene_or_gene_product", "text": [ "CXCR4" ], "offsets": [ [ 219, 224 ] ], "normalized": [] }, { "id": "PMID-19285061_T13", "type": "Gene_or_gene_product", "text": [ "SDF-1" ], "offsets": [ [ 291, 296 ] ], "normalized": [] }, { "id": "PMID-19285061_T14", "type": "Gene_or_gene_product", "text": [ "CXCR4" ], "offsets": [ [ 297, 302 ] ], "normalized": [] }, { "id": "PMID-19285061_T15", "type": "Gene_or_gene_product", "text": [ "SDF-1" ], "offsets": [ [ 365, 370 ] ], "normalized": [] }, { "id": "PMID-19285061_T16", "type": "Gene_or_gene_product", "text": [ "SDF-1alpha" ], "offsets": [ [ 536, 546 ] ], "normalized": [] }, { "id": "PMID-19285061_T17", "type": "Gene_or_gene_product", "text": [ "CXCR4" ], "offsets": [ [ 547, 552 ] ], "normalized": [] }, { "id": "PMID-19285061_T18", "type": "Gene_or_gene_product", "text": [ "SDF-1alpha" ], "offsets": [ [ 635, 645 ] ], "normalized": [] }, { "id": "PMID-19285061_T19", "type": "Gene_or_gene_product", "text": [ "IL-6" ], "offsets": [ [ 655, 659 ] ], "normalized": [] }, { "id": "PMID-19285061_T20", "type": "Gene_or_gene_product", "text": [ "IL-6" ], "offsets": [ [ 784, 788 ] ], "normalized": [] }, { "id": "PMID-19285061_T21", "type": "Gene_or_gene_product", "text": [ "SDF-1alpha" ], "offsets": [ [ 814, 824 ] ], "normalized": [] }, { "id": "PMID-19285061_T22", "type": "Gene_or_gene_product", "text": [ "SDF-1alpha" ], "offsets": [ [ 839, 849 ] ], "normalized": [] }, { "id": "PMID-19285061_T23", "type": "Gene_or_gene_product", 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[]

[ { "id": "PMID-19286999__text", "type": "abstract", "text": [ "NPM-ALK inhibits the p53 tumor suppressor pathway in an MDM2 and JNK-dependent manner. \nAnaplastic large cell lymphoma (ALCL) is characterized by the presence of the t(2;5)(p23;q35) generating the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion protein, a hyperactive kinase with transforming properties. Among these properties is the ability to regulate activity of the p53 tumor suppressor protein. In many human cancers, p53 is inactivated by mutation or other means, in some cases as a result of up-regulation of the negative regulator MDM2. However, the majority of ALK-expressing ALCL carry wild-type p53 and do not over express MDM2. We demonstrate a novel p53-dependent pathogenetic mechanism in ALK-expressing lymphoma. We confirm previously published reports of NPM-ALK-induced activation of the phosphoinositide (PI) 3-kinase and Jun N-terminal kinase (JNK) stress-activated protein (SAP) kinase proteins, but in this study demonstrate a role for these in the regulation of p53 activity in an intricate signaling system. Specifically, constitutive ALK signaling leads to the functional inactivation and/or degradation of p53 in JNK and MDM2 dependent manners. We also show nuclear exclusion of p53 in a PI 3-kinase-dependent manner. Furthermore, we demonstrate that reactivation of p53 in ALK-expressing cells as a result of pharmacologic inhibition of JNK, PI 3-kinase, and/or MDM2 activities results in the induction of apoptosis suggesting a novel therapeutic modality.\n" ], "offsets": [ [ 0, 1494 ] ] } ]

[ { "id": "PMID-19286999_T1", "type": "Gene_or_gene_product", "text": [ "NPM-ALK" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "PMID-19286999_T2", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 21, 24 ] ], "normalized": [] }, { "id": "PMID-19286999_T3", "type": "Gene_or_gene_product", "text": [ "MDM2" ], "offsets": [ [ 56, 60 ] ], "normalized": [] }, { "id": "PMID-19286999_T4", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 65, 68 ] ], "normalized": [] }, { "id": "PMID-19286999_T5", "type": "Gene_or_gene_product", "text": [ "nucleophosmin-anaplastic lymphoma kinase" ], "offsets": [ [ 197, 237 ] ], "normalized": [] }, { "id": "PMID-19286999_T6", "type": "Gene_or_gene_product", "text": [ "NPM-ALK" ], "offsets": [ [ 239, 246 ] ], "normalized": [] }, { "id": "PMID-19286999_T7", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 381, 384 ] ], "normalized": [] }, { "id": "PMID-19286999_T8", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 434, 437 ] ], "normalized": [] }, { "id": "PMID-19286999_T9", "type": "Gene_or_gene_product", "text": [ "MDM2" ], "offsets": [ [ 550, 554 ] ], "normalized": [] }, { "id": "PMID-19286999_T10", "type": "Gene_or_gene_product", "text": [ "ALK" ], "offsets": [ [ 581, 584 ] ], "normalized": [] }, { "id": "PMID-19286999_T11", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 617, 620 ] ], "normalized": [] }, { "id": "PMID-19286999_T12", "type": "Gene_or_gene_product", "text": [ "MDM2" ], "offsets": [ [ 645, 649 ] ], "normalized": [] }, { "id": "PMID-19286999_T13", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 674, 677 ] ], "normalized": [] }, { "id": "PMID-19286999_T14", "type": "Gene_or_gene_product", "text": [ "ALK" ], "offsets": [ [ 714, 717 ] ], "normalized": [] }, { "id": "PMID-19286999_T15", "type": "Gene_or_gene_product", "text": [ "NPM-ALK" ], "offsets": [ [ 782, 789 ] ], "normalized": [] }, { "id": "PMID-19286999_T16", "type": "Gene_or_gene_product", "text": [ "phosphoinositide (PI) 3-kinase" ], "offsets": [ [ 816, 846 ] ], "normalized": [] }, { "id": "PMID-19286999_T17", "type": "Gene_or_gene_product", "text": [ "Jun N-terminal kinase" ], "offsets": [ [ 851, 872 ] ], "normalized": [] }, { "id": "PMID-19286999_T18", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 874, 877 ] ], "normalized": [] }, { "id": "PMID-19286999_T19", "type": "Gene_or_gene_product", "text": [ "stress-activated protein (SAP) kinase" ], "offsets": [ [ 879, 916 ] ], "normalized": [] }, { "id": "PMID-19286999_T20", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 995, 998 ] ], "normalized": [] }, { "id": "PMID-19286999_T21", "type": "Gene_or_gene_product", "text": [ "ALK" ], "offsets": [ [ 1069, 1072 ] ], "normalized": [] }, { "id": "PMID-19286999_T22", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1142, 1145 ] ], "normalized": [] }, { "id": "PMID-19286999_T23", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 1149, 1152 ] ], "normalized": [] }, { "id": "PMID-19286999_T24", "type": "Gene_or_gene_product", "text": [ "MDM2" ], "offsets": [ [ 1157, 1161 ] ], "normalized": [] }, { "id": "PMID-19286999_T25", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1194, 1201 ] ], "normalized": [] }, { "id": "PMID-19286999_T26", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1215, 1218 ] ], "normalized": [] }, { "id": "PMID-19286999_T27", "type": "Gene_or_gene_product", "text": [ "PI 3-kinase" ], "offsets": [ [ 1224, 1235 ] ], "normalized": [] }, { "id": "PMID-19286999_T28", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1303, 1306 ] ], "normalized": [] }, { "id": "PMID-19286999_T29", "type": "Gene_or_gene_product", "text": [ "ALK" ], "offsets": [ [ 1310, 1313 ] ], "normalized": [] }, { "id": "PMID-19286999_T30", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 1374, 1377 ] ], "normalized": [] }, { "id": "PMID-19286999_T31", "type": "Gene_or_gene_product", "text": [ "PI 3-kinase" ], "offsets": [ [ 1379, 1390 ] ], "normalized": [] }, { "id": "PMID-19286999_T32", "type": "Gene_or_gene_product", "text": [ "MDM2" ], "offsets": [ [ 1399, 1403 ] ], "normalized": [] } ]

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[ "regulate" ], "offsets": [ [ 356, 364 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T7" } ] }, { "id": "PMID-19286999_E6", "type": "Inactivation", "trigger": { "text": [ "inactivated" ], "offsets": [ [ 441, 452 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T8" }, { "role": "Cause", "ref_id": "PMID-19286999_E7" } ] }, { "id": "PMID-19286999_E7", "type": "Positive_regulation", "trigger": { "text": [ "result" ], "offsets": [ [ 500, 506 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_E8" } ] }, { "id": "PMID-19286999_E8", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 510, 523 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T9" } ] }, { "id": "PMID-19286999_E9", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 585, 595 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T10" } ] }, { "id": "PMID-19286999_E10", "type": "Transport", "trigger": { "text": [ "carry" ], "offsets": [ [ 601, 606 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T11" } ] }, { "id": "PMID-19286999_E11", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 637, 644 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T12" } ] }, { "id": "PMID-19286999_E12", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 718, 728 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T14" } ] }, { "id": "PMID-19286999_E13", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 790, 797 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19286999_T15" }, { "role": "Theme", "ref_id": "PMID-19286999_E16" } ] }, { "id": "PMID-19286999_E14", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 790, 797 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19286999_T15" }, { "role": "Theme", "ref_id": "PMID-19286999_E17" } ] }, { "id": "PMID-19286999_E15", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 790, 797 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19286999_T15" }, { "role": "Theme", "ref_id": "PMID-19286999_E18" } ] }, { "id": "PMID-19286999_E16", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 798, 808 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T16" } ] }, { "id": "PMID-19286999_E17", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 798, 808 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T19" } ] }, { "id": "PMID-19286999_E18", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 798, 808 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T17" } ] }, { "id": "PMID-19286999_E19", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 981, 991 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T20" } ] }, { "id": "PMID-19286999_E20", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1073, 1082 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19286999_T21" } ] }, { "id": "PMID-19286999_E21", "type": "Positive_regulation", "trigger": { "text": [ "leads" ], "offsets": [ [ 1083, 1088 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19286999_E20" }, { "role": "Theme", "ref_id": "PMID-19286999_E23" } ] }, { "id": "PMID-19286999_E22", "type": "Positive_regulation", "trigger": { "text": [ "leads" ], "offsets": [ [ 1083, 1088 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19286999_E20" }, { "role": "Theme", "ref_id": "PMID-19286999_E24" } ] }, { "id": "PMID-19286999_E23", "type": "Inactivation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 1107, 1119 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T22" } ] }, { "id": "PMID-19286999_E24", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1127, 1138 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T22" } ] }, { "id": "PMID-19286999_E25", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1162, 1171 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19286999_T23" }, { "role": "Theme", "ref_id": "PMID-19286999_E23" } ] }, { "id": "PMID-19286999_E26", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1162, 1171 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19286999_T24" }, { "role": "Theme", "ref_id": "PMID-19286999_E23" } ] }, { "id": "PMID-19286999_E27", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1162, 1171 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19286999_T23" }, { "role": "Theme", "ref_id": "PMID-19286999_E24" } ] }, { "id": "PMID-19286999_E28", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1162, 1171 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19286999_T24" }, { "role": "Theme", "ref_id": "PMID-19286999_E24" } ] }, { "id": "PMID-19286999_E29", "type": "Localization", "trigger": { "text": [ "exclusion" ], "offsets": [ [ 1202, 1211 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-19286999_T25" }, { "role": "Theme", "ref_id": "PMID-19286999_T26" } ] }, { "id": "PMID-19286999_E30", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1236, 1245 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19286999_T27" }, { "role": "Theme", "ref_id": "PMID-19286999_E29" } ] }, { "id": "PMID-19286999_E31", "type": "Activation", "trigger": { "text": [ "reactivation" ], "offsets": [ [ 1287, 1299 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T28" }, { "role": "Cause", "ref_id": "PMID-19286999_E35" } ] }, { "id": "PMID-19286999_E32", "type": "Activation", "trigger": { "text": [ "reactivation" ], "offsets": [ [ 1287, 1299 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T28" }, { "role": "Cause", "ref_id": "PMID-19286999_E36" } ] }, { "id": "PMID-19286999_E33", "type": "Activation", "trigger": { "text": [ "reactivation" ], "offsets": [ [ 1287, 1299 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T28" }, { "role": "Cause", "ref_id": "PMID-19286999_E37" } ] }, { "id": "PMID-19286999_E34", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 1314, 1324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T29" } ] }, { "id": "PMID-19286999_E35", "type": "Positive_regulation", "trigger": { "text": [ "result" ], "offsets": [ [ 1336, 1342 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_E38" } ] }, { "id": "PMID-19286999_E36", "type": "Positive_regulation", "trigger": { "text": [ "result" ], "offsets": [ [ 1336, 1342 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_E39" } ] }, { "id": "PMID-19286999_E37", "type": "Positive_regulation", "trigger": { "text": [ "result" ], "offsets": [ [ 1336, 1342 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_E40" } ] }, { "id": "PMID-19286999_E38", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1360, 1370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T30" } ] }, { "id": "PMID-19286999_E39", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1360, 1370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T31" } ] }, { "id": "PMID-19286999_E40", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1360, 1370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19286999_T32" } ] }, { "id": "PMID-19286999_E41", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 1415, 1422 ] ] }, "arguments": [ { "role": 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[ { "id": "PMID-19286999_1", "entity_ids": [ "PMID-19286999_T5", "PMID-19286999_T6" ] }, { "id": "PMID-19286999_2", "entity_ids": [ "PMID-19286999_T17", "PMID-19286999_T18" ] } ]

[]