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bionlp_st_2011_epi

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[ { "id": "PMID-18247584__text", "type": "abstract", "text": [ "Complications in the assignment of 14 and 28 Da mass shift detected by mass spectrometry as in vivo methylation from endogenous proteins. \nIdentification of protein methylation sites typically starts with database searching of MS/MS spectra of proteolytic digest of the target protein by allowing addition of 14 and 28 Da in the selected amino acid residues that can be methylated. Despite the progress in our understanding of lysine and arginine methylation, substrates and functions of protein methylation at other amino acid residues remain unknown. Here we report the analysis of protein methylation for p53, SMC3, iNOS, and MeCP2. We found that a large number of peptides can be modified on the lysine, arginine, histidine, and glutamic acid residues with a mass increase of 14 or 28 Da, consistent with methylation. Surprisingly, a majority of which did not demonstrate a corresponding mass shift when cells were cultured with isotope-labeled methionine, a precursor for the synthesis of S-adenosyl-l-methionine (SAM), which is the most commonly used methyl donor for protein methylation. These results suggest the possibility of either exogenous protein methylation during sample handling and processing for mass spectrometry or the existence of SAM-independent pathways for protein methylation. Our study found a high occurrence of protein methylation from SDS-PAGE isolated endogenous proteins and identified complications for assigning such modifications as in vivo methylation. This study provides a cautionary note for solely relying on mass shift for mass spectrometric identification of protein methylation and highlights the importance of in vivo isotope labeling as a necessary validation method.\n" ], "offsets": [ [ 0, 1713 ] ] } ]

[ { "id": "PMID-18247584_T1", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 608, 611 ] ], "normalized": [] }, { "id": "PMID-18247584_T2", "type": "Protein", "text": [ "SMC3" ], "offsets": [ [ 613, 617 ] ], "normalized": [] }, { "id": "PMID-18247584_T3", "type": "Protein", "text": [ "iNOS" ], "offsets": [ [ 619, 623 ] ], "normalized": [] }, { "id": "PMID-18247584_T4", "type": "Protein", "text": [ "MeCP2" ], "offsets": [ [ 629, 634 ] ], "normalized": [] } ]

[ { "id": "PMID-18247584_E1", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 592, 603 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18247584_T1" } ] }, { "id": "PMID-18247584_E2", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 592, 603 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18247584_T2" } ] }, { "id": "PMID-18247584_E3", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 592, 603 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18247584_T3" } ] }, { "id": "PMID-18247584_E4", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 592, 603 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18247584_T4" } ] } ]

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[ { "id": "PMID-18264140__text", "type": "abstract", "text": [ "Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells. \nExpression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1 alpha (HIF-1 alpha) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1 alpha, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1 alpha. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1 alpha. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBx-transgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1 alpha, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.\n" ], "offsets": [ [ 0, 1593 ] ] } ]

[ { "id": "PMID-18264140_T1", "type": "Protein", "text": [ "X" ], "offsets": [ [ 18, 19 ] ], "normalized": [] }, { "id": "PMID-18264140_T2", "type": "Protein", "text": [ "MTA1" ], "offsets": [ [ 54, 58 ] ], "normalized": [] }, { "id": "PMID-18264140_T3", "type": "Protein", "text": [ "HDAC1" ], "offsets": [ [ 63, 68 ] ], "normalized": [] }, { "id": "PMID-18264140_T4", "type": "Protein", "text": [ "metastasis-associated protein 1" ], "offsets": [ [ 159, 190 ] ], "normalized": [] }, { "id": "PMID-18264140_T5", "type": "Protein", "text": [ "MTA1" ], "offsets": [ [ 192, 196 ] ], "normalized": [] }, { "id": "PMID-18264140_T6", "type": "Protein", "text": [ "MTA1" ], "offsets": [ [ 307, 311 ] ], "normalized": [] }, { "id": "PMID-18264140_T7", "type": "Protein", "text": [ "MTA1" ], "offsets": [ [ 368, 372 ] ], "normalized": [] }, { "id": "PMID-18264140_T8", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 392, 399 ] ], "normalized": [] }, { "id": "PMID-18264140_T9", "type": "Protein", "text": [ "HBx" ], "offsets": [ [ 527, 530 ] ], "normalized": [] }, { "id": "PMID-18264140_T10", "type": "Protein", "text": [ "MTA1" ], "offsets": [ [ 566, 570 ] ], "normalized": [] }, { "id": "PMID-18264140_T11", "type": "Protein", "text": [ "HDAC1" ], "offsets": [ [ 575, 580 ] ], "normalized": [] }, { "id": "PMID-18264140_T12", "type": "Protein", "text": [ "MTA1" ], "offsets": [ [ 611, 615 ] ], "normalized": [] }, { "id": "PMID-18264140_T13", "type": "Protein", "text": [ "HDAC1" ], "offsets": [ [ 620, 625 ] ], "normalized": [] }, { "id": "PMID-18264140_T14", "type": "Protein", "text": [ "2" ], "offsets": [ [ 626, 627 ] ], "normalized": [] }, { "id": "PMID-18264140_T15", "type": "Protein", "text": [ "hypoxia-inducible factor-1 alpha" ], "offsets": [ [ 655, 687 ] ], "normalized": [] }, { "id": "PMID-18264140_T16", "type": "Protein", "text": [ "HIF-1 alpha" ], "offsets": [ [ 689, 700 ] ], "normalized": [] }, { "id": "PMID-18264140_T17", "type": "Protein", "text": [ "HBx" ], "offsets": [ [ 729, 732 ] ], "normalized": [] }, { "id": "PMID-18264140_T18", "type": "Protein", "text": [ "MTA1" ], "offsets": [ [ 770, 774 ] ], "normalized": [] }, { "id": "PMID-18264140_T19", "type": "Protein", "text": [ "HBx" ], "offsets": [ [ 809, 812 ] ], "normalized": [] }, { "id": "PMID-18264140_T20", "type": "Protein", "text": [ "HIF-1 alpha" ], "offsets": [ [ 881, 892 ] ], "normalized": [] }, { "id": "PMID-18264140_T21", "type": "Protein", "text": [ "von Hippel-Lindau tumor suppressor" ], "offsets": [ [ 961, 995 ] ], "normalized": [] }, { "id": "PMID-18264140_T22", "type": "Protein", "text": [ "HIF-1 alpha" ], "offsets": [ [ 1001, 1012 ] ], "normalized": [] }, { "id": "PMID-18264140_T23", "type": "Protein", "text": [ "HBx" ], "offsets": [ [ 1042, 1045 ] ], "normalized": [] }, { "id": "PMID-18264140_T24", "type": "Protein", "text": [ "HIF-1 alpha" ], "offsets": [ [ 1112, 1123 ] ], "normalized": [] }, { "id": "PMID-18264140_T25", "type": "Protein", "text": [ "MTA1" ], "offsets": [ [ 1169, 1173 ] ], "normalized": [] }, { "id": "PMID-18264140_T26", "type": "Protein", "text": [ "HDAC1" ], "offsets": [ [ 1178, 1183 ] ], "normalized": [] }, { "id": "PMID-18264140_T27", "type": "Protein", "text": [ "HBx" ], "offsets": [ [ 1215, 1218 ] ], "normalized": [] }, { "id": "PMID-18264140_T28", "type": "Protein", "text": [ "HDAC1" ], "offsets": [ [ 1275, 1280 ] ], "normalized": [] }, { "id": "PMID-18264140_T29", "type": "Protein", "text": [ "HBx" ], "offsets": [ [ 1450, 1453 ] ], "normalized": [] }, { "id": "PMID-18264140_T30", "type": "Protein", "text": [ "MTA1" ], "offsets": [ [ 1462, 1466 ] ], "normalized": [] }, { "id": "PMID-18264140_T31", "type": "Protein", "text": [ "HIF-1 alpha" ], "offsets": [ [ 1495, 1506 ] ], "normalized": [] }, { "id": "PMID-18264140_T33", "type": "Entity", "text": [ "oxygen-dependent degradation domain" ], "offsets": [ [ 842, 877 ] ], "normalized": [] } ]

[ { "id": "PMID-18264140_E1", "type": "Deacetylation", "trigger": { "text": [ "deacetylation" ], "offsets": [ [ 821, 834 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18264140_T20" }, { "role": "Site", "ref_id": "PMID-18264140_T33" } ] }, { "id": "PMID-18264140_E2", "type": "Deacetylation", "trigger": { "text": [ "deacetylation" ], "offsets": [ [ 1054, 1067 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18264140_T24" } ] } ]

[ { "id": "PMID-18264140_1", "entity_ids": [ "PMID-18264140_T4", "PMID-18264140_T5" ] }, { "id": "PMID-18264140_2", "entity_ids": [ "PMID-18264140_T15", "PMID-18264140_T16" ] } ]

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[ { "id": "PMID-18281059__text", "type": "abstract", "text": [ "Crystal structures of the clock protein EA4 from the silkworm Bombyx mori. \nMany insects pass the winter in an arrested developmental stage called diapause, either as eggs, as pupae, or even as adults. Exposure to the prolonged cold of winter is required to permit awakening from diapause in the spring. In the diapause eggs of the silkworm Bombyx mori, a metalloglycoprotein, esterase A4 (EA4), has been suggested to serve as a cold-duration clock because its characteristic ATPase activity is transiently elevated at the end of the necessary cold period. This timer property of EA4 is known to start with the dissociation of an inhibitory peptide (called \"peptidyl inhibitory needle\") under cold conditions, but its time-measuring mechanism is completely unknown. Here we present the crystal structures and functional properties of EA4 with and without glycosylation. We show that EA4 is a homodimeric ATPase, with each subunit consisting of a copper-zinc superoxide dismutase fold. There is an additional short N-terminal region that is capable of binding one more copper ion, suggesting a timer mechanism in which this ion is involved. The sugar chain appears to reinforce the binding of peptidyl inhibitory needle, which may in turn stabilize the initial conformation of the N-terminal domain, explaining the requirement for glycosylation and for the peptide to set the clock.\n" ], "offsets": [ [ 0, 1382 ] ] } ]

[ { "id": "PMID-18281059_T1", "type": "Protein", "text": [ "EA4" ], "offsets": [ [ 40, 43 ] ], "normalized": [] }, { "id": "PMID-18281059_T2", "type": "Protein", "text": [ "esterase A4" ], "offsets": [ [ 377, 388 ] ], "normalized": [] }, { "id": "PMID-18281059_T3", "type": "Protein", "text": [ "EA4" ], "offsets": [ [ 390, 393 ] ], "normalized": [] }, { "id": "PMID-18281059_T4", "type": "Protein", "text": [ "EA4" ], "offsets": [ [ 580, 583 ] ], "normalized": [] }, { "id": "PMID-18281059_T5", "type": "Protein", "text": [ "EA4" ], "offsets": [ [ 834, 837 ] ], "normalized": [] }, { "id": "PMID-18281059_T6", "type": "Protein", "text": [ "EA4" ], "offsets": [ [ 883, 886 ] ], "normalized": [] } ]

[ { "id": "PMID-18281059_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 855, 868 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18281059_T5" } ] }, { "id": "PMID-18281059_E2", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 855, 868 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18281059_T5" } ] }, { "id": "PMID-18281059_E3", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 1330, 1343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18281059_T6" } ] } ]

[ { "id": "PMID-18281059_1", "entity_ids": [ "PMID-18281059_T2", "PMID-18281059_T3" ] } ]

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[ { "id": "PMID-18286479__text", "type": "abstract", "text": [ "Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization. \nThe adaptor protein Grb10 is an interacting partner of the IGF-I receptor (IGF-IR) and the insulin receptor (IR). Previous work from our laboratory has established the role of Grb10 as a negative regulator of IGF-IR-dependent cell proliferation. We have shown that Grb10 binds the E3 ubiquitin ligase Nedd4 and promotes IGF-I-stimulated ubiquitination, internalization, and degradation of the IGF-IR, thereby giving rise to long-term attenuation of signaling. Recent biochemical evidence suggests that tyrosine-kinase receptors (RTK) may not be polyubiquitinated but monoubiquitinated at multiple sites (multiubiquitinated). However, the type of ubiquitination of the IGF-IR is still not defined. Here we show that the Grb10/Nedd4 complex upon ligand stimulation mediates multiubiquitination of the IGF-IR, which is required for receptor internalization. Moreover, Nedd4 by promoting IGF-IR ubiquitination and internalization contributes with Grb10 to negatively regulate IGF-IR-dependent cell proliferation. We also demonstrate that the IGF-IR is internalized through clathrin-dependent and-independent pathways. Grb10 and Nedd4 remain associated with the IGF-IR in early endosomes and caveosomes, where they may participate in sorting internalized receptors. Grb10 and Nedd4, unlike the IGF-IR, which is targeted for lysosomal degradation are not degraded and likely directed into recycling endosomes. These results indicate that Grb10 and Nedd4 play a critical role in mediating IGF-IR down-regulation by promoting ligand-dependent multiubiquitination of the IGF-IR, which is required for receptor internalization and regulates mitogenesis.\n" ], "offsets": [ [ 0, 1765 ] ] } ]

[ { "id": "PMID-18286479_T1", "type": "Protein", "text": [ "Grb10" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-18286479_T2", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 6, 11 ] ], "normalized": [] }, { "id": "PMID-18286479_T3", "type": "Protein", "text": [ "insulin-like growth factor receptor" ], "offsets": [ [ 48, 83 ] ], "normalized": [] }, { "id": "PMID-18286479_T4", "type": "Protein", "text": [ "Grb10" ], "offsets": [ [ 141, 146 ] ], "normalized": [] }, { "id": "PMID-18286479_T5", "type": "Protein", "text": [ "IGF-I receptor" ], "offsets": [ [ 180, 194 ] ], "normalized": [] }, { "id": "PMID-18286479_T6", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 196, 202 ] ], "normalized": [] }, { "id": "PMID-18286479_T7", "type": "Protein", "text": [ "insulin receptor" ], "offsets": [ [ 212, 228 ] ], "normalized": [] }, { "id": "PMID-18286479_T8", "type": "Protein", "text": [ "IR" ], "offsets": [ [ 230, 232 ] ], "normalized": [] }, { "id": "PMID-18286479_T9", "type": "Protein", "text": [ "Grb10" ], "offsets": [ [ 297, 302 ] ], "normalized": [] }, { "id": "PMID-18286479_T10", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 330, 336 ] ], "normalized": [] }, { "id": "PMID-18286479_T11", "type": "Protein", "text": [ "Grb10" ], "offsets": [ [ 386, 391 ] ], "normalized": [] }, { "id": "PMID-18286479_T12", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 405, 414 ] ], "normalized": [] }, { "id": "PMID-18286479_T13", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 422, 427 ] ], "normalized": [] }, { "id": "PMID-18286479_T14", "type": "Protein", "text": [ "IGF-I" ], "offsets": [ [ 441, 446 ] ], "normalized": [] }, { "id": "PMID-18286479_T15", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 514, 520 ] ], "normalized": [] }, { "id": "PMID-18286479_T16", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 789, 795 ] ], "normalized": [] }, { "id": "PMID-18286479_T17", "type": "Protein", "text": [ "Grb10" ], "offsets": [ [ 840, 845 ] ], "normalized": [] }, { "id": "PMID-18286479_T18", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 846, 851 ] ], "normalized": [] }, { "id": "PMID-18286479_T19", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 920, 926 ] ], "normalized": [] }, { "id": "PMID-18286479_T20", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 986, 991 ] ], "normalized": [] }, { "id": "PMID-18286479_T21", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 1005, 1011 ] ], "normalized": [] }, { "id": "PMID-18286479_T22", "type": "Protein", "text": [ "Grb10" ], "offsets": [ [ 1064, 1069 ] ], "normalized": [] }, { "id": "PMID-18286479_T23", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 1093, 1099 ] ], "normalized": [] }, { "id": "PMID-18286479_T24", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 1159, 1165 ] ], "normalized": [] }, { "id": "PMID-18286479_T25", "type": "Protein", "text": [ "Grb10" ], "offsets": [ [ 1235, 1240 ] ], "normalized": [] }, { "id": "PMID-18286479_T26", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 1245, 1250 ] ], "normalized": [] }, { "id": "PMID-18286479_T27", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 1278, 1284 ] ], "normalized": [] }, { "id": "PMID-18286479_T28", "type": "Protein", "text": [ "Grb10" ], "offsets": [ [ 1382, 1387 ] ], "normalized": [] }, { "id": "PMID-18286479_T29", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 1392, 1397 ] ], "normalized": [] }, { "id": "PMID-18286479_T30", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 1410, 1416 ] ], "normalized": [] }, { "id": "PMID-18286479_T31", "type": "Protein", "text": [ "Grb10" ], "offsets": [ [ 1553, 1558 ] ], "normalized": [] }, { "id": "PMID-18286479_T32", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 1563, 1568 ] ], "normalized": [] }, { "id": "PMID-18286479_T33", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 1603, 1609 ] ], "normalized": [] }, { "id": "PMID-18286479_T34", "type": "Protein", "text": [ "IGF-IR" ], "offsets": [ [ 1683, 1689 ] ], "normalized": [] } ]

[ { "id": "PMID-18286479_E1", "type": "Ubiquitination", "trigger": { "text": [ "multiubiquitination" ], "offsets": [ [ 21, 40 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18286479_T3" } ] }, { "id": "PMID-18286479_E2", "type": "Catalysis", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 447, 457 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18286479_E3" }, { "role": "Cause", "ref_id": "PMID-18286479_T14" } ] }, { "id": "PMID-18286479_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 458, 472 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18286479_T15" } ] }, { "id": "PMID-18286479_E4", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 767, 781 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18286479_T16" } ] }, { "id": "PMID-18286479_E5", "type": "Ubiquitination", "trigger": { "text": [ "multiubiquitination" ], "offsets": [ [ 893, 912 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18286479_T19" } ] }, { "id": "PMID-18286479_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1012, 1026 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18286479_T21" } ] }, { "id": "PMID-18286479_E7", "type": "Ubiquitination", "trigger": { "text": [ "multiubiquitination" ], "offsets": [ [ 1656, 1675 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18286479_T34" } ] } ]

[ { "id": "PMID-18286479_1", "entity_ids": [ "PMID-18286479_T5", "PMID-18286479_T6" ] }, { "id": "PMID-18286479_2", "entity_ids": [ "PMID-18286479_T7", "PMID-18286479_T8" ] } ]

[]

[ { "id": "PMID-18287095__text", "type": "abstract", "text": [ "ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response. \nInterferons regulate diverse immune functions through the transcriptional activation of hundreds of genes involved in anti-viral responses. The interferon-inducible ubiquitin-like protein ISG15 is expressed in cells in response to a variety of stress conditions like viral or bacterial infection and is present in its free form or is conjugated to cellular proteins. In addition, protein ubiquitination plays a regulatory role in the immune system. Many viruses modulate the ubiquitin (Ub) pathway to alter cellular signaling and the antiviral response. Ubiquitination of retroviral group-specific antigen precursors and matrix proteins of the Ebola, vesicular stomatitis, and rabies viruses by Nedd4 family HECT domain E3 ligases is an important step in facilitating viral release. We found that Nedd4 is negatively regulated by ISG15. Free ISG15 specifically bound to Nedd4 and blocked its interaction with Ub-E2 molecules, thus preventing further Ub transfer from E2 to E3. Furthermore, overexpression of ISG15 diminished the ability of Nedd4 to ubiquitinate viral matrix proteins and led to a decrease in the release of Ebola VP40 virus-like particles from the cells. These results point to a mechanistically novel function of ISG15 in the enhancement of the innate anti-viral response through specific inhibition of Nedd4 Ub-E3 activity. To our knowledge, this is the first example of a Ub-like protein with the ability to interfere with Ub-E2 and E3 interaction to inhibit protein ubiquitination.\n" ], "offsets": [ [ 0, 1591 ] ] } ]

[ { "id": "PMID-18287095_T1", "type": "Protein", "text": [ "ISG15" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-18287095_T2", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 15, 20 ] ], "normalized": [] }, { "id": "PMID-18287095_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 253, 262 ] ], "normalized": [] }, { "id": "PMID-18287095_T4", "type": "Protein", "text": [ "ISG15" ], "offsets": [ [ 276, 281 ] ], "normalized": [] }, { "id": "PMID-18287095_T5", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 563, 572 ] ], "normalized": [] }, { "id": "PMID-18287095_T6", "type": "Protein", "text": [ "Ub" ], "offsets": [ [ 574, 576 ] ], "normalized": [] }, { "id": "PMID-18287095_T7", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 783, 788 ] ], "normalized": [] }, { "id": "PMID-18287095_T8", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 885, 890 ] ], "normalized": [] }, { "id": "PMID-18287095_T9", "type": "Protein", "text": [ "ISG15" ], "offsets": [ [ 918, 923 ] ], "normalized": [] }, { "id": "PMID-18287095_T10", "type": "Protein", "text": [ "ISG15" ], "offsets": [ [ 930, 935 ] ], "normalized": [] }, { "id": "PMID-18287095_T11", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 958, 963 ] ], "normalized": [] }, { "id": "PMID-18287095_T12", "type": "Protein", "text": [ "Ub" ], "offsets": [ [ 997, 999 ] ], "normalized": [] }, { "id": "PMID-18287095_T13", "type": "Protein", "text": [ "Ub" ], "offsets": [ [ 1038, 1040 ] ], "normalized": [] }, { "id": "PMID-18287095_T14", "type": "Protein", "text": [ "ISG15" ], "offsets": [ [ 1096, 1101 ] ], "normalized": [] }, { "id": "PMID-18287095_T15", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 1128, 1133 ] ], "normalized": [] }, { "id": "PMID-18287095_T16", "type": "Protein", "text": [ "ISG15" ], "offsets": [ [ 1319, 1324 ] ], "normalized": [] }, { "id": "PMID-18287095_T17", "type": "Protein", "text": [ "Nedd4" ], "offsets": [ [ 1409, 1414 ] ], "normalized": [] }, { "id": "PMID-18287095_T18", "type": "Protein", "text": [ "Ub" ], "offsets": [ [ 1415, 1417 ] ], "normalized": [] }, { "id": "PMID-18287095_T19", "type": "Protein", "text": [ "Ub" ], "offsets": [ [ 1480, 1482 ] ], "normalized": [] }, { "id": "PMID-18287095_T20", "type": "Protein", "text": [ "Ub" ], "offsets": [ [ 1531, 1533 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-18287095_1", "entity_ids": [ "PMID-18287095_T5", "PMID-18287095_T6" ] } ]

[]

[ { "id": "PMID-18296627__text", "type": "abstract", "text": [ "COP1-mediated ubiquitination of CONSTANS is implicated in cryptochrome regulation of flowering in Arabidopsis. \nIn Arabidopsis thaliana, the blue light photoreceptor cryptochromes (CRY) act to promote photomorphogenic development and the transition from vegetative to floral development in long days (LDs). We previously proposed that one of the mechanisms by which CRY regulates light responses is via its physical interaction with COP1, a RING motif-containing E3 ligase. Under LDs, the transcription of FLOWERING LOCUS T (FT) is activated by CONSTANS (CO) in leaf, and the FT protein moves to the shoot apex to induce flowering. CO protein is degraded in darkness, whereas it is stabilized by the CRY-mediated signal. However, the mechanism underlying this process is unknown. We show in this report that CO acts genetically downstream of COP1 and CRY to regulate flowering time. In addition, COP1 physically interacts with CO and functions as an E3 ligase, ubiquitinating CO in vitro and reducing CO levels in vivo. These results suggest that COP1 acts as a repressor of flowering by promoting the ubiquitin-mediated proteolysis of CO in darkness and that CRY-mediated signal may negatively regulate COP1, thereby stabilizing CO, activating FT transcription, and inducing flowering.\n" ], "offsets": [ [ 0, 1287 ] ] } ]

[ { "id": "PMID-18296627_T1", "type": "Protein", "text": [ "COP1" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-18296627_T2", "type": "Protein", "text": [ "CONSTANS" ], "offsets": [ [ 32, 40 ] ], "normalized": [] }, { "id": "PMID-18296627_T3", "type": "Protein", "text": [ "COP1" ], "offsets": [ [ 433, 437 ] ], "normalized": [] }, { "id": "PMID-18296627_T4", "type": "Protein", "text": [ "FLOWERING LOCUS T" ], "offsets": [ [ 506, 523 ] ], "normalized": [] }, { "id": "PMID-18296627_T5", "type": "Protein", "text": [ "FT" ], "offsets": [ [ 525, 527 ] ], "normalized": [] }, { "id": "PMID-18296627_T6", "type": "Protein", "text": [ "CONSTANS" ], "offsets": [ [ 545, 553 ] ], "normalized": [] }, { "id": "PMID-18296627_T7", "type": "Protein", "text": [ "CO" ], "offsets": [ [ 555, 557 ] ], "normalized": [] }, { "id": "PMID-18296627_T8", "type": "Protein", "text": [ "FT" ], "offsets": [ [ 576, 578 ] ], "normalized": [] }, { "id": "PMID-18296627_T9", "type": "Protein", "text": [ "CO" ], "offsets": [ [ 632, 634 ] ], "normalized": [] }, { "id": "PMID-18296627_T10", "type": "Protein", "text": [ "CO" ], "offsets": [ [ 808, 810 ] ], "normalized": [] }, { "id": "PMID-18296627_T11", "type": "Protein", "text": [ "COP1" ], "offsets": [ [ 842, 846 ] ], "normalized": [] }, { "id": "PMID-18296627_T12", "type": "Protein", "text": [ "COP1" ], "offsets": [ [ 896, 900 ] ], "normalized": [] }, { "id": "PMID-18296627_T13", "type": "Protein", "text": [ "CO" ], "offsets": [ [ 927, 929 ] ], "normalized": [] }, { "id": "PMID-18296627_T14", "type": "Protein", "text": [ "CO" ], "offsets": [ [ 976, 978 ] ], "normalized": [] }, { "id": "PMID-18296627_T15", "type": "Protein", "text": [ "CO" ], "offsets": [ [ 1001, 1003 ] ], "normalized": [] }, { "id": "PMID-18296627_T16", "type": "Protein", "text": [ "COP1" ], "offsets": [ [ 1047, 1051 ] ], "normalized": [] }, { "id": "PMID-18296627_T17", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1102, 1111 ] ], "normalized": [] }, { "id": "PMID-18296627_T18", "type": "Protein", "text": [ "CO" ], "offsets": [ [ 1136, 1138 ] ], "normalized": [] }, { "id": "PMID-18296627_T19", "type": "Protein", "text": [ "COP1" ], "offsets": [ [ 1204, 1208 ] ], "normalized": [] }, { "id": "PMID-18296627_T20", "type": "Protein", "text": [ "CO" ], "offsets": [ [ 1230, 1232 ] ], "normalized": [] }, { "id": "PMID-18296627_T21", "type": "Protein", "text": [ "FT" ], "offsets": [ [ 1245, 1247 ] ], "normalized": [] } ]

[ { "id": "PMID-18296627_E1", "type": "Catalysis", "trigger": { "text": [ "mediated" ], "offsets": [ [ 5, 13 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18296627_E2" }, { "role": "Cause", "ref_id": "PMID-18296627_T1" } ] }, { "id": "PMID-18296627_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 14, 28 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18296627_T2" } ] }, { "id": "PMID-18296627_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinating" ], "offsets": [ [ 961, 975 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18296627_T14" } ] }, { "id": "PMID-18296627_E4", "type": "Catalysis", "trigger": { "text": [ "ubiquitinating" ], "offsets": [ [ 961, 975 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18296627_E3" }, { "role": "Cause", "ref_id": "PMID-18296627_T12" } ] } ]

[ { "id": "PMID-18296627_1", "entity_ids": [ "PMID-18296627_T6", "PMID-18296627_T7" ] } ]

[]

[ { "id": "PMID-18305110__text", "type": "abstract", "text": [ "Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. \nTAR DNA-binding protein 43 (TDP-43) is the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Although normal TDP-43 is a nuclear protein, pathological TDP-43 is redistributed and sequestered as insoluble aggregates in neuronal nuclei, perikarya, and neurites. Here we recapitulate these pathological phenotypes in cultured cells by altering endogenous TDP-43 nuclear trafficking and by expressing mutants with defective nuclear localization (TDP-43-DeltaNLS) or nuclear export signals (TDP-43-DeltaNES). Restricting endogenous cytoplasmic TDP-43 from entering the nucleus or preventing its exit out of the nucleus resulted in TDP-43 aggregate formation. TDP-43-DeltaNLS accumulates as insoluble cytoplasmic aggregates and sequesters endogenous TDP-43, thereby depleting normal nuclear TDP-43, whereas TDP-43-DeltaNES forms insoluble nuclear aggregates with endogenous TDP-43. Mutant forms of TDP-43 also replicate the biochemical profile of pathological TDP-43 in FTLD-U/ALS. Thus, FTLD-U/ALS pathogenesis may be linked mechanistically to deleterious perturbations of nuclear trafficking and solubility of TDP-43.\n" ], "offsets": [ [ 0, 1352 ] ] } ]

[ { "id": "PMID-18305110_T1", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 64, 70 ] ], "normalized": [] }, { "id": "PMID-18305110_T2", "type": "Protein", "text": [ "TAR DNA-binding protein 43" ], "offsets": [ [ 150, 176 ] ], "normalized": [] }, { "id": "PMID-18305110_T3", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 178, 184 ] ], "normalized": [] }, { "id": "PMID-18305110_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 251, 260 ] ], "normalized": [] }, { "id": "PMID-18305110_T5", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 347, 353 ] ], "normalized": [] }, { "id": "PMID-18305110_T6", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 389, 395 ] ], "normalized": [] }, { "id": "PMID-18305110_T7", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 590, 596 ] ], "normalized": [] }, { "id": "PMID-18305110_T8", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 680, 686 ] ], "normalized": [] }, { "id": "PMID-18305110_T9", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 724, 730 ] ], "normalized": [] }, { "id": "PMID-18305110_T10", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 777, 783 ] ], "normalized": [] }, { "id": "PMID-18305110_T11", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 864, 870 ] ], "normalized": [] }, { "id": "PMID-18305110_T12", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 892, 898 ] ], "normalized": [] }, { "id": "PMID-18305110_T13", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 982, 988 ] ], "normalized": [] }, { "id": "PMID-18305110_T14", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 1023, 1029 ] ], "normalized": [] }, { "id": "PMID-18305110_T15", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 1039, 1045 ] ], "normalized": [] }, { "id": "PMID-18305110_T16", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 1106, 1112 ] ], "normalized": [] }, { "id": "PMID-18305110_T17", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 1130, 1136 ] ], "normalized": [] }, { "id": "PMID-18305110_T18", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 1192, 1198 ] ], "normalized": [] }, { "id": "PMID-18305110_T19", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 1344, 1350 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-18305110_1", "entity_ids": [ "PMID-18305110_T2", "PMID-18305110_T3" ] } ]

[]

[ { "id": "PMID-18321851__text", "type": "abstract", "text": [ "Cue1p is an activator of Ubc7p E2 activity in vitro and in vivo. \nUbc7p is a ubiquitin-conjugating enzyme (E2) that functions with endoplasmic reticulum (ER)-resident ubiquitin ligases (E3s) to promote endoplasmic reticulum-associated degradation (ERAD). Ubc7p only functions in ERAD if bound to the ER surface by Cue1p, a membrane-anchored ER protein. The role of Cue1p was thought to involve passive concentration of Ubc7p at the surface of the ER. However, our biochemical studies of Ubc7p suggested that Cue1p may, in addition, stimulate Ubc7p E2 activity. We have tested this idea and found it to be true both in vitro and in vivo. Ubc7p bound to the soluble domain of Cue1p showed strongly enhanced in vitro ubiquitination activity, both in the presence and absence of E3. Cue1p also enhanced Ubc7p function in vivo, and this activation was separable from the established ER-anchoring role of Cue1p. Finally, we tested in vivo activation of Ubc7p by Cue1p in an assay independent of the ER membrane and ERAD. A chimeric E2 linking Ubc7p to the Cdc34p/Ubc3p localization domain complemented the cdc34-2 TS phenotype, and co-expression of the soluble Cue1p domain enhanced complementation by this chimeric Ubc7p E2. These studies reveal a previously unobserved stimulation of Ubc7p E2 activity by Cue1p that is critical for full ERAD and that functions independently of the well known Cue1p anchoring function. Moreover, it suggests a previously unappreciated mode for regulation of E2s by Cue1p-like interacting partners.\n" ], "offsets": [ [ 0, 1527 ] ] } ]

[ { "id": "PMID-18321851_T1", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-18321851_T2", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 25, 30 ] ], "normalized": [] }, { "id": "PMID-18321851_T3", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 66, 71 ] ], "normalized": [] }, { "id": "PMID-18321851_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 77, 86 ] ], "normalized": [] }, { "id": "PMID-18321851_T5", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 167, 176 ] ], "normalized": [] }, { "id": "PMID-18321851_T6", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 255, 260 ] ], "normalized": [] }, { "id": "PMID-18321851_T7", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 314, 319 ] ], "normalized": [] }, { "id": "PMID-18321851_T8", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 365, 370 ] ], "normalized": [] }, { "id": "PMID-18321851_T9", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 419, 424 ] ], "normalized": [] }, { "id": "PMID-18321851_T10", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 487, 492 ] ], "normalized": [] }, { "id": "PMID-18321851_T11", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 508, 513 ] ], "normalized": [] }, { "id": "PMID-18321851_T12", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 542, 547 ] ], "normalized": [] }, { "id": "PMID-18321851_T13", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 637, 642 ] ], "normalized": [] }, { "id": "PMID-18321851_T14", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 674, 679 ] ], "normalized": [] }, { "id": "PMID-18321851_T15", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 779, 784 ] ], "normalized": [] }, { "id": "PMID-18321851_T16", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 799, 804 ] ], "normalized": [] }, { "id": "PMID-18321851_T17", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 899, 904 ] ], "normalized": [] }, { "id": "PMID-18321851_T18", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 947, 952 ] ], "normalized": [] }, { "id": "PMID-18321851_T19", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 956, 961 ] ], "normalized": [] }, { "id": "PMID-18321851_T20", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 1037, 1042 ] ], "normalized": [] }, { "id": "PMID-18321851_T21", "type": "Protein", "text": [ "Cdc34p" ], "offsets": [ [ 1050, 1056 ] ], "normalized": [] }, { "id": "PMID-18321851_T22", "type": "Protein", "text": [ "Ubc3p" ], "offsets": [ [ 1057, 1062 ] ], "normalized": [] }, { "id": "PMID-18321851_T23", "type": "Protein", "text": [ "cdc34" ], "offsets": [ [ 1100, 1105 ] ], "normalized": [] }, { "id": "PMID-18321851_T24", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 1155, 1160 ] ], "normalized": [] }, { "id": "PMID-18321851_T25", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 1210, 1215 ] ], "normalized": [] }, { "id": "PMID-18321851_T26", "type": "Protein", "text": [ "Ubc7p" ], "offsets": [ [ 1280, 1285 ] ], "normalized": [] }, { "id": "PMID-18321851_T27", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 1301, 1306 ] ], "normalized": [] }, { "id": "PMID-18321851_T28", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 1389, 1394 ] ], "normalized": [] }, { "id": "PMID-18321851_T29", "type": "Protein", "text": [ "Cue1p" ], "offsets": [ [ 1494, 1499 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18323654__text", "type": "abstract", "text": [ "Stabilization of p53 is involved in quercetin-induced cell cycle arrest and apoptosis in HepG2 cells. \nThere is evidence for defects in the mechanisms that allow the activation of p53 in many of the cancers that retain wild-type p53. Reactivation of p53 has been suggested to be an effective strategy for cancer therapy in wild-type p53-retained tumor cells. In the present study, we attempted to reactivate p53 in HepG2 retaining wild-type p53 by quercetin, an ubiquitous bioactive plant flavonoid. Our results show that quercetin inhibited the proliferation of HepG2 cells through the induction of cell cycle arrest and apoptosis, as characterized by the cell cycle distribution and DNA fragmentation. Molecular data revealed that quercetin induced p53 phosphorylation and total p53 protein, but that it did not up-regulate p53 mRNA at the transcription level. Consequently, quercetin stimulated p21 expression and suppressed cyclin D1 expression in favor of cell cycle arrest. Quercetin also increased the ratio of Bax/Bcl-2 in favor of apoptosis with such treatment. Interestingly, quercetin inhibited p53 ubiquitination and extended the half-life (t(1/2)) of p53 from 74 to 184 min. Quercetin also inhibited p53 mRNA degradation at the post-transcription stage. Silencing p53 with p53 small interfering RNA (siRNA) significantly abrogated the p53-dependent gene expression and apoptotic induction. Taken together, our data demonstrate that quercetin stabilized p53 at both the mRNA and protein levels to reactivate p53-dependent cell cycle arrest and apoptosis in HepG2 cells.\n" ], "offsets": [ [ 0, 1582 ] ] } ]

[ { "id": "PMID-18323654_T1", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 17, 20 ] ], "normalized": [] }, { "id": "PMID-18323654_T2", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 180, 183 ] ], "normalized": [] }, { "id": "PMID-18323654_T3", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 229, 232 ] ], "normalized": [] }, { "id": "PMID-18323654_T4", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 250, 253 ] ], "normalized": [] }, { "id": "PMID-18323654_T5", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 333, 336 ] ], "normalized": [] }, { "id": "PMID-18323654_T6", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 408, 411 ] ], "normalized": [] }, { "id": "PMID-18323654_T7", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 441, 444 ] ], "normalized": [] }, { "id": "PMID-18323654_T8", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 751, 754 ] ], "normalized": [] }, { "id": "PMID-18323654_T9", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 781, 784 ] ], "normalized": [] }, { "id": "PMID-18323654_T10", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 826, 829 ] ], "normalized": [] }, { "id": "PMID-18323654_T11", "type": "Protein", "text": [ "p21" ], "offsets": [ [ 898, 901 ] ], "normalized": [] }, { "id": "PMID-18323654_T12", "type": "Protein", "text": [ "cyclin D1" ], "offsets": [ [ 928, 937 ] ], "normalized": [] }, { "id": "PMID-18323654_T13", "type": "Protein", "text": [ "Bax" ], "offsets": [ [ 1018, 1021 ] ], "normalized": [] }, { "id": "PMID-18323654_T14", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1022, 1027 ] ], "normalized": [] }, { "id": "PMID-18323654_T15", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1106, 1109 ] ], "normalized": [] }, { "id": "PMID-18323654_T16", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1164, 1167 ] ], "normalized": [] }, { "id": "PMID-18323654_T17", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1213, 1216 ] ], "normalized": [] }, { "id": "PMID-18323654_T18", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1277, 1280 ] ], "normalized": [] }, { "id": "PMID-18323654_T19", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1286, 1289 ] ], "normalized": [] }, { "id": "PMID-18323654_T20", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1348, 1351 ] ], "normalized": [] }, { "id": "PMID-18323654_T21", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1466, 1469 ] ], "normalized": [] }, { "id": "PMID-18323654_T22", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1520, 1523 ] ], "normalized": [] } ]

[ { "id": "PMID-18323654_E1", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 755, 770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18323654_T8" } ] }, { "id": "PMID-18323654_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1110, 1124 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18323654_T15" } ] } ]

[]

[]

[ { "id": "PMID-18332137__text", "type": "abstract", "text": [ "Tumor suppressor cylindromatosis acts as a negative regulator for Streptococcus pneumoniae-induced NFAT signaling. \nGram-positive bacterium Streptococcus pneumoniae is an important human pathogen that colonizes the upper respiratory tract and is also the major cause of morbidity and mortality worldwide. S. pneumoniae causes invasive diseases such as pneumonia, meningitis, and otitis media. Despite the importance of pneumococcal diseases, little is known about the molecular mechanisms by which S. pneumoniae-induced inflammation is regulated, especially the negative regulatory mechanisms. Here we show that S. pneumoniae activates nuclear factor of activated T cells (NFAT) signaling pathway and the subsequent up-regulation of inflammatory mediators via a key pneumococcal virulence factor, pneumolysin. We also demonstrate that S. pneumoniae activates NFAT transcription factor independently of Toll-like receptors 2 and 4. Moreover, S. pneumoniae induces NFAT activation via both Ca(2+)-calcineurin and transforming growth factor-beta-activated kinase 1 (TAK1)-mitogen-activated protein kinase kinase (MKK) 3/6-p38alpha/beta-dependent signaling pathways. Interestingly, we found for the first time that tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for S. pneumoniae-induced NFAT signaling pathway via a deubiquitination-dependent mechanism. Finally, we showed that CYLD interacts with and deubiquitinates TAK1 to negatively regulate the activation of the downstream MKK3/6-p38alpha/beta pathway. Our studies thus bring new insights into the molecular pathogenesis of S. pneumoniae infections through the NFAT-dependent mechanism and further identify CYLD as a negative regulator for NFAT signaling, thereby opening up new therapeutic targets for these diseases.\n" ], "offsets": [ [ 0, 1794 ] ] } ]

[ { "id": "PMID-18332137_T1", "type": "Protein", "text": [ "pneumolysin" ], "offsets": [ [ 797, 808 ] ], "normalized": [] }, { "id": "PMID-18332137_T2", "type": "Protein", "text": [ "Toll-like receptors 2" ], "offsets": [ [ 902, 923 ] ], "normalized": [] }, { "id": "PMID-18332137_T3", "type": "Protein", "text": [ "4" ], "offsets": [ [ 928, 929 ] ], "normalized": [] }, { "id": "PMID-18332137_T4", "type": "Protein", "text": [ "transforming growth factor-beta-activated kinase 1" ], "offsets": [ [ 1011, 1061 ] ], "normalized": [] }, { "id": "PMID-18332137_T5", "type": "Protein", "text": [ "TAK1" ], "offsets": [ [ 1063, 1067 ] ], "normalized": [] }, { "id": "PMID-18332137_T6", "type": "Protein", "text": [ "protein kinase kinase (MKK) 3" ], "offsets": [ [ 1087, 1116 ] ], "normalized": [] }, { "id": "PMID-18332137_T7", "type": "Protein", "text": [ "6" ], "offsets": [ [ 1117, 1118 ] ], "normalized": [] }, { "id": "PMID-18332137_T8", "type": "Protein", "text": [ "p38alpha" ], "offsets": [ [ 1119, 1127 ] ], "normalized": [] }, { "id": "PMID-18332137_T9", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 1128, 1132 ] ], "normalized": [] }, { "id": "PMID-18332137_T10", "type": "Protein", "text": [ "cylindromatosis" ], "offsets": [ [ 1228, 1243 ] ], "normalized": [] }, { "id": "PMID-18332137_T11", "type": "Protein", "text": [ "CYLD" ], "offsets": [ [ 1245, 1249 ] ], "normalized": [] }, { "id": "PMID-18332137_T12", "type": "Protein", "text": [ "CYLD" ], "offsets": [ [ 1397, 1401 ] ], "normalized": [] }, { "id": "PMID-18332137_T13", "type": "Protein", "text": [ "TAK1" ], "offsets": [ [ 1437, 1441 ] ], "normalized": [] }, { "id": "PMID-18332137_T14", "type": "Protein", "text": [ "MKK3" ], "offsets": [ [ 1498, 1502 ] ], "normalized": [] }, { "id": "PMID-18332137_T15", "type": "Protein", "text": [ "6" ], "offsets": [ [ 1503, 1504 ] ], "normalized": [] }, { "id": "PMID-18332137_T16", "type": "Protein", "text": [ "p38alpha" ], "offsets": [ [ 1505, 1513 ] ], "normalized": [] }, { "id": "PMID-18332137_T17", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 1514, 1518 ] ], "normalized": [] }, { "id": "PMID-18332137_T18", "type": "Protein", "text": [ "CYLD" ], "offsets": [ [ 1682, 1686 ] ], "normalized": [] } ]

[ { "id": "PMID-18332137_E1", "type": "Deubiquitination", "trigger": { "text": [ "deubiquitinates" ], "offsets": [ [ 1421, 1436 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18332137_T13" } ] }, { "id": "PMID-18332137_E2", "type": "Catalysis", "trigger": { "text": [ "deubiquitinates" ], "offsets": [ [ 1421, 1436 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18332137_E1" }, { "role": "Cause", "ref_id": "PMID-18332137_T12" } ] } ]

[ { "id": "PMID-18332137_1", "entity_ids": [ "PMID-18332137_T4", "PMID-18332137_T5" ] } ]

[]

[ { "id": "PMID-18344599__text", "type": "abstract", "text": [ "Pirh2 interacts with and ubiquitylates signal recognition particle receptor beta subunit. \nPirh2 is a RING finger type ubiquitin ligase which ubiquitylates various proteins including p53, p27(Kip1), HDAC1, and epsilon-COP. In this study, we identified signal recognition particle receptor beta subunit (SRbeta), an integral membrane protein of the endoplasmic reticulum (ER), as a novel Pirh2-interacting protein by yeast two-hybrid screening. We confirmed that Pirh2 interacted with SRbeta in mammalian cells. An immunofluorescent staining revealed that Pirh2 colocalized with SRbeta in the ER. Pirh2 poly-ubiquitylated SRbeta in an intact RING finger domain-dependent manner in vivo and in vitro. Unexpectedly, different from other Pirh2 substrates, neither overexpression of Pirh2 nor depletion of cellular Pirh2 affected SRbeta protein stability. Pirh2 preferentially utilized lysine residues 6 and 29 of the ubiquitin to mediate the formation of polyubiquitin chains on SRbeta. These results suggest that Pirh2 may regulate SRbeta function by mediating poly-ubiquitylation of SRbeta without affecting the stability of SRbeta protein per se.\n" ], "offsets": [ [ 0, 1146 ] ] } ]

[ { "id": "PMID-18344599_T1", "type": "Protein", "text": [ "Pirh2" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-18344599_T2", "type": "Protein", "text": [ "signal recognition particle receptor beta subunit" ], "offsets": [ [ 39, 88 ] ], "normalized": [] }, { "id": "PMID-18344599_T3", "type": "Protein", "text": [ "Pirh2" ], "offsets": [ [ 91, 96 ] ], "normalized": [] }, { "id": "PMID-18344599_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 119, 128 ] ], "normalized": [] }, { "id": "PMID-18344599_T5", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 183, 186 ] ], "normalized": [] }, { "id": "PMID-18344599_T6", "type": "Protein", "text": [ "p27" ], "offsets": [ [ 188, 191 ] ], "normalized": [] }, { "id": "PMID-18344599_T7", "type": "Protein", "text": [ "Kip1" ], "offsets": [ [ 192, 196 ] ], "normalized": [] }, { "id": "PMID-18344599_T8", "type": "Protein", "text": [ "HDAC1" ], "offsets": [ [ 199, 204 ] ], "normalized": [] }, { "id": "PMID-18344599_T9", "type": "Protein", "text": [ "epsilon-COP" ], "offsets": [ [ 210, 221 ] ], "normalized": [] }, { "id": "PMID-18344599_T10", "type": "Protein", "text": [ "signal recognition particle receptor beta subunit" ], "offsets": [ [ 252, 301 ] ], "normalized": [] }, { "id": "PMID-18344599_T11", "type": "Protein", "text": [ "SRbeta" ], "offsets": [ [ 303, 309 ] ], "normalized": [] }, { "id": "PMID-18344599_T12", "type": "Protein", "text": [ "Pirh2" ], "offsets": [ [ 387, 392 ] ], "normalized": [] }, { "id": "PMID-18344599_T13", "type": "Protein", "text": [ "Pirh2" ], "offsets": [ [ 462, 467 ] ], "normalized": [] }, { "id": "PMID-18344599_T14", "type": "Protein", "text": [ "SRbeta" ], "offsets": [ [ 484, 490 ] ], "normalized": [] }, { "id": "PMID-18344599_T15", "type": "Protein", "text": [ "Pirh2" ], "offsets": [ [ 555, 560 ] ], "normalized": [] }, { "id": "PMID-18344599_T16", "type": "Protein", "text": [ "SRbeta" ], "offsets": [ [ 578, 584 ] ], "normalized": [] }, { "id": "PMID-18344599_T17", "type": "Protein", "text": [ "Pirh2" ], "offsets": [ [ 596, 601 ] ], "normalized": [] }, { "id": "PMID-18344599_T18", "type": "Protein", "text": [ "SRbeta" ], "offsets": [ [ 621, 627 ] ], "normalized": [] }, { "id": "PMID-18344599_T19", "type": "Protein", "text": [ "Pirh2" ], "offsets": [ [ 734, 739 ] ], "normalized": [] }, { "id": "PMID-18344599_T20", "type": "Protein", "text": [ "Pirh2" ], "offsets": [ [ 778, 783 ] ], "normalized": [] }, { "id": "PMID-18344599_T21", "type": "Protein", "text": [ "Pirh2" ], "offsets": [ [ 810, 815 ] ], "normalized": [] }, { "id": "PMID-18344599_T22", "type": "Protein", "text": [ "SRbeta" ], "offsets": [ [ 825, 831 ] ], "normalized": [] }, { "id": "PMID-18344599_T23", "type": "Protein", "text": [ "Pirh2" ], "offsets": [ [ 851, 856 ] ], "normalized": [] }, { "id": "PMID-18344599_T24", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 913, 922 ] ], "normalized": [] }, { "id": "PMID-18344599_T25", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 955, 964 ] ], "normalized": [] }, { "id": "PMID-18344599_T26", "type": "Protein", "text": [ "SRbeta" ], "offsets": [ [ 975, 981 ] ], "normalized": [] }, { "id": "PMID-18344599_T27", "type": "Protein", "text": [ "Pirh2" ], "offsets": [ [ 1010, 1015 ] ], "normalized": [] }, { "id": "PMID-18344599_T28", "type": "Protein", "text": [ "SRbeta" ], "offsets": [ [ 1029, 1035 ] ], "normalized": [] }, { "id": "PMID-18344599_T29", "type": "Protein", "text": [ "SRbeta" ], "offsets": [ [ 1081, 1087 ] ], "normalized": [] }, { "id": "PMID-18344599_T30", "type": "Protein", "text": [ "SRbeta" ], "offsets": [ [ 1123, 1129 ] ], "normalized": [] } ]

[ { "id": "PMID-18344599_E1", "type": "Catalysis", "trigger": { "text": [ "ubiquitylates" ], "offsets": [ [ 25, 38 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_E2" }, { "role": "Cause", "ref_id": "PMID-18344599_T1" } ] }, { "id": "PMID-18344599_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylates" ], "offsets": [ [ 25, 38 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_T2" } ] }, { "id": "PMID-18344599_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylates" ], "offsets": [ [ 142, 155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_T5" } ] }, { "id": "PMID-18344599_E4", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylates" ], "offsets": [ [ 142, 155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_T6" } ] }, { "id": "PMID-18344599_E5", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylates" ], "offsets": [ [ 142, 155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_T8" } ] }, { "id": "PMID-18344599_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylates" ], "offsets": [ [ 142, 155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_T9" } ] }, { "id": "PMID-18344599_E7", "type": "Catalysis", "trigger": { "text": [ "ubiquitylates" ], "offsets": [ [ 142, 155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_E3" }, { "role": "Cause", "ref_id": "PMID-18344599_T3" } ] }, { "id": "PMID-18344599_E8", "type": "Catalysis", "trigger": { "text": [ "ubiquitylates" ], "offsets": [ [ 142, 155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_E4" }, { "role": "Cause", "ref_id": "PMID-18344599_T3" } ] }, { "id": "PMID-18344599_E9", "type": "Catalysis", "trigger": { "text": [ "ubiquitylates" ], "offsets": [ [ 142, 155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_E5" }, { "role": "Cause", "ref_id": "PMID-18344599_T3" } ] }, { "id": "PMID-18344599_E10", "type": "Catalysis", "trigger": { "text": [ "ubiquitylates" ], "offsets": [ [ 142, 155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_E6" }, { "role": "Cause", "ref_id": "PMID-18344599_T3" } ] }, { "id": "PMID-18344599_E11", "type": "Ubiquitination", "trigger": { "text": [ "poly-ubiquitylated" ], "offsets": [ [ 602, 620 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_T18" } ] }, { "id": "PMID-18344599_E12", "type": "Catalysis", "trigger": { "text": [ "poly-ubiquitylated" ], "offsets": [ [ 602, 620 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_E11" }, { "role": "Cause", "ref_id": "PMID-18344599_T17" } ] }, { "id": "PMID-18344599_E13", "type": "Catalysis", "trigger": { "text": [ "mediate" ], "offsets": [ [ 926, 933 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_E14" }, { "role": "Cause", "ref_id": "PMID-18344599_T23" } ] }, { "id": "PMID-18344599_E14", "type": "Ubiquitination", "trigger": { "text": [ "formation" ], "offsets": [ [ 938, 947 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_T26" } ] }, { "id": "PMID-18344599_E15", "type": "Catalysis", "trigger": { "text": [ "mediating" ], "offsets": [ [ 1048, 1057 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_E16" }, { "role": "Cause", "ref_id": "PMID-18344599_T27" } ] }, { "id": "PMID-18344599_E16", "type": "Ubiquitination", "trigger": { "text": [ "poly-ubiquitylation" ], "offsets": [ [ 1058, 1077 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18344599_T29" } ] } ]

[ { "id": "PMID-18344599_1", "entity_ids": [ "PMID-18344599_T6", "PMID-18344599_T7" ] }, { "id": "PMID-18344599_2", "entity_ids": [ "PMID-18344599_T10", "PMID-18344599_T11" ] } ]

[]

[ { "id": "PMID-18381652__text", "type": "abstract", "text": [ "PKC-dependent endocytosis of the GLT1 glutamate transporter depends on ubiquitylation of lysines located in a C-terminal cluster. \nThe activity of the main glutamate transporter in the CNS, GLT1, can be regulated by protein kinase C (PKC). It is known that activation of PKC by phorbol esters promotes the clathrin-dependent internalization of the transporter, followed by its lysosomal degradation. However, the molecular mechanisms that link PKC activation and the internalization of GLT1 are not fully understood. In this article, we show that this internalization process is dependent on the ubiquitylation of lysine residues located in the C-terminal tail of GLT1. Exposure to PMA increases the ubiquitylation of GLT1 in transfected cells and in the rat brain, and this ubiquitylated GLT1 accumulates in the intracellular compartment. However, internalization of ubiquitylated GLT1 was blocked with a dominant negative dynamin 2 mutant, indicating that the addition of ubiquitin moieties to the transporter in the membrane precedes its endocytosis. The elimination of lysines from the C-terminus of the transporter (lysines 497, 517, 526, 550, 558, 570, and 573) blocked GLT1 ubiquitylation and endocytosis. However, reintroduction of lysine 517 alone into this mutant was sufficient to restore PMA dependent ubiquitylation and internalization of GLT1. Similarly, reintroduction of lysine 526 restored the endocytosis, while this was only partially recovered after the individual reintroduction of lysines 550 or 570. These data suggest that the activation of PKC induces the ubiquitylation of these C-terminal lysine residues in GLT1 and that this modification mediates the interaction of the transporter with the endocytic machinery.\n" ], "offsets": [ [ 0, 1741 ] ] } ]

[ { "id": "PMID-18381652_T1", "type": "Protein", "text": [ "GLT1" ], "offsets": [ [ 33, 37 ] ], "normalized": [] }, { "id": "PMID-18381652_T2", "type": "Protein", "text": [ "GLT1" ], "offsets": [ [ 190, 194 ] ], "normalized": [] }, { "id": "PMID-18381652_T3", "type": "Protein", "text": [ "GLT1" ], "offsets": [ [ 486, 490 ] ], "normalized": [] }, { "id": "PMID-18381652_T4", "type": "Protein", "text": [ "GLT1" ], "offsets": [ [ 664, 668 ] ], "normalized": [] }, { "id": "PMID-18381652_T5", "type": "Protein", "text": [ "GLT1" ], "offsets": [ [ 718, 722 ] ], "normalized": [] }, { "id": "PMID-18381652_T6", "type": "Protein", "text": [ "GLT1" ], "offsets": [ [ 789, 793 ] ], "normalized": [] }, { "id": "PMID-18381652_T7", "type": "Protein", "text": [ "GLT1" ], "offsets": [ [ 882, 886 ] ], "normalized": [] }, { "id": "PMID-18381652_T8", "type": "Protein", "text": [ "dynamin 2" ], "offsets": [ [ 924, 933 ] ], "normalized": [] }, { "id": "PMID-18381652_T9", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 974, 983 ] ], "normalized": [] }, { "id": "PMID-18381652_T10", "type": "Protein", "text": [ "GLT1" ], "offsets": [ [ 1176, 1180 ] ], "normalized": [] }, { "id": "PMID-18381652_T11", "type": "Protein", "text": [ "GLT1" ], "offsets": [ [ 1352, 1356 ] ], "normalized": [] }, { "id": "PMID-18381652_T12", "type": "Protein", "text": [ "GLT1" ], "offsets": [ [ 1635, 1639 ] ], "normalized": [] }, { "id": "PMID-18381652_T14", "type": "Entity", "text": [ "lysines" ], "offsets": [ [ 89, 96 ] ], "normalized": [] }, { "id": "PMID-18381652_T16", "type": "Entity", "text": [ "lysine" ], "offsets": [ [ 614, 620 ] ], "normalized": [] }, { "id": "PMID-18381652_T21", "type": "Entity", "text": [ "lysine 517" ], "offsets": [ [ 1240, 1250 ] ], "normalized": [] }, { "id": "PMID-18381652_T24", "type": "Entity", "text": [ "lysine" ], "offsets": [ [ 1616, 1622 ] ], "normalized": [] } ]

[ { "id": "PMID-18381652_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 71, 85 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18381652_T1" }, { "role": "Site", "ref_id": "PMID-18381652_T14" } ] }, { "id": "PMID-18381652_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 596, 610 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18381652_T4" }, { "role": "Site", "ref_id": "PMID-18381652_T16" } ] }, { "id": "PMID-18381652_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 700, 714 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18381652_T5" } ] }, { "id": "PMID-18381652_E4", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylated" ], "offsets": [ [ 775, 788 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18381652_T6" } ] }, { "id": "PMID-18381652_E5", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylated" ], "offsets": [ [ 868, 881 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18381652_T7" } ] }, { "id": "PMID-18381652_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 1181, 1195 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18381652_T10" } ] }, { "id": "PMID-18381652_E7", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 1314, 1328 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18381652_T11" }, { "role": "Site", "ref_id": "PMID-18381652_T21" } ] }, { "id": "PMID-18381652_E8", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 1581, 1595 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18381652_T12" }, { "role": "Site", "ref_id": "PMID-18381652_T24" } ] } ]

[]

[]

[ { "id": "PMID-18402654__text", "type": "abstract", "text": [ "A yeast three-hybrid system that reconstitutes mammalian hypoxia inducible factor regulatory machinery. \nBACKGROUND: Several human pathologies, including neoplasia and ischemic cardiovascular diseases, course with an unbalance between oxygen supply and demand (hypoxia). Cells within hypoxic regions respond with the induction of a specific genetic program, under the control of the Hypoxia Inducible Factor (HIF), that mediates their adaptation to the lack of oxygen. The activity of HIF is mainly regulated by the EGL-nine homolog (EGLN) enzymes that hydroxylate the alpha subunit of this transcription factor in an oxygen-dependent reaction. Hydroxylated HIF is then recognized and ubiquitinilated by the product of the tumor suppressor gene, pVHL, leading to its proteosomal degradation. Under hypoxia, the hydroxylation of HIF by the EGLNs is compromised due to the lack of oxygen, which is a reaction cosubstrate. Thus, HIF escapes degradation and drives the transcription of its target genes. Since the progression of the aforementioned pathologies might be influenced by activation of HIF-target genes, development of small molecules with the ability to interfere with the HIF-regulatory machinery is of great interest. RESULTS: Herein we describe a yeast three-hybrid system that reconstitutes mammalian HIF regulation by the EGLNs and VHL. In this system, yeast growth, under specific nutrient restrictions, is driven by the interaction between the beta domain of VHL and a hydroxyproline-containing HIFalpha peptide. In turn, this interaction is strictly dependent on EGLN activity that hydroxylates the HIFalpha peptide. Importantly, this system accurately preserves the specificity of the hydroxylation reaction toward specific substrates. We propose that this system, in combination with a matched control, can be used as a simple and inexpensive assay to identify molecules that specifically modulate EGLN activity. As a proof of principle we show that two known EGLN inhibitors, dimethyloxaloylglycine (DMOG) and 6-chlor-3-hydroxychinolin-2-carbonic acid-N-carboxymethylamide (S956711), have a profound and specific effect on the yeast HIF/EGLN/VHL system. CONCLUSION: The system described in this work accurately reconstitutes HIF regulation while preserving EGLN substrate specificity. Thus, it is a valuable tool to study HIF regulation, and particularly EGLN biochemistry, in a cellular context. In addition, we demonstrate that this system can be used to identify specific inhibitors of the EGLN enzymes.\n" ], "offsets": [ [ 0, 2526 ] ] } ]

[ { "id": "PMID-18402654_T1", "type": "Protein", "text": [ "pVHL" ], "offsets": [ [ 746, 750 ] ], "normalized": [] }, { "id": "PMID-18402654_T2", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 1345, 1348 ] ], "normalized": [] }, { "id": "PMID-18402654_T3", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 1474, 1477 ] ], "normalized": [] }, { "id": "PMID-18402654_T4", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 2161, 2164 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18413254__text", "type": "abstract", "text": [ "Biochemical and biophysical analyses of Ras modification by ubiquitin. \nRas proteins are small GTPases that play key roles in the regulation of several cellular processes such as growth, differentiation, and transformation. Although Ras signaling was thought to occur uniformly on the inner leaflet of the plasma membrane, a growing body of evidence indicates that Ras activation happens dynamically within defined plasma membrane microdomains and at other specific intracellular compartments, thus ensuring the generation of distinct signal outputs. Yet the mechanisms that control the spatiotemporal segregation of Ras proteins remain poorly characterized. We have recently shown that the differential modification of Ras proteins by ubiquitination is a crucial factor that controls Ras intracellular trafficking and signaling potential. To better understand the process of Ras ubiquitination, it is important to establish assays that not only provide information about the nature of the ubiquitin modification involved, but also enable the monitoring of the dynamics of this process. In this chapter, we will describe biochemical and biophysical methodologies, namely immunoprecipitation, nickel-chelate affinity chromatography, and bioluminescence resonance energy transfer (BRET), for monitoring the ubiquitination of Ras proteins. Although the description focuses on Ras, the assays described can in principle be applied to the study of a range of proteins of interest that may be subject to ubiquitination, and the use of the different methods in parallel should provide new insights into the nature and dynamics of protein ubiquitination.\n" ], "offsets": [ [ 0, 1647 ] ] } ]

[ { "id": "PMID-18413254_T1", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 60, 69 ] ], "normalized": [] }, { "id": "PMID-18413254_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 990, 999 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18414007__text", "type": "abstract", "text": [ "Repression of transcriptional activity of estrogen receptor alpha by a Cullin3/SPOP ubiquitin E3 ligase complex. \nThe role of SPOP in the ubiquitination of ER alpha by the Cullin3-based E3 ubiquitin ligase complex was investigated. We showed that the N-terminal region of SPOP containing the MATH domain interacts with the AF-2 domain of ER alpha in cultured human embryonic 293 cells. SPOP was required for coimmunoprecipitation of ER alpha; with Cullin3. This is the first report of the essential role of SPOP in ERalpha ubiquitination by the Cullin3-based E3 ubiquitin ligase complex. We also demonstrated repression of the transactivation capability of ER alpha; in cultured mammalian cells.\n" ], "offsets": [ [ 0, 696 ] ] } ]

[ { "id": "PMID-18414007_T1", "type": "Protein", "text": [ "estrogen receptor alpha" ], "offsets": [ [ 42, 65 ] ], "normalized": [] }, { "id": "PMID-18414007_T2", "type": "Protein", "text": [ "Cullin3" ], "offsets": [ [ 71, 78 ] ], "normalized": [] }, { "id": "PMID-18414007_T3", "type": "Protein", "text": [ "SPOP" ], "offsets": [ [ 79, 83 ] ], "normalized": [] }, { "id": "PMID-18414007_T4", "type": "Protein", "text": [ "SPOP" ], "offsets": [ [ 126, 130 ] ], "normalized": [] }, { "id": "PMID-18414007_T5", "type": "Protein", "text": [ "ER alpha" ], "offsets": [ [ 156, 164 ] ], "normalized": [] }, { "id": "PMID-18414007_T6", "type": "Protein", "text": [ "Cullin3" ], "offsets": [ [ 172, 179 ] ], "normalized": [] }, { "id": "PMID-18414007_T7", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 189, 198 ] ], "normalized": [] }, { "id": "PMID-18414007_T8", "type": "Protein", "text": [ "SPOP" ], "offsets": [ [ 272, 276 ] ], "normalized": [] }, { "id": "PMID-18414007_T9", "type": "Protein", "text": [ "ER alpha" ], "offsets": [ [ 338, 346 ] ], "normalized": [] }, { "id": "PMID-18414007_T10", "type": "Protein", "text": [ "SPOP" ], "offsets": [ [ 386, 390 ] ], "normalized": [] }, { "id": "PMID-18414007_T11", "type": "Protein", "text": [ "ER alpha" ], "offsets": [ [ 433, 441 ] ], "normalized": [] }, { "id": "PMID-18414007_T12", "type": "Protein", "text": [ "Cullin3" ], "offsets": [ [ 448, 455 ] ], "normalized": [] }, { "id": "PMID-18414007_T13", "type": "Protein", "text": [ "SPOP" ], "offsets": [ [ 507, 511 ] ], "normalized": [] }, { "id": "PMID-18414007_T14", "type": "Protein", "text": [ "ERalpha" ], "offsets": [ [ 515, 522 ] ], "normalized": [] }, { "id": "PMID-18414007_T15", "type": "Protein", "text": [ "Cullin3" ], "offsets": [ [ 545, 552 ] ], "normalized": [] }, { "id": "PMID-18414007_T16", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 562, 571 ] ], "normalized": [] }, { "id": "PMID-18414007_T17", "type": "Protein", "text": [ "ER alpha" ], "offsets": [ [ 657, 665 ] ], "normalized": [] } ]

[ { "id": "PMID-18414007_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 138, 152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18414007_T5" } ] }, { "id": "PMID-18414007_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 523, 537 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18414007_T14" } ] } ]

[]

[]

[ { "id": "PMID-18427550__text", "type": "abstract", "text": [ "siRNA-mediated knockdown of Pdcd4 expression causes upregulation of p21(Waf1/Cip1) expression. \nThe transformation suppressor gene, programmed cell death gene 4 (Pdcd4), inhibits tumor-promoter-mediated transformation of mouse keratinocytes and has been implicated as a tumor suppressor gene in the development of human cancer. The Pdcd4 protein interacts with translation initiation factors eIF4A and eIF4G and binds to RNA, suggesting that it might be involved in regulating protein translation or other aspects of RNA metabolism. To study the function of Pdcd4 in more detail, we have downregulated Pdcd4 expression in HeLa cells by stable expression of shRNA. We have found that diminished Pdcd4 expression leads to increased expression of p21(Waf1/Cip1) and several other p53-regulated genes. Reporter gene studies demonstrate that Pdcd4 interferes with the activation of p53-responsive promoters genes by p53. Pdcd4 knockdown cells show decreased apoptosis and increased survival after UV irradiation. Taken together, our observations suggest a model in which low Pdcd4 expression after DNA damage favors the survival of cells, which would be eliminated by apoptosis under normal levels of Pdcd4 expression. Our results provide the first evidence that Pdcd4 is important role in the DNA-damage response and suggest that low levels of Pdcd4 expression observed in certain tumor cells contribute to tumorigenesis by affecting the fate of DNA-damaged cells.\n" ], "offsets": [ [ 0, 1461 ] ] } ]

[ { "id": "PMID-18427550_T1", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 28, 33 ] ], "normalized": [] }, { "id": "PMID-18427550_T2", "type": "Protein", "text": [ "p21" ], "offsets": [ [ 68, 71 ] ], "normalized": [] }, { "id": "PMID-18427550_T3", "type": "Protein", "text": [ "Waf1" ], "offsets": [ [ 72, 76 ] ], "normalized": [] }, { "id": "PMID-18427550_T4", "type": "Protein", "text": [ "Cip1" ], "offsets": [ [ 77, 81 ] ], "normalized": [] }, { "id": "PMID-18427550_T5", "type": "Protein", "text": [ "programmed cell death gene 4" ], "offsets": [ [ 132, 160 ] ], "normalized": [] }, { "id": "PMID-18427550_T6", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 162, 167 ] ], "normalized": [] }, { "id": "PMID-18427550_T7", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 332, 337 ] ], "normalized": [] }, { "id": "PMID-18427550_T8", "type": "Protein", "text": [ "eIF4A" ], "offsets": [ [ 392, 397 ] ], "normalized": [] }, { "id": "PMID-18427550_T9", "type": "Protein", "text": [ "eIF4G" ], "offsets": [ [ 402, 407 ] ], "normalized": [] }, { "id": "PMID-18427550_T10", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 558, 563 ] ], "normalized": [] }, { "id": "PMID-18427550_T11", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 602, 607 ] ], "normalized": [] }, { "id": "PMID-18427550_T12", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 694, 699 ] ], "normalized": [] }, { "id": "PMID-18427550_T13", "type": "Protein", "text": [ "p21" ], "offsets": [ [ 744, 747 ] ], "normalized": [] }, { "id": "PMID-18427550_T14", "type": "Protein", "text": [ "Waf1" ], "offsets": [ [ 748, 752 ] ], "normalized": [] }, { "id": "PMID-18427550_T15", "type": "Protein", "text": [ "Cip1" ], "offsets": [ [ 753, 757 ] ], "normalized": [] }, { "id": "PMID-18427550_T16", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 777, 780 ] ], "normalized": [] }, { "id": "PMID-18427550_T17", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 837, 842 ] ], "normalized": [] }, { "id": "PMID-18427550_T18", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 877, 880 ] ], "normalized": [] }, { "id": "PMID-18427550_T19", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 911, 914 ] ], "normalized": [] }, { "id": "PMID-18427550_T20", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 916, 921 ] ], "normalized": [] }, { "id": "PMID-18427550_T21", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 1070, 1075 ] ], "normalized": [] }, { "id": "PMID-18427550_T22", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 1196, 1201 ] ], "normalized": [] }, { "id": "PMID-18427550_T23", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 1258, 1263 ] ], "normalized": [] }, { "id": "PMID-18427550_T24", "type": "Protein", "text": [ "Pdcd4" ], "offsets": [ [ 1340, 1345 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-18427550_1", "entity_ids": [ "PMID-18427550_T2", "PMID-18427550_T3", "PMID-18427550_T4" ] }, { "id": "PMID-18427550_2", "entity_ids": [ "PMID-18427550_T5", "PMID-18427550_T6" ] }, { "id": "PMID-18427550_3", "entity_ids": [ "PMID-18427550_T13", "PMID-18427550_T14", "PMID-18427550_T15" ] } ]

[]

[ { "id": "PMID-18448069__text", "type": "abstract", "text": [ "AIMP1/p43 downregulates TGF-beta signaling via stabilization of smurf2. \nAIMP1 (also known as p43) is a factor associated with a macromolecular aminoacyl-tRNA synthetase (ARS) complex but also plays diverse regulatory roles in various physiological processes. Here, we report that AIMP1 negatively regulates TGF-beta signaling via stabilization of Smurf2. TGF-beta-dependent phosphorylation and nuclear localization of R-Smads, induction of target genes, and growth arrest were increased in AIMP1-deficient or -suppressed cells. In AIMP1-deficient or suppressed cells, the Smurf2 level was decreased. Various binding assays demonstrated the direction interaction of the C-terminal region of AIMP1 directly with the Smad7-binding region of Smurf2. The association of Smurf2 with Smad7 and its ubiquitination were inhibited by AIMP1, thereby protecting its autocatalytic degradation stimulated by Smad7. Thus, this work suggests the novel activity of AIMP1 as a component of negative feedback loop of TGF-beta signaling.\n" ], "offsets": [ [ 0, 1019 ] ] } ]

[ { "id": "PMID-18448069_T1", "type": "Protein", "text": [ "AIMP1" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-18448069_T2", "type": "Protein", "text": [ "p43" ], "offsets": [ [ 6, 9 ] ], "normalized": [] }, { "id": "PMID-18448069_T3", "type": "Protein", "text": [ "smurf2" ], "offsets": [ [ 64, 70 ] ], "normalized": [] }, { "id": "PMID-18448069_T4", "type": "Protein", "text": [ "AIMP1" ], "offsets": [ [ 73, 78 ] ], "normalized": [] }, { "id": "PMID-18448069_T5", "type": "Protein", "text": [ "p43" ], "offsets": [ [ 94, 97 ] ], "normalized": [] }, { "id": "PMID-18448069_T6", "type": "Protein", "text": [ "AIMP1" ], "offsets": [ [ 281, 286 ] ], "normalized": [] }, { "id": "PMID-18448069_T7", "type": "Protein", "text": [ "Smurf2" ], "offsets": [ [ 348, 354 ] ], "normalized": [] }, { "id": "PMID-18448069_T8", "type": "Protein", "text": [ "AIMP1" ], "offsets": [ [ 491, 496 ] ], "normalized": [] }, { "id": "PMID-18448069_T9", "type": "Protein", "text": [ "AIMP1" ], "offsets": [ [ 532, 537 ] ], "normalized": [] }, { "id": "PMID-18448069_T10", "type": "Protein", "text": [ "Smurf2" ], "offsets": [ [ 573, 579 ] ], "normalized": [] }, { "id": "PMID-18448069_T11", "type": "Protein", "text": [ "AIMP1" ], "offsets": [ [ 691, 696 ] ], "normalized": [] }, { "id": "PMID-18448069_T12", "type": "Protein", "text": [ "Smad7" ], "offsets": [ [ 715, 720 ] ], "normalized": [] }, { "id": "PMID-18448069_T13", "type": "Protein", "text": [ "Smurf2" ], "offsets": [ [ 739, 745 ] ], "normalized": [] }, { "id": "PMID-18448069_T14", "type": "Protein", "text": [ "Smurf2" ], "offsets": [ [ 766, 772 ] ], "normalized": [] }, { "id": "PMID-18448069_T15", "type": "Protein", "text": [ "Smad7" ], "offsets": [ [ 778, 783 ] ], "normalized": [] }, { "id": "PMID-18448069_T16", "type": "Protein", "text": [ "AIMP1" ], "offsets": [ [ 825, 830 ] ], "normalized": [] }, { "id": "PMID-18448069_T17", "type": "Protein", "text": [ "Smad7" ], "offsets": [ [ 895, 900 ] ], "normalized": [] }, { "id": "PMID-18448069_T18", "type": "Protein", "text": [ "AIMP1" ], "offsets": [ [ 949, 954 ] ], "normalized": [] } ]

[ { "id": "PMID-18448069_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 792, 806 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18448069_T15" } ] }, { "id": "PMID-18448069_E2", "type": "Catalysis", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 792, 806 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18448069_E1" }, { "role": "Cause", "ref_id": "PMID-18448069_T14" } ] } ]

[ { "id": "PMID-18448069_1", "entity_ids": [ "PMID-18448069_T1", "PMID-18448069_T2" ] }, { "id": "PMID-18448069_2", "entity_ids": [ "PMID-18448069_T4", "PMID-18448069_T5" ] } ]

[]

[ { "id": "PMID-18453536__text", "type": "abstract", "text": [ "Polycomb group protein-associated chromatin is reproduced in post-mitotic G1 phase and is required for S phase progression. \nPolycomb group (PcG) proteins form two distinct complexes, PRC1 and PRC2, to regulate developmental target genes by maintaining the epigenetic state in cells. PRC2 methylates histone H3 at lysine 27 (H3K27), and PRC1 then recognizes methyl-H3K27 to form repressive chromatin. However, it remains unknown how PcG proteins maintain stable and plastic chromatin during cell division. Here we report that PcG-associated chromatin is reproduced in the G(1) phase in post-mitotic cells and is required for subsequent S phase progression. In dividing cells, H3K27 trimethylation (H3K27Me(3)) marked mitotic chromosome arms where PRC2 (Suz12 and Ezh2) co-existed, whereas PRC1 (Bmi1 and Pc2) appeared in distinct foci in the pericentromeric regions. As each PRC complex was increasingly assembled from mitosis to G(1) phase, PRC1 formed H3K27Me(3)-based chromatin intensively during middle and late G(1) phase; this chromatin was highly resistant to in situ nuclease treatment. Thus, the transition from mitosis to G(1) phase is crucial for PcG-mediated chromatin inheritance. Knockdown of Suz12 markedly reduced the amount of H3K27Me(3) on mitotic chromosomes, and as a consequence, PRC1 foci were not fully transmitted to post-mitotic daughter cells. S phase progression was markedly delayed in these Suz12-knockdown cells. The fact that PcG-associated chromatin is reproduced during post-mitotic G(1) phase suggests the possibility that PcG proteins enable their target chromatin to be remodeled in response to stimuli in the G(1) phase.\n" ], "offsets": [ [ 0, 1658 ] ] } ]

[ { "id": "PMID-18453536_T1", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 300, 310 ] ], "normalized": [] }, { "id": "PMID-18453536_T2", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 325, 327 ] ], "normalized": [] }, { "id": "PMID-18453536_T3", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 365, 367 ] ], "normalized": [] }, { "id": "PMID-18453536_T4", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 676, 678 ] ], "normalized": [] }, { "id": "PMID-18453536_T5", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 698, 700 ] ], "normalized": [] }, { "id": "PMID-18453536_T6", "type": "Protein", "text": [ "Suz12" ], "offsets": [ [ 753, 758 ] ], "normalized": [] }, { "id": "PMID-18453536_T7", "type": "Protein", "text": [ "Ezh2" ], "offsets": [ [ 763, 767 ] ], "normalized": [] }, { "id": "PMID-18453536_T8", "type": "Protein", "text": [ "Bmi1" ], "offsets": [ [ 795, 799 ] ], "normalized": [] }, { "id": "PMID-18453536_T9", "type": "Protein", "text": [ "Pc2" ], "offsets": [ [ 804, 807 ] ], "normalized": [] }, { "id": "PMID-18453536_T10", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 954, 956 ] ], "normalized": [] }, { "id": "PMID-18453536_T11", "type": "Protein", "text": [ "Suz12" ], "offsets": [ [ 1207, 1212 ] ], "normalized": [] }, { "id": "PMID-18453536_T12", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1244, 1246 ] ], "normalized": [] }, { "id": "PMID-18453536_T13", "type": "Protein", "text": [ "Suz12" ], "offsets": [ [ 1420, 1425 ] ], "normalized": [] }, { "id": "PMID-18453536_T15", "type": "Entity", "text": [ "lysine 27" ], "offsets": [ [ 314, 323 ] ], "normalized": [] }, { "id": "PMID-18453536_T16", "type": "Entity", "text": [ "K27" ], "offsets": [ [ 327, 330 ] ], "normalized": [] }, { "id": "PMID-18453536_T17", "type": "Entity", "text": [ "K27" ], "offsets": [ [ 678, 681 ] ], "normalized": [] } ]

[ { "id": "PMID-18453536_E1", "type": "Methylation", "trigger": { "text": [ "methylates" ], "offsets": [ [ 289, 299 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18453536_T1" }, { "role": "Site", "ref_id": "PMID-18453536_T15" } ] }, { "id": "PMID-18453536_E2", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 682, 696 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18453536_T4" }, { "role": "Site", "ref_id": "PMID-18453536_T17" } ] } ]

[ { "id": "PMID-18453536_1", "entity_ids": [ "PMID-18453536_T1", "PMID-18453536_T2" ] }, { "id": "PMID-18453536_2", "entity_ids": [ "PMID-18453536_T15", "PMID-18453536_T16" ] } ]

[]

[ { "id": "PMID-18460542__text", "type": "abstract", "text": [ "Cooperation between EZH2, NSPc1-mediated histone H2A ubiquitination and Dnmt1 in HOX gene silencing. \nAn intricate interplay between DNA methylation and polycomb-mediated gene silencing has been highlighted recently. Here we provided evidence that Nervous System Polycomb 1 (NSPc1), a BMI1 homologous polycomb protein, plays important roles in promoting H2A ubiquitination and cooperates with DNA methylation in HOX gene silencing. We showed that NSPc1 stimulates H2A ubiquitination in vivo and in vitro through direct interaction with both RING2 and H2A. RT-PCR analysis revealed that loss of NSPc1, EZH2 or DNA methyltransferase 1 (Dnmt1), or inhibition of DNA methylation in HeLa cells de-represses the expression of HOXA7. Chromatin immunoprecipitation (ChIP) assays demonstrated that NSPc1, EZH2 and Dnmt1 bind to the promoter of HOXA7, which is frequently hypermethylated in tumors. Knockdown of NSPc1 results in significant reduction of H2A ubiquitination and DNA demethylation as well as Dnmt1 dissociation in the HOXA7 promoter. Meanwhile Dnmt1 deficiency affects NSPc1 recruitment and H2A ubiquitination, whereas on both cases EZH2-mediated H3K27 trimethylation remains unaffected. When EZH2 was depleted, however, NSPc1 and Dnmt1 enrichment was abolished concomitant with local reduction of H3K27 trimethylation, H2A ubiquitination and DNA methylation. Taken together, our findings indicated that NSPc1-mediated H2A ubiquitination and DNA methylation, both being directed by EZH2, are interdependent in long-term target gene silencing within cancer cells.\n" ], "offsets": [ [ 0, 1567 ] ] } ]

[ { "id": "PMID-18460542_T1", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 20, 24 ] ], "normalized": [] }, { "id": "PMID-18460542_T2", "type": "Protein", "text": [ "NSPc1" ], "offsets": [ [ 26, 31 ] ], "normalized": [] }, { "id": "PMID-18460542_T3", "type": "Protein", "text": [ "histone H2A" ], "offsets": [ [ 41, 52 ] ], "normalized": [] }, { "id": "PMID-18460542_T4", "type": "Protein", "text": [ "Dnmt1" ], "offsets": [ [ 72, 77 ] ], "normalized": [] }, { "id": "PMID-18460542_T5", "type": "Protein", "text": [ "Nervous System Polycomb 1" ], "offsets": [ [ 248, 273 ] ], "normalized": [] }, { "id": "PMID-18460542_T6", "type": "Protein", "text": [ "NSPc1" ], "offsets": [ [ 275, 280 ] ], "normalized": [] }, { "id": "PMID-18460542_T7", "type": "Protein", "text": [ "BMI1" ], "offsets": [ [ 285, 289 ] ], "normalized": [] }, { "id": "PMID-18460542_T8", "type": "Protein", "text": [ "H2A" ], "offsets": [ [ 354, 357 ] ], "normalized": [] }, { "id": "PMID-18460542_T9", "type": "Protein", "text": [ "NSPc1" ], "offsets": [ [ 447, 452 ] ], "normalized": [] }, { "id": "PMID-18460542_T10", "type": "Protein", "text": [ "H2A" ], "offsets": [ [ 464, 467 ] ], "normalized": [] }, { "id": "PMID-18460542_T11", "type": "Protein", "text": [ "RING2" ], "offsets": [ [ 541, 546 ] ], "normalized": [] }, { "id": "PMID-18460542_T12", "type": "Protein", "text": [ "H2A" ], "offsets": [ [ 551, 554 ] ], "normalized": [] }, { "id": "PMID-18460542_T13", "type": "Protein", "text": [ "NSPc1" ], "offsets": [ [ 594, 599 ] ], "normalized": [] }, { "id": "PMID-18460542_T14", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 601, 605 ] ], "normalized": [] }, { "id": "PMID-18460542_T15", "type": "Protein", "text": [ "DNA methyltransferase 1" ], "offsets": [ [ 609, 632 ] ], "normalized": [] }, { "id": "PMID-18460542_T16", "type": "Protein", "text": [ "Dnmt1" ], "offsets": [ [ 634, 639 ] ], "normalized": [] }, { "id": "PMID-18460542_T17", "type": "Protein", "text": [ "HOXA7" ], "offsets": [ [ 720, 725 ] ], "normalized": [] }, { "id": "PMID-18460542_T18", "type": "Protein", "text": [ "NSPc1" ], "offsets": [ [ 789, 794 ] ], "normalized": [] }, { "id": "PMID-18460542_T19", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 796, 800 ] ], "normalized": [] }, { "id": "PMID-18460542_T20", "type": "Protein", "text": [ "Dnmt1" ], "offsets": [ [ 805, 810 ] ], "normalized": [] }, { "id": "PMID-18460542_T21", "type": "Protein", "text": [ "HOXA7" ], "offsets": [ [ 835, 840 ] ], "normalized": [] }, { "id": "PMID-18460542_T22", "type": "Protein", "text": [ "NSPc1" ], "offsets": [ [ 902, 907 ] ], "normalized": [] }, { "id": "PMID-18460542_T23", "type": "Protein", "text": [ "H2A" ], "offsets": [ [ 944, 947 ] ], "normalized": [] }, { "id": "PMID-18460542_T24", "type": "Protein", "text": [ "Dnmt1" ], "offsets": [ [ 996, 1001 ] ], "normalized": [] }, { "id": "PMID-18460542_T25", "type": "Protein", "text": [ "HOXA7" ], "offsets": [ [ 1022, 1027 ] ], "normalized": [] }, { "id": "PMID-18460542_T26", "type": "Protein", "text": [ "Dnmt1" ], "offsets": [ [ 1048, 1053 ] ], "normalized": [] }, { "id": "PMID-18460542_T27", "type": "Protein", "text": [ "NSPc1" ], "offsets": [ [ 1073, 1078 ] ], "normalized": [] }, { "id": "PMID-18460542_T28", "type": "Protein", "text": [ "H2A" ], "offsets": [ [ 1095, 1098 ] ], "normalized": [] }, { "id": "PMID-18460542_T29", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 1137, 1141 ] ], "normalized": [] }, { "id": "PMID-18460542_T30", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1151, 1153 ] ], "normalized": [] }, { "id": "PMID-18460542_T31", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 1197, 1201 ] ], "normalized": [] }, { "id": "PMID-18460542_T32", "type": "Protein", "text": [ "NSPc1" ], "offsets": [ [ 1225, 1230 ] ], "normalized": [] }, { "id": "PMID-18460542_T33", "type": "Protein", "text": [ "Dnmt1" ], "offsets": [ [ 1235, 1240 ] ], "normalized": [] }, { "id": "PMID-18460542_T34", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1302, 1304 ] ], "normalized": [] }, { "id": "PMID-18460542_T35", "type": "Protein", "text": [ "H2A" ], "offsets": [ [ 1324, 1327 ] ], "normalized": [] }, { "id": "PMID-18460542_T36", "type": "Protein", "text": [ "NSPc1" ], "offsets": [ [ 1408, 1413 ] ], "normalized": [] }, { "id": "PMID-18460542_T37", "type": "Protein", "text": [ "H2A" ], "offsets": [ [ 1423, 1426 ] ], "normalized": [] }, { "id": "PMID-18460542_T38", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 1486, 1490 ] ], "normalized": [] }, { "id": "PMID-18460542_T42", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 823, 831 ] ], "normalized": [] }, { "id": "PMID-18460542_T46", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1028, 1036 ] ], "normalized": [] }, { "id": "PMID-18460542_T49", "type": "Entity", "text": [ "K27" ], "offsets": [ [ 1153, 1156 ] ], "normalized": [] }, { "id": "PMID-18460542_T51", "type": "Entity", "text": [ "K27" ], "offsets": [ [ 1304, 1307 ] ], "normalized": [] } ]

[ { "id": "PMID-18460542_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 53, 67 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_T3" } ] }, { "id": "PMID-18460542_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 358, 372 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_T8" } ] }, { "id": "PMID-18460542_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 468, 482 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_T10" } ] }, { "id": "PMID-18460542_E4", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylated" ], "offsets": [ [ 862, 877 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_T21" }, { "role": "Site", "ref_id": "PMID-18460542_T42" } ] }, { "id": "PMID-18460542_E5", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 948, 962 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_T23" } ] }, { "id": "PMID-18460542_E6", "type": "DNA_demethylation", "trigger": { "text": [ "DNA demethylation" ], "offsets": [ [ 967, 984 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_T25" }, { "role": "Site", "ref_id": "PMID-18460542_T46" } ] }, { "id": "PMID-18460542_E7", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1099, 1113 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_T28" } ] }, { "id": "PMID-18460542_E8", "type": "Catalysis", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1142, 1150 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_E9" }, { "role": "Cause", "ref_id": "PMID-18460542_T29" } ] }, { "id": "PMID-18460542_E9", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 1157, 1171 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_T30" }, { "role": "Site", "ref_id": "PMID-18460542_T49" }, { "role": "Contextgene", "ref_id": "PMID-18460542_T25" } ] }, { "id": "PMID-18460542_E10", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 1308, 1322 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_T34" }, { "role": "Site", "ref_id": "PMID-18460542_T51" }, { "role": "Contextgene", "ref_id": "PMID-18460542_T25" } ] }, { "id": "PMID-18460542_E11", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1328, 1342 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_T35" } ] }, { "id": "PMID-18460542_E12", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1427, 1441 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18460542_T37" } ] } ]

[ { "id": "PMID-18460542_1", "entity_ids": [ "PMID-18460542_T5", "PMID-18460542_T6" ] }, { "id": "PMID-18460542_2", "entity_ids": [ "PMID-18460542_T15", "PMID-18460542_T16" ] } ]

[]

[ { "id": "PMID-1847136__text", "type": "abstract", "text": [ "Interaction of prolyl 4-hydroxylase with synthetic peptide substrates. A conformational model for collagen proline hydroxylation. \nWith the aim of understanding the structural basis for the substrate specificity of collagen prolyl 4-hydroxylase, we have studied the conformational features of synthetic oligopeptide substrates and their interaction with the enzyme purified from chicken embryo. Circular dichroism and infrared spectral data, taken in conjunction with relevant crystal structure data, indicated an equilibrium mixture of the polyproline-II (PP-II) helix, the beta-turn, and the random coil conformations in aqueous and trifluoroethanol solutions of the \"collagen-related\" peptides: t-Boc-Pro-Pro-Gly-Pro-OH, t-Boc-Pro-Pro-Gly-Pro-NHCH3, t-Pro-Pro-Gly-Pro-Pro-OH, t-Boc-Pro-Pro-Ala-Pro-OH, and t-Boc-Pro-Pro-Gln-Pro-OCH3, where t-Boc is tert-butoxycarbonyl. In another set of peptides related to elastin, t-Boc-Val-Pro-Gly-Val-OH and t-Boc-Gly-Val-Pro-Gly-Val-OH, the data indicated the beta-structure, rather than the PP-II helix, was in equilibrium with the beta-turn. Kinetic parameters for the enzymatic hydroxylation of the peptides showed that as a group, the first (proline-rich) set of peptides has higher Km values and lower Vmax and Kcat/Km values than the valine-rich peptides. Data on the inhibition of hydroxylation of the standard assay substrate (Pro-Pro-Gly)10 by the oligopeptides pointed to common binding sites for the peptides. Hydroxyproline-containing peptides had no effect on the hydroxylation of the standard substrate, showing the absence of product inhibition. Based on these and earlier data, we propose that in collagen and related peptides, a supersecondary structure consisting of the PP-II helix followed by the beta-turn is the minimal structural requirement for proline hydroxylation. The PP-II structure would aid effective interaction at the substrate binding subsites, while the beta-turn would be essential at the catalytic site of the enzyme. In elastin and related peptides, the beta-strand structure may be interchangeable with the PP-II structure. This conformational model for proline hydroxylation resolves the discrepancies in earlier proposals on the substrate specificity of prolyl 4-hydroxylase. It is also consistent with the available information on the active site geometry of the enzyme.\n" ], "offsets": [ [ 0, 2356 ] ] } ]

[ { "id": "PMID-1847136_T1", "type": "Protein", "text": [ "elastin" ], "offsets": [ [ 912, 919 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18482987__text", "type": "abstract", "text": [ "Recognition of polyubiquitin isoforms by the multiple ubiquitin binding modules of isopeptidase T. \nThe conjugation of polyubiquitin to target proteins acts as a signal that regulates target stability, localization, and function. Several ubiquitin binding domains have been described, and while much is known about ubiquitin binding to the isolated domains, little is known with regard to how the domains interact with polyubiquitin in the context of full-length proteins. Isopeptidase T (IsoT/USP5) is a deubiquitinating enzyme that is largely responsible for the disassembly of unanchored polyubiquitin in the cell. IsoT has four ubiquitin binding domains: a zinc finger domain (ZnF UBP), which binds the proximal ubiquitin, a UBP domain that forms the active site, and two ubiquitin-associated (UBA) domains whose roles are unknown. Here, we show that the UBA domains are involved in binding two different polyubiquitin isoforms, linear and K48-linked. Using isothermal titration calorimetry, we show that IsoT has at least four ubiquitin binding sites for both polyubiquitin isoforms. The thermodynamics of the interactions reveal that the binding is enthalpy-driven. Mutation of the UBA domains suggests that UBA1 and UBA2 domains of IsoT interact with the third and fourth ubiquitins in both polyubiquitin isoforms, respectively. These data suggest that recognition of the polyubiquitin isoforms by IsoT involves considerable conformational mobility in the polyubiquitin ligand, in the enzyme, or in both.\n" ], "offsets": [ [ 0, 1512 ] ] } ]

[ { "id": "PMID-18482987_T1", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 19, 28 ] ], "normalized": [] }, { "id": "PMID-18482987_T2", "type": "Protein", "text": [ "isopeptidase T" ], "offsets": [ [ 83, 97 ] ], "normalized": [] }, { "id": "PMID-18482987_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 123, 132 ] ], "normalized": [] }, { "id": "PMID-18482987_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 238, 247 ] ], "normalized": [] }, { "id": "PMID-18482987_T5", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 315, 324 ] ], "normalized": [] }, { "id": "PMID-18482987_T6", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 423, 432 ] ], "normalized": [] }, { "id": "PMID-18482987_T7", "type": "Protein", "text": [ "Isopeptidase T" ], "offsets": [ [ 473, 487 ] ], "normalized": [] }, { "id": "PMID-18482987_T8", "type": "Protein", "text": [ "IsoT" ], "offsets": [ [ 489, 493 ] ], "normalized": [] }, { "id": "PMID-18482987_T9", "type": "Protein", "text": [ "USP5" ], "offsets": [ [ 494, 498 ] ], "normalized": [] }, { "id": "PMID-18482987_T10", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 595, 604 ] ], "normalized": [] }, { "id": "PMID-18482987_T11", "type": "Protein", "text": [ "IsoT" ], "offsets": [ [ 618, 622 ] ], "normalized": [] }, { "id": "PMID-18482987_T12", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 632, 641 ] ], "normalized": [] }, { "id": "PMID-18482987_T13", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 716, 725 ] ], "normalized": [] }, { "id": "PMID-18482987_T14", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 913, 922 ] ], "normalized": [] }, { "id": "PMID-18482987_T15", "type": "Protein", "text": [ "IsoT" ], "offsets": [ [ 1009, 1013 ] ], "normalized": [] }, { "id": "PMID-18482987_T16", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1032, 1041 ] ], "normalized": [] }, { "id": "PMID-18482987_T17", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1069, 1078 ] ], "normalized": [] }, { "id": "PMID-18482987_T18", "type": "Protein", "text": [ "IsoT" ], "offsets": [ [ 1239, 1243 ] ], "normalized": [] }, { "id": "PMID-18482987_T19", "type": "Protein", "text": [ "ubiquitins" ], "offsets": [ [ 1279, 1289 ] ], "normalized": [] }, { "id": "PMID-18482987_T20", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1302, 1311 ] ], "normalized": [] }, { "id": "PMID-18482987_T21", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1383, 1392 ] ], "normalized": [] }, { "id": "PMID-18482987_T22", "type": "Protein", "text": [ "IsoT" ], "offsets": [ [ 1405, 1409 ] ], "normalized": [] }, { "id": "PMID-18482987_T23", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1467, 1476 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-18482987_1", "entity_ids": [ "PMID-18482987_T7", "PMID-18482987_T8", "PMID-18482987_T9" ] } ]

[]

[ { "id": "PMID-18488029__text", "type": "abstract", "text": [ "Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. \nEpigenetic silencing in cancer cells is mediated by at least two distinct histone modifications, polycomb-based histone H3 lysine 27 trimethylation (H3K27triM) and H3K9 dimethylation. The relationship between DNA hypermethylation and these histone modifications is not completely understood. Using chromatin immunoprecipitation microarrays (ChIP-chip) in prostate cancer cells compared to normal prostate, we found that up to 5% of promoters (16% CpG islands and 84% non-CpG islands) were enriched with H3K27triM. These genes were silenced specifically in prostate cancer, and those CpG islands affected showed low levels of DNA methylation. Downregulation of the EZH2 histone methyltransferase restored expression of the H3K27triM target genes alone or in synergy with histone deacetylase inhibition, without affecting promoter DNA methylation, and with no effect on the expression of genes silenced by DNA hypermethylation. These data establish EZH2-mediated H3K27triM as a mechanism of tumor-suppressor gene silencing in cancer that is potentially independent of promoter DNA methylation.\n" ], "offsets": [ [ 0, 1198 ] ] } ]

[ { "id": "PMID-18488029_T1", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 28, 38 ] ], "normalized": [] }, { "id": "PMID-18488029_T2", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 180, 187 ] ], "normalized": [] }, { "id": "PMID-18488029_T3", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 218, 228 ] ], "normalized": [] }, { "id": "PMID-18488029_T4", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 255, 257 ] ], "normalized": [] }, { "id": "PMID-18488029_T5", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 270, 272 ] ], "normalized": [] }, { "id": "PMID-18488029_T6", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 346, 353 ] ], "normalized": [] }, { "id": "PMID-18488029_T7", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 609, 611 ] ], "normalized": [] }, { "id": "PMID-18488029_T8", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 770, 774 ] ], "normalized": [] }, { "id": "PMID-18488029_T9", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 775, 782 ] ], "normalized": [] }, { "id": "PMID-18488029_T10", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 828, 830 ] ], "normalized": [] }, { "id": "PMID-18488029_T11", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 876, 883 ] ], "normalized": [] }, { "id": "PMID-18488029_T12", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 1053, 1057 ] ], "normalized": [] }, { "id": "PMID-18488029_T13", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1067, 1069 ] ], "normalized": [] }, { "id": "PMID-18488029_T14", "type": "Entity", "text": [ "lysine 27" ], "offsets": [ [ 39, 48 ] ], "normalized": [] }, { "id": "PMID-18488029_T16", "type": "Entity", "text": [ "lysine 27" ], "offsets": [ [ 229, 238 ] ], "normalized": [] }, { "id": "PMID-18488029_T18", "type": "Entity", "text": [ "K27" ], "offsets": [ [ 257, 260 ] ], "normalized": [] }, { "id": "PMID-18488029_T19", "type": "Entity", "text": [ "K9" ], "offsets": [ [ 272, 274 ] ], "normalized": [] } ]

[ { "id": "PMID-18488029_E1", "type": "DNA_methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 49, 63 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18488029_T1" }, { "role": "Site", "ref_id": "PMID-18488029_T14" } ] }, { "id": "PMID-18488029_E2", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 239, 253 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18488029_T3" }, { "role": "Site", "ref_id": "PMID-18488029_T16" } ] }, { "id": "PMID-18488029_E3", "type": "Methylation", "trigger": { "text": [ "dimethylation" ], "offsets": [ [ 275, 288 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18488029_T5" }, { "role": "Site", "ref_id": "PMID-18488029_T19" } ] } ]

[ { "id": "PMID-18488029_1", "entity_ids": [ "PMID-18488029_T3", "PMID-18488029_T4" ] }, { "id": "PMID-18488029_2", "entity_ids": [ "PMID-18488029_T16", "PMID-18488029_T18" ] } ]

[]

[ { "id": "PMID-18511557__text", "type": "abstract", "text": [ "Asymmetric mitosis: Unequal segregation of proteins destined for degradation. \nMitotic cell division ensures that two daughter somatic cells inherit identical genetic material. Previous work has shown that signaling by the Smad1 transcription factor is terminated by polyubiquitinylation and proteasomal degradation after essential phosphorylations by MAPK and glycogen synthase kinase 3 (GSK3). Here, we show that, unexpectedly, proteins specifically targeted for proteasomal degradation are inherited preferentially by one mitotic daughter during somatic cell division. Experiments with dividing human embryonic stem cells and other mammalian cultured cell lines demonstrated that in many supposedly equal mitoses the segregation of proteins destined for degradation (Smad1 phosphorylated by MAPK and GSK3, phospho-beta-catenin, and total polyubiquitinylated proteins) was asymmetric. Transport of pSmad1 targeted for degradation to the centrosome required functional microtubules. In vivo, an antibody specific for Mad phosphorylated by MAPK showed that this antigen was associated preferentially with one of the two centrosomes in Drosophila embryos at cellular blastoderm stage. We propose that this remarkable cellular property may be explained by the asymmetric inheritance of peripheral centrosomal proteins when centrioles separate and migrate to opposite poles of the cell, so that one mitotic daughter remains pristine. We conclude that many mitotic divisions are unequal, unlike what was previously thought.\n" ], "offsets": [ [ 0, 1520 ] ] } ]

[ { "id": "PMID-18511557_T1", "type": "Protein", "text": [ "Smad1" ], "offsets": [ [ 223, 228 ] ], "normalized": [] }, { "id": "PMID-18511557_T2", "type": "Protein", "text": [ "Smad1" ], "offsets": [ [ 770, 775 ] ], "normalized": [] }, { "id": "PMID-18511557_T3", "type": "Protein", "text": [ "beta-catenin" ], "offsets": [ [ 817, 829 ] ], "normalized": [] }, { "id": "PMID-18511557_T4", "type": "Protein", "text": [ "Smad1" ], "offsets": [ [ 901, 906 ] ], "normalized": [] }, { "id": "PMID-18511557_T5", "type": "Protein", "text": [ "Mad" ], "offsets": [ [ 1018, 1021 ] ], "normalized": [] } ]

[ { "id": "PMID-18511557_E1", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitinylation" ], "offsets": [ [ 267, 287 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18511557_T1" } ] }, { "id": "PMID-18511557_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylations" ], "offsets": [ [ 332, 348 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18511557_T1" } ] }, { "id": "PMID-18511557_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 776, 790 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18511557_T2" } ] }, { "id": "PMID-18511557_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 1022, 1036 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18511557_T5" } ] } ]

[]

[]

[ { "id": "PMID-18535780__text", "type": "abstract", "text": [ "Highly homologous HERC proteins localize to endosomes and exhibit specific interactions with hPLIC and Nm23B. \nSmall HERC proteins are defined by the presence of one RCC1-like domain and a HECT domain. Having evolved out of one common ancestor, the four members of the family exhibit a high degree of homology in genomic organization and amino acid sequence, thus it seems possible that they might accomplish similar functions. Here we show that small HERC proteins interact with each other and localize to the same cellular structures, which we identify as late endosomes and lysosomes. We demonstrate interaction of HERC3 with the ubiquitin-like proteins hPLIC-1 and hPLIC-2 and we establish interaction of HERC5 with the metastasis suppressor Nm23B. While hPLIC proteins are not ubiquitinated by HERC3, HERC5 plays an important role in ubiquitination of Nm23B. In summary, although small HERC proteins are highly homologous showing the same subcellular distribution, they undergo different molecular interactions.\n" ], "offsets": [ [ 0, 1017 ] ] } ]

[ { "id": "PMID-18535780_T1", "type": "Protein", "text": [ "Nm23B" ], "offsets": [ [ 103, 108 ] ], "normalized": [] }, { "id": "PMID-18535780_T2", "type": "Protein", "text": [ "RCC1" ], "offsets": [ [ 166, 170 ] ], "normalized": [] }, { "id": "PMID-18535780_T3", "type": "Protein", "text": [ "HERC3" ], "offsets": [ [ 618, 623 ] ], "normalized": [] }, { "id": "PMID-18535780_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 633, 642 ] ], "normalized": [] }, { "id": "PMID-18535780_T5", "type": "Protein", "text": [ "PLIC-1" ], "offsets": [ [ 658, 664 ] ], "normalized": [] }, { "id": "PMID-18535780_T6", "type": "Protein", "text": [ "PLIC-2" ], "offsets": [ [ 670, 676 ] ], "normalized": [] }, { "id": "PMID-18535780_T7", "type": "Protein", "text": [ "HERC5" ], "offsets": [ [ 709, 714 ] ], "normalized": [] }, { "id": "PMID-18535780_T8", "type": "Protein", "text": [ "Nm23B" ], "offsets": [ [ 746, 751 ] ], "normalized": [] }, { "id": "PMID-18535780_T9", "type": "Protein", "text": [ "HERC3" ], "offsets": [ [ 799, 804 ] ], "normalized": [] }, { "id": "PMID-18535780_T10", "type": "Protein", "text": [ "HERC5" ], "offsets": [ [ 806, 811 ] ], "normalized": [] }, { "id": "PMID-18535780_T11", "type": "Protein", "text": [ "Nm23B" ], "offsets": [ [ 857, 862 ] ], "normalized": [] } ]

[ { "id": "PMID-18535780_E1", "type": "Catalysis", "trigger": { "text": [ "plays an important role" ], "offsets": [ [ 812, 835 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18535780_E2" }, { "role": "Cause", "ref_id": "PMID-18535780_T10" } ] }, { "id": "PMID-18535780_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 839, 853 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18535780_T11" } ] } ]

[]

[]

[ { "id": "PMID-18562678__text", "type": "abstract", "text": [ "Inferring causal relationships among different histone modifications and gene expression. \nHistone modifications are major epigenetic factors regulating gene expression. They play important roles in maintaining stem cell pluripotency and in cancer pathogenesis. Different modifications may combine to form complex \"histone codes.\" Recent high-throughput technologies, such as \"ChIP-chip\" and \"ChIP-seq,\" have generated high-resolution maps for many histone modifications on the human genome. Here we use these maps to build a Bayesian network to infer causal and combinatorial relationships among histone modifications and gene expression. A pilot network derived by the same method among polycomb group (PcG) genes and H3K27 trimethylation is accurately supported by current literature. Our unbiased network model among histone modifications is also well supported by cross-validation results. It not only confirmed already known relationships, such as those of H3K27me3 to gene silencing, H3K4me3 to gene activation and the effect of bivalent modification of both H3K4me3 and H3K27me3, but also identified many other relationships that may predict new epigenetic interactions important in epigenetic gene regulation. Our automated inference method, which is potentially applicable to other ChIP-chip or ChIP-seq data analyses, provides a much-needed guide to deciphering the complex histone codes.\n" ], "offsets": [ [ 0, 1400 ] ] } ]

[ { "id": "PMID-18562678_T1", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 47, 54 ] ], "normalized": [] }, { "id": "PMID-18562678_T2", "type": "Protein", "text": [ "Histone" ], "offsets": [ [ 91, 98 ] ], "normalized": [] }, { "id": "PMID-18562678_T3", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 315, 322 ] ], "normalized": [] }, { "id": "PMID-18562678_T4", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 449, 456 ] ], "normalized": [] }, { "id": "PMID-18562678_T5", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 597, 604 ] ], "normalized": [] }, { "id": "PMID-18562678_T6", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 720, 722 ] ], "normalized": [] }, { "id": "PMID-18562678_T7", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 821, 828 ] ], "normalized": [] }, { "id": "PMID-18562678_T8", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 963, 965 ] ], "normalized": [] }, { "id": "PMID-18562678_T9", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 991, 993 ] ], "normalized": [] }, { "id": "PMID-18562678_T10", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1066, 1068 ] ], "normalized": [] }, { "id": "PMID-18562678_T11", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1078, 1080 ] ], "normalized": [] }, { "id": "PMID-18562678_T12", "type": "Entity", "text": [ "K27" ], "offsets": [ [ 722, 725 ] ], "normalized": [] } ]

[ { "id": "PMID-18562678_E1", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 726, 740 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18562678_T6" }, { "role": "Site", "ref_id": "PMID-18562678_T12" } ] } ]

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[]

[ { "id": "PMID-18566325__text", "type": "abstract", "text": [ "Antibody fucosylation differentially impacts cytotoxicity mediated by NK and PMN effector cells. \nGlycosylation of the antibody Fc fragment is essential for Fc receptor-mediated activity. Carbohydrate heterogeneity is known to modulate the activity of effector cells in the blood, in which fucosylation particularly affects NK cell-mediated killing. Here, we investigated how the glycosylation profile of 2F8, a human IgG(1) monoclonal antibody against epidermal growth factor receptor in clinical development, impacted effector function. Various 2F8 batches differing in fucosylation, galactosylation, and sialylation of the complex-type oligosaccharides in the Fc fragment were investigated. Our results confirmed that low fucose levels enhance mononuclear cell-mediated antibody-mediated cellular cytotoxicity (ADCC). In contrast, polymorphonuclear cells were found to preferentially kill via high-fucosylated antibody. Whole blood ADCC assays, containing both types of effector cells, revealed little differences in tumor cell killing between both batches. Significantly, however, high-fucose antibody induced superior ADCC in blood from granulocyte colony-stimulating factor-primed donors containing higher numbers of activated polymorphonuclear cells. In conclusion, our data demonstrated for the first time that lack of fucose does not generally increase the ADCC activity of therapeutic antibodies and that the impact of Fc glycosylation on ADCC is critically dependent on the recruited effector cell type.\n" ], "offsets": [ [ 0, 1515 ] ] } ]

[ { "id": "PMID-18566325_T1", "type": "Protein", "text": [ "epidermal growth factor receptor" ], "offsets": [ [ 453, 485 ] ], "normalized": [] }, { "id": "PMID-18566325_T2", "type": "Protein", "text": [ "granulocyte colony-stimulating factor" ], "offsets": [ [ 1142, 1179 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18566452__text", "type": "abstract", "text": [ "Substrate-binding sites of UBR1, the ubiquitin ligase of the N-end rule pathway. \nSubstrates of a ubiquitin-dependent proteolytic system called the N-end rule pathway include proteins with destabilizing N-terminal residues. N-recognins, the pathway's ubiquitin ligases, contain three substrate-binding sites. The type-1 site is specific for basic N-terminal residues (Arg, Lys, and His). The type-2 site is specific for bulky hydrophobic N-terminal residues (Trp, Phe, Tyr, Leu, and Ile). We show here that the type-1/2 sites of UBR1, the sole N-recognin of the yeast Saccharomyces cerevisiae, are located in the first approximately 700 residues of the 1,950-residue UBR1. These sites are distinct in that they can be selectively inactivated by mutations, identified through a genetic screen. Mutations inactivating the type-1 site are in the previously delineated approximately 70-residue UBR motif characteristic of N-recognins. Fluorescence polarization and surface plasmon resonance were used to determine that UBR1 binds, with a K(d) of approximately 1 microm, to either type-1 or type-2 destabilizing N-terminal residues of reporter peptides but does not bind to a stabilizing N-terminal residue such as Gly. A third substrate-binding site of UBR1 targets an internal degron of CUP9, a transcriptional repressor of peptide import. We show that the previously demonstrated in vivo dependence of CUP9 ubiquitylation on the binding of cognate dipeptides to the type-1/2 sites of UBR1 can be reconstituted in a completely defined in vitro system. We also found that purified UBR1 and CUP9 interact nonspecifically and that specific binding (which involves, in particular, the binding by cognate dipeptides to the UBR1 type-1/2 sites) can be restored either by a chaperone such as EF1A or through macromolecular crowding.\n" ], "offsets": [ [ 0, 1823 ] ] } ]

[ { "id": "PMID-18566452_T1", "type": "Protein", "text": [ "UBR1" ], "offsets": [ [ 27, 31 ] ], "normalized": [] }, { "id": "PMID-18566452_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 37, 46 ] ], "normalized": [] }, { "id": "PMID-18566452_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 98, 107 ] ], "normalized": [] }, { "id": "PMID-18566452_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 251, 260 ] ], "normalized": [] }, { "id": "PMID-18566452_T5", "type": "Protein", "text": [ "UBR1" ], "offsets": [ [ 529, 533 ] ], "normalized": [] }, { "id": "PMID-18566452_T6", "type": "Protein", "text": [ "UBR1" ], "offsets": [ [ 667, 671 ] ], "normalized": [] }, { "id": "PMID-18566452_T7", "type": "Protein", "text": [ "UBR1" ], "offsets": [ [ 1015, 1019 ] ], "normalized": [] }, { "id": "PMID-18566452_T8", "type": "Protein", "text": [ "UBR1" ], "offsets": [ [ 1249, 1253 ] ], "normalized": [] }, { "id": "PMID-18566452_T9", "type": "Protein", "text": [ "CUP9" ], "offsets": [ [ 1284, 1288 ] ], "normalized": [] }, { "id": "PMID-18566452_T10", "type": "Protein", "text": [ "CUP9" ], "offsets": [ [ 1400, 1404 ] ], "normalized": [] }, { "id": "PMID-18566452_T11", "type": "Protein", "text": [ "UBR1" ], "offsets": [ [ 1482, 1486 ] ], "normalized": [] }, { "id": "PMID-18566452_T12", "type": "Protein", "text": [ "UBR1" ], "offsets": [ [ 1577, 1581 ] ], "normalized": [] }, { "id": "PMID-18566452_T13", "type": "Protein", "text": [ "CUP9" ], "offsets": [ [ 1586, 1590 ] ], "normalized": [] }, { "id": "PMID-18566452_T14", "type": "Protein", "text": [ "UBR1" ], "offsets": [ [ 1715, 1719 ] ], "normalized": [] }, { "id": "PMID-18566452_T15", "type": "Protein", "text": [ "EF1A" ], "offsets": [ [ 1782, 1786 ] ], "normalized": [] } ]

[ { "id": "PMID-18566452_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 1405, 1419 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18566452_T10" } ] }, { "id": "PMID-18566452_E2", "type": "Catalysis", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 1405, 1419 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18566452_E1" }, { "role": "Cause", "ref_id": "PMID-18566452_T11" } ] } ]

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[ { "id": "PMID-18566480__text", "type": "abstract", "text": [ "Monoclonal antibody-based screening assay for factor inhibiting hypoxia-inducible factor inhibitors. \nThe factor-inhibiting hypoxia-inducible factor (FIH) hydroxylates the asparagine 803 (Asn803) residue of the hypoxia-inducible factor 1alpha (HIF-1alpha), and the modification abrogates the transcriptional activity of HIF-1alpha. Because FIH is more active on HIF-1alpha than prolyl hydroxylase domain proteins under hypoxic conditions, its inhibitors have potential to be developed as anti-ischemic drugs targeting normal cells stressed by hypoxia. In this study, the authors developed the first monoclonal antibody, SHN-HIF1alpha, specifically to Asn803 hydroxylated HIF-1alpha and a sensitive assay system for FIH inhibitors using the monoclonal antibody (Mab). SHN-HIF1alpha showed 740 times higher affinity to the Asn803 hydroxylated HIF-1alpha peptide than the unmodified one. An enzyme-linked immunosorbent assay-based system using SHN-HIF1alpha displayed at least 30 times more sensitivity than previous methods for screening FIH inhibitors and was easily applicable to develop a high-throughput screening system. SHN-HIF1alpha also showed an Asn803 hydroxylation-dependent specificity to HIF-1alpha in cells. Taken together, the results suggest that it may be used to analyze the in vivo and in vitro activities of FIH inhibitors.\n" ], "offsets": [ [ 0, 1342 ] ] } ]

[ { "id": "PMID-18566480_T1", "type": "Protein", "text": [ "factor inhibiting hypoxia-inducible factor" ], "offsets": [ [ 46, 88 ] ], "normalized": [] }, { "id": "PMID-18566480_T2", "type": "Protein", "text": [ "factor-inhibiting hypoxia-inducible factor" ], "offsets": [ [ 106, 148 ] ], "normalized": [] }, { "id": "PMID-18566480_T3", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 150, 153 ] ], "normalized": [] }, { "id": "PMID-18566480_T4", "type": "Protein", "text": [ "hypoxia-inducible factor 1alpha" ], "offsets": [ [ 211, 242 ] ], "normalized": [] }, { "id": "PMID-18566480_T5", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 244, 254 ] ], "normalized": [] }, { "id": "PMID-18566480_T6", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 320, 330 ] ], "normalized": [] }, { "id": "PMID-18566480_T7", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 340, 343 ] ], "normalized": [] }, { "id": "PMID-18566480_T8", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 362, 372 ] ], "normalized": [] }, { "id": "PMID-18566480_T9", "type": "Protein", "text": [ "HIF1alpha" ], "offsets": [ [ 624, 633 ] ], "normalized": [] }, { "id": "PMID-18566480_T10", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 671, 681 ] ], "normalized": [] }, { "id": "PMID-18566480_T11", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 715, 718 ] ], "normalized": [] }, { "id": "PMID-18566480_T12", "type": "Protein", "text": [ "HIF1alpha" ], "offsets": [ [ 771, 780 ] ], "normalized": [] }, { "id": "PMID-18566480_T13", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 841, 851 ] ], "normalized": [] }, { "id": "PMID-18566480_T14", "type": "Protein", "text": [ "HIF1alpha" ], "offsets": [ [ 945, 954 ] ], "normalized": [] }, { "id": "PMID-18566480_T15", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1036, 1039 ] ], "normalized": [] }, { "id": "PMID-18566480_T16", "type": "Protein", "text": [ "HIF1alpha" ], "offsets": [ [ 1128, 1137 ] ], "normalized": [] }, { "id": "PMID-18566480_T17", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 1199, 1209 ] ], "normalized": [] }, { "id": "PMID-18566480_T18", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1326, 1329 ] ], "normalized": [] }, { "id": "PMID-18566480_T21", "type": "Entity", "text": [ "asparagine 803" ], "offsets": [ [ 172, 186 ] ], "normalized": [] }, { "id": "PMID-18566480_T22", "type": "Entity", "text": [ "Asn803" ], "offsets": [ [ 188, 194 ] ], "normalized": [] }, { "id": "PMID-18566480_T23", "type": "Entity", "text": [ "Asn803" ], "offsets": [ [ 651, 657 ] ], "normalized": [] }, { "id": "PMID-18566480_T25", "type": "Entity", "text": [ "Asn803" ], "offsets": [ [ 821, 827 ] ], "normalized": [] }, { "id": "PMID-18566480_T27", "type": "Entity", "text": [ "Asn803" ], "offsets": [ [ 1153, 1159 ] ], "normalized": [] } ]

[ { "id": "PMID-18566480_E1", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylates" ], "offsets": [ [ 155, 167 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18566480_T4" }, { "role": "Site", "ref_id": "PMID-18566480_T21" } ] }, { "id": "PMID-18566480_E2", "type": "Catalysis", "trigger": { "text": [ "hydroxylates" ], "offsets": [ [ 155, 167 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18566480_E1" }, { "role": "Cause", "ref_id": "PMID-18566480_T2" } ] }, { "id": "PMID-18566480_E3", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylated" ], "offsets": [ [ 658, 670 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18566480_T10" }, { "role": "Site", "ref_id": "PMID-18566480_T23" } ] }, { "id": "PMID-18566480_E4", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylated" ], "offsets": [ [ 828, 840 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18566480_T13" }, { "role": "Site", "ref_id": "PMID-18566480_T25" } ] }, { "id": "PMID-18566480_E5", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 1160, 1173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18566480_T17" }, { "role": "Site", "ref_id": "PMID-18566480_T27" } ] } ]

[ { "id": "PMID-18566480_1", "entity_ids": [ "PMID-18566480_T2", "PMID-18566480_T3" ] }, { "id": "PMID-18566480_2", "entity_ids": [ "PMID-18566480_T21", "PMID-18566480_T22" ] }, { "id": "PMID-18566480_3", "entity_ids": [ "PMID-18566480_T4", "PMID-18566480_T5" ] } ]

[]

[ { "id": "PMID-18573314__text", "type": "abstract", "text": [ "PRMT3 inhibits ubiquitination of ribosomal protein S2 and together forms an active enzyme complex. \nProtein arginine methyltransferase 3 (PRMT3) comprises a region not required for catalytic activity in its amino-terminus and the core domain catalyzing protein arginine methylation. PRMT3 has been shown to interact with the 40S ribosomal protein S2 (rpS2) and methylate arginine residues in the arginine-glycine (RG) repeat region in the amino-terminus of rpS2. We investigated the biological implications of this interaction by delineating the domains that mediate binding between PRMT3 and rpS2. The rpS2 (100-293 amino acids) domain, but not the amino-terminus of rpS2 that includes the RG repeat region was essential for binding to PRMT3 and was susceptible to degradation. The amino-terminus of PRMT3, but not its catalytic core was required for binding to and the stability of rpS2. Overexpressed rpS2 was ubiquitinated in cells, but expression of PRMT3 reduced this ubiquitination and stabilized the rpS2 protein. Recombinant PRMT3 formed an active enzyme complex with endogenous rpS2 in vitro. Recombinant rpS2 in molar excess modestly increased the enzymatic activity of PRMT3 in vitro. Our results suggest that in addition to its catalytic function, PRMT3 may control the level of rpS2 protein in cells by inhibiting ubiquitin-mediated proteolysis of rpS2, while rpS2 may regulate the enzymatic activity of PRMT3 as a likely non-catalytic subunit.\n" ], "offsets": [ [ 0, 1459 ] ] } ]

[ { "id": "PMID-18573314_T1", "type": "Protein", "text": [ "PRMT3" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-18573314_T2", "type": "Protein", "text": [ "ribosomal protein S2" ], "offsets": [ [ 33, 53 ] ], "normalized": [] }, { "id": "PMID-18573314_T3", "type": "Protein", "text": [ "Protein arginine methyltransferase 3" ], "offsets": [ [ 100, 136 ] ], "normalized": [] }, { "id": "PMID-18573314_T4", "type": "Protein", "text": [ "PRMT3" ], "offsets": [ [ 138, 143 ] ], "normalized": [] }, { "id": "PMID-18573314_T5", "type": "Protein", "text": [ "PRMT3" ], "offsets": [ [ 283, 288 ] ], "normalized": [] }, { "id": "PMID-18573314_T6", "type": "Protein", "text": [ "40S ribosomal protein S2" ], "offsets": [ [ 325, 349 ] ], "normalized": [] }, { "id": "PMID-18573314_T7", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 351, 355 ] ], "normalized": [] }, { "id": "PMID-18573314_T8", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 457, 461 ] ], "normalized": [] }, { "id": "PMID-18573314_T9", "type": "Protein", "text": [ "PRMT3" ], "offsets": [ [ 583, 588 ] ], "normalized": [] }, { "id": "PMID-18573314_T10", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 593, 597 ] ], "normalized": [] }, { "id": "PMID-18573314_T11", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 603, 607 ] ], "normalized": [] }, { "id": "PMID-18573314_T12", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 668, 672 ] ], "normalized": [] }, { "id": "PMID-18573314_T13", "type": "Protein", "text": [ "PRMT3" ], "offsets": [ [ 737, 742 ] ], "normalized": [] }, { "id": "PMID-18573314_T14", "type": "Protein", "text": [ "PRMT3" ], "offsets": [ [ 801, 806 ] ], "normalized": [] }, { "id": "PMID-18573314_T15", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 884, 888 ] ], "normalized": [] }, { "id": "PMID-18573314_T16", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 904, 908 ] ], "normalized": [] }, { "id": "PMID-18573314_T17", "type": "Protein", "text": [ "PRMT3" ], "offsets": [ [ 955, 960 ] ], "normalized": [] }, { "id": "PMID-18573314_T18", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 1008, 1012 ] ], "normalized": [] }, { "id": "PMID-18573314_T19", "type": "Protein", "text": [ "PRMT3" ], "offsets": [ [ 1034, 1039 ] ], "normalized": [] }, { "id": "PMID-18573314_T20", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 1088, 1092 ] ], "normalized": [] }, { "id": "PMID-18573314_T21", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 1115, 1119 ] ], "normalized": [] }, { "id": "PMID-18573314_T22", "type": "Protein", "text": [ "PRMT3" ], "offsets": [ [ 1181, 1186 ] ], "normalized": [] }, { "id": "PMID-18573314_T23", "type": "Protein", "text": [ "PRMT3" ], "offsets": [ [ 1261, 1266 ] ], "normalized": [] }, { "id": "PMID-18573314_T24", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 1292, 1296 ] ], "normalized": [] }, { "id": "PMID-18573314_T25", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1328, 1337 ] ], "normalized": [] }, { "id": "PMID-18573314_T26", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 1362, 1366 ] ], "normalized": [] }, { "id": "PMID-18573314_T27", "type": "Protein", "text": [ "rpS2" ], "offsets": [ [ 1374, 1378 ] ], "normalized": [] }, { "id": "PMID-18573314_T28", "type": "Protein", "text": [ "PRMT3" ], "offsets": [ [ 1418, 1423 ] ], "normalized": [] }, { "id": "PMID-18573314_T32", "type": "Entity", "text": [ "arginine residues" ], "offsets": [ [ 371, 388 ] ], "normalized": [] } ]

[ { "id": "PMID-18573314_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 15, 29 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18573314_T2" } ] }, { "id": "PMID-18573314_E2", "type": "Methylation", "trigger": { "text": [ "methylate" ], "offsets": [ [ 361, 370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18573314_T8" }, { "role": "Site", "ref_id": "PMID-18573314_T32" } ] }, { "id": "PMID-18573314_E3", "type": "Catalysis", "trigger": { "text": [ "methylate" ], "offsets": [ [ 361, 370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18573314_E2" }, { "role": "Cause", "ref_id": "PMID-18573314_T5" } ] }, { "id": "PMID-18573314_E4", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 913, 926 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18573314_T16" } ] }, { "id": "PMID-18573314_E5", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 974, 988 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18573314_T18" } ] } ]

[ { "id": "PMID-18573314_1", "entity_ids": [ "PMID-18573314_T3", "PMID-18573314_T4" ] }, { "id": "PMID-18573314_2", "entity_ids": [ "PMID-18573314_T6", "PMID-18573314_T7" ] } ]

[]

[ { "id": "PMID-18577513__text", "type": "abstract", "text": [ "The ubiquitin-protein ligase Nedd4-2 differentially interacts with and regulates members of the Tweety family of chloride ion channels. \nThe Tweety proteins comprise a family of chloride ion channels with three members identified in humans (TTYH1-3) and orthologues in fly and murine species. In humans, increased TTYH2 expression is associated with cancer progression, whereas fly Tweety is associated with developmental processes. Structurally, Tweety proteins are characterized by five membrane-spanning domains and N-glycan modifications important for trafficking to the plasma membrane, where these proteins are oriented with the amino terminus located extracellularly and the carboxyl terminus cytoplasmically. In addition to N-glycosylation, ubiquitination mediated by the HECT type E3 ubiquitin ligase Nedd4-2 is a post-translation modification important in regulating membrane proteins. In the present study, we performed a comprehensive analysis of the ability of each of TTYH1-3 to interact with Nedd4-2 and to be ubiquitinated and regulated by this ligase. Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3, which contain consensus PY ((L/P)PXY) binding sites for HECT type E3 ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently, Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the TTYH2 PY motif is essential for these interactions. We have also shown that Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell surface and total cellular levels of this protein. These data, indicating that Nedd4-2 differentially interacts with and regulates TTYH1-3, will be important for understanding mechanisms controlling Tweety proteins in physiology and disease.\n" ], "offsets": [ [ 0, 1833 ] ] } ]

[ { "id": "PMID-18577513_T1", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 4, 13 ] ], "normalized": [] }, { "id": "PMID-18577513_T2", "type": "Protein", "text": [ "Nedd4-2" ], "offsets": [ [ 29, 36 ] ], "normalized": [] }, { "id": "PMID-18577513_T3", "type": "Protein", "text": [ "Tweety" ], "offsets": [ [ 141, 147 ] ], "normalized": [] }, { "id": "PMID-18577513_T4", "type": "Protein", "text": [ "TTYH1" ], "offsets": [ [ 241, 246 ] ], "normalized": [] }, { "id": "PMID-18577513_T5", "type": "Protein", "text": [ "3" ], "offsets": [ [ 247, 248 ] ], "normalized": [] }, { "id": "PMID-18577513_T6", "type": "Protein", "text": [ "TTYH2" ], "offsets": [ [ 314, 319 ] ], "normalized": [] }, { "id": "PMID-18577513_T7", "type": "Protein", "text": [ "Tweety" ], "offsets": [ [ 382, 388 ] ], "normalized": [] }, { "id": "PMID-18577513_T8", "type": "Protein", "text": [ "Tweety" ], "offsets": [ [ 447, 453 ] ], "normalized": [] }, { "id": "PMID-18577513_T9", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 793, 802 ] ], "normalized": [] }, { "id": "PMID-18577513_T10", "type": "Protein", "text": [ "Nedd4-2" ], "offsets": [ [ 810, 817 ] ], "normalized": [] }, { "id": "PMID-18577513_T11", "type": "Protein", "text": [ "TTYH1" ], "offsets": [ [ 982, 987 ] ], "normalized": [] }, { "id": "PMID-18577513_T12", "type": "Protein", "text": [ "3" ], "offsets": [ [ 988, 989 ] ], "normalized": [] }, { "id": "PMID-18577513_T13", "type": "Protein", "text": [ "Nedd4-2" ], "offsets": [ [ 1007, 1014 ] ], "normalized": [] }, { "id": "PMID-18577513_T14", "type": "Protein", "text": [ "Nedd4-2" ], "offsets": [ [ 1092, 1099 ] ], "normalized": [] }, { "id": "PMID-18577513_T15", "type": "Protein", "text": [ "TTYH2" ], "offsets": [ [ 1129, 1134 ] ], "normalized": [] }, { "id": "PMID-18577513_T16", "type": "Protein", "text": [ "TTYH3" ], "offsets": [ [ 1139, 1144 ] ], "normalized": [] }, { "id": "PMID-18577513_T17", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1215, 1224 ] ], "normalized": [] }, { "id": "PMID-18577513_T18", "type": "Protein", "text": [ "TTYH1" ], "offsets": [ [ 1245, 1250 ] ], "normalized": [] }, { "id": "PMID-18577513_T19", "type": "Protein", "text": [ "Nedd4-2" ], "offsets": [ [ 1290, 1297 ] ], "normalized": [] }, { "id": "PMID-18577513_T20", "type": "Protein", "text": [ "TTYH2" ], "offsets": [ [ 1317, 1322 ] ], "normalized": [] }, { "id": "PMID-18577513_T21", "type": "Protein", "text": [ "TTYH3" ], "offsets": [ [ 1327, 1332 ] ], "normalized": [] }, { "id": "PMID-18577513_T22", "type": "Protein", "text": [ "TTYH2" ], "offsets": [ [ 1377, 1382 ] ], "normalized": [] }, { "id": "PMID-18577513_T23", "type": "Protein", "text": [ "Nedd4-2" ], "offsets": [ [ 1387, 1394 ] ], "normalized": [] }, { "id": "PMID-18577513_T24", "type": "Protein", "text": [ "TTYH2" ], "offsets": [ [ 1442, 1447 ] ], "normalized": [] }, { "id": "PMID-18577513_T25", "type": "Protein", "text": [ "Nedd4-2" ], "offsets": [ [ 1518, 1525 ] ], "normalized": [] }, { "id": "PMID-18577513_T26", "type": "Protein", "text": [ "TTYH2" ], "offsets": [ [ 1553, 1558 ] ], "normalized": [] }, { "id": "PMID-18577513_T27", "type": "Protein", "text": [ "Nedd4-2" ], "offsets": [ [ 1670, 1677 ] ], "normalized": [] }, { "id": "PMID-18577513_T28", "type": "Protein", "text": [ "TTYH1" ], "offsets": [ [ 1722, 1727 ] ], "normalized": [] }, { "id": "PMID-18577513_T29", "type": "Protein", "text": [ "3" ], "offsets": [ [ 1728, 1729 ] ], "normalized": [] }, { "id": "PMID-18577513_T30", "type": "Protein", "text": [ "Tweety" ], "offsets": [ [ 1790, 1796 ] ], "normalized": [] } ]

[ { "id": "PMID-18577513_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinates" ], "offsets": [ [ 1298, 1311 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18577513_T20" } ] }, { "id": "PMID-18577513_E2", "type": "Catalysis", "trigger": { "text": [ "ubiquitinates" ], "offsets": [ [ 1298, 1311 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18577513_E1" }, { "role": "Cause", "ref_id": "PMID-18577513_T19" } ] }, { "id": "PMID-18577513_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinates" ], "offsets": [ [ 1298, 1311 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18577513_T21" } ] }, { "id": "PMID-18577513_E4", "type": "Catalysis", "trigger": { "text": [ "ubiquitinates" ], "offsets": [ [ 1298, 1311 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18577513_E3" }, { "role": "Cause", "ref_id": "PMID-18577513_T19" } ] }, { "id": "PMID-18577513_E5", "type": "Catalysis", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1526, 1534 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18577513_E6" }, { "role": "Cause", "ref_id": "PMID-18577513_T25" } ] }, { "id": "PMID-18577513_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1535, 1549 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18577513_T26" } ] } ]

[]

[]

[ { "id": "PMID-18596098__text", "type": "abstract", "text": [ "Viral genome methylation as an epigenetic defense against geminiviruses. \nGeminiviruses encapsidate single-stranded DNA genomes that replicate in plant cell nuclei through double-stranded DNA intermediates that associate with cellular histone proteins to form minichromosomes. Like most plant viruses, geminiviruses are targeted by RNA silencing and encode suppressor proteins such as AL2 and L2 to counter this defense. These related proteins can suppress silencing by multiple mechanisms, one of which involves interacting with and inhibiting adenosine kinase (ADK), a cellular enzyme associated with the methyl cycle that generates S-adenosyl-methionine, an essential methyltransferase cofactor. Thus, we hypothesized that the viral genome is targeted by small-RNA-directed methylation. Here, we show that Arabidopsis plants with mutations in genes encoding cytosine or histone H3 lysine 9 (H3K9) methyltransferases, RNA-directed methylation pathway components, or ADK are hypersensitive to geminivirus infection. We also demonstrate that viral DNA and associated histone H3 are methylated in infected plants and that cytosine methylation levels are significantly reduced in viral DNA isolated from methylation-deficient mutants. Finally, we demonstrate that Beet curly top virus L2- mutant DNA present in tissues that have recovered from infection is hypermethylated and that host recovery requires AGO4, a component of the RNA-directed methylation pathway. We propose that plants use chromatin methylation as a defense against DNA viruses, which geminiviruses counter by inhibiting global methylation. In addition, our results establish that geminiviruses can be useful models for genome methylation in plants and suggest that there are redundant pathways leading to cytosine methylation.\n" ], "offsets": [ [ 0, 1794 ] ] } ]

[ { "id": "PMID-18596098_T1", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 235, 242 ] ], "normalized": [] }, { "id": "PMID-18596098_T2", "type": "Protein", "text": [ "AL2" ], "offsets": [ [ 385, 388 ] ], "normalized": [] }, { "id": "PMID-18596098_T3", "type": "Protein", "text": [ "L2" ], "offsets": [ [ 393, 395 ] ], "normalized": [] }, { "id": "PMID-18596098_T4", "type": "Protein", "text": [ "adenosine kinase" ], "offsets": [ [ 545, 561 ] ], "normalized": [] }, { "id": "PMID-18596098_T5", "type": "Protein", "text": [ "ADK" ], "offsets": [ [ 563, 566 ] ], "normalized": [] }, { "id": "PMID-18596098_T6", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 873, 883 ] ], "normalized": [] }, { "id": "PMID-18596098_T7", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 894, 896 ] ], "normalized": [] }, { "id": "PMID-18596098_T8", "type": "Protein", "text": [ "ADK" ], "offsets": [ [ 968, 971 ] ], "normalized": [] }, { "id": "PMID-18596098_T9", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 1067, 1077 ] ], "normalized": [] }, { "id": "PMID-18596098_T10", "type": "Protein", "text": [ "L2" ], "offsets": [ [ 1283, 1285 ] ], "normalized": [] }, { "id": "PMID-18596098_T11", "type": "Protein", "text": [ "AGO4" ], "offsets": [ [ 1403, 1407 ] ], "normalized": [] } ]

[ { "id": "PMID-18596098_E1", "type": "Methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1082, 1092 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18596098_T9" } ] } ]

[ { "id": "PMID-18596098_1", "entity_ids": [ "PMID-18596098_T4", "PMID-18596098_T5" ] } ]

[]

[ { "id": "PMID-18647882__text", "type": "abstract", "text": [ "CaMK activation during exercise is required for histone hyperacetylation and MEF2A binding at the MEF2 site on the Glut4 gene. \nThe role of CaMK II in regulating GLUT4 expression in response to intermittent exercise was investigated. Wistar rats completed 5 x 17-min bouts of swimming after receiving 5 mg/kg KN93 (a CaMK II inhibitor), KN92 (an analog of KN93 that does not inhibit CaMK II), or an equivalent volume of vehicle. Triceps muscles that were harvested at 0, 6, or 18 h postexercise were assayed for 1) CaMK II phosphorylation by Western blot, 2) acetylation of histone H3 at the Glut4 MEF2 site by chromatin immunoprecipitation (ChIP) assay, 3) bound MEF2A at the Glut4 MEF2 cis-element by ChIP, and 4) GLUT4 expression by RT-PCR and Western blot. Compared with controls, exercise caused a twofold increase in CaMK II phosphorylation. Immunohistochemical stains indicated increased CaMK II phosphorylation in nuclear and perinuclear regions of the muscle fiber. Acetylation of histone H3 in the region surrounding the MEF2 binding site on the Glut4 gene and the amount of MEF2A that bind to the site increased approximately twofold postexercise. GLUT4 mRNA and protein increased approximately 2.2- and 1.8-fold, respectively, after exercise. The exercise-induced increases in CaMK II phosphorylation, histone H3 acetylation, MEF2A binding, and GLUT4 expression were attenuated or abolished when KN93 was administered to rats prior to exercise. KN92 did not affect the increases in pCaMK II and GLUT4. These data support the hypothesis that CaMK II activation by exercise increases GLUT4 expression via increased accessibility of MEF2A to its cis-element on the gene.\n" ], "offsets": [ [ 0, 1680 ] ] } ]

[ { "id": "PMID-18647882_T1", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 48, 55 ] ], "normalized": [] }, { "id": "PMID-18647882_T2", "type": "Protein", "text": [ "MEF2A" ], "offsets": [ [ 77, 82 ] ], "normalized": [] }, { "id": "PMID-18647882_T3", "type": "Protein", "text": [ "Glut4" ], "offsets": [ [ 115, 120 ] ], "normalized": [] }, { "id": "PMID-18647882_T4", "type": "Protein", "text": [ "GLUT4" ], "offsets": [ [ 162, 167 ] ], "normalized": [] }, { "id": "PMID-18647882_T5", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 574, 584 ] ], "normalized": [] }, { "id": "PMID-18647882_T6", "type": "Protein", "text": [ "Glut4" ], "offsets": [ [ 592, 597 ] ], "normalized": [] }, { "id": "PMID-18647882_T7", "type": "Protein", "text": [ "MEF2A" ], "offsets": [ [ 664, 669 ] ], "normalized": [] }, { "id": "PMID-18647882_T8", "type": "Protein", "text": [ "Glut4" ], "offsets": [ [ 677, 682 ] ], "normalized": [] }, { "id": "PMID-18647882_T9", "type": "Protein", "text": [ "GLUT4" ], "offsets": [ [ 716, 721 ] ], "normalized": [] }, { "id": "PMID-18647882_T10", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 990, 1000 ] ], "normalized": [] }, { "id": "PMID-18647882_T11", "type": "Protein", "text": [ "Glut4" ], "offsets": [ [ 1056, 1061 ] ], "normalized": [] }, { "id": "PMID-18647882_T12", "type": "Protein", "text": [ "MEF2A" ], "offsets": [ [ 1085, 1090 ] ], "normalized": [] }, { "id": "PMID-18647882_T13", "type": "Protein", "text": [ "GLUT4" ], "offsets": [ [ 1159, 1164 ] ], "normalized": [] }, { "id": "PMID-18647882_T14", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 1314, 1324 ] ], "normalized": [] }, { "id": "PMID-18647882_T15", "type": "Protein", "text": [ "MEF2A" ], "offsets": [ [ 1338, 1343 ] ], "normalized": [] }, { "id": "PMID-18647882_T16", "type": "Protein", "text": [ "GLUT4" ], "offsets": [ [ 1357, 1362 ] ], "normalized": [] }, { "id": "PMID-18647882_T17", "type": "Protein", "text": [ "GLUT4" ], "offsets": [ [ 1507, 1512 ] ], "normalized": [] }, { "id": "PMID-18647882_T18", "type": "Protein", "text": [ "GLUT4" ], "offsets": [ [ 1594, 1599 ] ], "normalized": [] }, { "id": "PMID-18647882_T19", "type": "Protein", "text": [ "MEF2A" ], "offsets": [ [ 1642, 1647 ] ], "normalized": [] } ]

[ { "id": "PMID-18647882_E1", "type": "Acetylation", "trigger": { "text": [ "hyperacetylation" ], "offsets": [ [ 56, 72 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18647882_T1" }, { "role": "Contextgene", "ref_id": "PMID-18647882_T3" } ] }, { "id": "PMID-18647882_E2", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 559, 570 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18647882_T5" }, { "role": "Contextgene", "ref_id": "PMID-18647882_T6" } ] }, { "id": "PMID-18647882_E3", "type": "Acetylation", "trigger": { "text": [ "Acetylation" ], "offsets": [ [ 975, 986 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18647882_T10" }, { "role": "Contextgene", "ref_id": "PMID-18647882_T11" } ] }, { "id": "PMID-18647882_E4", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1325, 1336 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18647882_T14" }, { "role": "Contextgene", "ref_id": "PMID-18647882_T16" } ] } ]

[]

[]

[ { "id": "PMID-18664619__text", "type": "abstract", "text": [ "Global analysis of the medulloblastoma epigenome identifies disease-subgroup-specific inactivation of COL1A2. \nCandidate gene investigations have indicated a significant role for epigenetic events in the pathogenesis of medulloblastoma, the most common malignant brain tumor of childhood. To assess the medulloblastoma epigenome more comprehensively, we undertook a genomewide investigation to identify genes that display evidence of methylation-dependent regulation. Expression microarray analysis of medulloblastoma cell lines following treatment with a DNA methyltransferase inhibitor revealed deregulation of multiple transcripts (3%-6% of probes per cell line). Eighteen independent genes demonstrated >3-fold reactivation in all cell lines tested. Bisulfite sequence analysis revealed dense CpG island methylation associated with transcriptional silencing for 12 of these genes. Extension of this analysis to primary tumors and the normal cerebellum revealed three major classes of epigenetically regulated genes: (1) normally methylated genes (DAZL, ZNF157, ASN) whose methylation reflects somatic patterns observed in the cerebellum, (2) X-linked genes (MSN, POU3F4, HTR2C) that show disruption of their sex-specific methylation patterns in tumors, and (3) tumor-specific methylated genes (COL1A2, S100A10, S100A6, HTATIP2, CDH1, LXN) that display enhanced methylation levels in tumors compared with the cerebellum. Detailed analysis of COL1A2 supports a key role in medulloblastoma tumorigenesis; dense biallelic methylation associated with transcriptional silencing was observed in 46 of 60 cases (77%). Moreover, COL1A2 status distinguished infant medulloblastomas of the desmoplastic histopathological subtype, indicating that distinct molecular pathogenesis may underlie these tumors and their more favorable prognosis. These data reveal a more diverse and expansive medulloblastoma epi genome than previously understood and provide strong evidence that the methylation status of specific genes may contribute to the biological subclassification of medulloblastoma.\n" ], "offsets": [ [ 0, 2079 ] ] } ]

[ { "id": "PMID-18664619_T1", "type": "Protein", "text": [ "COL1A2" ], "offsets": [ [ 102, 108 ] ], "normalized": [] }, { "id": "PMID-18664619_T2", "type": "Protein", "text": [ "DAZL" ], "offsets": [ [ 1051, 1055 ] ], "normalized": [] }, { "id": "PMID-18664619_T3", "type": "Protein", "text": [ "ZNF157" ], "offsets": [ [ 1057, 1063 ] ], "normalized": [] }, { "id": "PMID-18664619_T4", "type": "Protein", "text": [ "ASN" ], "offsets": [ [ 1065, 1068 ] ], "normalized": [] }, { "id": "PMID-18664619_T5", "type": "Protein", "text": [ "MSN" ], "offsets": [ [ 1162, 1165 ] ], "normalized": [] }, { "id": "PMID-18664619_T6", "type": "Protein", "text": [ "POU3F4" ], "offsets": [ [ 1167, 1173 ] ], "normalized": [] }, { "id": "PMID-18664619_T7", "type": "Protein", "text": [ "HTR2C" ], "offsets": [ [ 1175, 1180 ] ], "normalized": [] }, { "id": "PMID-18664619_T8", "type": "Protein", "text": [ "COL1A2" ], "offsets": [ [ 1298, 1304 ] ], "normalized": [] }, { "id": "PMID-18664619_T9", "type": "Protein", "text": [ "S100A10" ], "offsets": [ [ 1306, 1313 ] ], "normalized": [] }, { "id": "PMID-18664619_T10", "type": "Protein", "text": [ "S100A6" ], "offsets": [ [ 1315, 1321 ] ], "normalized": [] }, { "id": "PMID-18664619_T11", "type": "Protein", "text": [ "HTATIP2" ], "offsets": [ [ 1323, 1330 ] ], "normalized": [] }, { "id": "PMID-18664619_T12", "type": "Protein", "text": [ "CDH1" ], "offsets": [ [ 1332, 1336 ] ], "normalized": [] }, { "id": "PMID-18664619_T13", "type": "Protein", "text": [ "LXN" ], "offsets": [ [ 1338, 1341 ] ], "normalized": [] }, { "id": "PMID-18664619_T14", "type": "Protein", "text": [ "COL1A2" ], "offsets": [ [ 1445, 1451 ] ], "normalized": [] }, { "id": "PMID-18664619_T15", "type": "Protein", "text": [ "COL1A2" ], "offsets": [ [ 1624, 1630 ] ], "normalized": [] } ]

[ { "id": "PMID-18664619_E1", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1033, 1043 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T2" } ] }, { "id": "PMID-18664619_E2", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1033, 1043 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T3" } ] }, { "id": "PMID-18664619_E3", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1033, 1043 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T4" } ] }, { "id": "PMID-18664619_E4", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1225, 1236 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T5" } ] }, { "id": "PMID-18664619_E5", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1225, 1236 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T6" } ] }, { "id": "PMID-18664619_E6", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1225, 1236 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T7" } ] }, { "id": "PMID-18664619_E7", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1280, 1290 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T11" } ] }, { "id": "PMID-18664619_E8", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1280, 1290 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T12" } ] }, { "id": "PMID-18664619_E9", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1280, 1290 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T13" } ] }, { "id": "PMID-18664619_E10", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1280, 1290 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T8" } ] }, { "id": "PMID-18664619_E11", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1280, 1290 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T9" } ] }, { "id": "PMID-18664619_E12", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1280, 1290 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T10" } ] }, { "id": "PMID-18664619_E13", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1522, 1533 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18664619_T14" } ] } ]

[]

[]

[ { "id": "PMID-18719106__text", "type": "abstract", "text": [ "Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks. \nChronic stalling of DNA replication forks caused by DNA damage can lead to genomic instability. Cells have evolved lesion bypass pathways such as postreplication repair (PRR) to resolve these arrested forks. In yeast, one branch of PRR involves proliferating cell nuclear antigen (PCNA) polyubiquitination mediated by the Rad5-Ubc13-Mms2 complex that allows bypass of DNA lesion by a template-switching mechanism. Previously, we identified human SHPRH as a functional homologue of yeast Rad5 and revealed the existence of RAD5-like pathway in human cells. Here we report the identification of HLTF as a second RAD5 homologue in human cells. HLTF, like SHPRH, shares a unique domain architecture with Rad5 and promotes lysine 63-linked polyubiquitination of PCNA. Similar to yeast Rad5, HLTF is able to interact with UBC13 and PCNA, as well as SHPRH; and the reduction of either SHPRH or HLTF expression enhances spontaneous mutagenesis. Moreover, Hltf-deficient mouse embryonic fibroblasts show elevated chromosome breaks and fusions after methyl methane sulfonate treatment. Our results suggest that HLTF and SHPRH are functional homologues of yeast Rad5 that cooperatively mediate PCNA polyubiquitination and maintain genomic stability.\n" ], "offsets": [ [ 0, 1376 ] ] } ]

[ { "id": "PMID-18719106_T1", "type": "Protein", "text": [ "proliferating cell nuclear antigen" ], "offsets": [ [ 22, 56 ] ], "normalized": [] }, { "id": "PMID-18719106_T2", "type": "Protein", "text": [ "HLTF" ], "offsets": [ [ 60, 64 ] ], "normalized": [] }, { "id": "PMID-18719106_T3", "type": "Protein", "text": [ "SHPRH" ], "offsets": [ [ 69, 74 ] ], "normalized": [] }, { "id": "PMID-18719106_T4", "type": "Protein", "text": [ "proliferating cell nuclear antigen" ], "offsets": [ [ 382, 416 ] ], "normalized": [] }, { "id": "PMID-18719106_T5", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 418, 422 ] ], "normalized": [] }, { "id": "PMID-18719106_T6", "type": "Protein", "text": [ "Rad5" ], "offsets": [ [ 459, 463 ] ], "normalized": [] }, { "id": "PMID-18719106_T7", "type": "Protein", "text": [ "Ubc13" ], "offsets": [ [ 464, 469 ] ], "normalized": [] }, { "id": "PMID-18719106_T8", "type": "Protein", "text": [ "Mms2" ], "offsets": [ [ 470, 474 ] ], "normalized": [] }, { "id": "PMID-18719106_T9", "type": "Protein", "text": [ "SHPRH" ], "offsets": [ [ 583, 588 ] ], "normalized": [] }, { "id": "PMID-18719106_T10", "type": "Protein", "text": [ "Rad5" ], "offsets": [ [ 624, 628 ] ], "normalized": [] }, { "id": "PMID-18719106_T11", "type": "Protein", "text": [ "RAD5" ], "offsets": [ [ 659, 663 ] ], "normalized": [] }, { "id": "PMID-18719106_T12", "type": "Protein", "text": [ "HLTF" ], "offsets": [ [ 730, 734 ] ], "normalized": [] }, { "id": "PMID-18719106_T13", "type": "Protein", "text": [ "RAD5" ], "offsets": [ [ 747, 751 ] ], "normalized": [] }, { "id": "PMID-18719106_T14", "type": "Protein", "text": [ "HLTF" ], "offsets": [ [ 778, 782 ] ], "normalized": [] }, { "id": "PMID-18719106_T15", "type": "Protein", "text": [ "SHPRH" ], "offsets": [ [ 789, 794 ] ], "normalized": [] }, { "id": "PMID-18719106_T16", "type": "Protein", "text": [ "Rad5" ], "offsets": [ [ 837, 841 ] ], "normalized": [] }, { "id": "PMID-18719106_T17", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 894, 898 ] ], "normalized": [] }, { "id": "PMID-18719106_T18", "type": "Protein", "text": [ "Rad5" ], "offsets": [ [ 917, 921 ] ], "normalized": [] }, { "id": "PMID-18719106_T19", "type": "Protein", "text": [ "HLTF" ], "offsets": [ [ 923, 927 ] ], "normalized": [] }, { "id": "PMID-18719106_T20", "type": "Protein", "text": [ "UBC13" ], "offsets": [ [ 953, 958 ] ], "normalized": [] }, { "id": "PMID-18719106_T21", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 963, 967 ] ], "normalized": [] }, { "id": "PMID-18719106_T22", "type": "Protein", "text": [ "SHPRH" ], "offsets": [ [ 980, 985 ] ], "normalized": [] }, { "id": "PMID-18719106_T23", "type": "Protein", "text": [ "SHPRH" ], "offsets": [ [ 1015, 1020 ] ], "normalized": [] }, { "id": "PMID-18719106_T24", "type": "Protein", "text": [ "HLTF" ], "offsets": [ [ 1024, 1028 ] ], "normalized": [] }, { "id": "PMID-18719106_T25", "type": "Protein", "text": [ "Hltf" ], "offsets": [ [ 1084, 1088 ] ], "normalized": [] }, { "id": "PMID-18719106_T26", "type": "Protein", "text": [ "HLTF" ], "offsets": [ [ 1238, 1242 ] ], "normalized": [] }, { "id": "PMID-18719106_T27", "type": "Protein", "text": [ "SHPRH" ], "offsets": [ [ 1247, 1252 ] ], "normalized": [] }, { "id": "PMID-18719106_T28", "type": "Protein", "text": [ "Rad5" ], "offsets": [ [ 1288, 1292 ] ], "normalized": [] }, { "id": "PMID-18719106_T29", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 1320, 1324 ] ], "normalized": [] } ]

[ { "id": "PMID-18719106_E1", "type": "Catalysis", "trigger": { "text": [ "Polyubiquitination" ], "offsets": [ [ 0, 18 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18719106_E3" }, { "role": "Cause", "ref_id": "PMID-18719106_T2" } ] }, { "id": "PMID-18719106_E2", "type": "Catalysis", "trigger": { "text": [ "Polyubiquitination" ], "offsets": [ [ 0, 18 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18719106_E3" }, { "role": "Cause", "ref_id": "PMID-18719106_T3" } ] }, { "id": "PMID-18719106_E3", "type": "Ubiquitination", "trigger": { "text": [ "Polyubiquitination" ], "offsets": [ [ 0, 18 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18719106_T1" } ] }, { "id": "PMID-18719106_E4", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 424, 442 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18719106_T4" } ] }, { "id": "PMID-18719106_E5", "type": "Catalysis", "trigger": { "text": [ "promotes" ], "offsets": [ [ 846, 854 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18719106_E7" }, { "role": "Cause", "ref_id": "PMID-18719106_T14" } ] }, { "id": "PMID-18719106_E6", "type": "Catalysis", "trigger": { "text": [ "promotes" ], "offsets": [ [ 846, 854 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18719106_E7" }, { "role": "Cause", "ref_id": "PMID-18719106_T15" } ] }, { "id": "PMID-18719106_E7", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 872, 890 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18719106_T17" } ] }, { "id": "PMID-18719106_E8", "type": "Catalysis", "trigger": { "text": [ "mediate" ], "offsets": [ [ 1312, 1319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18719106_E10" }, { "role": "Cause", "ref_id": "PMID-18719106_T26" } ] }, { "id": "PMID-18719106_E9", "type": "Catalysis", "trigger": { "text": [ "mediate" ], "offsets": [ [ 1312, 1319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18719106_E10" }, { "role": "Cause", "ref_id": "PMID-18719106_T27" } ] }, { "id": "PMID-18719106_E10", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 1325, 1343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18719106_T29" } ] } ]

[ { "id": "PMID-18719106_1", "entity_ids": [ "PMID-18719106_T4", "PMID-18719106_T5" ] } ]

[]

[ { "id": "PMID-18722180__text", "type": "abstract", "text": [ "The unique N terminus of the UbcH10 E2 enzyme controls the threshold for APC activation and enhances checkpoint regulation of the APC. \nIn vitro, the anaphase-promoting complex (APC) E3 ligase functions with E2 ubiquitin-conjugating enzymes of the E2-C and Ubc4/5 families to ubiquitinate substrates. However, only the use of the E2-C family, notably UbcH10, is genetically well validated. Here, we biochemically demonstrate preferential use of UbcH10 by the APC, specified by the E2 core domain. Importantly, an additional E2-E3 interaction mediated by the N-terminal extension of UbcH10 regulates APC activity. Mutating the highly conserved N terminus increases substrate ubiquitination and the number of substrate lysines targeted, allows ubiquitination of APC substrates lacking their destruction boxes, increases resistance to the APC inhibitors Emi1 and BubR1 in vitro, and bypasses the spindle checkpoint in vivo. Fusion of the UbcH10 N terminus to UbcH5 restricts ubiquitination activity but does not direct specific interactions with the APC. Thus, UbcH10 combines a specific E2-E3 interface and regulation via its N-terminal extension to limit APC activity for substrate selection and checkpoint control.\n" ], "offsets": [ [ 0, 1215 ] ] } ]

[ { "id": "PMID-18722180_T1", "type": "Protein", "text": [ "UbcH10" ], "offsets": [ [ 29, 35 ] ], "normalized": [] }, { "id": "PMID-18722180_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 211, 220 ] ], "normalized": [] }, { "id": "PMID-18722180_T3", "type": "Protein", "text": [ "E2-C" ], "offsets": [ [ 248, 252 ] ], "normalized": [] }, { "id": "PMID-18722180_T4", "type": "Protein", "text": [ "Ubc4" ], "offsets": [ [ 257, 261 ] ], "normalized": [] }, { "id": "PMID-18722180_T5", "type": "Protein", "text": [ "5" ], "offsets": [ [ 262, 263 ] ], "normalized": [] }, { "id": "PMID-18722180_T6", "type": "Protein", "text": [ "UbcH10" ], "offsets": [ [ 351, 357 ] ], "normalized": [] }, { "id": "PMID-18722180_T7", "type": "Protein", "text": [ "UbcH10" ], "offsets": [ [ 445, 451 ] ], "normalized": [] }, { "id": "PMID-18722180_T8", "type": "Protein", "text": [ "UbcH10" ], "offsets": [ [ 582, 588 ] ], "normalized": [] }, { "id": "PMID-18722180_T9", "type": "Protein", "text": [ "Emi1" ], "offsets": [ [ 851, 855 ] ], "normalized": [] }, { "id": "PMID-18722180_T10", "type": "Protein", "text": [ "BubR1" ], "offsets": [ [ 860, 865 ] ], "normalized": [] }, { "id": "PMID-18722180_T11", "type": "Protein", "text": [ "UbcH10" ], "offsets": [ [ 935, 941 ] ], "normalized": [] }, { "id": "PMID-18722180_T12", "type": "Protein", "text": [ "UbcH5" ], "offsets": [ [ 956, 961 ] ], "normalized": [] }, { "id": "PMID-18722180_T13", "type": "Protein", "text": [ "UbcH10" ], "offsets": [ [ 1058, 1064 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18757745__text", "type": "abstract", "text": [ "RCS1, a substrate of APC/C, controls the metaphase to anaphase transition. \nThe anaphase-promoting complex/cyclosome (APC/C) controls the onset of anaphase by targeting securin for destruction. We report here the identification and characterization of a substrate of APC/C, RCS1, as a mitotic regulator that controls the metaphase-to-anaphase transition. We showed that the levels of RCS1 fluctuate in the cell cycle, peaking in mitosis and dropping drastically as cells exit into G(1). Indeed, RCS1 is efficiently ubiquitinated by APC/C in vitro and degraded during mitotic exit in a Cdh1-dependent manner in vivo. APC/C recognizes a unique D-box at the N terminus of RCS1, as mutations of this D-box abolished ubiquitination in vitro and stabilized the mutant protein in vivo. RCS1 controls the timing of the anaphase onset, because the loss of RCS1 resulted in a faster progression from the metaphase to anaphase and accelerated degradation of securin and cyclin B. Biochemically, mitotic RCS1 associates with the NuRD chromatin-remodeling complex, and this RCS1 complex is likely involved in regulating gene expression or chromatin structure, which in turn may control anaphase onset. Our study uncovers a complex regulatory network for the metaphase-to-anaphase transition.\n" ], "offsets": [ [ 0, 1279 ] ] } ]

[ { "id": "PMID-18757745_T1", "type": "Protein", "text": [ "RCS1" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-18757745_T2", "type": "Protein", "text": [ "securin" ], "offsets": [ [ 169, 176 ] ], "normalized": [] }, { "id": "PMID-18757745_T3", "type": "Protein", "text": [ "RCS1" ], "offsets": [ [ 274, 278 ] ], "normalized": [] }, { "id": "PMID-18757745_T4", "type": "Protein", "text": [ "RCS1" ], "offsets": [ [ 384, 388 ] ], "normalized": [] }, { "id": "PMID-18757745_T5", "type": "Protein", "text": [ "RCS1" ], "offsets": [ [ 495, 499 ] ], "normalized": [] }, { "id": "PMID-18757745_T6", "type": "Protein", "text": [ "Cdh1" ], "offsets": [ [ 585, 589 ] ], "normalized": [] }, { "id": "PMID-18757745_T7", "type": "Protein", "text": [ "RCS1" ], "offsets": [ [ 669, 673 ] ], "normalized": [] }, { "id": "PMID-18757745_T8", "type": "Protein", "text": [ "RCS1" ], "offsets": [ [ 779, 783 ] ], "normalized": [] }, { "id": "PMID-18757745_T9", "type": "Protein", "text": [ "RCS1" ], "offsets": [ [ 847, 851 ] ], "normalized": [] }, { "id": "PMID-18757745_T10", "type": "Protein", "text": [ "securin" ], "offsets": [ [ 947, 954 ] ], "normalized": [] }, { "id": "PMID-18757745_T11", "type": "Protein", "text": [ "RCS1" ], "offsets": [ [ 992, 996 ] ], "normalized": [] }, { "id": "PMID-18757745_T12", "type": "Protein", "text": [ "RCS1" ], "offsets": [ [ 1061, 1065 ] ], "normalized": [] } ]

[ { "id": "PMID-18757745_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 515, 528 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18757745_T5" } ] }, { "id": "PMID-18757745_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 712, 726 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18757745_T7" } ] } ]

[]

[]

[ { "id": "PMID-1875909__text", "type": "abstract", "text": [ "Molecular genetic basis of rapid and slow acetylation in mice. \nThe molecular genetic basis of N-acetylation polymorphism has been investigated in inbred mouse models of the human acetylation polymorphism. Two genomic clones, Nat1 and Nat2, were isolated from a C57BL/6J (B6) mouse (rapid acetylator) genomic library. The Nat1 and Nat2 genes both have intronless coding regions of 870 nucleotides and display greater than 47% deduced amino acid similarity with human, rabbit, and chicken N-acetyltransferases. Amplification of Nat1 and Nat2 from A/J (A) mouse (slow acetylator) genomic DNA by the polymerase chain reaction and subsequent sequencing revealed that Nat1 was identical in B6 and A mice, whereas Nat2 contained a single nucleotide change from adenine in B6 to thymine in A mice. This nucleotide substitution changes the deduced amino acid at position 99 from asparagine in B6 to isoleucine in A mice. Hydropathy analysis revealed that this amino acid change alters the hydropathy of the flanking peptide segment in NAT2 from hydrophilic in the B6 mouse to hydrophobic in the A mouse. The amino acid change occurs in a region of the gene where no polymorphism has yet been reported in human or rabbit NAT2 and may represent an important structural domain for N-acetyltransferase activity. Nat1 and Nat2 have the same 5' to 3' orientation in the B6 mouse; the two genes are separated by approximately 9 kilobases, with Nat1 located 5' of Nat2.\n" ], "offsets": [ [ 0, 1454 ] ] } ]

[ { "id": "PMID-1875909_T1", "type": "Protein", "text": [ "Nat1" ], "offsets": [ [ 226, 230 ] ], "normalized": [] }, { "id": "PMID-1875909_T2", "type": "Protein", "text": [ "Nat2" ], "offsets": [ [ 235, 239 ] ], "normalized": [] }, { "id": "PMID-1875909_T3", "type": "Protein", "text": [ "Nat1" ], "offsets": [ [ 322, 326 ] ], "normalized": [] }, { "id": "PMID-1875909_T4", "type": "Protein", "text": [ "Nat2" ], "offsets": [ [ 331, 335 ] ], "normalized": [] }, { "id": "PMID-1875909_T5", "type": "Protein", "text": [ "Nat1" ], "offsets": [ [ 527, 531 ] ], "normalized": [] }, { "id": "PMID-1875909_T6", "type": "Protein", "text": [ "Nat2" ], "offsets": [ [ 536, 540 ] ], "normalized": [] }, { "id": "PMID-1875909_T7", "type": "Protein", "text": [ "Nat1" ], "offsets": [ [ 663, 667 ] ], "normalized": [] }, { "id": "PMID-1875909_T8", "type": "Protein", "text": [ "Nat2" ], "offsets": [ [ 708, 712 ] ], "normalized": [] }, { "id": "PMID-1875909_T9", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 1027, 1031 ] ], "normalized": [] }, { "id": "PMID-1875909_T10", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 1212, 1216 ] ], "normalized": [] }, { "id": "PMID-1875909_T11", "type": "Protein", "text": [ "Nat1" ], "offsets": [ [ 1300, 1304 ] ], "normalized": [] }, { "id": "PMID-1875909_T12", "type": "Protein", "text": [ "Nat2" ], "offsets": [ [ 1309, 1313 ] ], "normalized": [] }, { "id": "PMID-1875909_T13", "type": "Protein", "text": [ "Nat1" ], "offsets": [ [ 1429, 1433 ] ], "normalized": [] }, { "id": "PMID-1875909_T14", "type": "Protein", "text": [ "Nat2" ], "offsets": [ [ 1448, 1452 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18772114__text", "type": "abstract", "text": [ "Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis. \nHeat-shock protein 70 (HSP70) isoforms contribute to tumorigenesis through their well-documented antiapoptotic activity and via their role as cochaperones for the HSP90 molecular chaperone. HSP70 expression is induced following treatment with HSP90 inhibitors, which may attenuate the cell death effects of this class of inhibitor. Here we show that silencing either heat-shock cognate 70 (HSC70) or HSP72 expression in human cancer cell lines has no effect on HSP90 activity or cell proliferation. However, simultaneously reducing the expression of both of these isoforms induces proteasome-dependent degradation of HSP90 client proteins, G1 cell-cycle arrest, and extensive tumor-specific apoptosis. Importantly, simultaneous silencing of HSP70 isoforms in nontumorigenic cell lines does not result in comparable growth arrest or induction of apoptosis, indicating a potential therapeutic window.\n" ], "offsets": [ [ 0, 996 ] ] } ]

[ { "id": "PMID-18772114_T1", "type": "Protein", "text": [ "HSC70" ], "offsets": [ [ 18, 23 ] ], "normalized": [] }, { "id": "PMID-18772114_T2", "type": "Protein", "text": [ "HSP72" ], "offsets": [ [ 28, 33 ] ], "normalized": [] }, { "id": "PMID-18772114_T3", "type": "Protein", "text": [ "HSP90" ], "offsets": [ [ 43, 48 ] ], "normalized": [] }, { "id": "PMID-18772114_T4", "type": "Protein", "text": [ "HSP90" ], "offsets": [ [ 260, 265 ] ], "normalized": [] }, { "id": "PMID-18772114_T5", "type": "Protein", "text": [ "HSP90" ], "offsets": [ [ 340, 345 ] ], "normalized": [] }, { "id": "PMID-18772114_T6", "type": "Protein", "text": [ "heat-shock cognate 70" ], "offsets": [ [ 464, 485 ] ], "normalized": [] }, { "id": "PMID-18772114_T7", "type": "Protein", "text": [ "HSC70" ], "offsets": [ [ 487, 492 ] ], "normalized": [] }, { "id": "PMID-18772114_T8", "type": "Protein", "text": [ "HSP72" ], "offsets": [ [ 497, 502 ] ], "normalized": [] }, { "id": "PMID-18772114_T9", "type": "Protein", "text": [ "HSP90" ], "offsets": [ [ 558, 563 ] ], "normalized": [] }, { "id": "PMID-18772114_T10", "type": "Protein", "text": [ "HSP90" ], "offsets": [ [ 714, 719 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-18772114_1", "entity_ids": [ "PMID-18772114_T6", "PMID-18772114_T7" ] } ]

[]

[ { "id": "PMID-18784257__text", "type": "abstract", "text": [ "MDM2 E3 ubiquitin ligase mediates UT-A1 urea transporter ubiquitination and degradation. \nUT-A1 is the primary urea transporter in the apical plasma membrane responsible for urea reabsorption in the inner medullary collecting duct. Although the physiological function of UT-A1 has been well established, the molecular mechanisms that regulate its activity are less well understood. Analysis of the UT-A1 amino acid sequence revealed a potential MDM2 E3 ubiquitin ligase-binding motif in the large intracellular loop of UT-A1, suggesting that UT-A1 urea transporter protein may be regulated by the ubiquitin-proteasome pathway. Here, we report that UT-A1 is ubiquitinated and degraded by the proteasome but not the lysosome proteolytic pathway. Inhibition of proteasome activity causes UT-A1 cell surface accumulation and concomitantly increases urea transport activity. UT-A1 interacts directly with MDM2; the binding site is located in the NH2-terminal p53-binding region of MDM2. MDM2 mediates UT-A1 ubiquitination both in vivo and in vitro. Overexpression of MDM2 promotes UT-A1 degradation. The mechanism is likely to be physiologically important as UT-A1 ubiquitination was identified in kidney inner medullary tissue. The ubiquitin-proteasome degradation pathway provides an important novel mechanism for UT-A1 regulation.\n" ], "offsets": [ [ 0, 1329 ] ] } ]

[ { "id": "PMID-18784257_T1", "type": "Protein", "text": [ "MDM2" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-18784257_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 8, 17 ] ], "normalized": [] }, { "id": "PMID-18784257_T3", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 34, 39 ] ], "normalized": [] }, { "id": "PMID-18784257_T4", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 90, 95 ] ], "normalized": [] }, { "id": "PMID-18784257_T5", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 271, 276 ] ], "normalized": [] }, { "id": "PMID-18784257_T6", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 398, 403 ] ], "normalized": [] }, { "id": "PMID-18784257_T7", "type": "Protein", "text": [ "MDM2" ], "offsets": [ [ 445, 449 ] ], "normalized": [] }, { "id": "PMID-18784257_T8", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 453, 462 ] ], "normalized": [] }, { "id": "PMID-18784257_T9", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 519, 524 ] ], "normalized": [] }, { "id": "PMID-18784257_T10", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 542, 547 ] ], "normalized": [] }, { "id": "PMID-18784257_T11", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 597, 606 ] ], "normalized": [] }, { "id": "PMID-18784257_T12", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 648, 653 ] ], "normalized": [] }, { "id": "PMID-18784257_T13", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 785, 790 ] ], "normalized": [] }, { "id": "PMID-18784257_T14", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 870, 875 ] ], "normalized": [] }, { "id": "PMID-18784257_T15", "type": "Protein", "text": [ "MDM2" ], "offsets": [ [ 900, 904 ] ], "normalized": [] }, { "id": "PMID-18784257_T16", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 954, 957 ] ], "normalized": [] }, { "id": "PMID-18784257_T17", "type": "Protein", "text": [ "MDM2" ], "offsets": [ [ 976, 980 ] ], "normalized": [] }, { "id": "PMID-18784257_T18", "type": "Protein", "text": [ "MDM2" ], "offsets": [ [ 982, 986 ] ], "normalized": [] }, { "id": "PMID-18784257_T19", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 996, 1001 ] ], "normalized": [] }, { "id": "PMID-18784257_T20", "type": "Protein", "text": [ "MDM2" ], "offsets": [ [ 1062, 1066 ] ], "normalized": [] }, { "id": "PMID-18784257_T21", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 1076, 1081 ] ], "normalized": [] }, { "id": "PMID-18784257_T22", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 1154, 1159 ] ], "normalized": [] }, { "id": "PMID-18784257_T23", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1228, 1237 ] ], "normalized": [] }, { "id": "PMID-18784257_T24", "type": "Protein", "text": [ "UT-A1" ], "offsets": [ [ 1311, 1316 ] ], "normalized": [] } ]

[ { "id": "PMID-18784257_E1", "type": "Catalysis", "trigger": { "text": [ "mediates" ], "offsets": [ [ 25, 33 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18784257_E2" }, { "role": "Cause", "ref_id": "PMID-18784257_T1" } ] }, { "id": "PMID-18784257_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 57, 71 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18784257_T3" } ] }, { "id": "PMID-18784257_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 657, 670 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18784257_T12" } ] }, { "id": "PMID-18784257_E4", "type": "Catalysis", "trigger": { "text": [ "mediates" ], "offsets": [ [ 987, 995 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18784257_E5" }, { "role": "Cause", "ref_id": "PMID-18784257_T18" } ] }, { "id": "PMID-18784257_E5", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1002, 1016 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18784257_T19" } ] }, { "id": "PMID-18784257_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1160, 1174 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18784257_T22" } ] } ]

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[ { "id": "PMID-18799611__text", "type": "abstract", "text": [ "Effect of proliferating cell nuclear antigen ubiquitination and chromatin structure on the dynamic properties of the Y-family DNA polymerases. \nY-family DNA polymerases carry out translesion synthesis past damaged DNA. DNA polymerases (pol) eta and iota are usually uniformly distributed through the nucleus but accumulate in replication foci during S phase. DNA-damaging treatments result in an increase in S phase cells containing polymerase foci. Using photobleaching techniques, we show that poleta is highly mobile in human fibroblasts. Even when localized in replication foci, it is only transiently immobilized. Although ubiquitination of proliferating cell nuclear antigen (PCNA) is not required for the localization of poleta in foci, it results in an increased residence time in foci. poliota is even more mobile than poleta, both when uniformly distributed and when localized in foci. Kinetic modeling suggests that both poleta and poliota diffuse through the cell but that they are transiently immobilized for approximately 150 ms, with a larger proportion of poleta than poliota immobilized at any time. Treatment of cells with DRAQ5, which results in temporary opening of the chromatin structure, causes a dramatic immobilization of poleta but not poliota. Our data are consistent with a model in which the polymerases are transiently probing the DNA/chromatin. When DNA is exposed at replication forks, the polymerase residence times increase, and this is further facilitated by the ubiquitination of PCNA.\n" ], "offsets": [ [ 0, 1522 ] ] } ]

[ { "id": "PMID-18799611_T1", "type": "Protein", "text": [ "DNA polymerases (pol) eta" ], "offsets": [ [ 219, 244 ] ], "normalized": [] }, { "id": "PMID-18799611_T2", "type": "Protein", "text": [ "iota" ], "offsets": [ [ 249, 253 ] ], "normalized": [] }, { "id": "PMID-18799611_T3", "type": "Protein", "text": [ "poleta" ], "offsets": [ [ 496, 502 ] ], "normalized": [] }, { "id": "PMID-18799611_T4", "type": "Protein", "text": [ "proliferating cell nuclear antigen" ], "offsets": [ [ 646, 680 ] ], "normalized": [] }, { "id": "PMID-18799611_T5", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 682, 686 ] ], "normalized": [] }, { "id": "PMID-18799611_T6", "type": "Protein", "text": [ "poleta" ], "offsets": [ [ 728, 734 ] ], "normalized": [] }, { "id": "PMID-18799611_T7", "type": "Protein", "text": [ "poliota" ], "offsets": [ [ 795, 802 ] ], "normalized": [] }, { "id": "PMID-18799611_T8", "type": "Protein", "text": [ "poleta" ], "offsets": [ [ 828, 834 ] ], "normalized": [] }, { "id": "PMID-18799611_T9", "type": "Protein", "text": [ "poleta" ], "offsets": [ [ 932, 938 ] ], "normalized": [] }, { "id": "PMID-18799611_T10", "type": "Protein", "text": [ "poliota" ], "offsets": [ [ 943, 950 ] ], "normalized": [] }, { "id": "PMID-18799611_T11", "type": "Protein", "text": [ "poleta" ], "offsets": [ [ 1072, 1078 ] ], "normalized": [] }, { "id": "PMID-18799611_T12", "type": "Protein", "text": [ "poliota" ], "offsets": [ [ 1084, 1091 ] ], "normalized": [] }, { "id": "PMID-18799611_T13", "type": "Protein", "text": [ "poleta" ], "offsets": [ [ 1247, 1253 ] ], "normalized": [] }, { "id": "PMID-18799611_T14", "type": "Protein", "text": [ "poliota" ], "offsets": [ [ 1262, 1269 ] ], "normalized": [] }, { "id": "PMID-18799611_T15", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 1516, 1520 ] ], "normalized": [] } ]

[ { "id": "PMID-18799611_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 628, 642 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18799611_T4" } ] }, { "id": "PMID-18799611_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1498, 1512 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18799611_T15" } ] } ]

[ { "id": "PMID-18799611_1", "entity_ids": [ "PMID-18799611_T4", "PMID-18799611_T5" ] } ]

[]

[ { "id": "PMID-18805448__text", "type": "abstract", "text": [ "Ubiquitination-mediated internalization and degradation of the astroglial glutamate transporter, GLT-1. \nSodium-dependent glutamate uptake is essential for limiting excitotoxicity, and dysregulation of this process has been implicated in a wide array of neurological disorders. The majority of forebrain glutamate uptake is mediated by the astroglial glutamate transporter, GLT-1. We and others have shown that this transporter undergoes endocytosis and degradation in response to activation of protein kinase C (PKC), however, the mechanisms involved remain unclear. In the current study, transfected C6 glioma cells or primary cortical cultures were used to show that PKC activation results in incorporation of ubiquitin into GLT-1 immunoprecipitates. Mutation of all 11 lysine residues in the amino and carboxyl-terminal domains to arginine (11R) abolished this signal. Selective mutation of the seven lysine residues in the carboxyl terminus (C7K-R) did not eliminate ubiquitination, but it completely blocked PKC-dependent internalization and degradation. Two families of variants of GLT-1 were prepared with various lysine residues mutated to arginine. Analyses of these constructs indicated that redundant lysine residues in the carboxyl terminus were sufficient for the appearance of ubiquitinated product and degradation of GLT-1. Together these data define a novel mechanism by which the predominant forebrain glutamate transporter can be rapidly targeted for degradation.\n" ], "offsets": [ [ 0, 1483 ] ] } ]

[ { "id": "PMID-18805448_T1", "type": "Protein", "text": [ "GLT-1" ], "offsets": [ [ 97, 102 ] ], "normalized": [] }, { "id": "PMID-18805448_T2", "type": "Protein", "text": [ "GLT-1" ], "offsets": [ [ 374, 379 ] ], "normalized": [] }, { "id": "PMID-18805448_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 713, 722 ] ], "normalized": [] }, { "id": "PMID-18805448_T4", "type": "Protein", "text": [ "GLT-1" ], "offsets": [ [ 728, 733 ] ], "normalized": [] }, { "id": "PMID-18805448_T5", "type": "Protein", "text": [ "GLT-1" ], "offsets": [ [ 1089, 1094 ] ], "normalized": [] }, { "id": "PMID-18805448_T6", "type": "Protein", "text": [ "GLT-1" ], "offsets": [ [ 1333, 1338 ] ], "normalized": [] }, { "id": "PMID-18805448_T9", "type": "Entity", "text": [ "lysine" ], "offsets": [ [ 1213, 1219 ] ], "normalized": [] } ]

[ { "id": "PMID-18805448_E1", "type": "Ubiquitination", "trigger": { "text": [ "Ubiquitination" ], "offsets": [ [ 0, 14 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18805448_T1" } ] }, { "id": "PMID-18805448_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 972, 986 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18805448_T4" } ] }, { "id": "PMID-18805448_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 1292, 1305 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18805448_T6" }, { "role": "Site", "ref_id": "PMID-18805448_T9" } ] } ]

[]

[]

[ { "id": "PMID-18805587__text", "type": "abstract", "text": [ "Coordination changes and auto-hydroxylation of FIH-1: uncoupled O2-activation in a human hypoxia sensor. \nHypoxia sensing is the generic term for pO2-sensing in humans and other higher organisms. These cellular responses to pO2 are largely controlled by enzymes that belong to the Fe(II) alpha-ketoglutarate (alphaKG) dependent dioxygenase superfamily, including the human enzyme called the factor inhibiting HIF (FIH-1), which couples O2-activation to the hydroxylation of the hypoxia inducible factor alpha (HIFalpha). Uncoupled O2-activation by human FIH-1 was studied by exposing the resting form of FIH-1 (alphaKG + Fe)FIH-1, to air in the absence of HIFalpha. Uncoupling lead to two distinct enzyme oxidations, one a purple chromophore (lambda(max) = 583 nm) arising from enzyme auto-hydroxylation of Trp296, forming an Fe(III)-O-Trp296 chromophore [Y.-H. Chen, L.M. Comeaux, S.J. Eyles, M.J. Knapp, Chem. Commun. (2008), doi:10.1039/B809099H]; the other a yellow chromophore due to Fe(III) in the active site, which under some conditions also contained variable levels of an oxygenated surface residue (oxo)Met275. The kinetics of purple FIH-1 formation were independent of Fe(II) and alphaKG concentrations, however, product yield was saturable with increasing [alphaKG] and required excess Fe(II). Yellow FIH-1 was formed from (succinate+Fe)FIH-1, or by glycerol addition to (alphaKG+Fe)FIH-1, suggesting that glycerol could intercept the active oxidant from the FIH-1 active site and prevent hydroxylation. Both purple and yellow FIH-1 contained high-spin, rhombic Fe(III) centers, as shown by low temperature EPR. XAS indicated distorted octahedral Fe(III) geometries, with subtle differences in inner-shell ligands for yellow and purple FIH-1. EPR of Co(II)-substituted FIH-1 (alphaKG + Co)FIH-1, indicated a mixture of 5-coordinate and 6-coordinate enzyme forms, suggesting that resting FIH-1 can readily undergo uncoupled O2-activation by loss of an H2O ligand from the metal center.\n" ], "offsets": [ [ 0, 1998 ] ] } ]

[ { "id": "PMID-18805587_T1", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 47, 52 ] ], "normalized": [] }, { "id": "PMID-18805587_T2", "type": "Protein", "text": [ "factor inhibiting HIF" ], "offsets": [ [ 391, 412 ] ], "normalized": [] }, { "id": "PMID-18805587_T3", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 414, 419 ] ], "normalized": [] }, { "id": "PMID-18805587_T4", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 554, 559 ] ], "normalized": [] }, { "id": "PMID-18805587_T5", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 604, 609 ] ], "normalized": [] }, { "id": "PMID-18805587_T6", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 624, 629 ] ], "normalized": [] }, { "id": "PMID-18805587_T7", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 1145, 1150 ] ], "normalized": [] }, { "id": "PMID-18805587_T8", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 1314, 1319 ] ], "normalized": [] }, { "id": "PMID-18805587_T9", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 1350, 1355 ] ], "normalized": [] }, { "id": "PMID-18805587_T10", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 1396, 1401 ] ], "normalized": [] }, { "id": "PMID-18805587_T11", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 1472, 1477 ] ], "normalized": [] }, { "id": "PMID-18805587_T12", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 1540, 1545 ] ], "normalized": [] }, { "id": "PMID-18805587_T13", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 1749, 1754 ] ], "normalized": [] }, { "id": "PMID-18805587_T14", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 1782, 1787 ] ], "normalized": [] }, { "id": "PMID-18805587_T15", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 1802, 1807 ] ], "normalized": [] }, { "id": "PMID-18805587_T16", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 1900, 1905 ] ], "normalized": [] }, { "id": "PMID-18805587_T21", "type": "Entity", "text": [ "Trp296" ], "offsets": [ [ 807, 813 ] ], "normalized": [] }, { "id": "PMID-18805587_T22", "type": "Entity", "text": [ "active site" ], "offsets": [ [ 1478, 1489 ] ], "normalized": [] } ]

[ { "id": "PMID-18805587_E1", "type": "Hydroxylation", "trigger": { "text": [ "auto-hydroxylation" ], "offsets": [ [ 25, 43 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18805587_T1" } ] }, { "id": "PMID-18805587_E2", "type": "Catalysis", "trigger": { "text": [ "auto-hydroxylation" ], "offsets": [ [ 25, 43 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18805587_E1" }, { "role": "Cause", "ref_id": "PMID-18805587_T1" } ] }, { "id": "PMID-18805587_E3", "type": "Hydroxylation", "trigger": { "text": [ "auto-hydroxylation" ], "offsets": [ [ 785, 803 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18805587_T4" }, { "role": "Site", "ref_id": "PMID-18805587_T21" } ] }, { "id": "PMID-18805587_E4", "type": "Catalysis", "trigger": { "text": [ "auto-hydroxylation" ], "offsets": [ [ 785, 803 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18805587_E3" }, { "role": "Cause", "ref_id": "PMID-18805587_T4" } ] }, { "id": "PMID-18805587_E5", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 1502, 1515 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18805587_T11" }, { "role": "Site", "ref_id": "PMID-18805587_T22" } ] } ]

[ { "id": "PMID-18805587_1", "entity_ids": [ "PMID-18805587_T2", "PMID-18805587_T3" ] } ]

[]

[ { "id": "PMID-18815311__text", "type": "abstract", "text": [ "Crystal structure and carbohydrate analysis of Nipah virus attachment glycoprotein: a template for antiviral and vaccine design. \nTwo members of the paramyxovirus family, Nipah virus (NiV) and Hendra virus (HeV), are recent additions to a growing number of agents of emergent diseases which use bats as a natural host. Identification of ephrin-B2 and ephrin-B3 as cellular receptors for these viruses has enabled the development of immunotherapeutic reagents which prevent virus attachment and subsequent fusion. Here we present the structural analysis of the protein and carbohydrate components of the unbound viral attachment glycoprotein of NiV glycoprotein (NiV-G) at a 2.2-A resolution. Comparison with its ephrin-B2-bound form reveals that conformational changes within the envelope glycoprotein are required to achieve viral attachment. Structural differences are particularly pronounced in the 579-590 loop, a major component of the ephrin binding surface. In addition, the 236-245 loop is rather disordered in the unbound structure. We extend our structural characterization of NiV-G with mass spectrometric analysis of the carbohydrate moieties. We demonstrate that NiV-G is largely devoid of the oligomannose-type glycans that in viruses such as human immunodeficiency virus type 1 and Ebola virus influence viral tropism and the host immune response. Nevertheless, we find putative ligands for the endothelial cell lectin, LSECtin. Finally, by mapping structural conservation and glycosylation site positions from other members of the paramyxovirus family, we suggest the molecular surface involved in oligomerization. These results suggest possible pathways of virus-host interaction and strategies for the optimization of recombinant vaccines.\n" ], "offsets": [ [ 0, 1758 ] ] } ]

[ { "id": "PMID-18815311_T1", "type": "Protein", "text": [ "ephrin-B2" ], "offsets": [ [ 337, 346 ] ], "normalized": [] }, { "id": "PMID-18815311_T2", "type": "Protein", "text": [ "ephrin-B3" ], "offsets": [ [ 351, 360 ] ], "normalized": [] }, { "id": "PMID-18815311_T3", "type": "Protein", "text": [ "G" ], "offsets": [ [ 666, 667 ] ], "normalized": [] }, { "id": "PMID-18815311_T4", "type": "Protein", "text": [ "ephrin-B2" ], "offsets": [ [ 712, 721 ] ], "normalized": [] }, { "id": "PMID-18815311_T5", "type": "Protein", "text": [ "G" ], "offsets": [ [ 1091, 1092 ] ], "normalized": [] }, { "id": "PMID-18815311_T6", "type": "Protein", "text": [ "G" ], "offsets": [ [ 1180, 1181 ] ], "normalized": [] }, { "id": "PMID-18815311_T7", "type": "Protein", "text": [ "LSECtin" ], "offsets": [ [ 1435, 1442 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18823280__text", "type": "abstract", "text": [ "Synergistic induction of nuclear factor-kappaB by transforming growth factor-beta and tumour necrosis factor-alpha is mediated by protein kinase A-dependent RelA acetylation. \nThe TGF-beta (transforming growth factor-beta) pathway represents an important signalling pathway involved in regulating diverse biological processes, including cell proliferation, differentiation and inflammation. Despite the critical role for TGF-beta in inflammatory responses, its role in regulating NF-kappaB (nuclear factor-kappaB)-dependent inflammatory responses still remains unknown. In the present study we show that TGF-beta1 synergizes with proinflammatory cytokine TNF-alpha (tumour necrosis factor-alpha) to induce NF-kappaB activation and the resultant inflammatory response in vitro and in vivo. TGF-beta1 synergistically enhances TNF-alpha-induced NF-kappaB DNA binding activity via induction of RelA acetylation. Moreover, synergistic enhancement of TNF-alpha-induced RelA acetylation and DNA-binding activity by TGF-beta1 is mediated by PKA (protein kinase A). Thus the present study reveals a novel role for TGF-beta in inflammatory responses and provides new insight into the regulation of NF-kappaB by TGF-beta signalling.\n" ], "offsets": [ [ 0, 1222 ] ] } ]

[ { "id": "PMID-18823280_T1", "type": "Protein", "text": [ "tumour necrosis factor-alpha" ], "offsets": [ [ 86, 114 ] ], "normalized": [] }, { "id": "PMID-18823280_T2", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 157, 161 ] ], "normalized": [] }, { "id": "PMID-18823280_T3", "type": "Protein", "text": [ "TGF-beta1" ], "offsets": [ [ 604, 613 ] ], "normalized": [] }, { "id": "PMID-18823280_T4", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 655, 664 ] ], "normalized": [] }, { "id": "PMID-18823280_T5", "type": "Protein", "text": [ "tumour necrosis factor-alpha" ], "offsets": [ [ 666, 694 ] ], "normalized": [] }, { "id": "PMID-18823280_T6", "type": "Protein", "text": [ "TGF-beta1" ], "offsets": [ [ 789, 798 ] ], "normalized": [] }, { "id": "PMID-18823280_T7", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 824, 833 ] ], "normalized": [] }, { "id": "PMID-18823280_T8", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 890, 894 ] ], "normalized": [] }, { "id": "PMID-18823280_T9", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 945, 954 ] ], "normalized": [] }, { "id": "PMID-18823280_T10", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 963, 967 ] ], "normalized": [] }, { "id": "PMID-18823280_T11", "type": "Protein", "text": [ "TGF-beta1" ], "offsets": [ [ 1008, 1017 ] ], "normalized": [] } ]

[ { "id": "PMID-18823280_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 162, 173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18823280_T2" } ] }, { "id": "PMID-18823280_E2", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 895, 906 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18823280_T8" } ] }, { "id": "PMID-18823280_E3", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 968, 979 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18823280_T10" } ] } ]

[ { "id": "PMID-18823280_1", "entity_ids": [ "PMID-18823280_T4", "PMID-18823280_T5" ] } ]

[]

[ { "id": "PMID-18828177__text", "type": "abstract", "text": [ "Production, purification, and characterization of human alpha1 proteinase inhibitor from Aspergillus niger. \nHuman alpha one proteinase inhibitor (alpha1-PI) was cloned and expressed in Aspergillus niger, filamentious fungus that can grow in defined media and can perform glycosylation. Submerged culture conditions were established using starch as carbon source, 30% dissolved oxygen concentration, pH 7.0 and 28 degrees C. Eight milligrams per liter of active alpha1-PI were secreted to the growth media in about 40 h. Controlling the protein proteolysis was found to be an important factor in the production. The effects of various carbon sources, pH and temperature on the production and stability of the protein were tested and the product was purified and characterized. Two molecular weights variants of the recombinant alpha1-PI were produced by the fungus; the difference is attributed to the glycosylated part of the molecule. The two glycoproteins were treated with PNGAse F and the released glycans were analyzed by HPAEC, MALDI/TOF-MS, NSI-MS(n), and GC-MS. The MALDI and NSI- full MS spectra of permethylated N-glycans revealed that the N-glycans of both variants contain a series of high-mannose type glycans with 5-20 hexose units. Monosaccharide analysis showed that these were composed of N-acetylglucos-amine, mannose, and galactose. Linkage analysis revealed that the galactosyl component was in the furanoic conformation, which was attaching in a terminal non-reducing position. The Galactofuranose-containing high-mannnose type N-glycans are typical structures, which recently have been found as part of several glycoproteins produced by Aspergillus niger.\n" ], "offsets": [ [ 0, 1679 ] ] } ]

[ { "id": "PMID-18828177_T1", "type": "Protein", "text": [ "alpha1 proteinase inhibitor" ], "offsets": [ [ 56, 83 ] ], "normalized": [] }, { "id": "PMID-18828177_T2", "type": "Protein", "text": [ "alpha one proteinase inhibitor" ], "offsets": [ [ 115, 145 ] ], "normalized": [] }, { "id": "PMID-18828177_T3", "type": "Protein", "text": [ "alpha1-PI" ], "offsets": [ [ 147, 156 ] ], "normalized": [] }, { "id": "PMID-18828177_T4", "type": "Protein", "text": [ "alpha1-PI" ], "offsets": [ [ 462, 471 ] ], "normalized": [] }, { "id": "PMID-18828177_T5", "type": "Protein", "text": [ "alpha1-PI" ], "offsets": [ [ 827, 836 ] ], "normalized": [] }, { "id": "PMID-18828177_T6", "type": "Protein", "text": [ "PNGAse F" ], "offsets": [ [ 977, 985 ] ], "normalized": [] } ]

[ { "id": "PMID-18828177_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 272, 285 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18828177_T2" } ] }, { "id": "PMID-18828177_E2", "type": "Glycosylation", "trigger": { "text": [ "glycosylated" ], "offsets": [ [ 902, 914 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18828177_T5" } ] } ]

[ { "id": "PMID-18828177_1", "entity_ids": [ "PMID-18828177_T2", "PMID-18828177_T3" ] } ]

[]

[ { "id": "PMID-18830757__text", "type": "abstract", "text": [ "Predictive value of expression and promoter hypermethylation of XAF1 in hepatitis B virus-associated hepatocellular carcinoma treated with transplantation. \nBACKGROUND: Transcriptional regulation of the putative tumor suppressor gene X-linked inhibitor of apoptosis protein-associated factor 1 (XAF1) by promoter methylation has been related to tumor progression in gastric and bladder cancer. The aim of this study was to investigate the methylation status and expression level of XAF1 in human hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) treated with liver transplantation (LT), and to evaluate potential predictive value for tumor recurrence. METHODS: The expression level and methylation status of XAF1 in three liver cancer cell lines (SMMC-7721, HepG2, and Hep3B) and 65 cases of HBV-associated HCC following LT were analyzed by RT-PCR (RT, reverse-transcriptase), immunohistochemistry, and methylation-specific polymerase chain reaction (PCR). RESULTS: XAF1 transcripts were not observed or present at low levels in liver cancer cell lines and were restored by treatment with demethylating agent 5-aza-2'-deoxycytidine (5-Aza-dC). In vivo, methylation status was associated with protein level of XAF1 (P < 0.001) and serum level of alpha-fetoprotein (AFP) (P = 0.009). The expression pattern of XAF1 was associated with portal vein tumor thrombi (PVTT), preoperative AFP level, tumor size, and recurrence. Multivariate analysis revealed that expression level of XAF1 was an independent factor for predicting recurrence-free survival [hazard ratio 0.237, 95% confidence interval (CI) 0.095-0.592, P = 0.002]. However, no significant association was found between methylation status and the risk of tumor recurrence. CONCLUSION: Promoter hypermethylation is a critical, but not the sole, mechanism for gene silencing of XAF1 in HCC. Protein level of XAF1 may serve as a potential biomarker for tumor recurrence after LT.\n" ], "offsets": [ [ 0, 1948 ] ] } ]

[ { "id": "PMID-18830757_T1", "type": "Protein", "text": [ "XAF1" ], "offsets": [ [ 64, 68 ] ], "normalized": [] }, { "id": "PMID-18830757_T2", "type": "Protein", "text": [ "X-linked inhibitor of apoptosis protein-associated factor 1" ], "offsets": [ [ 234, 293 ] ], "normalized": [] }, { "id": "PMID-18830757_T3", "type": "Protein", "text": [ "XAF1" ], "offsets": [ [ 295, 299 ] ], "normalized": [] }, { "id": "PMID-18830757_T4", "type": "Protein", "text": [ "XAF1" ], "offsets": [ [ 482, 486 ] ], "normalized": [] }, { "id": "PMID-18830757_T5", "type": "Protein", "text": [ "XAF1" ], "offsets": [ [ 724, 728 ] ], "normalized": [] }, { "id": "PMID-18830757_T6", "type": "Protein", "text": [ "RT" ], "offsets": [ [ 865, 867 ] ], "normalized": [] }, { "id": "PMID-18830757_T7", "type": "Protein", "text": [ "reverse-transcriptase" ], "offsets": [ [ 869, 890 ] ], "normalized": [] }, { "id": "PMID-18830757_T8", "type": "Protein", "text": [ "XAF1" ], "offsets": [ [ 982, 986 ] ], "normalized": [] }, { "id": "PMID-18830757_T9", "type": "Protein", "text": [ "XAF1" ], "offsets": [ [ 1225, 1229 ] ], "normalized": [] }, { "id": "PMID-18830757_T10", "type": "Protein", "text": [ "alpha-fetoprotein" ], "offsets": [ [ 1261, 1278 ] ], "normalized": [] }, { "id": "PMID-18830757_T11", "type": "Protein", "text": [ "AFP" ], "offsets": [ [ 1280, 1283 ] ], "normalized": [] }, { "id": "PMID-18830757_T12", "type": "Protein", "text": [ "XAF1" ], "offsets": [ [ 1324, 1328 ] ], "normalized": [] }, { "id": "PMID-18830757_T13", "type": "Protein", "text": [ "XAF1" ], "offsets": [ [ 1491, 1495 ] ], "normalized": [] }, { "id": "PMID-18830757_T14", "type": "Protein", "text": [ "XAF1" ], "offsets": [ [ 1847, 1851 ] ], "normalized": [] }, { "id": "PMID-18830757_T15", "type": "Protein", "text": [ "XAF1" ], "offsets": [ [ 1877, 1881 ] ], "normalized": [] }, { "id": "PMID-18830757_T16", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 35, 43 ] ], "normalized": [] }, { "id": "PMID-18830757_T18", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 304, 312 ] ], "normalized": [] }, { "id": "PMID-18830757_T23", "type": "Entity", "text": [ "Promoter" ], "offsets": [ [ 1756, 1764 ] ], "normalized": [] } ]

[ { "id": "PMID-18830757_E1", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 44, 60 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18830757_T1" }, { "role": "Site", "ref_id": "PMID-18830757_T16" } ] }, { "id": "PMID-18830757_E2", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 313, 324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18830757_T2" }, { "role": "Site", "ref_id": "PMID-18830757_T18" } ] }, { "id": "PMID-18830757_E3", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 439, 450 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18830757_T4" } ] }, { "id": "PMID-18830757_E4", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 702, 713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18830757_T5" } ] }, { "id": "PMID-18830757_E5", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1169, 1180 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18830757_T9" } ] }, { "id": "PMID-18830757_E6", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 1765, 1781 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18830757_T14" }, { "role": "Site", "ref_id": "PMID-18830757_T23" } ] } ]

[ { "id": "PMID-18830757_1", "entity_ids": [ "PMID-18830757_T2", "PMID-18830757_T3" ] }, { "id": "PMID-18830757_2", "entity_ids": [ "PMID-18830757_T6", "PMID-18830757_T7" ] }, { "id": "PMID-18830757_3", "entity_ids": [ "PMID-18830757_T10", "PMID-18830757_T11" ] } ]

[]

[ { "id": "PMID-18834144__text", "type": "abstract", "text": [ "Biochemical characterization of human prolyl hydroxylase domain protein 2 variants associated with erythrocytosis. \nProlyl hydroxylase domain proteins (PHD isozymes 1-3) regulate levels of the alpha-subunit of the hypoxia inducible factor (HIF) through proline hydroxylation, earmarking HIFalpha for proteosome-mediated degradation. Under hypoxic conditions, HIF stabilization leads to enhanced transcription and regulation of a multitude of processes, including erythropoiesis. Herein, we examine the biochemical characterization of PHD2 variants, Arg371His and Pro317Arg, identified from patients with familial erythrocytosis. The variants display differential effects on catalytic rate and substrate binding, implying that partial inhibition or selective inhibition with regard to HIFalpha isoforms of PHD2 could result in the phenotype displayed by patients with familial erythrocytosis.\n" ], "offsets": [ [ 0, 892 ] ] } ]

[ { "id": "PMID-18834144_T1", "type": "Protein", "text": [ "prolyl hydroxylase domain protein 2" ], "offsets": [ [ 38, 73 ] ], "normalized": [] }, { "id": "PMID-18834144_T2", "type": "Protein", "text": [ "PHD isozymes 1" ], "offsets": [ [ 152, 166 ] ], "normalized": [] }, { "id": "PMID-18834144_T3", "type": "Protein", "text": [ "3" ], "offsets": [ [ 167, 168 ] ], "normalized": [] }, { "id": "PMID-18834144_T4", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 534, 538 ] ], "normalized": [] }, { "id": "PMID-18834144_T5", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 805, 809 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18849490__text", "type": "abstract", "text": [ "Histone H2B monoubiquitination in the chromatin of FLOWERING LOCUS C regulates flowering time in Arabidopsis. \nUbiquitination is one of many known histone modifications that regulate gene expression. Here, we examine the Arabidopsis thaliana homologs of the yeast E2 and E3 enzymes responsible for H2B monoubiquitination (H2Bub1). Arabidopsis has two E3 homologs (HISTONE MONOUBIQUITINATION1 [HUB1] and HUB2) and three E2 homologs (UBIQUITIN CARRIER PROTEIN [UBC1] to UBC3). hub1 and hub2 mutants show the loss of H2Bub1 and early flowering. By contrast, single ubc1, ubc2, or ubc3 mutants show no flowering defect; only ubc1 ubc2 double mutants, and not double mutants with ubc3, show early flowering and H2Bub1 defects. This suggests that ubc1 and ubc2 are redundant, but ubc3 is not involved in flowering time regulation. Protein interaction analysis showed that HUB1 and HUB2 interact with each other and with UBC1 and UBC2, as well as self-associating. The expression of FLOWERING LOCUS C (FLC) and its homologs was repressed in hub1, hub2, and ubc1 ubc2 mutant plants. Association of H2Bub1 with the chromatin of FLC clade genes depended on UBC1,2 and HUB1,2, as did the dynamics of methylated histones H3K4me3 and H3K36me2. The monoubiquitination of H2B via UBC1,2 and HUB1,2 represents a novel form of histone modification that is involved in flowering time regulation.\n" ], "offsets": [ [ 0, 1378 ] ] } ]

[ { "id": "PMID-18849490_T1", "type": "Protein", "text": [ "Histone H2B" ], "offsets": [ [ 0, 11 ] ], "normalized": [] }, { "id": "PMID-18849490_T2", "type": "Protein", "text": [ "FLOWERING LOCUS C" ], "offsets": [ [ 51, 68 ] ], "normalized": [] }, { "id": "PMID-18849490_T3", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 147, 154 ] ], "normalized": [] }, { "id": "PMID-18849490_T4", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 298, 301 ] ], "normalized": [] }, { "id": "PMID-18849490_T5", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 322, 325 ] ], "normalized": [] }, { "id": "PMID-18849490_T6", "type": "Protein", "text": [ "HISTONE MONOUBIQUITINATION1" ], "offsets": [ [ 364, 391 ] ], "normalized": [] }, { "id": "PMID-18849490_T7", "type": "Protein", "text": [ "HUB1" ], "offsets": [ [ 393, 397 ] ], "normalized": [] }, { "id": "PMID-18849490_T8", "type": "Protein", "text": [ "HUB2" ], "offsets": [ [ 403, 407 ] ], "normalized": [] }, { "id": "PMID-18849490_T9", "type": "Protein", "text": [ "UBC1" ], "offsets": [ [ 459, 463 ] ], "normalized": [] }, { "id": "PMID-18849490_T10", "type": "Protein", "text": [ "UBC3" ], "offsets": [ [ 468, 472 ] ], "normalized": [] }, { "id": "PMID-18849490_T11", "type": "Protein", "text": [ "hub1" ], "offsets": [ [ 475, 479 ] ], "normalized": [] }, { "id": "PMID-18849490_T12", "type": "Protein", "text": [ "hub2" ], "offsets": [ [ 484, 488 ] ], "normalized": [] }, { "id": "PMID-18849490_T13", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 514, 517 ] ], "normalized": [] }, { "id": "PMID-18849490_T14", "type": "Protein", "text": [ "ubc1" ], "offsets": [ [ 562, 566 ] ], "normalized": [] }, { "id": "PMID-18849490_T15", "type": "Protein", "text": [ "ubc2" ], "offsets": [ [ 568, 572 ] ], "normalized": [] }, { "id": "PMID-18849490_T16", "type": "Protein", "text": [ "ubc3" ], "offsets": [ [ 577, 581 ] ], "normalized": [] }, { "id": "PMID-18849490_T17", "type": "Protein", "text": [ "ubc1" ], "offsets": [ [ 621, 625 ] ], "normalized": [] }, { "id": "PMID-18849490_T18", "type": "Protein", "text": [ "ubc2" ], "offsets": [ [ 626, 630 ] ], "normalized": [] }, { "id": "PMID-18849490_T19", "type": "Protein", "text": [ "ubc3" ], "offsets": [ [ 675, 679 ] ], "normalized": [] }, { "id": "PMID-18849490_T20", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 706, 709 ] ], "normalized": [] }, { "id": "PMID-18849490_T21", "type": "Protein", "text": [ "ubc1" ], "offsets": [ [ 741, 745 ] ], "normalized": [] }, { "id": "PMID-18849490_T22", "type": "Protein", "text": [ "ubc2" ], "offsets": [ [ 750, 754 ] ], "normalized": [] }, { "id": "PMID-18849490_T23", "type": "Protein", "text": [ "ubc3" ], "offsets": [ [ 774, 778 ] ], "normalized": [] }, { "id": "PMID-18849490_T24", "type": "Protein", "text": [ "HUB1" ], "offsets": [ [ 866, 870 ] ], "normalized": [] }, { "id": "PMID-18849490_T25", "type": "Protein", "text": [ "HUB2" ], "offsets": [ [ 875, 879 ] ], "normalized": [] }, { "id": "PMID-18849490_T26", "type": "Protein", "text": [ "UBC1" ], "offsets": [ [ 914, 918 ] ], "normalized": [] }, { "id": "PMID-18849490_T27", "type": "Protein", "text": [ "UBC2" ], "offsets": [ [ 923, 927 ] ], "normalized": [] }, { "id": "PMID-18849490_T28", "type": "Protein", "text": [ "FLOWERING LOCUS C" ], "offsets": [ [ 976, 993 ] ], "normalized": [] }, { "id": "PMID-18849490_T29", "type": "Protein", "text": [ "FLC" ], "offsets": [ [ 995, 998 ] ], "normalized": [] }, { "id": "PMID-18849490_T30", "type": "Protein", "text": [ "hub1" ], "offsets": [ [ 1034, 1038 ] ], "normalized": [] }, { "id": "PMID-18849490_T31", "type": "Protein", "text": [ "hub2" ], "offsets": [ [ 1040, 1044 ] ], "normalized": [] }, { "id": "PMID-18849490_T32", "type": "Protein", "text": [ "ubc1" ], "offsets": [ [ 1050, 1054 ] ], "normalized": [] }, { "id": "PMID-18849490_T33", "type": "Protein", "text": [ "ubc2" ], "offsets": [ [ 1055, 1059 ] ], "normalized": [] }, { "id": "PMID-18849490_T34", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 1090, 1093 ] ], "normalized": [] }, { "id": "PMID-18849490_T35", "type": "Protein", "text": [ "FLC" ], "offsets": [ [ 1119, 1122 ] ], "normalized": [] }, { "id": "PMID-18849490_T36", "type": "Protein", "text": [ "UBC1" ], "offsets": [ [ 1147, 1151 ] ], "normalized": [] }, { "id": "PMID-18849490_T37", "type": "Protein", "text": [ "2" ], "offsets": [ [ 1152, 1153 ] ], "normalized": [] }, { "id": "PMID-18849490_T38", "type": "Protein", "text": [ "HUB1" ], "offsets": [ [ 1158, 1162 ] ], "normalized": [] }, { "id": "PMID-18849490_T39", "type": "Protein", "text": [ "2" ], "offsets": [ [ 1163, 1164 ] ], "normalized": [] }, { "id": "PMID-18849490_T40", "type": "Protein", "text": [ "histones H3" ], "offsets": [ [ 1200, 1211 ] ], "normalized": [] }, { "id": "PMID-18849490_T41", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1221, 1223 ] ], "normalized": [] }, { "id": "PMID-18849490_T42", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 1257, 1260 ] ], "normalized": [] }, { "id": "PMID-18849490_T43", "type": "Protein", "text": [ "UBC1" ], "offsets": [ [ 1265, 1269 ] ], "normalized": [] }, { "id": "PMID-18849490_T44", "type": "Protein", "text": [ "2" ], "offsets": [ [ 1270, 1271 ] ], "normalized": [] }, { "id": "PMID-18849490_T45", "type": "Protein", "text": [ "HUB1" ], "offsets": [ [ 1276, 1280 ] ], "normalized": [] }, { "id": "PMID-18849490_T46", "type": "Protein", "text": [ "2" ], "offsets": [ [ 1281, 1282 ] ], "normalized": [] }, { "id": "PMID-18849490_T47", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1310, 1317 ] ], "normalized": [] }, { "id": "PMID-18849490_T52", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 1211, 1213 ] ], "normalized": [] }, { "id": "PMID-18849490_T53", "type": "Entity", "text": [ "K36" ], "offsets": [ [ 1223, 1226 ] ], "normalized": [] } ]

[ { "id": "PMID-18849490_E1", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitination" ], "offsets": [ [ 12, 30 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18849490_T1" } ] }, { "id": "PMID-18849490_E2", "type": "Ubiquitination", "trigger": { "text": [ "Ubiquitination" ], "offsets": [ [ 111, 125 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18849490_T3" } ] }, { "id": "PMID-18849490_E3", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitination" ], "offsets": [ [ 302, 320 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18849490_T4" } ] }, { "id": "PMID-18849490_E4", "type": "Methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1189, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18849490_T40" }, { "role": "Site", "ref_id": "PMID-18849490_T52" }, { "role": "Contextgene", "ref_id": "PMID-18849490_T35" } ] }, { "id": "PMID-18849490_E5", "type": "Methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1189, 1199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18849490_T41" }, { "role": "Site", "ref_id": "PMID-18849490_T53" }, { "role": "Contextgene", "ref_id": "PMID-18849490_T35" } ] }, { "id": "PMID-18849490_E6", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitination" ], "offsets": [ [ 1235, 1253 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18849490_T42" } ] } ]

[ { "id": "PMID-18849490_1", "entity_ids": [ "PMID-18849490_T6", "PMID-18849490_T7" ] }, { "id": "PMID-18849490_2", "entity_ids": [ "PMID-18849490_T28", "PMID-18849490_T29" ] } ]

[]

[ { "id": "PMID-18851979__text", "type": "abstract", "text": [ "RBBP6 interacts with multifunctional protein YB-1 through its RING finger domain, leading to ubiquitination and proteosomal degradation of YB-1. \nRBBP6 (retinoblastoma binding protein 6) is a 250-kDa multifunctional protein that interacts with both p53 and pRb and has been implicated in mRNA processing. It has also been identified as a putative E3 ubiquitin ligase due to the presence of a RING finger domain, although no substrate has been identified up to now. Using the RING finger domain as bait in a yeast two-hybrid screen, we identified YB-1 (Y-box binding protein 1) as a binding partner of RBBP6, localising the interaction to the last 62 residues of YB-1. We showed, furthermore, that both full-length RBBP6 and the isolated RING finger domain were able to ubiquitinate YB-1, resulting in its degradation in the proteosome. As a result, RBBP6 was able to suppress the levels of YB-1 in vivo and to reduce its transactivational ability. In the light of the important role that YB-1 appears to play in tumourigenesis, our results suggest that RBBP6 may be a relevant target for therapeutic drugs aimed at modifying the activity of YB-1.\n" ], "offsets": [ [ 0, 1147 ] ] } ]

[ { "id": "PMID-18851979_T1", "type": "Protein", "text": [ "RBBP6" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-18851979_T2", "type": "Protein", "text": [ "YB-1" ], "offsets": [ [ 45, 49 ] ], "normalized": [] }, { "id": "PMID-18851979_T3", "type": "Protein", "text": [ "YB-1" ], "offsets": [ [ 139, 143 ] ], "normalized": [] }, { "id": "PMID-18851979_T4", "type": "Protein", "text": [ "RBBP6" ], "offsets": [ [ 146, 151 ] ], "normalized": [] }, { "id": "PMID-18851979_T5", "type": "Protein", "text": [ "retinoblastoma binding protein 6" ], "offsets": [ [ 153, 185 ] ], "normalized": [] }, { "id": "PMID-18851979_T6", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 249, 252 ] ], "normalized": [] }, { "id": "PMID-18851979_T7", "type": "Protein", "text": [ "pRb" ], "offsets": [ [ 257, 260 ] ], "normalized": [] }, { "id": "PMID-18851979_T8", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 350, 359 ] ], "normalized": [] }, { "id": "PMID-18851979_T9", "type": "Protein", "text": [ "YB-1" ], "offsets": [ [ 546, 550 ] ], "normalized": [] }, { "id": "PMID-18851979_T10", "type": "Protein", "text": [ "Y-box binding protein 1" ], "offsets": [ [ 552, 575 ] ], "normalized": [] }, { "id": "PMID-18851979_T11", "type": "Protein", "text": [ "RBBP6" ], "offsets": [ [ 601, 606 ] ], "normalized": [] }, { "id": "PMID-18851979_T12", "type": "Protein", "text": [ "YB-1" ], "offsets": [ [ 662, 666 ] ], "normalized": [] }, { "id": "PMID-18851979_T13", "type": "Protein", "text": [ "RBBP6" ], "offsets": [ [ 714, 719 ] ], "normalized": [] }, { "id": "PMID-18851979_T14", "type": "Protein", "text": [ "YB-1" ], "offsets": [ [ 782, 786 ] ], "normalized": [] }, { "id": "PMID-18851979_T15", "type": "Protein", "text": [ "RBBP6" ], "offsets": [ [ 849, 854 ] ], "normalized": [] }, { "id": "PMID-18851979_T16", "type": "Protein", "text": [ "YB-1" ], "offsets": [ [ 890, 894 ] ], "normalized": [] }, { "id": "PMID-18851979_T17", "type": "Protein", "text": [ "YB-1" ], "offsets": [ [ 988, 992 ] ], "normalized": [] }, { "id": "PMID-18851979_T18", "type": "Protein", "text": [ "RBBP6" ], "offsets": [ [ 1053, 1058 ] ], "normalized": [] }, { "id": "PMID-18851979_T19", "type": "Protein", "text": [ "YB-1" ], "offsets": [ [ 1141, 1145 ] ], "normalized": [] } ]

[ { "id": "PMID-18851979_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinate" ], "offsets": [ [ 769, 781 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18851979_T14" } ] }, { "id": "PMID-18851979_E2", "type": "Catalysis", "trigger": { "text": [ "ubiquitinate" ], "offsets": [ [ 769, 781 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18851979_E1" }, { "role": "Cause", "ref_id": "PMID-18851979_T13" } ] } ]

[ { "id": "PMID-18851979_1", "entity_ids": [ "PMID-18851979_T4", "PMID-18851979_T5" ] }, { "id": "PMID-18851979_2", "entity_ids": [ "PMID-18851979_T9", "PMID-18851979_T10" ] } ]

[]

[ { "id": "PMID-18854435__text", "type": "abstract", "text": [ "Abnormal proteins can form aggresome in yeast: aggresome-targeting signals and components of the machinery. \nIn mammalian cells, abnormal proteins that escape proteasome-dependent degradation form small aggregates that can be transported into a centrosome-associated structure, called an aggresome. Here we demonstrate that in yeast a single aggregate formed by the huntingtin exon 1 with an expanded polyglutamine domain (103QP) represents a bona fide aggresome that colocalizes with the spindle pole body (the yeast centrosome) in a microtubule-dependent fashion. Since a polypeptide lacking the proline-rich region (P-region) of huntingtin (103Q) cannot form aggresomes, this domain serves as an aggresome-targeting signal. Coexpression of 103Q with 25QP, a soluble polypeptide that also carries the P-region, led to the recruitment of 103Q to the aggresome via formation of hetero-oligomers, indicating the aggresome targeting in trans. To identify additional factors involved in aggresome formation and targeting, we purified 103QP aggresomes and 103Q aggregates and identified the associated proteins using mass spectrometry. Among the aggresome-associated proteins we identified, Cdc48 (VCP/p97) and its cofactors, Ufd1 and Nlp4, were shown genetically to be essential for aggresome formation. The 14-3-3 protein, Bmh1, was also found to be critical for aggresome targeting. Its interaction with the huntingtin fragment and its role in aggresome formation required the huntingtin N-terminal N17 domain, adjacent to the polyQ domain. Accordingly, the huntingtin N17 domain, along with the P-region, plays a role in aggresome targeting. We also present direct genetic evidence for the protective role of aggresomes by demonstrating genetically that aggresome targeting of polyglutamine polypeptides relieves their toxicity.\n" ], "offsets": [ [ 0, 1829 ] ] } ]

[ { "id": "PMID-18854435_T1", "type": "Protein", "text": [ "huntingtin" ], "offsets": [ [ 366, 376 ] ], "normalized": [] }, { "id": "PMID-18854435_T2", "type": "Protein", "text": [ "huntingtin" ], "offsets": [ [ 632, 642 ] ], "normalized": [] }, { "id": "PMID-18854435_T3", "type": "Protein", "text": [ "Cdc48" ], "offsets": [ [ 1187, 1192 ] ], "normalized": [] }, { "id": "PMID-18854435_T4", "type": "Protein", "text": [ "VCP" ], "offsets": [ [ 1194, 1197 ] ], "normalized": [] }, { "id": "PMID-18854435_T5", "type": "Protein", "text": [ "p97" ], "offsets": [ [ 1198, 1201 ] ], "normalized": [] }, { "id": "PMID-18854435_T6", "type": "Protein", "text": [ "Ufd1" ], "offsets": [ [ 1222, 1226 ] ], "normalized": [] }, { "id": "PMID-18854435_T7", "type": "Protein", "text": [ "Nlp4" ], "offsets": [ [ 1231, 1235 ] ], "normalized": [] }, { "id": "PMID-18854435_T8", "type": "Protein", "text": [ "Bmh1" ], "offsets": [ [ 1321, 1325 ] ], "normalized": [] }, { "id": "PMID-18854435_T9", "type": "Protein", "text": [ "huntingtin" ], "offsets": [ [ 1407, 1417 ] ], "normalized": [] }, { "id": "PMID-18854435_T10", "type": "Protein", "text": [ "huntingtin" ], "offsets": [ [ 1476, 1486 ] ], "normalized": [] }, { "id": "PMID-18854435_T11", "type": "Protein", "text": [ "huntingtin" ], "offsets": [ [ 1557, 1567 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-18854435_1", "entity_ids": [ "PMID-18854435_T3", "PMID-18854435_T4", "PMID-18854435_T5" ] } ]

[]

[ { "id": "PMID-18936059__text", "type": "abstract", "text": [ "Proteomics-based identification of novel factor inhibiting hypoxia-inducible factor (FIH) substrates indicates widespread asparaginyl hydroxylation of ankyrin repeat domain-containing proteins. \nPost-translational hydroxylation has been considered an unusual modification on intracellular proteins. However, following the recognition that oxygen-sensitive prolyl and asparaginyl hydroxylation are central to the regulation of the transcription factor hypoxia-inducible factor (HIF), interest has centered on the possibility that these enzymes may have other substrates in the proteome. In support of this certain ankyrin repeat domain (ARD)-containing proteins, including members of the IkappaB and Notch families, have been identified as alternative substrates of the HIF asparaginyl hydroxylase factor inhibiting HIF (FIH). Although these findings imply a potentially broad range of substrates for FIH, the precise extent of this range has been difficult to determine because of the difficulty of capturing transient enzyme-substrate interactions. Here we describe the use of pharmacological \"substrate trapping\" together with stable isotope labeling by amino acids in cell culture (SILAC) technology to stabilize and identify potential FIH-substrate interactions by mass spectrometry. To pursue these potential FIH substrates we used conventional data-directed tandem MS together with alternating low/high collision energy tandem MS to assign and quantitate hydroxylation at target asparaginyl residues. Overall the work has defined 13 new FIH-dependent hydroxylation sites with a degenerate consensus corresponding to that of the ankyrin repeat and a range of ARD-containing proteins as actual and potential substrates for FIH. Several ARD-containing proteins were multiply hydroxylated, and detailed studies of one, Tankyrase-2, revealed eight sites that were differentially sensitive to FIH-catalyzed hydroxylation. These findings indicate that asparaginyl hydroxylation is likely to be widespread among the approximately 300 ARD-containing species in the human proteome.\n" ], "offsets": [ [ 0, 2078 ] ] } ]

[ { "id": "PMID-18936059_T1", "type": "Protein", "text": [ "factor inhibiting hypoxia-inducible factor" ], "offsets": [ [ 41, 83 ] ], "normalized": [] }, { "id": "PMID-18936059_T2", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 85, 88 ] ], "normalized": [] }, { "id": "PMID-18936059_T3", "type": "Protein", "text": [ "HIF asparaginyl hydroxylase" ], "offsets": [ [ 769, 796 ] ], "normalized": [] }, { "id": "PMID-18936059_T4", "type": "Protein", "text": [ "factor inhibiting HIF" ], "offsets": [ [ 797, 818 ] ], "normalized": [] }, { "id": "PMID-18936059_T5", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 820, 823 ] ], "normalized": [] }, { "id": "PMID-18936059_T6", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 900, 903 ] ], "normalized": [] }, { "id": "PMID-18936059_T7", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1239, 1242 ] ], "normalized": [] }, { "id": "PMID-18936059_T8", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1314, 1317 ] ], "normalized": [] }, { "id": "PMID-18936059_T9", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1543, 1546 ] ], "normalized": [] }, { "id": "PMID-18936059_T10", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1727, 1730 ] ], "normalized": [] }, { "id": "PMID-18936059_T11", "type": "Protein", "text": [ "Tankyrase-2" ], "offsets": [ [ 1821, 1832 ] ], "normalized": [] }, { "id": "PMID-18936059_T12", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1893, 1896 ] ], "normalized": [] }, { "id": "PMID-18936059_T13", "type": "Entity", "text": [ "eight sites" ], "offsets": [ [ 1843, 1854 ] ], "normalized": [] } ]

[ { "id": "PMID-18936059_E1", "type": "Catalysis", "trigger": { "text": [ "catalyzed" ], "offsets": [ [ 1897, 1906 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18936059_E2" }, { "role": "Cause", "ref_id": "PMID-18936059_T12" } ] }, { "id": "PMID-18936059_E2", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 1907, 1920 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18936059_T11" }, { "role": "Site", "ref_id": "PMID-18936059_T13" } ] } ]

[ { "id": "PMID-18936059_1", "entity_ids": [ "PMID-18936059_T1", "PMID-18936059_T2" ] }, { "id": "PMID-18936059_2", "entity_ids": [ "PMID-18936059_T3", "PMID-18936059_T4", "PMID-18936059_T5" ] } ]

[]

[ { "id": "PMID-18948082__text", "type": "abstract", "text": [ "Galphaq reduces cAMP production by decreasing Galphas protein abundance. \nThe heterotrimeric guanine nucleotide-binding protein Galphaq transduces signals from heptahelical transmembrane receptors (e.g., alpha(1)-adrenergic, endothelin 1A, and angiotensin II) to stimulate generation of inositol-1,4,5-trisphosphate and diacylglycerol. In addition, Galphaq decreases cAMP production, through unknown mechanisms, and thus affects physiological responsiveness of cardiac myocytes and other cells. Here, we provide evidence that Galphaq expression increases Galphas ubiquitination, decreases Galphas protein content, and impairs basal and beta(1)-adrenergic receptor-stimulated cAMP production. These biochemical and functional changes are associated with Akt activation. Expression of constitutively active Akt also decreases Galphas protein content and inhibits basal and beta(1)-adrenergic receptor-stimulated cAMP production. Akt knockdown inhibits Galphaq-induced reduction of Galphas protein. In addition, MDM2, an E3 ubiquitin ligase, binds Galphas and promotes its degradation. Therefore, increased expression of Galphaq decreases cAMP production through Akt-mediated Galphas protein ubiquitination and proteasomal degradation.\n" ], "offsets": [ [ 0, 1233 ] ] } ]

[ { "id": "PMID-18948082_T1", "type": "Protein", "text": [ "Galphaq" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "PMID-18948082_T2", "type": "Protein", "text": [ "Galphas" ], "offsets": [ [ 46, 53 ] ], "normalized": [] }, { "id": "PMID-18948082_T3", "type": "Protein", "text": [ "Galphaq" ], "offsets": [ [ 128, 135 ] ], "normalized": [] }, { "id": "PMID-18948082_T4", "type": "Protein", "text": [ "angiotensin II" ], "offsets": [ [ 244, 258 ] ], "normalized": [] }, { "id": "PMID-18948082_T5", "type": "Protein", "text": [ "Galphaq" ], "offsets": [ [ 349, 356 ] ], "normalized": [] }, { "id": "PMID-18948082_T6", "type": "Protein", "text": [ "Galphaq" ], "offsets": [ [ 526, 533 ] ], "normalized": [] }, { "id": "PMID-18948082_T7", "type": "Protein", "text": [ "Galphas" ], "offsets": [ [ 555, 562 ] ], "normalized": [] }, { "id": "PMID-18948082_T8", "type": "Protein", "text": [ "Galphas" ], "offsets": [ [ 589, 596 ] ], "normalized": [] }, { "id": "PMID-18948082_T9", "type": "Protein", "text": [ "beta(1)-adrenergic receptor" ], "offsets": [ [ 636, 663 ] ], "normalized": [] }, { "id": "PMID-18948082_T10", "type": "Protein", "text": [ "Galphas" ], "offsets": [ [ 824, 831 ] ], "normalized": [] }, { "id": "PMID-18948082_T11", "type": "Protein", "text": [ "beta(1)-adrenergic receptor" ], "offsets": [ [ 871, 898 ] ], "normalized": [] }, { "id": "PMID-18948082_T12", "type": "Protein", "text": [ "Galphaq" ], "offsets": [ [ 950, 957 ] ], "normalized": [] }, { "id": "PMID-18948082_T13", "type": "Protein", "text": [ "Galphas" ], "offsets": [ [ 979, 986 ] ], "normalized": [] }, { "id": "PMID-18948082_T14", "type": "Protein", "text": [ "MDM2" ], "offsets": [ [ 1009, 1013 ] ], "normalized": [] }, { "id": "PMID-18948082_T15", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1021, 1030 ] ], "normalized": [] }, { "id": "PMID-18948082_T16", "type": "Protein", "text": [ "Galphas" ], "offsets": [ [ 1045, 1052 ] ], "normalized": [] }, { "id": "PMID-18948082_T17", "type": "Protein", "text": [ "Galphaq" ], "offsets": [ [ 1118, 1125 ] ], "normalized": [] }, { "id": "PMID-18948082_T18", "type": "Protein", "text": [ "Galphas" ], "offsets": [ [ 1173, 1180 ] ], "normalized": [] } ]

[ { "id": "PMID-18948082_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 563, 577 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18948082_T7" } ] }, { "id": "PMID-18948082_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1189, 1203 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18948082_T18" } ] } ]

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[ { "id": "PMID-18972367__text", "type": "abstract", "text": [ "Assessment of histone acetylation levels in relation to cell cycle phase. \nHistone acetylation affects chromatin structural organization, thus regulating gene expression and DNA-related cellular events. Levels of histone acetylation are tightly modulated in normal cells and frequently altered in tumors. Consequently, histone deacetylase inhibitors are currently being tested in clinical trials as anticancer drugs. Presented here is a protocol for measuring the degree of cellular histone tail acetylation, alone or in combination with DNA content to simultaneously evaluate cell ploidy and/or cell cycle progression. The procedure can also be employed to stain peripheral blood samples in order to assess mean histone acetylation levels in patients treated with histone deacetylase inhibitors.\n" ], "offsets": [ [ 0, 797 ] ] } ]

[ { "id": "PMID-18972367_T1", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 14, 21 ] ], "normalized": [] }, { "id": "PMID-18972367_T2", "type": "Protein", "text": [ "Histone" ], "offsets": [ [ 75, 82 ] ], "normalized": [] }, { "id": "PMID-18972367_T3", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 213, 220 ] ], "normalized": [] }, { "id": "PMID-18972367_T4", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 319, 326 ] ], "normalized": [] }, { "id": "PMID-18972367_T5", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 483, 490 ] ], "normalized": [] }, { "id": "PMID-18972367_T6", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 713, 720 ] ], "normalized": [] }, { "id": "PMID-18972367_T7", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 765, 772 ] ], "normalized": [] }, { "id": "PMID-18972367_T11", "type": "Entity", "text": [ "tail" ], "offsets": [ [ 491, 495 ] ], "normalized": [] } ]

[ { "id": "PMID-18972367_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 22, 33 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18972367_T1" } ] }, { "id": "PMID-18972367_E2", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 83, 94 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18972367_T2" } ] }, { "id": "PMID-18972367_E3", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 221, 232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18972367_T3" } ] }, { "id": "PMID-18972367_E4", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 496, 507 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18972367_T5" }, { "role": "Site", "ref_id": "PMID-18972367_T11" } ] }, { "id": "PMID-18972367_E5", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 721, 732 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18972367_T6" } ] } ]

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[ { "id": "PMID-1898096__text", "type": "abstract", "text": [ "gp160 of HIV-I synthesized by persistently infected Molt-3 cells is terminally glycosylated: evidence that cleavage of gp160 occurs subsequent to oligosaccharide processing. \nThe envelope glycoprotein of HIV-I in infected, cultured human T cells is synthesized as a precursor of apparent Mr 160 kDa (gp160) and is cleaved to two glycoproteins, gp120 and gp41, which are the mature envelope glycoproteins in the virus. Neither the temporal and spatial features of glycosylation nor the oligosaccharide processing and proteolytic cleavage of the envelope glycoprotein are well understood. To understand more about these events, we investigated the glycosylation and cleavage of the envelope glycoproteins in the CD4+ human cell line, Molt-3, persistently infected with HIV-I (HTLV IIIB). The carbohydrate analysis of gp160 and gp120 and the behavior of the glycoproteins and glycopeptides derived from them on immobilized lectins demonstrate that both of these glycoproteins contain complex- and high-mannose-type Asn-linked oligosaccharides. In addition, the N-glycanase-resistant oligosaccharides of gp120 were found to contain N-acetyl-galactosamine, a common constituent of Ser/Thr-linked oligosaccharides. Pulse-chase analysis of the conversion of [35S]cysteine-labeled gp160 showed that in Molt-3 cells it takes about 2 h for gp120 to arise with a half-time of conversion of about 5 h. At its earliest detectable occurrence, gp120 was found to contain complex-type Asn-linked oligosaccharides. Taken together, these results indicate that proteolytic cleavage of gp160 to gp120 and gp41 occurs either within the trans-Golgi or in a distal compartment.\n" ], "offsets": [ [ 0, 1655 ] ] } ]

[ { "id": "PMID-1898096_T1", "type": "Protein", "text": [ "gp160" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-1898096_T2", "type": "Protein", "text": [ "gp160" ], "offsets": [ [ 119, 124 ] ], "normalized": [] }, { "id": "PMID-1898096_T3", "type": "Protein", "text": [ "gp160" ], "offsets": [ [ 300, 305 ] ], "normalized": [] }, { "id": "PMID-1898096_T4", "type": "Protein", "text": [ "gp120" ], "offsets": [ [ 344, 349 ] ], "normalized": [] }, { "id": "PMID-1898096_T5", "type": "Protein", "text": [ "gp41" ], "offsets": [ [ 354, 358 ] ], "normalized": [] }, { "id": "PMID-1898096_T6", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 710, 713 ] ], "normalized": [] }, { "id": "PMID-1898096_T7", "type": "Protein", "text": [ "gp160" ], "offsets": [ [ 815, 820 ] ], "normalized": [] }, { "id": "PMID-1898096_T8", "type": "Protein", "text": [ "gp120" ], "offsets": [ [ 825, 830 ] ], "normalized": [] }, { "id": "PMID-1898096_T9", "type": "Protein", "text": [ "gp120" ], "offsets": [ [ 1100, 1105 ] ], "normalized": [] }, { "id": "PMID-1898096_T10", "type": "Protein", "text": [ "gp160" ], "offsets": [ [ 1273, 1278 ] ], "normalized": [] }, { "id": "PMID-1898096_T11", "type": "Protein", "text": [ "gp120" ], "offsets": [ [ 1330, 1335 ] ], "normalized": [] }, { "id": "PMID-1898096_T12", "type": "Protein", "text": [ "gp120" ], "offsets": [ [ 1429, 1434 ] ], "normalized": [] }, { "id": "PMID-1898096_T13", "type": "Protein", "text": [ "gp160" ], "offsets": [ [ 1566, 1571 ] ], "normalized": [] }, { "id": "PMID-1898096_T14", "type": "Protein", "text": [ "gp120" ], "offsets": [ [ 1575, 1580 ] ], "normalized": [] }, { "id": "PMID-1898096_T15", "type": "Protein", "text": [ "gp41" ], "offsets": [ [ 1585, 1589 ] ], "normalized": [] }, { "id": "PMID-1898096_T18", "type": "Entity", "text": [ "oligosaccharides" ], "offsets": [ [ 1023, 1039 ] ], "normalized": [] }, { "id": "PMID-1898096_T20", "type": "Entity", "text": [ "oligosaccharides" ], "offsets": [ [ 1480, 1496 ] ], "normalized": [] } ]

[ { "id": "PMID-1898096_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylated" ], "offsets": [ [ 79, 91 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1898096_T1" } ] }, { "id": "PMID-1898096_E2", "type": "Glycosylation", "trigger": { "text": [ "Asn-linked" ], "offsets": [ [ 1012, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1898096_T7" }, { "role": "Sidechain", "ref_id": "PMID-1898096_T18" } ] }, { "id": "PMID-1898096_E3", "type": "Glycosylation", "trigger": { "text": [ "Asn-linked" ], "offsets": [ [ 1012, 1022 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1898096_T8" }, { "role": "Sidechain", "ref_id": "PMID-1898096_T18" } ] }, { "id": "PMID-1898096_E4", "type": "Glycosylation", "trigger": { "text": [ "Asn-linked" ], "offsets": [ [ 1469, 1479 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1898096_T12" }, { "role": "Sidechain", "ref_id": "PMID-1898096_T20" } ] } ]

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[ { "id": "PMID-1898347__text", "type": "abstract", "text": [ "Studies on the biotin-binding site of avidin. Minimized fragments that bind biotin. \nThe object of this study was to define minimized biotin-binding fragments, or 'prorecognition sites', of either the egg-white glycoprotein avidin or its bacterial analogue streptavidin. Because of the extreme stability to enzymic hydrolysis, fragments of avidin were prepared by chemical means and examined for their individual biotin-binding capacity. Treatment of avidin with hydroxylamine was shown to result in new cleavage sites in addition to the known Asn-Gly cleavage site (position 88-89 in avidin). Notably, the Asn-Glu and Asp-Lys peptide bonds (positions 42-43 and 57-58 respectively) were readily cleaved; in addition, lesser levels of hydrolysis of the Gln-Pro (61-62) and Asn-Asp (12-13 and 104-105) bonds could be detected. The smallest biotin-binding peptide fragment, derived from hydroxylamine cleavage of either native or non-glycosylated avidin, was identified to comprise residues 1-42. CNBr cleavage resulted in a 78-amino acid-residue fragment (residues 19-96) that still retained activity. The data ascribe an important biotin-binding function to the overlapping region (residues 19-42) of avidin, which bears the single tyrosine moiety. This contention was corroborated by synthesizing a tridecapeptide corresponding to residues 26-38 of avidin; this peptide was shown to recognize biotin. Streptavidin was not susceptible to either enzymic or chemical cleavage methods used in this work. The approach taken in this study enabled the experimental distinction between the chemical and structural elements of the binding site. The capacity to assign biotin-binding activity to the tyrosine-containing domain of avidin underscores its primary chemical contribution to the binding of biotin by avidin.\n" ], "offsets": [ [ 0, 1810 ] ] } ]

[ { "id": "PMID-1898347_T1", "type": "Protein", "text": [ "avidin" ], "offsets": [ [ 38, 44 ] ], "normalized": [] }, { "id": "PMID-1898347_T2", "type": "Protein", "text": [ "avidin" ], "offsets": [ [ 225, 231 ] ], "normalized": [] }, { "id": "PMID-1898347_T3", "type": "Protein", "text": [ "streptavidin" ], "offsets": [ [ 258, 270 ] ], "normalized": [] }, { "id": "PMID-1898347_T4", "type": "Protein", "text": [ "avidin" ], "offsets": [ [ 586, 592 ] ], "normalized": [] }, { "id": "PMID-1898347_T5", "type": "Protein", "text": [ "avidin" ], "offsets": [ [ 945, 951 ] ], "normalized": [] }, { "id": "PMID-1898347_T6", "type": "Protein", "text": [ "avidin" ], "offsets": [ [ 1201, 1207 ] ], "normalized": [] }, { "id": "PMID-1898347_T7", "type": "Protein", "text": [ "avidin" ], "offsets": [ [ 1350, 1356 ] ], "normalized": [] }, { "id": "PMID-1898347_T8", "type": "Protein", "text": [ "Streptavidin" ], "offsets": [ [ 1402, 1414 ] ], "normalized": [] }, { "id": "PMID-1898347_T9", "type": "Protein", "text": [ "avidin" ], "offsets": [ [ 1721, 1727 ] ], "normalized": [] }, { "id": "PMID-1898347_T10", "type": "Protein", "text": [ "avidin" ], "offsets": [ [ 1802, 1808 ] ], "normalized": [] } ]

[ { "id": "PMID-1898347_E1", "type": "Glycosylation", "trigger": { "text": [ "non-glycosylated" ], "offsets": [ [ 928, 944 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1898347_T5" } ] } ]

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[ { "id": "PMID-19007788__text", "type": "abstract", "text": [ "Complex patterns of histidine, hydroxylated amino acids and the GxxxG motif mediate high-affinity transmembrane domain interactions. \nSpecific interactions of transmembrane helices play a pivotal role in the folding and oligomerization of integral membrane proteins. The helix-helix interfaces frequently depend on specific amino acid patterns. In this study, a heptad repeat pattern was randomized with all naturally occurring amino acids to uncover novel sequence motifs promoting transmembrane domain interactions. Self-interacting transmembrane domains were selected from the resulting combinatorial library by means of the ToxR/POSSYCCAT system. A comparison of the amino acid composition of high-and low-affinity sequences revealed that high-affinity transmembrane domains exhibit position-specific enrichment of histidine. Further, sequences containing His preferentially display Gly, Ser, and/or Thr residues at flanking positions and frequently contain a C-terminal GxxxG motif. Mutational analysis of selected sequences confirmed the importance of these residues in homotypic interaction. Probing heterotypic interaction indicated that His interacts in trans with hydroxylated residues. Reconstruction of minimal interaction motifs within the context of an oligo-Leu sequence confirmed that His is part of a hydrogen bonded cluster that is brought into register by the GxxxG motif. Notably, a similar motif contributes to self-interaction of the BNIP3 transmembrane domain.\n" ], "offsets": [ [ 0, 1484 ] ] } ]

[ { "id": "PMID-19007788_T1", "type": "Protein", "text": [ "ToxR" ], "offsets": [ [ 628, 632 ] ], "normalized": [] }, { "id": "PMID-19007788_T2", "type": "Protein", "text": [ "BNIP3" ], "offsets": [ [ 1456, 1461 ] ], "normalized": [] } ]

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[ { "id": "PMID-19008038__text", "type": "abstract", "text": [ "Selective activation of apoptosis by a novel set of 4-aryl-3-(3-aryl-1-oxo-2-propenyl)-2(1H)-quinolinones through a Myc-dependent pathway. \nOncogene addiction due to Myc deregulation has been identified in a variety of tumor types. In order to identify pharmacological agents that cause selective apoptosis in tumors with deregulated Myc expression, we designed a cell-based screening assay based on our Anti-cancer Screening Apoptosis Program (ASAP) technology targeting increased activity in a \"Myc-addicted\" cancer cell panel. We have identified a novel set of substituted 4-aryl-3-(3-aryl-1-oxo-2-propenyl)-2(1H)-quinolinones that activates apoptosis in cancer cell lines with deregulated Myc, but show low activity in cell lines where Myc is not deregulated. Apoptosis induced by these compounds is rapid, and is associated with a significant downregulation of Myc protein. Selective knockdown of Myc levels in these cells by RNA interference increased sensitivity to apoptosis with compound treatment. By targeting the Myc pathway in Myc-addicted cancer cells, we have identified a novel class of apoptotic inducers that selectively and efficiently target cancer cells with deregulated Myc.\n" ], "offsets": [ [ 0, 1197 ] ] } ]

[ { "id": "PMID-19008038_T1", "type": "Protein", "text": [ "Myc" ], "offsets": [ [ 116, 119 ] ], "normalized": [] }, { "id": "PMID-19008038_T2", "type": "Protein", "text": [ "Myc" ], "offsets": [ [ 166, 169 ] ], "normalized": [] }, { "id": "PMID-19008038_T3", "type": "Protein", "text": [ "Myc" ], "offsets": [ [ 334, 337 ] ], "normalized": [] }, { "id": "PMID-19008038_T4", "type": "Protein", "text": [ "Myc" ], "offsets": [ [ 497, 500 ] ], "normalized": [] }, { "id": "PMID-19008038_T5", "type": "Protein", "text": [ "Myc" ], "offsets": [ [ 693, 696 ] ], "normalized": [] }, { "id": "PMID-19008038_T6", "type": "Protein", "text": [ "Myc" ], "offsets": [ [ 740, 743 ] ], "normalized": [] }, { "id": "PMID-19008038_T7", "type": "Protein", "text": [ "Myc" ], "offsets": [ [ 866, 869 ] ], "normalized": [] }, { "id": "PMID-19008038_T8", "type": "Protein", "text": [ "Myc" ], "offsets": [ [ 902, 905 ] ], "normalized": [] }, { "id": "PMID-19008038_T9", "type": "Protein", "text": [ "Myc" ], "offsets": [ [ 1025, 1028 ] ], "normalized": [] }, { "id": "PMID-19008038_T10", "type": "Protein", "text": [ "Myc" ], "offsets": [ [ 1040, 1043 ] ], "normalized": [] }, { "id": "PMID-19008038_T11", "type": "Protein", "text": [ "Myc" ], "offsets": [ [ 1192, 1195 ] ], "normalized": [] } ]

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[ { "id": "PMID-19013150__text", "type": "abstract", "text": [ "The trafficking and regulation of membrane receptors by the RING-CH ubiquitin E3 ligases. \nUbiquitylation of membrane receptors is recognised as a critical post-translational modification, governing their regulation and function. Following ubiquitylation, membrane proteins may be internalised, recycled or degraded via lysosomal or proteasomal pathways. Viruses have appropriated these cellular pathways as a mechanism of immune evasion. RING (really interesting new gene)-CH ubiquitin E3 ligases were initially identified from the Kaposi's associated herpesvirus (KSHV) and their founding members, K3 and K5, downregulate several critical immunoreceptors to prevent detection by the host immune system. K3 promotes formation of lysine-63 linked polyubiquitin chains on MHC Class I, signalling Class I internalisation and endolysosomal degradation. K5 targets multiple immunoreceptors, including MHC Class I, CD86, intracellular adhesion molecule (ICAM) 1 and MHC Class I-related chain (MIC)-A/B, thereby preventing detection from cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. The cellular homologues of K3 and K5, the Membrane Associated RING-CH (MARCH) genes, represent eleven proteins that also appear to be important in the downregulation of membrane receptors. While overexpression of several MARCH genes downregulate cell surface receptors such as MHC Class I, MHC Class II, CD86 and ICAM 1, determining their physiological roles has proved difficult. Elucidating the transcriptional regulation, localisation and trafficking of MARCH genes may provide insights into their cellular functions.\n" ], "offsets": [ [ 0, 1615 ] ] } ]

[ { "id": "PMID-19013150_T1", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 68, 77 ] ], "normalized": [] }, { "id": "PMID-19013150_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 477, 486 ] ], "normalized": [] }, { "id": "PMID-19013150_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 751, 760 ] ], "normalized": [] }, { "id": "PMID-19013150_T4", "type": "Protein", "text": [ "CD86" ], "offsets": [ [ 910, 914 ] ], "normalized": [] }, { "id": "PMID-19013150_T5", "type": "Protein", "text": [ "intracellular adhesion molecule (ICAM) 1" ], "offsets": [ [ 916, 956 ] ], "normalized": [] }, { "id": "PMID-19013150_T6", "type": "Protein", "text": [ "MHC Class I-related chain (MIC)-A" ], "offsets": [ [ 961, 994 ] ], "normalized": [] }, { "id": "PMID-19013150_T7", "type": "Protein", "text": [ "B" ], "offsets": [ [ 995, 996 ] ], "normalized": [] }, { "id": "PMID-19013150_T8", "type": "Protein", "text": [ "CD86" ], "offsets": [ [ 1398, 1402 ] ], "normalized": [] }, { "id": "PMID-19013150_T9", "type": "Protein", "text": [ "ICAM 1" ], "offsets": [ [ 1407, 1413 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-19019316__text", "type": "abstract", "text": [ "Muscular dystrophies due to glycosylation defects. \nIn the last few years, muscular dystrophies due to reduced glycosylation of alpha-dystroglycan (ADG) have emerged as a common group of conditions, now referred to as dystroglycanopathies. Mutations in six genes (POMT1, POMT2, POMGnT1, Fukutin, FKRP and LARGE) have so far been identified in patients with a dystroglycanopathy. Allelic mutations in each of these genes can result in a wide spectrum of clinical conditions, ranging from severe congenital onset with associated structural brain malformations (Walker Warburg syndrome; muscle-eye-brain disease; Fukuyama muscular dystrophy; congenital muscular dystrophy type 1D) to a relatively milder congenital variant with no brain involvement (congenital muscular dystrophy type 1C), and to limb-girdle muscular dystrophy (LGMD) type 2 variants with onset in childhood or adult life (LGMD2I, LGMD2L, and LGMD2N). ADG is a peripheral membrane protein that undergoes multiple and complex glycosylation steps to regulate its ability to effectively interact with extracellular matrix proteins, such as laminin, agrin, and perlecan. Although the precise composition of the glycans present on ADG are not known, it has been demonstrated that the forced overexpression of LARGE, or its paralog LARGE2, is capable of increasing the glycosylation of ADG in normal cells. In addition, its overexpression is capable of restoring dystroglycan glycosylation and laminin binding properties in primary cell cultures of patients affected by different genetically defined dystroglycanopathy variants. These observations suggest that there could be a role for therapeutic strategies to overcome the glycosylation defect in these conditions via the overexpression of LARGE.\n" ], "offsets": [ [ 0, 1758 ] ] } ]

[ { "id": "PMID-19019316_T1", "type": "Protein", "text": [ "alpha-dystroglycan" ], "offsets": [ [ 128, 146 ] ], "normalized": [] }, { "id": "PMID-19019316_T2", "type": "Protein", "text": [ "ADG" ], "offsets": [ [ 148, 151 ] ], "normalized": [] }, { "id": "PMID-19019316_T3", "type": "Protein", "text": [ "POMT1" ], "offsets": [ [ 264, 269 ] ], "normalized": [] }, { "id": "PMID-19019316_T4", "type": "Protein", "text": [ "POMT2" ], "offsets": [ [ 271, 276 ] ], "normalized": [] }, { "id": "PMID-19019316_T5", "type": "Protein", "text": [ "POMGnT1" ], "offsets": [ [ 278, 285 ] ], "normalized": [] }, { "id": "PMID-19019316_T6", "type": "Protein", "text": [ "Fukutin" ], "offsets": [ [ 287, 294 ] ], "normalized": [] }, { "id": "PMID-19019316_T7", "type": "Protein", "text": [ "FKRP" ], "offsets": [ [ 296, 300 ] ], "normalized": [] }, { "id": "PMID-19019316_T8", "type": "Protein", "text": [ "LARGE" ], "offsets": [ [ 305, 310 ] ], "normalized": [] }, { "id": "PMID-19019316_T9", "type": "Protein", "text": [ "ADG" ], "offsets": [ [ 916, 919 ] ], "normalized": [] }, { "id": "PMID-19019316_T10", "type": "Protein", "text": [ "agrin" ], "offsets": [ [ 1110, 1115 ] ], "normalized": [] }, { "id": "PMID-19019316_T11", "type": "Protein", "text": [ "perlecan" ], "offsets": [ [ 1121, 1129 ] ], "normalized": [] }, { "id": "PMID-19019316_T12", "type": "Protein", "text": [ "ADG" ], "offsets": [ [ 1190, 1193 ] ], "normalized": [] }, { "id": "PMID-19019316_T13", "type": "Protein", "text": [ "LARGE" ], "offsets": [ [ 1268, 1273 ] ], "normalized": [] }, { "id": "PMID-19019316_T14", "type": "Protein", "text": [ "LARGE2" ], "offsets": [ [ 1290, 1296 ] ], "normalized": [] }, { "id": "PMID-19019316_T15", "type": "Protein", "text": [ "ADG" ], "offsets": [ [ 1344, 1347 ] ], "normalized": [] }, { "id": "PMID-19019316_T16", "type": "Protein", "text": [ "dystroglycan" ], "offsets": [ [ 1421, 1433 ] ], "normalized": [] }, { "id": "PMID-19019316_T17", "type": "Protein", "text": [ "LARGE" ], "offsets": [ [ 1751, 1756 ] ], "normalized": [] } ]

[ { "id": "PMID-19019316_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 111, 124 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19019316_T1" } ] }, { "id": "PMID-19019316_E2", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 989, 1002 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19019316_T9" } ] }, { "id": "PMID-19019316_E3", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 1327, 1340 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19019316_T15" } ] }, { "id": "PMID-19019316_E4", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 1434, 1447 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19019316_T16" } ] }, { "id": "PMID-19019316_E5", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 1684, 1697 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19019316_T16" } ] } ]

[ { "id": "PMID-19019316_1", "entity_ids": [ "PMID-19019316_T1", "PMID-19019316_T2" ] } ]

[]

[ { "id": "PMID-19038776__text", "type": "abstract", "text": [ "APOBEC proteins and intrinsic resistance to HIV-1 infection. \nMembers of the APOBEC family of cellular polynucleotide cytidine deaminases, most notably APOBEC3G and APOBEC3F, are potent inhibitors of HIV-1 infection. Wild type HIV-1 infections are largely spared from APOBEC3G/F function through the action of the essential viral protein, Vif. In the absence of Vif, APOBEC3G/F are encapsidated by budding virus particles leading to excessive cytidine (C) to uridine (U) editing of negative sense reverse transcripts in newly infected cells. This registers as guanosine (G) to adenosine (A) hypermutations in plus-stranded cDNA. In addition to this profoundly debilitating effect on genetic integrity, APOBEC3G/F also appear to inhibit viral DNA synthesis by impeding the translocation of reverse transcriptase along template RNA. Because the functions of Vif and APOBEC3G/F proteins oppose each other, it is likely that fluctuations in the Vif-APOBEC balance may influence the natural history of HIV-1 infection, as well as viral sequence diversification and evolution. Given Vif's critical role in suppressing APOBEC3G/F function, it can be argued that pharmacologic strategies aimed at restoring the activity of these intrinsic anti-viral factors in the context of infected cells in vivo have clear therapeutic merit, and therefore deserve aggressive pursuit.\n" ], "offsets": [ [ 0, 1363 ] ] } ]

[ { "id": "PMID-19038776_T1", "type": "Protein", "text": [ "APOBEC3G" ], "offsets": [ [ 152, 160 ] ], "normalized": [] }, { "id": "PMID-19038776_T2", "type": "Protein", "text": [ "APOBEC3F" ], "offsets": [ [ 165, 173 ] ], "normalized": [] }, { "id": "PMID-19038776_T3", "type": "Protein", "text": [ "APOBEC3G" ], "offsets": [ [ 268, 276 ] ], "normalized": [] }, { "id": "PMID-19038776_T4", "type": "Protein", "text": [ "F" ], "offsets": [ [ 277, 278 ] ], "normalized": [] }, { "id": "PMID-19038776_T5", "type": "Protein", "text": [ "Vif" ], "offsets": [ [ 339, 342 ] ], "normalized": [] }, { "id": "PMID-19038776_T6", "type": "Protein", "text": [ "Vif" ], "offsets": [ [ 362, 365 ] ], "normalized": [] }, { "id": "PMID-19038776_T7", "type": "Protein", "text": [ "APOBEC3G" ], "offsets": [ [ 367, 375 ] ], "normalized": [] }, { "id": "PMID-19038776_T8", "type": "Protein", "text": [ "F" ], "offsets": [ [ 376, 377 ] ], "normalized": [] }, { "id": "PMID-19038776_T9", "type": "Protein", "text": [ "APOBEC3G" ], "offsets": [ [ 702, 710 ] ], "normalized": [] }, { "id": "PMID-19038776_T10", "type": "Protein", "text": [ "F" ], "offsets": [ [ 711, 712 ] ], "normalized": [] }, { "id": "PMID-19038776_T11", "type": "Protein", "text": [ "reverse transcriptase" ], "offsets": [ [ 789, 810 ] ], "normalized": [] }, { "id": "PMID-19038776_T12", "type": "Protein", "text": [ "Vif" ], "offsets": [ [ 856, 859 ] ], "normalized": [] }, { "id": "PMID-19038776_T13", "type": "Protein", "text": [ "APOBEC3G" ], "offsets": [ [ 864, 872 ] ], "normalized": [] }, { "id": "PMID-19038776_T14", "type": "Protein", "text": [ "F" ], "offsets": [ [ 873, 874 ] ], "normalized": [] }, { "id": "PMID-19038776_T15", "type": "Protein", "text": [ "Vif" ], "offsets": [ [ 941, 944 ] ], "normalized": [] }, { "id": "PMID-19038776_T16", "type": "Protein", "text": [ "Vif" ], "offsets": [ [ 1077, 1080 ] ], "normalized": [] }, { "id": "PMID-19038776_T17", "type": "Protein", "text": [ "APOBEC3G" ], "offsets": [ [ 1112, 1120 ] ], "normalized": [] }, { "id": "PMID-19038776_T18", "type": "Protein", "text": [ "F" ], "offsets": [ [ 1121, 1122 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-19047059__text", "type": "abstract", "text": [ "Substrate filtering by the active site crossover loop in UCHL3 revealed by sortagging and gain-of-function mutations. \nDetermining how deubiquitinating enzymes discriminate between ubiquitin-conjugated substrates is critical to understand their function. Through application of a novel protein cleavage and tagging technique, sortagging, we show that human UCHL3 and the Plasmodium falciparum homologue, members of the ubiquitin C-terminal hydrolase family, use a unique active site crossover loop to restrict access of bulky ubiquitin adducts to the active site. Although it provides connectivity for critical active site residues in UCHL3, physical integrity of the crossover loop is dispensable for catalysis. By enlarging the active site crossover loop, we have constructed gain-of-function mutants that can accept substrates that the parent enzyme cannot, including ubiquitin chains of various linkages.\n" ], "offsets": [ [ 0, 909 ] ] } ]

[ { "id": "PMID-19047059_T1", "type": "Protein", "text": [ "UCHL3" ], "offsets": [ [ 57, 62 ] ], "normalized": [] }, { "id": "PMID-19047059_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 181, 190 ] ], "normalized": [] }, { "id": "PMID-19047059_T3", "type": "Protein", "text": [ "UCHL3" ], "offsets": [ [ 357, 362 ] ], "normalized": [] }, { "id": "PMID-19047059_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 419, 428 ] ], "normalized": [] }, { "id": "PMID-19047059_T5", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 526, 535 ] ], "normalized": [] }, { "id": "PMID-19047059_T6", "type": "Protein", "text": [ "UCHL3" ], "offsets": [ [ 635, 640 ] ], "normalized": [] }, { "id": "PMID-19047059_T7", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 871, 880 ] ], "normalized": [] } ]

[]

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[ { "id": "PMID-19064727__text", "type": "abstract", "text": [ "Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-kappaB. \nAdult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). The activation of NF-kappaB by Tax has been reported to play a crucial role in HTLV-1-induced transformation. The HTLV-1 bZIP factor (HBZ), which is encoded by an mRNA of the opposite polarity of the viral genomic RNA, is involved in both T cell proliferation and suppression of Tax-mediated viral gene transcription, suggesting that HBZ cooperates closely with Tax. In the present study, we observed that HBZ specifically suppressed NF-kappaB-driven transcription mediated by p65 (the classical pathway) without inhibiting the alternative NF-kappaB signaling pathway. In an immunoprecipitation assay, HBZ bound to p65 and diminished the DNA binding capacity of p65. In addition, HBZ induced p65 degradation through increasing the expression of the PDLIM2 gene, which encodes a ubiquitin E3 ligase for p65. Finally, HBZ actually repressed the transcription of some classical NF-kappaB target genes, such as IL-8, IL2RA, IRF4, VCAM-1, and VEGF. Selective suppression of the classical NF-kappaB pathway by HBZ renders the alternative NF-kappaB pathway predominant after activation of NF-kappaB by Tax or other stimuli, which might be critical for oncogenesis.\n" ], "offsets": [ [ 0, 1389 ] ] } ]

[ { "id": "PMID-19064727_T1", "type": "Protein", "text": [ "Human T-cell leukemia virus type 1 bZIP factor" ], "offsets": [ [ 0, 46 ] ], "normalized": [] }, { "id": "PMID-19064727_T2", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 262, 265 ] ], "normalized": [] }, { "id": "PMID-19064727_T3", "type": "Protein", "text": [ "HTLV-1 bZIP factor" ], "offsets": [ [ 345, 363 ] ], "normalized": [] }, { "id": "PMID-19064727_T4", "type": "Protein", "text": [ "HBZ" ], "offsets": [ [ 365, 368 ] ], "normalized": [] }, { "id": "PMID-19064727_T5", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 510, 513 ] ], "normalized": [] }, { "id": "PMID-19064727_T6", "type": "Protein", "text": [ "HBZ" ], "offsets": [ [ 565, 568 ] ], "normalized": [] }, { "id": "PMID-19064727_T7", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 593, 596 ] ], "normalized": [] }, { "id": "PMID-19064727_T8", "type": "Protein", "text": [ "HBZ" ], "offsets": [ [ 637, 640 ] ], "normalized": [] }, { "id": "PMID-19064727_T9", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 708, 711 ] ], "normalized": [] }, { "id": "PMID-19064727_T10", "type": "Protein", "text": [ "HBZ" ], "offsets": [ [ 833, 836 ] ], "normalized": [] }, { "id": "PMID-19064727_T11", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 846, 849 ] ], "normalized": [] }, { "id": "PMID-19064727_T12", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 893, 896 ] ], "normalized": [] }, { "id": "PMID-19064727_T13", "type": "Protein", "text": [ "HBZ" ], "offsets": [ [ 911, 914 ] ], "normalized": [] }, { "id": "PMID-19064727_T14", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 923, 926 ] ], "normalized": [] }, { "id": "PMID-19064727_T15", "type": "Protein", "text": [ "PDLIM2" ], "offsets": [ [ 980, 986 ] ], "normalized": [] }, { "id": "PMID-19064727_T16", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1009, 1018 ] ], "normalized": [] }, { "id": "PMID-19064727_T17", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1033, 1036 ] ], "normalized": [] }, { "id": "PMID-19064727_T18", "type": "Protein", "text": [ "HBZ" ], "offsets": [ [ 1047, 1050 ] ], "normalized": [] }, { "id": "PMID-19064727_T19", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1138, 1142 ] ], "normalized": [] }, { "id": "PMID-19064727_T20", "type": "Protein", "text": [ "IL2RA" ], "offsets": [ [ 1144, 1149 ] ], "normalized": [] }, { "id": "PMID-19064727_T21", "type": "Protein", "text": [ "IRF4" ], "offsets": [ [ 1151, 1155 ] ], "normalized": [] }, { "id": "PMID-19064727_T22", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1157, 1163 ] ], "normalized": [] }, { "id": "PMID-19064727_T23", "type": "Protein", "text": [ "VEGF" ], "offsets": [ [ 1169, 1173 ] ], "normalized": [] }, { "id": "PMID-19064727_T24", "type": "Protein", "text": [ "HBZ" ], "offsets": [ [ 1235, 1238 ] ], "normalized": [] }, { "id": "PMID-19064727_T25", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 1326, 1329 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-19064727_1", "entity_ids": [ "PMID-19064727_T3", "PMID-19064727_T4" ] } ]

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[ { "id": "PMID-19099279__text", "type": "abstract", "text": [ "A novel peptide motif binding to and blocking the intracellular activity of the human papillomavirus E6 oncoprotein. \nSpecific types of human papillomaviruses (HPVs) cause cervical cancer. The viral E6 oncogene is a critical factor for maintaining the malignant phenotype of HPV-positive tumour cells. By yeast two-hybrid screening of a randomised peptide expression library, we isolated linear short peptides, which specifically bind to the HPV16 E6 oncoprotein. Sequence alignments and mutational analyses of the peptides identified a hitherto undiscovered E6-binding motif. Intracellular expression of a peptide containing the novel E6-binding motif resulted in inhibition of colony formation capacity, specifically of HPV16-positive cancer cells. A solubility-optimised variant of the peptide was created, which binds to HPV16 E6 with high affinity. Its intracellular expression efficiently induced apoptosis in HPV16-positive cancer cells. This was linked to restoration of intracellular p53 activities. Thus, this newly identified E6-binding motif could form a novel basis for the development of rational strategies for the treatment of HPV16-positive preneoplastic and neoplastic lesions.\n" ], "offsets": [ [ 0, 1196 ] ] } ]

[ { "id": "PMID-19099279_T1", "type": "Protein", "text": [ "E6" ], "offsets": [ [ 101, 103 ] ], "normalized": [] }, { "id": "PMID-19099279_T2", "type": "Protein", "text": [ "E6" ], "offsets": [ [ 199, 201 ] ], "normalized": [] }, { "id": "PMID-19099279_T3", "type": "Protein", "text": [ "E6" ], "offsets": [ [ 448, 450 ] ], "normalized": [] }, { "id": "PMID-19099279_T4", "type": "Protein", "text": [ "E6" ], "offsets": [ [ 559, 561 ] ], "normalized": [] }, { "id": "PMID-19099279_T5", "type": "Protein", "text": [ "E6" ], "offsets": [ [ 636, 638 ] ], "normalized": [] }, { "id": "PMID-19099279_T6", "type": "Protein", "text": [ "E6" ], "offsets": [ [ 831, 833 ] ], "normalized": [] }, { "id": "PMID-19099279_T7", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 993, 996 ] ], "normalized": [] }, { "id": "PMID-19099279_T8", "type": "Protein", "text": [ "E6" ], "offsets": [ [ 1037, 1039 ] ], "normalized": [] } ]

[]

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[ { "id": "PMID-19111550__text", "type": "abstract", "text": [ "Phosphorylated and ubiquitinated TDP-43 pathological inclusions in ALS and FTLD-U are recapitulated in SH-SY5Y cells. \nWe report phosphorylated and ubiquitinated aggregates of TAR DNA binding protein of 43 kDa (TDP-43) in SH-SY5Y cells similar to those in brains of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). Two candidate sequences for the nuclear localization signal were examined. Deletion of residues 78-84 resulted in cytoplasmic localization of TDP-43, whereas the mutant lacking residues 187-192 localized in nuclei, forming unique dot-like structures. Proteasome inhibition caused these to assemble into phosphorylated and ubiquitinated TDP-43 aggregates. The deletion mutants lacked the exon skipping activity of cystic fibrosis transmembrane conductance regulator (CFTR) exon 9. Our results suggest that intracellular localization of TDP-43 and proteasomal function may be involved in inclusion formation and neurodegeneration in TDP-43 proteinopathies.\n" ], "offsets": [ [ 0, 1035 ] ] } ]

[ { "id": "PMID-19111550_T1", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 33, 39 ] ], "normalized": [] }, { "id": "PMID-19111550_T2", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 211, 217 ] ], "normalized": [] }, { "id": "PMID-19111550_T3", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 522, 528 ] ], "normalized": [] }, { "id": "PMID-19111550_T4", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 716, 722 ] ], "normalized": [] }, { "id": "PMID-19111550_T5", "type": "Protein", "text": [ "cystic fibrosis transmembrane conductance regulator" ], "offsets": [ [ 793, 844 ] ], "normalized": [] }, { "id": "PMID-19111550_T6", "type": "Protein", "text": [ "CFTR" ], "offsets": [ [ 846, 850 ] ], "normalized": [] }, { "id": "PMID-19111550_T7", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 915, 921 ] ], "normalized": [] }, { "id": "PMID-19111550_T8", "type": "Protein", "text": [ "TDP-43" ], "offsets": [ [ 1011, 1017 ] ], "normalized": [] } ]

[ { "id": "PMID-19111550_E1", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylated" ], "offsets": [ [ 0, 14 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19111550_T1" } ] }, { "id": "PMID-19111550_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 19, 32 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19111550_T1" } ] }, { "id": "PMID-19111550_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 129, 143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19111550_T2" } ] }, { "id": "PMID-19111550_E4", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 148, 161 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19111550_T2" } ] }, { "id": "PMID-19111550_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 683, 697 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19111550_T4" } ] }, { "id": "PMID-19111550_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 702, 715 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19111550_T4" } ] } ]

[ { "id": "PMID-19111550_1", "entity_ids": [ "PMID-19111550_T5", "PMID-19111550_T6" ] } ]

[]

[ { "id": "PMID-19117940__text", "type": "abstract", "text": [ "The HLA-DRalpha chain is modified by polyubiquitination. \nUbiquitination plays a major role in regulating cell surface and intracellular localization of major histocompatibility complex class II molecules. Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. Each chain of the HLA-DR heterodimer is independently recognized and ubiquitinated, but DRbeta is more extensively modified. In the cytoplasmic tail of DRbeta lysine, residue 225 is the only residue that is absolutely required for ubiquitination; all other residues can be deleted or substituted without loss of function. In contrast, although lysine 219 is absolutely required for modification of DRalpha, other features of the DRalpha tail act to limit the extent of ubiquitination.\n" ], "offsets": [ [ 0, 943 ] ] } ]

[ { "id": "PMID-19117940_T1", "type": "Protein", "text": [ "HLA-DRalpha chain" ], "offsets": [ [ 4, 21 ] ], "normalized": [] }, { "id": "PMID-19117940_T2", "type": "Protein", "text": [ "MARCH I" ], "offsets": [ [ 222, 229 ] ], "normalized": [] }, { "id": "PMID-19117940_T3", "type": "Protein", "text": [ "MARCH VIII" ], "offsets": [ [ 234, 244 ] ], "normalized": [] }, { "id": "PMID-19117940_T4", "type": "Protein", "text": [ "I-Abeta" ], "offsets": [ [ 328, 335 ] ], "normalized": [] }, { "id": "PMID-19117940_T5", "type": "Protein", "text": [ "DRalpha" ], "offsets": [ [ 411, 418 ] ], "normalized": [] }, { "id": "PMID-19117940_T6", "type": "Protein", "text": [ "DRalpha" ], "offsets": [ [ 856, 863 ] ], "normalized": [] }, { "id": "PMID-19117940_T7", "type": "Protein", "text": [ "DRalpha" ], "offsets": [ [ 887, 894 ] ], "normalized": [] }, { "id": "PMID-19117940_T10", "type": "Entity", "text": [ "lysine residue 225" ], "offsets": [ [ 282, 300 ] ], "normalized": [] }, { "id": "PMID-19117940_T11", "type": "Entity", "text": [ "lysine residue 219" ], "offsets": [ [ 365, 383 ] ], "normalized": [] } ]

[ { "id": "PMID-19117940_E1", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 37, 55 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19117940_T1" } ] }, { "id": "PMID-19117940_E2", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitinate" ], "offsets": [ [ 265, 281 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19117940_T4" }, { "role": "Site", "ref_id": "PMID-19117940_T10" } ] }, { "id": "PMID-19117940_E3", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 438, 456 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19117940_T5" }, { "role": "Site", "ref_id": "PMID-19117940_T11" } ] }, { "id": "PMID-19117940_E4", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 927, 941 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19117940_T7" } ] } ]

[]

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[ { "id": "PMID-1911902__text", "type": "abstract", "text": [ "Methylation status of cKi-ras and MHC genes in rat pituitary glands during aging and tumorigenesis. \nMethylation patterns of MHC (major histocompatibility complex) class I and vKi-ras (viral Kirsten-ras) homologous sequences in normal and adenomatous rat pituitary glands were studied as a function of age by Southern hybridization analysis using the isoschizomers Hpa II and Msp I. Both MHC class I and vKi-ras homologous sequences were found to be hypomethylated in a number of tumors, compared to normal pituitary gland tissue. However, despite reports indicating a general demethylation in mammalian tissues in relation to donor age, age-related methylation changes in this apparently methylation-unstable and cancer-prone organ were not observed.\n" ], "offsets": [ [ 0, 752 ] ] } ]

[ { "id": "PMID-1911902_T1", "type": "Protein", "text": [ "cKi-ras" ], "offsets": [ [ 22, 29 ] ], "normalized": [] }, { "id": "PMID-1911902_T2", "type": "Protein", "text": [ "Ki-ras" ], "offsets": [ [ 177, 183 ] ], "normalized": [] }, { "id": "PMID-1911902_T3", "type": "Protein", "text": [ "Kirsten-ras" ], "offsets": [ [ 191, 202 ] ], "normalized": [] }, { "id": "PMID-1911902_T4", "type": "Protein", "text": [ "Hpa II" ], "offsets": [ [ 365, 371 ] ], "normalized": [] }, { "id": "PMID-1911902_T5", "type": "Protein", "text": [ "Msp I" ], "offsets": [ [ 376, 381 ] ], "normalized": [] }, { "id": "PMID-1911902_T6", "type": "Protein", "text": [ "Ki-ras" ], "offsets": [ [ 405, 411 ] ], "normalized": [] } ]

[ { "id": "PMID-1911902_E1", "type": "Methylation", "trigger": { "text": [ "Methylation" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1911902_T1" } ] }, { "id": "PMID-1911902_E2", "type": "DNA_methylation", "trigger": { "text": [ "Methylation" ], "offsets": [ [ 101, 112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1911902_T2" } ] }, { "id": "PMID-1911902_E3", "type": "DNA_demethylation", "trigger": { "text": [ "hypomethylated" ], "offsets": [ [ 450, 464 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-1911902_T6" } ] } ]

[ { "id": "PMID-1911902_1", "entity_ids": [ "PMID-1911902_T2", "PMID-1911902_T3" ] } ]

[]

[ { "id": "PMID-19126544__text", "type": "abstract", "text": [ "A phosphorylation cascade controls the degradation of active SREBP1. \nSterol regulatory element-binding proteins (SREBPs) are a family of transcription factors that regulates cholesterol and lipid metabolism. The active forms of these transcription factors are targeted by a number of post-translational modifications, including phosphorylation. Phosphorylation of Thr-426 and Ser-430 in SREBP1a creates a docking site for the ubiquitin ligase Fbw7, resulting in the degradation of the transcription factor. Here, we identify a novel phosphorylation site in SREBP1a, Ser-434, which regulates the Fbw7-dependent degradation of SREBP1. We demonstrate that both SREBP1a and SREBP1c are phosphorylated on this residue (Ser-410 in SREBP1c). Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. Consequently, mutation of Ser-434 blocks the interaction between SREBP1 and Fbw7 and attenuates Fbw7-dependent degradation of SREBP1. Importantly, insulin fails to enhance the levels of mature SREBP1 in cells lacking Fbw7. Thus, the degradation of mature SREBP1 is controlled by cross-talk between multiple phosphorylated residues in its C-terminal domain and the phosphorylation of Ser-434 could function as a molecular switch to control these processes.\n" ], "offsets": [ [ 0, 1587 ] ] } ]

[ { "id": "PMID-19126544_T1", "type": "Protein", "text": [ "SREBP1" ], "offsets": [ [ 61, 67 ] ], "normalized": [] }, { "id": "PMID-19126544_T2", "type": "Protein", "text": [ "SREBP1a" ], "offsets": [ [ 388, 395 ] ], "normalized": [] }, { "id": "PMID-19126544_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 427, 436 ] ], "normalized": [] }, { "id": "PMID-19126544_T4", "type": "Protein", "text": [ "Fbw7" ], "offsets": [ [ 444, 448 ] ], "normalized": [] }, { "id": "PMID-19126544_T5", "type": "Protein", "text": [ "SREBP1a" ], "offsets": [ [ 558, 565 ] ], "normalized": [] }, { "id": "PMID-19126544_T6", "type": "Protein", "text": [ "Fbw7" ], "offsets": [ [ 596, 600 ] ], "normalized": [] }, { "id": "PMID-19126544_T7", "type": "Protein", "text": [ "SREBP1" ], "offsets": [ [ 626, 632 ] ], "normalized": [] }, { "id": "PMID-19126544_T8", "type": "Protein", "text": [ "SREBP1a" ], "offsets": [ [ 659, 666 ] ], "normalized": [] }, { "id": "PMID-19126544_T9", "type": "Protein", "text": [ "SREBP1c" ], "offsets": [ [ 671, 678 ] ], "normalized": [] }, { "id": "PMID-19126544_T10", "type": "Protein", "text": [ "SREBP1c" ], "offsets": [ [ 726, 733 ] ], "normalized": [] }, { "id": "PMID-19126544_T11", "type": "Protein", "text": [ "SREBP1" ], "offsets": [ [ 799, 805 ] ], "normalized": [] }, { "id": "PMID-19126544_T12", "type": "Protein", "text": [ "insulin" ], "offsets": [ [ 956, 963 ] ], "normalized": [] }, { "id": "PMID-19126544_T13", "type": "Protein", "text": [ "SREBP1" ], "offsets": [ [ 1123, 1129 ] ], "normalized": [] }, { "id": "PMID-19126544_T14", "type": "Protein", "text": [ "SREBP1" ], "offsets": [ [ 1196, 1202 ] ], "normalized": [] }, { "id": "PMID-19126544_T15", "type": "Protein", "text": [ "Fbw7" ], "offsets": [ [ 1207, 1211 ] ], "normalized": [] }, { "id": "PMID-19126544_T16", "type": "Protein", "text": [ "Fbw7" ], "offsets": [ [ 1227, 1231 ] ], "normalized": [] }, { "id": "PMID-19126544_T17", "type": "Protein", "text": [ "SREBP1" ], "offsets": [ [ 1257, 1263 ] ], "normalized": [] }, { "id": "PMID-19126544_T18", "type": "Protein", "text": [ "insulin" ], "offsets": [ [ 1278, 1285 ] ], "normalized": [] }, { "id": "PMID-19126544_T19", "type": "Protein", "text": [ "SREBP1" ], "offsets": [ [ 1324, 1330 ] ], "normalized": [] }, { "id": "PMID-19126544_T20", "type": "Protein", "text": [ "Fbw7" ], "offsets": [ [ 1348, 1352 ] ], "normalized": [] }, { "id": "PMID-19126544_T21", "type": "Protein", "text": [ "SREBP1" ], "offsets": [ [ 1386, 1392 ] ], "normalized": [] }, { "id": "PMID-19126544_T23", "type": "Entity", "text": [ "Thr-426" ], "offsets": [ [ 365, 372 ] ], "normalized": [] }, { "id": "PMID-19126544_T24", "type": "Entity", "text": [ "Ser-430" ], "offsets": [ [ 377, 384 ] ], "normalized": [] }, { "id": "PMID-19126544_T26", "type": "Entity", "text": [ "Ser-434" ], "offsets": [ [ 567, 574 ] ], "normalized": [] }, { "id": "PMID-19126544_T28", "type": "Entity", "text": [ "Ser-410" ], "offsets": [ [ 715, 722 ] ], "normalized": [] }, { "id": "PMID-19126544_T30", "type": "Entity", "text": [ "Ser-434" ], "offsets": [ [ 827, 834 ] ], "normalized": [] }, { "id": "PMID-19126544_T32", "type": "Entity", "text": [ "Ser-434" ], "offsets": [ [ 878, 885 ] ], "normalized": [] }, { "id": "PMID-19126544_T34", "type": "Entity", "text": [ "Ser-434" ], "offsets": [ [ 1009, 1016 ] ], "normalized": [] }, { "id": "PMID-19126544_T36", "type": "Entity", "text": [ "Thr-426" ], "offsets": [ [ 1086, 1093 ] ], "normalized": [] }, { "id": "PMID-19126544_T37", "type": "Entity", "text": [ "Ser-430" ], "offsets": [ [ 1098, 1105 ] ], "normalized": [] }, { "id": "PMID-19126544_T39", "type": "Entity", "text": [ "C-terminal domain" ], "offsets": [ [ 1469, 1486 ] ], "normalized": [] }, { "id": "PMID-19126544_T41", "type": "Entity", "text": [ "Ser-434" ], "offsets": [ [ 1514, 1521 ] ], "normalized": [] } ]

[ { "id": "PMID-19126544_E1", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 346, 361 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T2" }, { "role": "Site", "ref_id": "PMID-19126544_T23" } ] }, { "id": "PMID-19126544_E2", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 346, 361 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T2" }, { "role": "Site", "ref_id": "PMID-19126544_T24" } ] }, { "id": "PMID-19126544_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 534, 549 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T5" }, { "role": "Site", "ref_id": "PMID-19126544_T26" } ] }, { "id": "PMID-19126544_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 683, 697 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T8" } ] }, { "id": "PMID-19126544_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 683, 697 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T9" }, { "role": "Site", "ref_id": "PMID-19126544_T28" } ] }, { "id": "PMID-19126544_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 809, 823 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T11" }, { "role": "Site", "ref_id": "PMID-19126544_T30" } ] }, { "id": "PMID-19126544_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 863, 877 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T11" }, { "role": "Site", "ref_id": "PMID-19126544_T32" } ] }, { "id": "PMID-19126544_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 990, 1005 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T13" }, { "role": "Site", "ref_id": "PMID-19126544_T34" } ] }, { "id": "PMID-19126544_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1067, 1082 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T13" }, { "role": "Site", "ref_id": "PMID-19126544_T37" } ] }, { "id": "PMID-19126544_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1067, 1082 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T13" }, { "role": "Site", "ref_id": "PMID-19126544_T36" } ] }, { "id": "PMID-19126544_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 1438, 1452 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T21" }, { "role": "Site", "ref_id": "PMID-19126544_T39" } ] }, { "id": "PMID-19126544_E12", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1495, 1510 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126544_T21" }, { "role": "Site", "ref_id": "PMID-19126544_T41" } ] } ]

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[ { "id": "PMID-19126970__text", "type": "abstract", "text": [ "Glycosylation of serum proteins in inflammatory diseases. \nInflammatory diseases are accompanied by numerous changes at the site of inflammation as well as many systemic physiological and biochemical changes. In the past two decades more and more attention is being paid to changes in glycosylation and in this review we describe some of the changes found on main serum proteins (alpha1-acid glycoprotein, immunoglobulin G, immunoglobulin A, transferrin, haptoglobin, alpha2-macroglobulin, C-reactive protein, and others). Molecular background and physiological importance of most of these changes are yet to be discovered, but it is evident that glycosylation plays an important role in the inflammatory response. Maybe the greatest value of these changes currently lays in their potential diagnostic and prognostic usage, either in combination with current diagnostic markers or on their own. However, determining glycan structures is still technically too complex for most clinical laboratories and further efforts have to be made to develop simple analytical tools to study changes in glycosylation.\n" ], "offsets": [ [ 0, 1104 ] ] } ]

[ { "id": "PMID-19126970_T1", "type": "Protein", "text": [ "transferrin" ], "offsets": [ [ 442, 453 ] ], "normalized": [] }, { "id": "PMID-19126970_T2", "type": "Protein", "text": [ "haptoglobin" ], "offsets": [ [ 455, 466 ] ], "normalized": [] }, { "id": "PMID-19126970_T3", "type": "Protein", "text": [ "alpha2-macroglobulin" ], "offsets": [ [ 468, 488 ] ], "normalized": [] }, { "id": "PMID-19126970_T4", "type": "Protein", "text": [ "C-reactive protein" ], "offsets": [ [ 490, 508 ] ], "normalized": [] } ]

[ { "id": "PMID-19126970_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 285, 298 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126970_T1" } ] }, { "id": "PMID-19126970_E2", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 285, 298 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126970_T2" } ] }, { "id": "PMID-19126970_E3", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 285, 298 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126970_T3" } ] }, { "id": "PMID-19126970_E4", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 285, 298 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19126970_T4" } ] } ]

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[ { "id": "PMID-19129460__text", "type": "abstract", "text": [ "Papillomavirus E2 proteins and the host BRD4 protein associate with transcriptionally active cellular chromatin. \nThe interaction of papillomavirus E2 proteins with cellular Brd4 protein is important for transcriptional regulation of viral genes and partitioning of viral genomes. Bovine papillomavirus type 1 (BPV-1) E2 binds cellular chromatin in complex with Brd4 in both mitotic and interphase cells. To identify specific sites of E2 interaction on cellular chromatin, a genome-wide chromatin immunoprecipitation-on-chip analysis was carried out using human promoter sequences. Both E2 and Brd4 were found bound to most transcriptionally active promoters in C33A cells. These promoters were also bound by RNA polymerase II and were modified by histone H3 acetylation and K4 trimethylation, all indicators of active transcription. E2 binding strongly correlated with Brd4 and RNA polymerase II occupancy and H3K4me3 modification at all human promoters, indicating that E2 bound to active promoters. E2 binding did not correlate with the presence of consensus E2 binding sites in the promoters. Furthermore, the mRNA levels of E2-bound cellular genes were not significantly changed by E2 expression. Thus, the papillomavirus E2 proteins bind to transcriptionally active cellular genes but do not change their activity. We propose that this may be a way for the virus to ensure that the viral genome is retained in transcriptionally active regions of the nucleus to escape silencing. Therefore, E2-mediated tethering of viral genomes to host chromatin has multiple roles: to partition the viral genome to daughter cells, to ensure that the genomes are retained in the nucleus, and to make certain that the genomes are retained in functionally active nuclear domains.\n" ], "offsets": [ [ 0, 1768 ] ] } ]

[ { "id": "PMID-19129460_T1", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 15, 17 ] ], "normalized": [] }, { "id": "PMID-19129460_T2", "type": "Protein", "text": [ "BRD4" ], "offsets": [ [ 40, 44 ] ], "normalized": [] }, { "id": "PMID-19129460_T3", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 148, 150 ] ], "normalized": [] }, { "id": "PMID-19129460_T4", "type": "Protein", "text": [ "Brd4" ], "offsets": [ [ 174, 178 ] ], "normalized": [] }, { "id": "PMID-19129460_T5", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 318, 320 ] ], "normalized": [] }, { "id": "PMID-19129460_T6", "type": "Protein", "text": [ "Brd4" ], "offsets": [ [ 362, 366 ] ], "normalized": [] }, { "id": "PMID-19129460_T7", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 435, 437 ] ], "normalized": [] }, { "id": "PMID-19129460_T8", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 587, 589 ] ], "normalized": [] }, { "id": "PMID-19129460_T9", "type": "Protein", "text": [ "Brd4" ], "offsets": [ [ 594, 598 ] ], "normalized": [] }, { "id": "PMID-19129460_T10", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 748, 758 ] ], "normalized": [] }, { "id": "PMID-19129460_T11", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 834, 836 ] ], "normalized": [] }, { "id": "PMID-19129460_T12", "type": "Protein", "text": [ "Brd4" ], "offsets": [ [ 870, 874 ] ], "normalized": [] }, { "id": "PMID-19129460_T13", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 911, 913 ] ], "normalized": [] }, { "id": "PMID-19129460_T14", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 972, 974 ] ], "normalized": [] }, { "id": "PMID-19129460_T15", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 1002, 1004 ] ], "normalized": [] }, { "id": "PMID-19129460_T16", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 1062, 1064 ] ], "normalized": [] }, { "id": "PMID-19129460_T17", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 1129, 1131 ] ], "normalized": [] }, { "id": "PMID-19129460_T18", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 1187, 1189 ] ], "normalized": [] }, { "id": "PMID-19129460_T19", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 1227, 1229 ] ], "normalized": [] }, { "id": "PMID-19129460_T20", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 1496, 1498 ] ], "normalized": [] }, { "id": "PMID-19129460_T22", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 775, 777 ] ], "normalized": [] } ]

[ { "id": "PMID-19129460_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 759, 770 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19129460_T10" } ] }, { "id": "PMID-19129460_E2", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 778, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19129460_T10" }, { "role": "Site", "ref_id": "PMID-19129460_T22" } ] } ]

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[ { "id": "PMID-19148291__text", "type": "abstract", "text": [ "Overexpression of myocilin in the Drosophila eye activates the unfolded protein response: implications for glaucoma. \nBACKGROUND: Glaucoma is the world's second leading cause of bilateral blindness with progressive loss of vision due to retinal ganglion cell death. Myocilin has been associated with congenital glaucoma and 2-4% of primary open angle glaucoma (POAG) cases, but the pathogenic mechanisms remain largely unknown. Among several hypotheses, activation of the unfolded protein response (UPR) has emerged as a possible disease mechanism. METHODOLOGY / PRINCIPAL FINDINGS: We used a transgenic Drosophila model to analyze whole-genome transcriptional profiles in flies that express human wild-type or mutant MYOC in their eyes. The transgenic flies display ocular fluid discharge, reflecting ocular hypertension, and a progressive decline in their behavioral responses to light. Transcriptional analysis shows that genes associated with the UPR, ubiquitination, and proteolysis, as well as metabolism of reactive oxygen species and photoreceptor activity undergo altered transcriptional regulation. Following up on the results from these transcriptional analyses, we used immunoblots to demonstrate the formation of MYOC aggregates and showed that the formation of such aggregates leads to induction of the UPR, as evident from activation of the fluorescent UPR marker, xbp1-EGFP. CONCLUSIONS / SIGNIFICANCE: Our results show that aggregation of MYOC in the endoplasmic reticulum activates the UPR, an evolutionarily conserved stress pathway that culminates in apoptosis. We infer from the Drosophila model that MYOC-associated ocular hypertension in the human eye may result from aggregation of MYOC and induction of the UPR in trabecular meshwork cells. This process could occur at a late age with wild-type MYOC, but might be accelerated by MYOC mutants to account for juvenile onset glaucoma.\n" ], "offsets": [ [ 0, 1907 ] ] } ]

[ { "id": "PMID-19148291_T1", "type": "Protein", "text": [ "myocilin" ], "offsets": [ [ 18, 26 ] ], "normalized": [] }, { "id": "PMID-19148291_T2", "type": "Protein", "text": [ "Myocilin" ], "offsets": [ [ 266, 274 ] ], "normalized": [] }, { "id": "PMID-19148291_T3", "type": "Protein", "text": [ "MYOC" ], "offsets": [ [ 718, 722 ] ], "normalized": [] }, { "id": "PMID-19148291_T4", "type": "Protein", "text": [ "MYOC" ], "offsets": [ [ 1226, 1230 ] ], "normalized": [] }, { "id": "PMID-19148291_T5", "type": "Protein", "text": [ "xbp1" ], "offsets": [ [ 1380, 1384 ] ], "normalized": [] }, { "id": "PMID-19148291_T6", "type": "Protein", "text": [ "EGFP" ], "offsets": [ [ 1385, 1389 ] ], "normalized": [] }, { "id": "PMID-19148291_T7", "type": "Protein", "text": [ "MYOC" ], "offsets": [ [ 1456, 1460 ] ], "normalized": [] }, { "id": "PMID-19148291_T8", "type": "Protein", "text": [ "MYOC" ], "offsets": [ [ 1622, 1626 ] ], "normalized": [] }, { "id": "PMID-19148291_T9", "type": "Protein", "text": [ "MYOC" ], "offsets": [ [ 1706, 1710 ] ], "normalized": [] }, { "id": "PMID-19148291_T10", "type": "Protein", "text": [ "MYOC" ], "offsets": [ [ 1820, 1824 ] ], "normalized": [] }, { "id": "PMID-19148291_T11", "type": "Protein", "text": [ "MYOC" ], "offsets": [ [ 1854, 1858 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-19166848__text", "type": "abstract", "text": [ "Degradation of FAT10 by the 26S proteasome is independent of ubiquitylation but relies on NUB1L. \nThe ubiquitin-like modifier FAT10 targets proteins for degradation by the proteasome, a process accelerated by the UBL-UBA domain protein NEDD8 ultimate buster 1-long. Here, we show that FAT10-mediated degradation occurs independently of poly-ubiquitylation as purified 26S proteasome readily degraded FAT10-dihydrofolate reductase (DHFR) but not ubiquitin-DHFR in vitro. Interestingly, the 26S proteasome could only degrade FAT10-DHFR when NUB1L was present. Knock-down of NUB1L attenuated the degradation of FAT10-DHFR in intact cells suggesting that NUB1L determines the degradation rate of FAT10-linked proteins. In conclusion, our data establish FAT10 as a ubiquitin-independent but NUB1L-dependent targeting signal for proteasomal degradation.\n" ], "offsets": [ [ 0, 848 ] ] } ]

[ { "id": "PMID-19166848_T1", "type": "Protein", "text": [ "FAT10" ], "offsets": [ [ 15, 20 ] ], "normalized": [] }, { "id": "PMID-19166848_T2", "type": "Protein", "text": [ "NUB1L" ], "offsets": [ [ 90, 95 ] ], "normalized": [] }, { "id": "PMID-19166848_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 102, 111 ] ], "normalized": [] }, { "id": "PMID-19166848_T4", "type": "Protein", "text": [ "FAT10" ], "offsets": [ [ 126, 131 ] ], "normalized": [] }, { "id": "PMID-19166848_T5", "type": "Protein", "text": [ "NEDD8 ultimate buster 1-long" ], "offsets": [ [ 236, 264 ] ], "normalized": [] }, { "id": "PMID-19166848_T6", "type": "Protein", "text": [ "FAT10" ], "offsets": [ [ 285, 290 ] ], "normalized": [] }, { "id": "PMID-19166848_T7", "type": "Protein", "text": [ "FAT10" ], "offsets": [ [ 400, 405 ] ], "normalized": [] }, { "id": "PMID-19166848_T8", "type": "Protein", "text": [ "dihydrofolate reductase" ], "offsets": [ [ 406, 429 ] ], "normalized": [] }, { "id": "PMID-19166848_T9", "type": "Protein", "text": [ "DHFR" ], "offsets": [ [ 431, 435 ] ], "normalized": [] }, { "id": "PMID-19166848_T10", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 445, 454 ] ], "normalized": [] }, { "id": "PMID-19166848_T11", "type": "Protein", "text": [ "DHFR" ], "offsets": [ [ 455, 459 ] ], "normalized": [] }, { "id": "PMID-19166848_T12", "type": "Protein", "text": [ "FAT10" ], "offsets": [ [ 523, 528 ] ], "normalized": [] }, { "id": "PMID-19166848_T13", "type": "Protein", "text": [ "DHFR" ], "offsets": [ [ 529, 533 ] ], "normalized": [] }, { "id": "PMID-19166848_T14", "type": "Protein", "text": [ "NUB1L" ], "offsets": [ [ 539, 544 ] ], "normalized": [] }, { "id": "PMID-19166848_T15", "type": "Protein", "text": [ "NUB1L" ], "offsets": [ [ 572, 577 ] ], "normalized": [] }, { "id": "PMID-19166848_T16", "type": "Protein", "text": [ "FAT10" ], "offsets": [ [ 608, 613 ] ], "normalized": [] }, { "id": "PMID-19166848_T17", "type": "Protein", "text": [ "DHFR" ], "offsets": [ [ 614, 618 ] ], "normalized": [] }, { "id": "PMID-19166848_T18", "type": "Protein", "text": [ "NUB1L" ], "offsets": [ [ 651, 656 ] ], "normalized": [] }, { "id": "PMID-19166848_T19", "type": "Protein", "text": [ "FAT10" ], "offsets": [ [ 692, 697 ] ], "normalized": [] }, { "id": "PMID-19166848_T20", "type": "Protein", "text": [ "FAT10" ], "offsets": [ [ 749, 754 ] ], "normalized": [] }, { "id": "PMID-19166848_T21", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 760, 769 ] ], "normalized": [] }, { "id": "PMID-19166848_T22", "type": "Protein", "text": [ "NUB1L" ], "offsets": [ [ 786, 791 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-19166848_1", "entity_ids": [ "PMID-19166848_T8", "PMID-19166848_T9" ] } ]

[]

[ { "id": "PMID-19171932__text", "type": "abstract", "text": [ "AMP-activated protein kinase phosphorylates R5/PTG, the glycogen targeting subunit of the R5/PTG-protein phosphatase 1 holoenzyme, and accelerates its down-regulation by the laforin-malin complex. \nR5/PTG is one of the glycogen targeting subunits of type 1 protein phosphatase, a master regulator of glycogen synthesis. R5/PTG recruits the phosphatase to the places where glycogen synthesis occurs, allowing the activation of glycogen synthase and the inactivation of glycogen phosphorylase, thus increasing glycogen synthesis and decreasing its degradation. In this report, we show that the activity of R5/PTG is regulated by AMP-activated protein kinase (AMPK). We demonstrate that AMPK interacts physically with R5/PTG and modifies its basal phosphorylation status. We have also mapped the major phosphorylation sites of R5/PTG by mass spectrometry analysis, observing that phosphorylation of Ser-8 and Ser-268 increased upon activation of AMPK. We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity. Thus, our results define a novel role of AMPK in glycogen homeostasis.\n" ], "offsets": [ [ 0, 1430 ] ] } ]

[ { "id": "PMID-19171932_T1", "type": "Protein", "text": [ "R5" ], "offsets": [ [ 44, 46 ] ], "normalized": [] }, { "id": "PMID-19171932_T2", "type": "Protein", "text": [ "PTG" ], "offsets": [ [ 47, 50 ] ], "normalized": [] }, { "id": "PMID-19171932_T3", "type": "Protein", "text": [ "R5" ], "offsets": [ [ 90, 92 ] ], "normalized": [] }, { "id": "PMID-19171932_T4", "type": "Protein", "text": [ "PTG" ], "offsets": [ [ 93, 96 ] ], "normalized": [] }, { "id": "PMID-19171932_T5", "type": "Protein", "text": [ "laforin" ], "offsets": [ [ 174, 181 ] ], "normalized": [] }, { "id": "PMID-19171932_T6", "type": "Protein", "text": [ "malin" ], "offsets": [ [ 182, 187 ] ], "normalized": [] }, { "id": "PMID-19171932_T7", "type": "Protein", "text": [ "R5" ], "offsets": [ [ 198, 200 ] ], "normalized": [] }, { "id": "PMID-19171932_T8", "type": "Protein", "text": [ "PTG" ], "offsets": [ [ 201, 204 ] ], "normalized": [] }, { "id": "PMID-19171932_T9", "type": "Protein", "text": [ "R5" ], "offsets": [ [ 320, 322 ] ], "normalized": [] }, { "id": "PMID-19171932_T10", "type": "Protein", "text": [ "PTG" ], "offsets": [ [ 323, 326 ] ], "normalized": [] }, { "id": "PMID-19171932_T11", "type": "Protein", "text": [ "R5" ], "offsets": [ [ 604, 606 ] ], "normalized": [] }, { "id": "PMID-19171932_T12", "type": "Protein", "text": [ "PTG" ], "offsets": [ [ 607, 610 ] ], "normalized": [] }, { "id": "PMID-19171932_T13", "type": "Protein", "text": [ "R5" ], "offsets": [ [ 715, 717 ] ], "normalized": [] }, { "id": "PMID-19171932_T14", "type": "Protein", "text": [ "PTG" ], "offsets": [ [ 718, 721 ] ], "normalized": [] }, { "id": "PMID-19171932_T15", "type": "Protein", "text": [ "R5" ], "offsets": [ [ 824, 826 ] ], "normalized": [] }, { "id": "PMID-19171932_T16", "type": "Protein", "text": [ "PTG" ], "offsets": [ [ 827, 830 ] ], "normalized": [] }, { "id": "PMID-19171932_T17", "type": "Protein", "text": [ "R5" ], "offsets": [ [ 997, 999 ] ], "normalized": [] }, { "id": "PMID-19171932_T18", "type": "Protein", "text": [ "PTG" ], "offsets": [ [ 1000, 1003 ] ], "normalized": [] }, { "id": "PMID-19171932_T19", "type": "Protein", "text": [ "laforin" ], "offsets": [ [ 1029, 1036 ] ], "normalized": [] }, { "id": "PMID-19171932_T20", "type": "Protein", "text": [ "malin" ], "offsets": [ [ 1037, 1042 ] ], "normalized": [] }, { "id": "PMID-19171932_T21", "type": "Protein", "text": [ "laforin" ], "offsets": [ [ 1096, 1103 ] ], "normalized": [] }, { "id": "PMID-19171932_T22", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1115, 1124 ] ], "normalized": [] }, { "id": "PMID-19171932_T23", "type": "Protein", "text": [ "malin" ], "offsets": [ [ 1133, 1138 ] ], "normalized": [] }, { "id": "PMID-19171932_T24", "type": "Protein", "text": [ "R5" ], "offsets": [ [ 1184, 1186 ] ], "normalized": [] }, { "id": "PMID-19171932_T25", "type": "Protein", "text": [ "PTG" ], "offsets": [ [ 1187, 1190 ] ], "normalized": [] }, { "id": "PMID-19171932_T26", "type": "Protein", "text": [ "laforin" ], "offsets": [ [ 1224, 1231 ] ], "normalized": [] }, { "id": "PMID-19171932_T27", "type": "Protein", "text": [ "malin" ], "offsets": [ [ 1232, 1237 ] ], "normalized": [] }, { "id": "PMID-19171932_T30", "type": "Entity", "text": [ "Ser-8" ], "offsets": [ [ 896, 901 ] ], "normalized": [] }, { "id": "PMID-19171932_T31", "type": "Entity", "text": [ "Ser-268" ], "offsets": [ [ 906, 913 ] ], "normalized": [] }, { "id": "PMID-19171932_T33", "type": "Entity", "text": [ "Ser-8" ], "offsets": [ [ 1194, 1199 ] ], "normalized": [] } ]

[ { "id": "PMID-19171932_E1", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 29, 43 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19171932_T1" } ] }, { "id": "PMID-19171932_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 877, 892 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19171932_T15" }, { "role": "Site", "ref_id": "PMID-19171932_T30" } ] }, { "id": "PMID-19171932_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 877, 892 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19171932_T15" }, { "role": "Site", "ref_id": "PMID-19171932_T31" } ] }, { "id": "PMID-19171932_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1165, 1180 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19171932_T24" }, { "role": "Site", "ref_id": "PMID-19171932_T33" } ] }, { "id": "PMID-19171932_E5", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1248, 1262 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19171932_T24" } ] } ]

[ { "id": "PMID-19171932_1", "entity_ids": [ "PMID-19171932_T1", "PMID-19171932_T2" ] }, { "id": "PMID-19171932_2", "entity_ids": [ "PMID-19171932_T3", "PMID-19171932_T4" ] }, { "id": "PMID-19171932_3", "entity_ids": [ "PMID-19171932_T7", "PMID-19171932_T8" ] }, { "id": "PMID-19171932_4", "entity_ids": [ "PMID-19171932_T9", "PMID-19171932_T10" ] }, { "id": "PMID-19171932_5", "entity_ids": [ "PMID-19171932_T11", "PMID-19171932_T12" ] }, { "id": "PMID-19171932_6", "entity_ids": [ "PMID-19171932_T13", "PMID-19171932_T14" ] }, { "id": "PMID-19171932_7", "entity_ids": [ "PMID-19171932_T15", "PMID-19171932_T16" ] }, { "id": "PMID-19171932_8", "entity_ids": [ "PMID-19171932_T17", "PMID-19171932_T18" ] }, { "id": "PMID-19171932_9", "entity_ids": [ "PMID-19171932_T24", "PMID-19171932_T25" ] } ]

[]

[ { "id": "PMID-19187765__text", "type": "abstract", "text": [ "ING4 mediates crosstalk between histone H3 K4 trimethylation and H3 acetylation to attenuate cellular transformation. \nAberrations in chromatin dynamics play a fundamental role in tumorigenesis, yet relatively little is known of the molecular mechanisms linking histone lysine methylation to neoplastic disease. ING4 (Inhibitor of Growth 4) is a native subunit of an HBO1 histone acetyltransferase (HAT) complex and a tumor suppressor protein. Here we show a critical role for specific recognition of histone H3 trimethylated at lysine 4 (H3K4me3) by the ING4 PHD finger in mediating ING4 gene expression and tumor suppressor functions. The interaction between ING4 and H3K4me3 augments HBO1 acetylation activity on H3 tails and drives H3 acetylation at ING4 target promoters. Further, ING4 facilitates apoptosis in response to genotoxic stress and inhibits anchorage-independent cell growth, and these functions depend on ING4 interactions with H3K4me3. Together, our results demonstrate a mechanism for brokering crosstalk between H3K4 methylation and H3 acetylation and reveal a molecular link between chromatin modulation and tumor suppressor mechanisms.\n" ], "offsets": [ [ 0, 1159 ] ] } ]

[ { "id": "PMID-19187765_T1", "type": "Protein", "text": [ "ING4" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-19187765_T2", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 32, 42 ] ], "normalized": [] }, { "id": "PMID-19187765_T3", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 65, 67 ] ], "normalized": [] }, { "id": "PMID-19187765_T4", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 262, 269 ] ], "normalized": [] }, { "id": "PMID-19187765_T5", "type": "Protein", "text": [ "ING4" ], "offsets": [ [ 312, 316 ] ], "normalized": [] }, { "id": "PMID-19187765_T6", "type": "Protein", "text": [ "Inhibitor of Growth 4" ], "offsets": [ [ 318, 339 ] ], "normalized": [] }, { "id": "PMID-19187765_T7", "type": "Protein", "text": [ "HBO1" ], "offsets": [ [ 367, 371 ] ], "normalized": [] }, { "id": "PMID-19187765_T8", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 501, 511 ] ], "normalized": [] }, { "id": "PMID-19187765_T9", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 539, 541 ] ], "normalized": [] }, { "id": "PMID-19187765_T10", "type": "Protein", "text": [ "ING4" ], "offsets": [ [ 555, 559 ] ], "normalized": [] }, { "id": "PMID-19187765_T11", "type": "Protein", "text": [ "ING4" ], "offsets": [ [ 584, 588 ] ], "normalized": [] }, { "id": "PMID-19187765_T12", "type": "Protein", "text": [ "ING4" ], "offsets": [ [ 661, 665 ] ], "normalized": [] }, { "id": "PMID-19187765_T13", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 670, 672 ] ], "normalized": [] }, { "id": "PMID-19187765_T14", "type": "Protein", "text": [ "HBO1" ], "offsets": [ [ 687, 691 ] ], "normalized": [] }, { "id": "PMID-19187765_T15", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 716, 718 ] ], "normalized": [] }, { "id": "PMID-19187765_T16", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 736, 738 ] ], "normalized": [] }, { "id": "PMID-19187765_T17", "type": "Protein", "text": [ "ING4" ], "offsets": [ [ 754, 758 ] ], "normalized": [] }, { "id": "PMID-19187765_T18", "type": "Protein", "text": [ "ING4" ], "offsets": [ [ 786, 790 ] ], "normalized": [] }, { "id": "PMID-19187765_T19", "type": "Protein", "text": [ "ING4" ], "offsets": [ [ 923, 927 ] ], "normalized": [] }, { "id": "PMID-19187765_T20", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 946, 948 ] ], "normalized": [] }, { "id": "PMID-19187765_T21", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1033, 1035 ] ], "normalized": [] }, { "id": "PMID-19187765_T22", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1054, 1056 ] ], "normalized": [] }, { "id": "PMID-19187765_T23", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 43, 45 ] ], "normalized": [] }, { "id": "PMID-19187765_T26", "type": "Entity", "text": [ "lysine" ], "offsets": [ [ 270, 276 ] ], "normalized": [] }, { "id": "PMID-19187765_T29", "type": "Entity", "text": [ "lysine 4" ], "offsets": [ [ 529, 537 ] ], "normalized": [] }, { "id": "PMID-19187765_T30", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 541, 543 ] ], "normalized": [] }, { "id": "PMID-19187765_T32", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 1035, 1037 ] ], "normalized": [] } ]

[ { "id": "PMID-19187765_E1", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 46, 60 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19187765_T2" }, { "role": "Site", "ref_id": "PMID-19187765_T23" } ] }, { "id": "PMID-19187765_E2", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 68, 79 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19187765_T3" } ] }, { "id": "PMID-19187765_E3", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 277, 288 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19187765_T4" }, { "role": "Site", "ref_id": "PMID-19187765_T26" } ] }, { "id": "PMID-19187765_E4", "type": "Methylation", "trigger": { "text": [ "trimethylated" ], "offsets": [ [ 512, 525 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19187765_T8" }, { "role": "Site", "ref_id": "PMID-19187765_T29" } ] }, { "id": "PMID-19187765_E5", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 739, 750 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19187765_T16" } ] }, { "id": "PMID-19187765_E6", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1038, 1049 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19187765_T21" }, { "role": "Site", "ref_id": "PMID-19187765_T32" } ] }, { "id": "PMID-19187765_E7", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1057, 1068 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19187765_T22" } ] } ]

[ { "id": "PMID-19187765_1", "entity_ids": [ "PMID-19187765_T5", "PMID-19187765_T6" ] }, { "id": "PMID-19187765_2", "entity_ids": [ "PMID-19187765_T8", "PMID-19187765_T9" ] }, { "id": "PMID-19187765_3", "entity_ids": [ "PMID-19187765_T29", "PMID-19187765_T30" ] } ]

[]

[ { "id": "PMID-19196961__text", "type": "abstract", "text": [ "CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. \nMutation in leucine-rich repeat kinase-2 (LRRK2) is the most common cause of late-onset Parkinson's disease (PD). Although most cases of PD are sporadic, some are inherited, including those caused by LRRK2 mutations. Because these mutations may be associated with a toxic gain of function, controlling the expression of LRRK2 may decrease its cytotoxicity. Here we show that the carboxyl terminus of HSP70-interacting protein (CHIP) binds, ubiquitinates, and promotes the ubiquitin proteasomal degradation of LRRK2. Overexpression of CHIP protects against and knockdown of CHIP exacerbates toxicity mediated by mutant LRRK2. Moreover, HSP90 forms a complex with LRRK2, and inhibition of HSP90 chaperone activity by 17AAG leads to proteasomal degradation of LRRK2, resulting in increased cell viability. Thus, increasing CHIP E3 ligase activity and blocking HSP90 chaperone activity can prevent the deleterious effects of LRRK2. These findings point to potential treatment options for LRRK2-associated PD.\n" ], "offsets": [ [ 0, 1093 ] ] } ]

[ { "id": "PMID-19196961_T1", "type": "Protein", "text": [ "CHIP" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-19196961_T2", "type": "Protein", "text": [ "leucine-rich repeat kinase-2" ], "offsets": [ [ 15, 43 ] ], "normalized": [] }, { "id": "PMID-19196961_T3", "type": "Protein", "text": [ "leucine-rich repeat kinase-2" ], "offsets": [ [ 100, 128 ] ], "normalized": [] }, { "id": "PMID-19196961_T4", "type": "Protein", "text": [ "LRRK2" ], "offsets": [ [ 130, 135 ] ], "normalized": [] }, { "id": "PMID-19196961_T5", "type": "Protein", "text": [ "LRRK2" ], "offsets": [ [ 288, 293 ] ], "normalized": [] }, { "id": "PMID-19196961_T6", "type": "Protein", "text": [ "LRRK2" ], "offsets": [ [ 408, 413 ] ], "normalized": [] }, { "id": "PMID-19196961_T7", "type": "Protein", "text": [ "carboxyl terminus of HSP70-interacting protein" ], "offsets": [ [ 467, 513 ] ], "normalized": [] }, { "id": "PMID-19196961_T8", "type": "Protein", "text": [ "CHIP" ], "offsets": [ [ 515, 519 ] ], "normalized": [] }, { "id": "PMID-19196961_T9", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 560, 569 ] ], "normalized": [] }, { "id": "PMID-19196961_T10", "type": "Protein", "text": [ "LRRK2" ], "offsets": [ [ 597, 602 ] ], "normalized": [] }, { "id": "PMID-19196961_T11", "type": "Protein", "text": [ "CHIP" ], "offsets": [ [ 622, 626 ] ], "normalized": [] }, { "id": "PMID-19196961_T12", "type": "Protein", "text": [ "CHIP" ], "offsets": [ [ 661, 665 ] ], "normalized": [] }, { "id": "PMID-19196961_T13", "type": "Protein", "text": [ "LRRK2" ], "offsets": [ [ 706, 711 ] ], "normalized": [] }, { "id": "PMID-19196961_T14", "type": "Protein", "text": [ "LRRK2" ], "offsets": [ [ 750, 755 ] ], "normalized": [] }, { "id": "PMID-19196961_T15", "type": "Protein", "text": [ "LRRK2" ], "offsets": [ [ 845, 850 ] ], "normalized": [] }, { "id": "PMID-19196961_T16", "type": "Protein", "text": [ "CHIP" ], "offsets": [ [ 908, 912 ] ], "normalized": [] }, { "id": "PMID-19196961_T17", "type": "Protein", "text": [ "LRRK2" ], "offsets": [ [ 1009, 1014 ] ], "normalized": [] }, { "id": "PMID-19196961_T18", "type": "Protein", "text": [ "LRRK2" ], "offsets": [ [ 1072, 1077 ] ], "normalized": [] } ]

[ { "id": "PMID-19196961_E1", "type": "Catalysis", "trigger": { "text": [ "regulates" ], "offsets": [ [ 5, 14 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19196961_E2" }, { "role": "Cause", "ref_id": "PMID-19196961_T1" } ] }, { "id": "PMID-19196961_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 44, 58 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19196961_T2" } ] }, { "id": "PMID-19196961_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinates" ], "offsets": [ [ 528, 541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19196961_T10" } ] }, { "id": "PMID-19196961_E4", "type": "Catalysis", "trigger": { "text": [ "ubiquitinates" ], "offsets": [ [ 528, 541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19196961_E3" }, { "role": "Cause", "ref_id": "PMID-19196961_T7" } ] } ]

[ { "id": "PMID-19196961_1", "entity_ids": [ "PMID-19196961_T3", "PMID-19196961_T4" ] }, { "id": "PMID-19196961_2", "entity_ids": [ "PMID-19196961_T7", "PMID-19196961_T8" ] } ]

[]

[ { "id": "PMID-19208354__text", "type": "abstract", "text": [ "Impaired trafficking and subcellular localization of a mutant lactase associated with congenital lactase deficiency. \nBACKGROUND & AIMS: Congenital lactase deficiency (CLD) is a cause of disaccharide intolerance and malabsorption characterized by watery diarrhea in infants fed breast milk or lactose-containing formulas. The molecular basis of CLD is unknown. Mutations in the coding region of the brush border enzyme lactase phlorizin hydrolase (LPH) were found to cause CLD in a study of 19 Finnish families. We analyzed the effects of one of these mutations, G1363S, on LPH folding, trafficking, and function. METHODS: We introduced a mutation into the LPH complementary DNA that resulted in the amino acid substitution G1363S. The mutant gene was transiently expressed in COS-1 cells, and the effects were assessed at the protein, structural, and subcellular levels. RESULTS: The mutant protein LPH-G1363S was misfolded and could not exit the endoplasmic reticulum. Interestingly, the mutation creates an additional N-glycosylation site that is characteristic of a temperature-sensitive protein. The intracellular transport and enzymatic activity, but not correct folding, of LPH-G1363S were partially restored by expression at 20 degrees C. However, a form of LPH that contains the mutations G1363S and N1361A, which eliminates the N-glycosylation site, did not restore the features of wild-type LPH. Thus, the additional glycosyl group is not required for the LPH-G1363S defects. CONCLUSIONS: This is the first characterization, at the molecular and subcellular levels, of a mutant form of LPH that is involved in the pathogenesis of CLD. Mutant LPH accumulates predominantly in the endoplasmic reticulum but can partially mature at a permissive temperature; these features are unique for a protein involved in a carbohydrate malabsorption defect implicating LPH.\n" ], "offsets": [ [ 0, 1871 ] ] } ]

[ { "id": "PMID-19208354_T1", "type": "Protein", "text": [ "lactase phlorizin hydrolase" ], "offsets": [ [ 419, 446 ] ], "normalized": [] }, { "id": "PMID-19208354_T2", "type": "Protein", "text": [ "LPH" ], "offsets": [ [ 448, 451 ] ], "normalized": [] }, { "id": "PMID-19208354_T3", "type": "Protein", "text": [ "LPH" ], "offsets": [ [ 574, 577 ] ], "normalized": [] }, { "id": "PMID-19208354_T4", "type": "Protein", "text": [ "LPH" ], "offsets": [ [ 657, 660 ] ], "normalized": [] }, { "id": "PMID-19208354_T5", "type": "Protein", "text": [ "LPH" ], "offsets": [ [ 900, 903 ] ], "normalized": [] }, { "id": "PMID-19208354_T6", "type": "Protein", "text": [ "LPH" ], "offsets": [ [ 1181, 1184 ] ], "normalized": [] }, { "id": "PMID-19208354_T7", "type": "Protein", "text": [ "LPH" ], "offsets": [ [ 1266, 1269 ] ], "normalized": [] }, { "id": "PMID-19208354_T8", "type": "Protein", "text": [ "LPH" ], "offsets": [ [ 1402, 1405 ] ], "normalized": [] }, { "id": "PMID-19208354_T9", "type": "Protein", "text": [ "LPH" ], "offsets": [ [ 1467, 1470 ] ], "normalized": [] }, { "id": "PMID-19208354_T10", "type": "Protein", "text": [ "LPH" ], "offsets": [ [ 1597, 1600 ] ], "normalized": [] }, { "id": "PMID-19208354_T11", "type": "Protein", "text": [ "LPH" ], "offsets": [ [ 1653, 1656 ] ], "normalized": [] }, { "id": "PMID-19208354_T12", "type": "Protein", "text": [ "LPH" ], "offsets": [ [ 1866, 1869 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-19208354_1", "entity_ids": [ "PMID-19208354_T1", "PMID-19208354_T2" ] } ]

[]

[ { "id": "PMID-19228710__text", "type": "abstract", "text": [ "RAD18 promotes DNA double-strand break repair during G1 phase through chromatin retention of 53BP1. \nRecruitment of RAD18 to stalled replication forks facilitates monoubiquitination of PCNA during S-phase, promoting translesion synthesis at sites of UV irradiation-induced DNA damage. In this study, we show that RAD18 is also recruited to ionizing radiation (IR)-induced sites of DNA double-strand breaks (DSBs) forming foci which are co-localized with 53BP1, NBS1, phosphorylated ATM, BRCA1 and gamma-H2AX. RAD18 associates with 53BP1 and is recruited to DSB sites in a 53BP1-dependent manner specifically during G1-phase, RAD18 monoubiquitinates KBD domain of 53BP1 at lysine 1268 in vitro. A monoubiquitination-resistant 53BP1 mutant harboring a substitution at lysine 1268 is not retained efficiently at the chromatin in the vicinity of DSBs. In Rad18-null cells, retention of 53BP1 foci, efficiency of DSB repair and post-irradiation viability are impaired compared with wild-type cells. Taken together, these results suggest that RAD18 promotes 53BP1-directed DSB repair by enhancing retention of 53BP1, possibly through an interaction between RAD18 and 53BP1 and the modification of 53BP1.\n" ], "offsets": [ [ 0, 1198 ] ] } ]

[ { "id": "PMID-19228710_T1", "type": "Protein", "text": [ "RAD18" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-19228710_T2", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 93, 98 ] ], "normalized": [] }, { "id": "PMID-19228710_T3", "type": "Protein", "text": [ "RAD18" ], "offsets": [ [ 116, 121 ] ], "normalized": [] }, { "id": "PMID-19228710_T4", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 185, 189 ] ], "normalized": [] }, { "id": "PMID-19228710_T5", "type": "Protein", "text": [ "RAD18" ], "offsets": [ [ 313, 318 ] ], "normalized": [] }, { "id": "PMID-19228710_T6", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 454, 459 ] ], "normalized": [] }, { "id": "PMID-19228710_T7", "type": "Protein", "text": [ "NBS1" ], "offsets": [ [ 461, 465 ] ], "normalized": [] }, { "id": "PMID-19228710_T8", "type": "Protein", "text": [ "ATM" ], "offsets": [ [ 482, 485 ] ], "normalized": [] }, { "id": "PMID-19228710_T9", "type": "Protein", "text": [ "BRCA1" ], "offsets": [ [ 487, 492 ] ], "normalized": [] }, { "id": "PMID-19228710_T10", "type": "Protein", "text": [ "H2AX" ], "offsets": [ [ 503, 507 ] ], "normalized": [] }, { "id": "PMID-19228710_T11", "type": "Protein", "text": [ "RAD18" ], "offsets": [ [ 509, 514 ] ], "normalized": [] }, { "id": "PMID-19228710_T12", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 531, 536 ] ], "normalized": [] }, { "id": "PMID-19228710_T13", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 572, 577 ] ], "normalized": [] }, { "id": "PMID-19228710_T14", "type": "Protein", "text": [ "RAD18" ], "offsets": [ [ 625, 630 ] ], "normalized": [] }, { "id": "PMID-19228710_T15", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 663, 668 ] ], "normalized": [] }, { "id": "PMID-19228710_T16", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 725, 730 ] ], "normalized": [] }, { "id": "PMID-19228710_T17", "type": "Protein", "text": [ "Rad18" ], "offsets": [ [ 851, 856 ] ], "normalized": [] }, { "id": "PMID-19228710_T18", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 882, 887 ] ], "normalized": [] }, { "id": "PMID-19228710_T19", "type": "Protein", "text": [ "RAD18" ], "offsets": [ [ 1037, 1042 ] ], "normalized": [] }, { "id": "PMID-19228710_T20", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 1052, 1057 ] ], "normalized": [] }, { "id": "PMID-19228710_T21", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 1104, 1109 ] ], "normalized": [] }, { "id": "PMID-19228710_T22", "type": "Protein", "text": [ "RAD18" ], "offsets": [ [ 1151, 1156 ] ], "normalized": [] }, { "id": "PMID-19228710_T23", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 1161, 1166 ] ], "normalized": [] }, { "id": "PMID-19228710_T24", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 1191, 1196 ] ], "normalized": [] }, { "id": "PMID-19228710_T29", "type": "Entity", "text": [ "lysine 1268" ], "offsets": [ [ 672, 683 ] ], "normalized": [] } ]

[ { "id": "PMID-19228710_E1", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitination" ], "offsets": [ [ 163, 181 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19228710_T4" } ] }, { "id": "PMID-19228710_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 467, 481 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19228710_T8" } ] }, { "id": "PMID-19228710_E3", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitinates" ], "offsets": [ [ 631, 648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19228710_T15" }, { "role": "Site", "ref_id": "PMID-19228710_T29" } ] }, { "id": "PMID-19228710_E4", "type": "Catalysis", "trigger": { "text": [ "monoubiquitinates" ], "offsets": [ [ 631, 648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19228710_E3" }, { "role": "Cause", "ref_id": "PMID-19228710_T14" } ] }, { "id": "PMID-19228710_E5", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitination-resistant" ], "offsets": [ [ 696, 724 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19228710_T16" } ] } ]

[]

[]

[ { "id": "PMID-19228967__text", "type": "abstract", "text": [ "The cochaperone BAG2 sweeps paired helical filament- insoluble tau from the microtubule. \nTau inclusions are a prominent feature of many neurodegenerative diseases including Alzheimer's disease. Their accumulation in neurons as ubiquitinated filaments suggests a failure in the degradation limb of the Tau pathway. The components of a Tau protein triage system consisting of CHIP/Hsp70 and other chaperones have begun to emerge. However, the site of triage and the master regulatory elements are unknown. Here, we report an elegant mechanism of Tau degradation involving the cochaperone BAG2. The BAG2/Hsp70 complex is tethered to the microtubule and this complex can capture and deliver Tau to the proteasome for ubiquitin-independent degradation. This complex preferentially degrades Sarkosyl insoluble Tau and phosphorylated Tau. BAG2 levels in cells are under the physiological control of the microRNA miR-128a, which can tune paired helical filament Tau levels in neurons. Thus, we propose that ubiquitinated Tau inclusions arise due to shunting of Tau degradation toward a less efficient ubiquitin-dependent pathway.\n" ], "offsets": [ [ 0, 1123 ] ] } ]

[ { "id": "PMID-19228967_T1", "type": "Protein", "text": [ "BAG2" ], "offsets": [ [ 16, 20 ] ], "normalized": [] }, { "id": "PMID-19228967_T2", "type": "Protein", "text": [ "tau" ], "offsets": [ [ 63, 66 ] ], "normalized": [] }, { "id": "PMID-19228967_T3", "type": "Protein", "text": [ "Tau" ], "offsets": [ [ 90, 93 ] ], "normalized": [] }, { "id": "PMID-19228967_T4", "type": "Protein", "text": [ "Tau" ], "offsets": [ [ 302, 305 ] ], "normalized": [] }, { "id": "PMID-19228967_T5", "type": "Protein", "text": [ "Tau" ], "offsets": [ [ 335, 338 ] ], "normalized": [] }, { "id": "PMID-19228967_T6", "type": "Protein", "text": [ "CHIP" ], "offsets": [ [ 375, 379 ] ], "normalized": [] }, { "id": "PMID-19228967_T7", "type": "Protein", "text": [ "Tau" ], "offsets": [ [ 545, 548 ] ], "normalized": [] }, { "id": "PMID-19228967_T8", "type": "Protein", "text": [ "BAG2" ], "offsets": [ [ 587, 591 ] ], "normalized": [] }, { "id": "PMID-19228967_T9", "type": "Protein", "text": [ "BAG2" ], "offsets": [ [ 597, 601 ] ], "normalized": [] }, { "id": "PMID-19228967_T10", "type": "Protein", "text": [ "Tau" ], "offsets": [ [ 688, 691 ] ], "normalized": [] }, { "id": "PMID-19228967_T11", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 714, 723 ] ], "normalized": [] }, { "id": "PMID-19228967_T12", "type": "Protein", "text": [ "Tau" ], "offsets": [ [ 805, 808 ] ], "normalized": [] }, { "id": "PMID-19228967_T13", "type": "Protein", "text": [ "Tau" ], "offsets": [ [ 828, 831 ] ], "normalized": [] }, { "id": "PMID-19228967_T14", "type": "Protein", "text": [ "BAG2" ], "offsets": [ [ 833, 837 ] ], "normalized": [] }, { "id": "PMID-19228967_T15", "type": "Protein", "text": [ "miR-128a" ], "offsets": [ [ 906, 914 ] ], "normalized": [] }, { "id": "PMID-19228967_T16", "type": "Protein", "text": [ "Tau" ], "offsets": [ [ 955, 958 ] ], "normalized": [] }, { "id": "PMID-19228967_T17", "type": "Protein", "text": [ "Tau" ], "offsets": [ [ 1014, 1017 ] ], "normalized": [] }, { "id": "PMID-19228967_T18", "type": "Protein", "text": [ "Tau" ], "offsets": [ [ 1054, 1057 ] ], "normalized": [] }, { "id": "PMID-19228967_T19", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1094, 1103 ] ], "normalized": [] } ]

[ { "id": "PMID-19228967_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 228, 241 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19228967_T3" } ] }, { "id": "PMID-19228967_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 813, 827 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19228967_T13" } ] }, { "id": "PMID-19228967_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 1000, 1013 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19228967_T17" } ] } ]

[]

[]

[ { "id": "PMID-19229105__text", "type": "abstract", "text": [ "Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. \nMutations in PARKIN, pten-induced putative kinase 1 (PINK1), and DJ-1 are individually linked to autosomal recessive early-onset familial forms of Parkinson disease (PD). Although mutations in these genes lead to the same disease state, the functional relationships between them and how their respective disease-associated mutations cause PD are largely unknown. Here, we show that Parkin, PINK1, and DJ-1 formed a complex (termed PPD complex) to promote ubiquitination and degradation of Parkin substrates, including Parkin itself and Synphilin-1 in neuroblastoma cells and human brain lysates. Genetic ablation of either Pink1 or Dj-1 resulted in reduced ubiquitination of endogenous Parkin as well as decreased degradation and increased accumulation of aberrantly expressed Parkin substrates. Expression of PINK1 enhanced Parkin-mediated degradation of heat shock-induced misfolded protein. In contrast, PD-pathogenic Parkin and PINK1 mutations showed reduced ability to promote degradation of Parkin substrates. This study identified a functional ubiquitin E3 ligase complex consisting of PD-associated Parkin, PINK1, and DJ-1 to promote degradation of un-/misfolded proteins and suggests that their PD-pathogenic mutations impair E3 ligase activity of the complex, which may constitute a mechanism underlying PD pathogenesis.\n" ], "offsets": [ [ 0, 1431 ] ] } ]

[ { "id": "PMID-19229105_T1", "type": "Protein", "text": [ "Parkin" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "PMID-19229105_T2", "type": "Protein", "text": [ "PINK1" ], "offsets": [ [ 8, 13 ] ], "normalized": [] }, { "id": "PMID-19229105_T3", "type": "Protein", "text": [ "DJ-1" ], "offsets": [ [ 19, 23 ] ], "normalized": [] }, { "id": "PMID-19229105_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 31, 40 ] ], "normalized": [] }, { "id": "PMID-19229105_T5", "type": "Protein", "text": [ "PARKIN" ], "offsets": [ [ 113, 119 ] ], "normalized": [] }, { "id": "PMID-19229105_T6", "type": "Protein", "text": [ "pten-induced putative kinase 1" ], "offsets": [ [ 121, 151 ] ], "normalized": [] }, { "id": "PMID-19229105_T7", "type": "Protein", "text": [ "PINK1" ], "offsets": [ [ 153, 158 ] ], "normalized": [] }, { "id": "PMID-19229105_T8", "type": "Protein", "text": [ "DJ-1" ], "offsets": [ [ 165, 169 ] ], "normalized": [] }, { "id": "PMID-19229105_T9", "type": "Protein", "text": [ "Parkin" ], "offsets": [ [ 482, 488 ] ], "normalized": [] }, { "id": "PMID-19229105_T10", "type": "Protein", "text": [ "PINK1" ], "offsets": [ [ 490, 495 ] ], "normalized": [] }, { "id": "PMID-19229105_T11", "type": "Protein", "text": [ "DJ-1" ], "offsets": [ [ 501, 505 ] ], "normalized": [] }, { "id": "PMID-19229105_T12", "type": "Protein", "text": [ "Parkin" ], "offsets": [ [ 589, 595 ] ], "normalized": [] }, { "id": "PMID-19229105_T13", "type": "Protein", "text": [ "Parkin" ], "offsets": [ [ 618, 624 ] ], "normalized": [] }, { "id": "PMID-19229105_T14", "type": "Protein", "text": [ "Synphilin-1" ], "offsets": [ [ 636, 647 ] ], "normalized": [] }, { "id": "PMID-19229105_T15", "type": "Protein", "text": [ "Pink1" ], "offsets": [ [ 723, 728 ] ], "normalized": [] }, { "id": "PMID-19229105_T16", "type": "Protein", "text": [ "Dj-1" ], "offsets": [ [ 732, 736 ] ], "normalized": [] }, { "id": "PMID-19229105_T17", "type": "Protein", "text": [ "Parkin" ], "offsets": [ [ 786, 792 ] ], "normalized": [] }, { "id": "PMID-19229105_T18", "type": "Protein", "text": [ "Parkin" ], "offsets": [ [ 877, 883 ] ], "normalized": [] }, { "id": "PMID-19229105_T19", "type": "Protein", "text": [ "PINK1" ], "offsets": [ [ 910, 915 ] ], "normalized": [] }, { "id": "PMID-19229105_T20", "type": "Protein", "text": [ "Parkin" ], "offsets": [ [ 925, 931 ] ], "normalized": [] }, { "id": "PMID-19229105_T21", "type": "Protein", "text": [ "Parkin" ], "offsets": [ [ 1021, 1027 ] ], "normalized": [] }, { "id": "PMID-19229105_T22", "type": "Protein", "text": [ "PINK1" ], "offsets": [ [ 1032, 1037 ] ], "normalized": [] }, { "id": "PMID-19229105_T23", "type": "Protein", "text": [ "Parkin" ], "offsets": [ [ 1097, 1103 ] ], "normalized": [] }, { "id": "PMID-19229105_T24", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1151, 1160 ] ], "normalized": [] }, { "id": "PMID-19229105_T25", "type": "Protein", "text": [ "Parkin" ], "offsets": [ [ 1207, 1213 ] ], "normalized": [] }, { "id": "PMID-19229105_T26", "type": "Protein", "text": [ "PINK1" ], "offsets": [ [ 1215, 1220 ] ], "normalized": [] }, { "id": "PMID-19229105_T27", "type": "Protein", "text": [ "DJ-1" ], "offsets": [ [ 1226, 1230 ] ], "normalized": [] } ]

[ { "id": "PMID-19229105_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 555, 569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19229105_T13" } ] }, { "id": "PMID-19229105_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 555, 569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19229105_T14" } ] }, { "id": "PMID-19229105_E3", "type": "Catalysis", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 555, 569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19229105_E1" }, { "role": "Cause", "ref_id": "PMID-19229105_T12" } ] }, { "id": "PMID-19229105_E4", "type": "Catalysis", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 555, 569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19229105_E2" }, { "role": "Cause", "ref_id": "PMID-19229105_T12" } ] }, { "id": "PMID-19229105_E5", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 757, 771 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19229105_T17" } ] } ]

[ { "id": "PMID-19229105_1", "entity_ids": [ "PMID-19229105_T6", "PMID-19229105_T7" ] } ]

[]

[ { "id": "PMID-19230796__text", "type": "abstract", "text": [ "The role of RAD6 in recombinational repair, checkpoints and meiosis via histone modification. \nThe Rad6 ubiquitin-conjugating enzyme in Saccharomyces cerevisiae is known to interact with three separate ubiquitin ligase proteins (Ubr1, Rad18, and Bre1) specific to different targets. The Rad6/Rad18 complex is central to translesion synthesis and the family of DNA transactions known as post-replication repair (PRR). A less well-known aspect of Rad6-mediated DNA repair, however, involves its function with Bre1 in mono-ubiquitinating the histone H2B residue lysine 123. Here, we review how this ubiquitination impacts histone H3 methylation, and how this in turn impacts the DNA damage response. In S. cerevisiae this pathway is required for checkpoint activation in G1, and contributes to DNA repair via the homologous recombination pathway (HRR) in G2 cells. Thus, RAD6 clearly plays a role in HRR in addition to its central role in PRR. We also summarize what is known about related repair pathways in other eukaryotes, including mammals. Recent literature emphasizes the role of methylated histones in S. cerevisiae, Schizosaccharomyces pombe and mammals in attracting the related DNA damage checkpoint proteins Rad9, Crb2 and 53BP1, respectively, to chromatin at the sites of DNA double-strand breaks. However, the specific histone modification pathways involved diverge in these different eukaryotes.\n" ], "offsets": [ [ 0, 1408 ] ] } ]

[ { "id": "PMID-19230796_T1", "type": "Protein", "text": [ "RAD6" ], "offsets": [ [ 12, 16 ] ], "normalized": [] }, { "id": "PMID-19230796_T2", "type": "Protein", "text": [ "Rad6" ], "offsets": [ [ 99, 103 ] ], "normalized": [] }, { "id": "PMID-19230796_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 104, 113 ] ], "normalized": [] }, { "id": "PMID-19230796_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 202, 211 ] ], "normalized": [] }, { "id": "PMID-19230796_T5", "type": "Protein", "text": [ "Ubr1" ], "offsets": [ [ 229, 233 ] ], "normalized": [] }, { "id": "PMID-19230796_T6", "type": "Protein", "text": [ "Rad18" ], "offsets": [ [ 235, 240 ] ], "normalized": [] }, { "id": "PMID-19230796_T7", "type": "Protein", "text": [ "Bre1" ], "offsets": [ [ 246, 250 ] ], "normalized": [] }, { "id": "PMID-19230796_T8", "type": "Protein", "text": [ "Rad6" ], "offsets": [ [ 287, 291 ] ], "normalized": [] }, { "id": "PMID-19230796_T9", "type": "Protein", "text": [ "Rad18" ], "offsets": [ [ 292, 297 ] ], "normalized": [] }, { "id": "PMID-19230796_T10", "type": "Protein", "text": [ "Rad6" ], "offsets": [ [ 445, 449 ] ], "normalized": [] }, { "id": "PMID-19230796_T11", "type": "Protein", "text": [ "Bre1" ], "offsets": [ [ 507, 511 ] ], "normalized": [] }, { "id": "PMID-19230796_T12", "type": "Protein", "text": [ "histone H2B" ], "offsets": [ [ 539, 550 ] ], "normalized": [] }, { "id": "PMID-19230796_T13", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 619, 629 ] ], "normalized": [] }, { "id": "PMID-19230796_T14", "type": "Protein", "text": [ "RAD6" ], "offsets": [ [ 868, 872 ] ], "normalized": [] }, { "id": "PMID-19230796_T15", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 1095, 1103 ] ], "normalized": [] }, { "id": "PMID-19230796_T16", "type": "Protein", "text": [ "Rad9" ], "offsets": [ [ 1217, 1221 ] ], "normalized": [] }, { "id": "PMID-19230796_T17", "type": "Protein", "text": [ "Crb2" ], "offsets": [ [ 1223, 1227 ] ], "normalized": [] }, { "id": "PMID-19230796_T18", "type": "Protein", "text": [ "53BP1" ], "offsets": [ [ 1232, 1237 ] ], "normalized": [] }, { "id": "PMID-19230796_T19", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1330, 1337 ] ], "normalized": [] }, { "id": "PMID-19230796_T21", "type": "Entity", "text": [ "lysine 123" ], "offsets": [ [ 559, 569 ] ], "normalized": [] } ]

[ { "id": "PMID-19230796_E1", "type": "Ubiquitination", "trigger": { "text": [ "mono-ubiquitinating" ], "offsets": [ [ 515, 534 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19230796_T12" }, { "role": "Site", "ref_id": "PMID-19230796_T21" } ] }, { "id": "PMID-19230796_E2", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 630, 641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19230796_T13" } ] }, { "id": "PMID-19230796_E3", "type": "Methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1084, 1094 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19230796_T15" } ] } ]

[]

[]

[ { "id": "PMID-19230833__text", "type": "abstract", "text": [ "PKR-mediated degradation of STAT1 regulates osteoblast differentiation. \nThe double-stranded RNA-dependent protein kinase (PKR) plays a critical role in various biological responses including antiviral defense, cell differentiation, apoptosis, and tumorigenesis. In this study, we investigated whether PKR could affect the post-translational modifications of STAT1 protein and whether these modifications regulate osteoblast differentiation. We demonstrated that PKR was necessary for the ubiquitination of STAT1 protein. The expressions of bone-related genes such as type I collagen, integrin binding sialoprotein, osteopontin, and osterix were suppressed in osteoblasts lacking PKR activity. In contrast, the expressions of interleukin-6 and matrix metalloproteinases 8 and 13 increased in PKR-mutated osteoblasts. The expression and degradation of STAT1 protein were regulated by PKR in a SLIM-dependent pathway. Inhibition of SLIM by RNA interference resulted in the decreased activity of Runx2 in osteoblasts. Stimulation of interleukin-6 expression and suppression of alkaline phosphatase activity were regulated through by SLIM-dependent pathway. However, expressions of bone-related genes and MMPs were regulated by SLIM-independent pathway. Our present results suggest that the aberrant accumulation of STAT1 protein induced by loss of PKR regulate osteoblast differentiation through both SLIM/STAT1-dependent and -independent pathways.\n" ], "offsets": [ [ 0, 1446 ] ] } ]

[ { "id": "PMID-19230833_T1", "type": "Protein", "text": [ "PKR" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-19230833_T2", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 28, 33 ] ], "normalized": [] }, { "id": "PMID-19230833_T3", "type": "Protein", "text": [ "double-stranded RNA-dependent protein kinase" ], "offsets": [ [ 77, 121 ] ], "normalized": [] }, { "id": "PMID-19230833_T4", "type": "Protein", "text": [ "PKR" ], "offsets": [ [ 123, 126 ] ], "normalized": [] }, { "id": "PMID-19230833_T5", "type": "Protein", "text": [ "PKR" ], "offsets": [ [ 302, 305 ] ], "normalized": [] }, { "id": "PMID-19230833_T6", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 359, 364 ] ], "normalized": [] }, { "id": "PMID-19230833_T7", "type": "Protein", "text": [ "PKR" ], "offsets": [ [ 463, 466 ] ], "normalized": [] }, { "id": "PMID-19230833_T8", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 507, 512 ] ], "normalized": [] }, { "id": "PMID-19230833_T9", "type": "Protein", "text": [ "integrin binding sialoprotein" ], "offsets": [ [ 585, 614 ] ], "normalized": [] }, { "id": "PMID-19230833_T10", "type": "Protein", "text": [ "osteopontin" ], "offsets": [ [ 616, 627 ] ], "normalized": [] }, { "id": "PMID-19230833_T11", "type": "Protein", "text": [ "osterix" ], "offsets": [ [ 633, 640 ] ], "normalized": [] }, { "id": "PMID-19230833_T12", "type": "Protein", "text": [ "PKR" ], "offsets": [ [ 680, 683 ] ], "normalized": [] }, { "id": "PMID-19230833_T13", "type": "Protein", "text": [ "interleukin-6" ], "offsets": [ [ 726, 739 ] ], "normalized": [] }, { "id": "PMID-19230833_T14", "type": "Protein", "text": [ "matrix metalloproteinases 8" ], "offsets": [ [ 744, 771 ] ], "normalized": [] }, { "id": "PMID-19230833_T15", "type": "Protein", "text": [ "13" ], "offsets": [ [ 776, 778 ] ], "normalized": [] }, { "id": "PMID-19230833_T16", "type": "Protein", "text": [ "PKR" ], "offsets": [ [ 792, 795 ] ], "normalized": [] }, { "id": "PMID-19230833_T17", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 851, 856 ] ], "normalized": [] }, { "id": "PMID-19230833_T18", "type": "Protein", "text": [ "PKR" ], "offsets": [ [ 883, 886 ] ], "normalized": [] }, { "id": "PMID-19230833_T19", "type": "Protein", "text": [ "SLIM" ], "offsets": [ [ 892, 896 ] ], "normalized": [] }, { "id": "PMID-19230833_T20", "type": "Protein", "text": [ "SLIM" ], "offsets": [ [ 930, 934 ] ], "normalized": [] }, { "id": "PMID-19230833_T21", "type": "Protein", "text": [ "Runx2" ], "offsets": [ [ 993, 998 ] ], "normalized": [] }, { "id": "PMID-19230833_T22", "type": "Protein", "text": [ "interleukin-6" ], "offsets": [ [ 1030, 1043 ] ], "normalized": [] }, { "id": "PMID-19230833_T23", "type": "Protein", "text": [ "alkaline phosphatase" ], "offsets": [ [ 1074, 1094 ] ], "normalized": [] }, { "id": "PMID-19230833_T24", "type": "Protein", "text": [ "SLIM" ], "offsets": [ [ 1130, 1134 ] ], "normalized": [] }, { "id": "PMID-19230833_T25", "type": "Protein", "text": [ "SLIM" ], "offsets": [ [ 1224, 1228 ] ], "normalized": [] }, { "id": "PMID-19230833_T26", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1312, 1317 ] ], "normalized": [] }, { "id": "PMID-19230833_T27", "type": "Protein", "text": [ "PKR" ], "offsets": [ [ 1345, 1348 ] ], "normalized": [] }, { "id": "PMID-19230833_T28", "type": "Protein", "text": [ "SLIM" ], "offsets": [ [ 1398, 1402 ] ], "normalized": [] }, { "id": "PMID-19230833_T29", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1403, 1408 ] ], "normalized": [] } ]

[ { "id": "PMID-19230833_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 489, 503 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19230833_T8" } ] } ]

[ { "id": "PMID-19230833_1", "entity_ids": [ "PMID-19230833_T3", "PMID-19230833_T4" ] } ]

[]

[ { "id": "PMID-19233847__text", "type": "abstract", "text": [ "The ubiquitin ligase E6-AP is induced and recruited to aggresomes in response to proteasome inhibition and may be involved in the ubiquitination of Hsp70-bound misfolded proteins. \nCells are equipped with an efficient quality control system to selectively eliminate abnormally folded and damaged proteins. Initially the cell tries to refold the unfolded proteins with the help of molecular chaperones, and failure to refold leads to their degradation by the ubiquitin proteasome system. But how this proteolytic machinery recognizes the abnormally folded proteins is poorly understood. Here, we report that E6-AP, a HECT domain family ubiquitin ligase implicated in Angelman syndrome, interacts with the substrate binding domain of Hsp70/Hsc70 chaperones and promotes the degradation of chaperone bound substrates. The expression of E6-AP was dramatically induced under a variety of stresses, and overexpression of E6-AP was found to protect against endoplasmic reticulum stress-induced cell death. The inhibition of proteasome function not only increases the expression of E6-AP but also causes its redistribution around microtubule-organizing center, a subcellular structure for the degradation of the cytoplasmic misfolded proteins. E6-AP is also recruited to aggresomes containing the cystic fibrosis transmembrane conductance regulator or expanded polyglutamine proteins. Finally, we demonstrate that E6-AP ubiquitinates misfolded luciferase that is bound by Hsp70. Our results suggest that E6-AP functions as a cellular quality control ubiquitin ligase and, therefore, can be implicated not only in the pathogenesis of Angelman syndrome but also in the biology of neurodegenerative disorders involving protein aggregation.\n" ], "offsets": [ [ 0, 1729 ] ] } ]

[ { "id": "PMID-19233847_T1", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 4, 13 ] ], "normalized": [] }, { "id": "PMID-19233847_T2", "type": "Protein", "text": [ "E6-AP" ], "offsets": [ [ 21, 26 ] ], "normalized": [] }, { "id": "PMID-19233847_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 458, 467 ] ], "normalized": [] }, { "id": "PMID-19233847_T4", "type": "Protein", "text": [ "E6-AP" ], "offsets": [ [ 607, 612 ] ], "normalized": [] }, { "id": "PMID-19233847_T5", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 635, 644 ] ], "normalized": [] }, { "id": "PMID-19233847_T6", "type": "Protein", "text": [ "Hsc70" ], "offsets": [ [ 738, 743 ] ], "normalized": [] }, { "id": "PMID-19233847_T7", "type": "Protein", "text": [ "E6-AP" ], "offsets": [ [ 833, 838 ] ], "normalized": [] }, { "id": "PMID-19233847_T8", "type": "Protein", "text": [ "E6-AP" ], "offsets": [ [ 915, 920 ] ], "normalized": [] }, { "id": "PMID-19233847_T9", "type": "Protein", "text": [ "E6-AP" ], "offsets": [ [ 1074, 1079 ] ], "normalized": [] }, { "id": "PMID-19233847_T10", "type": "Protein", "text": [ "E6-AP" ], "offsets": [ [ 1236, 1241 ] ], "normalized": [] }, { "id": "PMID-19233847_T11", "type": "Protein", "text": [ "cystic fibrosis transmembrane conductance regulator" ], "offsets": [ [ 1289, 1340 ] ], "normalized": [] }, { "id": "PMID-19233847_T12", "type": "Protein", "text": [ "E6-AP" ], "offsets": [ [ 1406, 1411 ] ], "normalized": [] }, { "id": "PMID-19233847_T13", "type": "Protein", "text": [ "luciferase" ], "offsets": [ [ 1436, 1446 ] ], "normalized": [] }, { "id": "PMID-19233847_T14", "type": "Protein", "text": [ "E6-AP" ], "offsets": [ [ 1496, 1501 ] ], "normalized": [] }, { "id": "PMID-19233847_T15", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1542, 1551 ] ], "normalized": [] } ]

[ { "id": "PMID-19233847_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinates" ], "offsets": [ [ 1412, 1425 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19233847_T13" } ] }, { "id": "PMID-19233847_E2", "type": "Catalysis", "trigger": { "text": [ "ubiquitinates" ], "offsets": [ [ 1412, 1425 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19233847_E1" }, { "role": "Cause", "ref_id": "PMID-19233847_T12" } ] } ]

[]

[]

[ { "id": "PMID-19234109__text", "type": "abstract", "text": [ "Induction of SOX4 by DNA damage is critical for p53 stabilization and function. \nDNA damage response (DDR) acts as a tumorigenesis barrier, and any defects in the DDR machinery may lead to cancer. SOX4 expression is elevated in many types of tumors; however, its role in DDR is still largely unknown. Here, we show that SOX4, a new DNA damage sensor, is required for the activation of p53 tumor suppressor in response to DNA damage. Notably, SOX4 interacts with and stabilizes p53 protein by blocking Mdm2-mediated p53 ubiquitination and degradation. Furthermore, SOX4 enhances p53 acetylation by interacting with p300/CBP and facilitating p300/CBP/p53 complex formation. In concert with these results, SOX4 promotes cell cycle arrest and apoptosis, and it inhibits tumorigenesis in a p53-dependent manner. Therefore, these findings highlight SOX4 as a potential key factor in regulating DDR-associated cancer.\n" ], "offsets": [ [ 0, 911 ] ] } ]

[ { "id": "PMID-19234109_T1", "type": "Protein", "text": [ "SOX4" ], "offsets": [ [ 13, 17 ] ], "normalized": [] }, { "id": "PMID-19234109_T2", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 48, 51 ] ], "normalized": [] }, { "id": "PMID-19234109_T3", "type": "Protein", "text": [ "SOX4" ], "offsets": [ [ 197, 201 ] ], "normalized": [] }, { "id": "PMID-19234109_T4", "type": "Protein", "text": [ "SOX4" ], "offsets": [ [ 320, 324 ] ], "normalized": [] }, { "id": "PMID-19234109_T5", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 385, 388 ] ], "normalized": [] }, { "id": "PMID-19234109_T6", "type": "Protein", "text": [ "SOX4" ], "offsets": [ [ 442, 446 ] ], "normalized": [] }, { "id": "PMID-19234109_T7", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 477, 480 ] ], "normalized": [] }, { "id": "PMID-19234109_T8", "type": "Protein", "text": [ "Mdm2" ], "offsets": [ [ 501, 505 ] ], "normalized": [] }, { "id": "PMID-19234109_T9", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 515, 518 ] ], "normalized": [] }, { "id": "PMID-19234109_T10", "type": "Protein", "text": [ "SOX4" ], "offsets": [ [ 564, 568 ] ], "normalized": [] }, { "id": "PMID-19234109_T11", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 578, 581 ] ], "normalized": [] }, { "id": "PMID-19234109_T12", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 614, 618 ] ], "normalized": [] }, { "id": "PMID-19234109_T13", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 619, 622 ] ], "normalized": [] }, { "id": "PMID-19234109_T14", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 640, 644 ] ], "normalized": [] }, { "id": "PMID-19234109_T15", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 645, 648 ] ], "normalized": [] }, { "id": "PMID-19234109_T16", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 649, 652 ] ], "normalized": [] }, { "id": "PMID-19234109_T17", "type": "Protein", "text": [ "SOX4" ], "offsets": [ [ 703, 707 ] ], "normalized": [] }, { "id": "PMID-19234109_T18", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 785, 788 ] ], "normalized": [] }, { "id": "PMID-19234109_T19", "type": "Protein", "text": [ "SOX4" ], "offsets": [ [ 843, 847 ] ], "normalized": [] } ]

[ { "id": "PMID-19234109_E1", "type": "Catalysis", "trigger": { "text": [ "mediated" ], "offsets": [ [ 506, 514 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19234109_E2" }, { "role": "Cause", "ref_id": "PMID-19234109_T8" } ] }, { "id": "PMID-19234109_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 519, 533 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19234109_T9" } ] }, { "id": "PMID-19234109_E3", "type": "Catalysis", "trigger": { "text": [ "enhances" ], "offsets": [ [ 569, 577 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19234109_T11" }, { "role": "Cause", "ref_id": "PMID-19234109_T10" } ] }, { "id": "PMID-19234109_E4", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 582, 593 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19234109_T11" } ] } ]

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[ { "id": "PMID-19240031__text", "type": "abstract", "text": [ "An endoplasmic reticulum (ER) membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of inositol 1,4,5-trisphosphate receptors. \nHow endoplasmic reticulum (ER) proteins that are substrates for the ER-associated degradation (ERAD) pathway are recognized for polyubiquitination and proteasomal degradation is largely unresolved. Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) form tetrameric calcium channels in ER membranes, whose primary role is to control the release of ER calcium stores, but whose levels are also regulated, in an activation-dependent manner, by the ERAD pathway. Here we report that the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex that binds to IP(3)R tetramers immediately after their activation and is required for their processing. The complex is ring-shaped (diameter approximately 250A(),) and RNA interference-mediated depletion of SPFH1 and SPFH2 blocks IP(3)R polyubiquitination and degradation. We propose that this novel SPFH1/2 complex is a recognition factor that targets IP(3)Rs and perhaps other substrates for ERAD.\n" ], "offsets": [ [ 0, 1134 ] ] } ]

[ { "id": "PMID-19240031_T1", "type": "Protein", "text": [ "SPFH1" ], "offsets": [ [ 59, 64 ] ], "normalized": [] }, { "id": "PMID-19240031_T2", "type": "Protein", "text": [ "SPFH2" ], "offsets": [ [ 69, 74 ] ], "normalized": [] }, { "id": "PMID-19240031_T3", "type": "Protein", "text": [ "SPFH1" ], "offsets": [ [ 659, 664 ] ], "normalized": [] }, { "id": "PMID-19240031_T4", "type": "Protein", "text": [ "SPFH2" ], "offsets": [ [ 681, 686 ] ], "normalized": [] }, { "id": "PMID-19240031_T5", "type": "Protein", "text": [ "SPFH1" ], "offsets": [ [ 941, 946 ] ], "normalized": [] }, { "id": "PMID-19240031_T6", "type": "Protein", "text": [ "SPFH2" ], "offsets": [ [ 951, 956 ] ], "normalized": [] }, { "id": "PMID-19240031_T7", "type": "Protein", "text": [ "SPFH1" ], "offsets": [ [ 1034, 1039 ] ], "normalized": [] }, { "id": "PMID-19240031_T8", "type": "Protein", "text": [ "2" ], "offsets": [ [ 1040, 1041 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-19245366__text", "type": "abstract", "text": [ "MYPT1, the targeting subunit of smooth-muscle myosin phosphatase, is a substrate for the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (FIH). \nThe asparaginyl hydroxylase FIH [factor inhibiting HIF (hypoxia-inducible factor)] was first identified as a protein that inhibits transcriptional activation by HIF, through hydroxylation of an asparagine residue in the CAD (C-terminal activation domain). More recently, several ARD [AR (ankyrin repeat) domain]-containing proteins were identified as FIH substrates using FIH interaction assays. Although the function(s) of these ARD hydroxylations is unclear, expression of the ARD protein Notch1 was shown to compete efficiently with HIF CAD for asparagine hydroxylation and thus to enhance HIF activity. The ARD is a common protein domain with over 300 examples in the human proteome. However, the extent of hydroxylation among ARD proteins, and the ability of other members to compete with HIF-CAD for FIH, is not known. In the present study we assay for asparagine hydroxylation in a bioinformatically predicted FIH substrate, the targeting subunit of myosin phosphatase, MYPT1. Our results confirm hydroxylation both in cultured cells and in endogenous protein purified from animal tissue. We show that the extent of hydroxylation at three sites is dependent on FIH expression level and that hydroxylation is incomplete under basal conditions even in the animal tissue. We also show that expression of MYPT1 enhances HIF-CAD activity in a manner consistent with competition for FIH and that this property extends to other ARD proteins. These results extend the range of FIH substrates and suggest that cross-competition between ARDs and HIF-CAD, and between ARDs themselves, may be extensive and have important effects on hypoxia signalling.\n" ], "offsets": [ [ 0, 1812 ] ] } ]

[ { "id": "PMID-19245366_T1", "type": "Protein", "text": [ "MYPT1" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-19245366_T2", "type": "Protein", "text": [ "factor inhibiting hypoxia-inducible factor" ], "offsets": [ [ 113, 155 ] ], "normalized": [] }, { "id": "PMID-19245366_T3", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 157, 160 ] ], "normalized": [] }, { "id": "PMID-19245366_T4", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 192, 195 ] ], "normalized": [] }, { "id": "PMID-19245366_T5", "type": "Protein", "text": [ "factor inhibiting HIF" ], "offsets": [ [ 197, 218 ] ], "normalized": [] }, { "id": "PMID-19245366_T6", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 515, 518 ] ], "normalized": [] }, { "id": "PMID-19245366_T7", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 536, 539 ] ], "normalized": [] }, { "id": "PMID-19245366_T8", "type": "Protein", "text": [ "Notch1" ], "offsets": [ [ 655, 661 ] ], "normalized": [] }, { "id": "PMID-19245366_T9", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 970, 973 ] ], "normalized": [] }, { "id": "PMID-19245366_T10", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1081, 1084 ] ], "normalized": [] }, { "id": "PMID-19245366_T11", "type": "Protein", "text": [ "MYPT1" ], "offsets": [ [ 1141, 1146 ] ], "normalized": [] }, { "id": "PMID-19245366_T12", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1332, 1335 ] ], "normalized": [] }, { "id": "PMID-19245366_T13", "type": "Protein", "text": [ "MYPT1" ], "offsets": [ [ 1472, 1477 ] ], "normalized": [] }, { "id": "PMID-19245366_T14", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1548, 1551 ] ], "normalized": [] }, { "id": "PMID-19245366_T15", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1640, 1643 ] ], "normalized": [] }, { "id": "PMID-19245366_T16", "type": "Entity", "text": [ "asparagine" ], "offsets": [ [ 1023, 1033 ] ], "normalized": [] }, { "id": "PMID-19245366_T21", "type": "Entity", "text": [ "three sites" ], "offsets": [ [ 1304, 1315 ] ], "normalized": [] } ]

[ { "id": "PMID-19245366_E1", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 1034, 1047 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19245366_T11" }, { "role": "Site", "ref_id": "PMID-19245366_T16" } ] }, { "id": "PMID-19245366_E2", "type": "Catalysis", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 1034, 1047 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19245366_E1" }, { "role": "Cause", "ref_id": "PMID-19245366_T10" } ] }, { "id": "PMID-19245366_E3", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 1168, 1181 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19245366_T11" } ] }, { "id": "PMID-19245366_E4", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 1287, 1300 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19245366_T11" }, { "role": "Site", "ref_id": "PMID-19245366_T21" } ] }, { "id": "PMID-19245366_E5", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 1362, 1375 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19245366_T11" } ] } ]

[ { "id": "PMID-19245366_1", "entity_ids": [ "PMID-19245366_T2", "PMID-19245366_T3" ] }, { "id": "PMID-19245366_2", "entity_ids": [ "PMID-19245366_T4", "PMID-19245366_T5" ] } ]

[]

[ { "id": "PMID-19250910__text", "type": "abstract", "text": [ "Modification by single ubiquitin moieties rather than polyubiquitination is sufficient for proteasomal processing of the p105 NF-kappaB precursor. \nActivation of NF-kappaB is regulated via numerous ubiquitin- and proteasome-mediated steps; an important one is processing of the precursor p105 to the p50 active subunit. The mechanisms involved are largely unknown, because this is an exceptional case where the ubiquitin system does not destroy its substrate completely. Here, we demonstrate that proteasomal processing of p105 requires ubiquitin but not generation of polyubiquitin chains. In vitro, ubiquitin species that cannot polymerize mediate processing. In yeasts that express nonpolymerizable ubiquitins, processing proceeds normally, whereas degradation of substrates that are dependent on polyubiquitination is inhibited. Similar results were obtained in mammalian cells. Interestingly, processing requires multiple monoubiquitinations, because progressive elimination of lysines in p105 is accompanied by gradual inhibition of p50 generation. Finally, the proteasome recognizes the multiply monoubiquitinated p105. These findings suggest that a proteolytic signal can be composed of a cluster of single ubiquitins, not necessarily a chain.\n" ], "offsets": [ [ 0, 1252 ] ] } ]

[ { "id": "PMID-19250910_T1", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 23, 32 ] ], "normalized": [] }, { "id": "PMID-19250910_T2", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 121, 125 ] ], "normalized": [] }, { "id": "PMID-19250910_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 198, 207 ] ], "normalized": [] }, { "id": "PMID-19250910_T4", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 288, 292 ] ], "normalized": [] }, { "id": "PMID-19250910_T5", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 300, 303 ] ], "normalized": [] }, { "id": "PMID-19250910_T6", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 411, 420 ] ], "normalized": [] }, { "id": "PMID-19250910_T7", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 523, 527 ] ], "normalized": [] }, { "id": "PMID-19250910_T8", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 537, 546 ] ], "normalized": [] }, { "id": "PMID-19250910_T9", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 573, 582 ] ], "normalized": [] }, { "id": "PMID-19250910_T10", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 601, 610 ] ], "normalized": [] }, { "id": "PMID-19250910_T11", "type": "Protein", "text": [ "ubiquitins" ], "offsets": [ [ 702, 712 ] ], "normalized": [] }, { "id": "PMID-19250910_T12", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 994, 998 ] ], "normalized": [] }, { "id": "PMID-19250910_T13", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1039, 1042 ] ], "normalized": [] }, { "id": "PMID-19250910_T14", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 1121, 1125 ] ], "normalized": [] } ]

[ { "id": "PMID-19250910_E1", "type": "Ubiquitination", "trigger": { "text": [ "Modification" ], "offsets": [ [ 0, 12 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19250910_T2" } ] }, { "id": "PMID-19250910_E2", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 54, 72 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19250910_T2" } ] }, { "id": "PMID-19250910_E3", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitinations" ], "offsets": [ [ 927, 946 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19250910_T12" } ] }, { "id": "PMID-19250910_E4", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitinated" ], "offsets": [ [ 1103, 1120 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19250910_T14" } ] } ]

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[ { "id": "PMID-19255247__text", "type": "abstract", "text": [ "Methylation of H3 K4 and K79 is not strictly dependent on H2B K123 ubiquitylation. \nCovalent modifications of histone proteins have profound consequences on chromatin structure and function. Specific modification patterns constitute a code read by effector proteins. Studies from yeast found that H3 trimethylation at K4 and K79 is dependent on ubiquitylation of H2B K123, which is termed a \"trans-tail pathway.\" In this study, we show that a strain unable to be ubiquitylated on H2B (K123R) is still proficient for H3 trimethylation at both K4 and K79, indicating that H3 methylation status is not solely dependent on H2B ubiquitylation. However, additional mutations in H2B result in loss of H3 methylation when combined with htb1-K123R. Consistent with this, we find that the original strain used to identify the trans-tail pathway has a genomic mutation that, when combined with H2B K123R, results in defective H3 methylation. Finally, we show that strains lacking the ubiquitin ligase Bre1 are defective for H3 methylation, suggesting that there is an additional Bre1 substrate that in combination with H2B K123 facilitates H3 methylation.\n" ], "offsets": [ [ 0, 1145 ] ] } ]

[ { "id": "PMID-19255247_T1", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 15, 17 ] ], "normalized": [] }, { "id": "PMID-19255247_T2", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 58, 61 ] ], "normalized": [] }, { "id": "PMID-19255247_T3", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 110, 117 ] ], "normalized": [] }, { "id": "PMID-19255247_T4", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 297, 299 ] ], "normalized": [] }, { "id": "PMID-19255247_T5", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 363, 366 ] ], "normalized": [] }, { "id": "PMID-19255247_T6", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 480, 483 ] ], "normalized": [] }, { "id": "PMID-19255247_T7", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 516, 518 ] ], "normalized": [] }, { "id": "PMID-19255247_T8", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 570, 572 ] ], "normalized": [] }, { "id": "PMID-19255247_T9", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 619, 622 ] ], "normalized": [] }, { "id": "PMID-19255247_T10", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 672, 675 ] ], "normalized": [] }, { "id": "PMID-19255247_T11", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 694, 696 ] ], "normalized": [] }, { "id": "PMID-19255247_T12", "type": "Protein", "text": [ "htb1" ], "offsets": [ [ 728, 732 ] ], "normalized": [] }, { "id": "PMID-19255247_T13", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 883, 886 ] ], "normalized": [] }, { "id": "PMID-19255247_T14", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 915, 917 ] ], "normalized": [] }, { "id": "PMID-19255247_T15", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 973, 982 ] ], "normalized": [] }, { "id": "PMID-19255247_T16", "type": "Protein", "text": [ "Bre1" ], "offsets": [ [ 990, 994 ] ], "normalized": [] }, { "id": "PMID-19255247_T17", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1013, 1015 ] ], "normalized": [] }, { "id": "PMID-19255247_T18", "type": "Protein", "text": [ "Bre1" ], "offsets": [ [ 1068, 1072 ] ], "normalized": [] }, { "id": "PMID-19255247_T19", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 1108, 1111 ] ], "normalized": [] }, { "id": "PMID-19255247_T20", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1129, 1131 ] ], "normalized": [] }, { "id": "PMID-19255247_T22", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 18, 20 ] ], "normalized": [] }, { "id": "PMID-19255247_T23", "type": "Entity", "text": [ "K79" ], "offsets": [ [ 25, 28 ] ], "normalized": [] }, { "id": "PMID-19255247_T24", "type": "Entity", "text": [ "K123" ], "offsets": [ [ 62, 66 ] ], "normalized": [] }, { "id": "PMID-19255247_T27", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 318, 320 ] ], "normalized": [] }, { "id": "PMID-19255247_T28", "type": "Entity", "text": [ "K79" ], "offsets": [ [ 325, 328 ] ], "normalized": [] }, { "id": "PMID-19255247_T30", "type": "Entity", "text": [ "K123" ], "offsets": [ [ 367, 371 ] ], "normalized": [] }, { "id": "PMID-19255247_T33", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 542, 544 ] ], "normalized": [] }, { "id": "PMID-19255247_T34", "type": "Entity", "text": [ "K79" ], "offsets": [ [ 549, 552 ] ], "normalized": [] } ]

[ { "id": "PMID-19255247_E1", "type": "Methylation", "trigger": { "text": [ "Methylation" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T1" }, { "role": "Site", "ref_id": "PMID-19255247_T22" } ] }, { "id": "PMID-19255247_E2", "type": "Methylation", "trigger": { "text": [ "Methylation" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T1" }, { "role": "Site", "ref_id": "PMID-19255247_T23" } ] }, { "id": "PMID-19255247_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 67, 81 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T2" }, { "role": "Site", "ref_id": "PMID-19255247_T24" } ] }, { "id": "PMID-19255247_E4", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 300, 314 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T4" }, { "role": "Site", "ref_id": "PMID-19255247_T27" } ] }, { "id": "PMID-19255247_E5", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 300, 314 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T4" }, { "role": "Site", "ref_id": "PMID-19255247_T28" } ] }, { "id": "PMID-19255247_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 345, 359 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T5" }, { "role": "Site", "ref_id": "PMID-19255247_T30" } ] }, { "id": "PMID-19255247_E7", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylated" ], "offsets": [ [ 463, 476 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T6" } ] }, { "id": "PMID-19255247_E8", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 519, 533 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T7" }, { "role": "Site", "ref_id": "PMID-19255247_T34" } ] }, { "id": "PMID-19255247_E9", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 519, 533 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T7" }, { "role": "Site", "ref_id": "PMID-19255247_T33" } ] }, { "id": "PMID-19255247_E10", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 573, 584 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T8" } ] }, { "id": "PMID-19255247_E11", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 623, 637 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T9" } ] }, { "id": "PMID-19255247_E12", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 697, 708 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T11" } ] }, { "id": "PMID-19255247_E13", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 918, 929 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T14" } ] }, { "id": "PMID-19255247_E14", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1016, 1027 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T17" } ] }, { "id": "PMID-19255247_E15", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1132, 1143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19255247_T20" } ] } ]

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[]

[ { "id": "PMID-19261749__text", "type": "abstract", "text": [ "NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control. \nThe ability to sense and respond to DNA damage is critical to maintenance of genomic stability and the prevention of cancer. In this study, we employed a genetic screen to identify a gene, NBA1 (new component of the BRCA1 A complex), that is required for resistance to ionizing radiation. The NBA1 protein localizes to sites of DNA damage and is required for G2/M checkpoint control. Proteomic analysis revealed that NBA1 is a component of the BRCA1 A complex, which also contains Brca1/Bard1, Abra1, RAP80, BRCC36, and BRE. NBA1 is required to maintain BRE and Abra1 abundance and for the recruitment of BRCA1 to sites of DNA damage. In depth bioinformatics analysis revealed that the BRCA1 A complex bears striking similarities to the 19S proteasome complex. Furthermore, we show that four members of the BRCA1-A complex possess a polyubiquitin chain-binding capability, thus forming a complex that might facilitate the deubiquitinating activity of the deubiquitination enzyme BRCC36 or the E3 ligase activity of the BRCA1/BARD1 ligase. These findings provide a new perspective from which to view the BRCA1 A complex.\n" ], "offsets": [ [ 0, 1226 ] ] } ]

[ { "id": "PMID-19261749_T1", "type": "Protein", "text": [ "NBA1" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-19261749_T2", "type": "Protein", "text": [ "NBA1" ], "offsets": [ [ 295, 299 ] ], "normalized": [] }, { "id": "PMID-19261749_T3", "type": "Protein", "text": [ "NBA1" ], "offsets": [ [ 399, 403 ] ], "normalized": [] }, { "id": "PMID-19261749_T4", "type": "Protein", "text": [ "NBA1" ], "offsets": [ [ 523, 527 ] ], "normalized": [] }, { "id": "PMID-19261749_T5", "type": "Protein", "text": [ "Brca1" ], "offsets": [ [ 587, 592 ] ], "normalized": [] }, { "id": "PMID-19261749_T6", "type": "Protein", "text": [ "Bard1" ], "offsets": [ [ 593, 598 ] ], "normalized": [] }, { "id": "PMID-19261749_T7", "type": "Protein", "text": [ "Abra1" ], "offsets": [ [ 600, 605 ] ], "normalized": [] }, { "id": "PMID-19261749_T8", "type": "Protein", "text": [ "RAP80" ], "offsets": [ [ 607, 612 ] ], "normalized": [] }, { "id": "PMID-19261749_T9", "type": "Protein", "text": [ "BRCC36" ], "offsets": [ [ 614, 620 ] ], "normalized": [] }, { "id": "PMID-19261749_T10", "type": "Protein", "text": [ "BRE" ], "offsets": [ [ 626, 629 ] ], "normalized": [] }, { "id": "PMID-19261749_T11", "type": "Protein", "text": [ "NBA1" ], "offsets": [ [ 631, 635 ] ], "normalized": [] }, { "id": "PMID-19261749_T12", "type": "Protein", "text": [ "BRE" ], "offsets": [ [ 660, 663 ] ], "normalized": [] }, { "id": "PMID-19261749_T13", "type": "Protein", "text": [ "Abra1" ], "offsets": [ [ 668, 673 ] ], "normalized": [] }, { "id": "PMID-19261749_T14", "type": "Protein", "text": [ "BRCA1" ], "offsets": [ [ 711, 716 ] ], "normalized": [] }, { "id": "PMID-19261749_T15", "type": "Protein", "text": [ "BRCC36" ], "offsets": [ [ 1085, 1091 ] ], "normalized": [] }, { "id": "PMID-19261749_T16", "type": "Protein", "text": [ "BRCA1" ], "offsets": [ [ 1125, 1130 ] ], "normalized": [] }, { "id": "PMID-19261749_T17", "type": "Protein", "text": [ "BARD1" ], "offsets": [ [ 1131, 1136 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-19270745__text", "type": "abstract", "text": [ "Functional conservation of asxl2, a murine homolog for the Drosophila enhancer of trithorax and polycomb group gene asx. \nBACKGROUND: Polycomb-group (PcG) and trithorax-group (trxG) proteins regulate histone methylation to establish repressive and active chromatin configurations at target loci, respectively. These chromatin configurations are passed on from mother to daughter cells, thereby causing heritable changes in gene expression. The activities of PcG and trxG proteins are regulated by a special class of proteins known as Enhancers of trithorax and Polycomb (ETP). The Drosophila gene Additional sex combs (Asx) encodes an ETP protein and mutations in Asx enhance both PcG and trxG mutant phenotypes. The mouse and human genomes each contain three Asx homologues, Asx-like 1, 2, and 3. In order to understand the functions of mammalian Asx-like (Asxl) proteins, we generated an Asxl2 mutant mouse from a gene-trap ES cell line. METHODOLOGY/PRINCIPAL FINDINGS: We show that the Asxl2 gene trap is expressed at high levels in specific tissues including the heart, the axial skeleton, the neocortex, the retina, spermatogonia and developing oocytes. The gene trap mutation is partially embryonic lethal and approximately half of homozygous animals die before birth. Homozygotes that survive embryogenesis are significantly smaller than controls and have a shortened life span. Asxl2(-/-) mice display both posterior transformations and anterior transformation in the axial skeleton, suggesting that the loss of Asxl2 disrupts the activities of both PcG and trxG proteins. The PcG-associated histone modification, trimethylation of histone H3 lysine 27, is reduced in Asxl2(-/-) heart. Necropsy and histological analysis show that mutant mice have enlarged hearts and may have impaired heart function. CONCLUSIONS/SIGNIFICANCE: Our results suggest that murine Asxl2 has conserved ETP function and plays dual roles in the promotion of PcG and trxG activity. We have also revealed an unexpected role for Asxl2 in the heart, suggesting that the PcG/trxG system may be involved in the regulation of cardiac function.\n" ], "offsets": [ [ 0, 2121 ] ] } ]

[ { "id": "PMID-19270745_T1", "type": "Protein", "text": [ "asxl2" ], "offsets": [ [ 27, 32 ] ], "normalized": [] }, { "id": "PMID-19270745_T2", "type": "Protein", "text": [ "asx" ], "offsets": [ [ 116, 119 ] ], "normalized": [] }, { "id": "PMID-19270745_T3", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 200, 207 ] ], "normalized": [] }, { "id": "PMID-19270745_T4", "type": "Protein", "text": [ "Additional sex combs" ], "offsets": [ [ 597, 617 ] ], "normalized": [] }, { "id": "PMID-19270745_T5", "type": "Protein", "text": [ "Asx" ], "offsets": [ [ 619, 622 ] ], "normalized": [] }, { "id": "PMID-19270745_T6", "type": "Protein", "text": [ "Asx" ], "offsets": [ [ 664, 667 ] ], "normalized": [] }, { "id": "PMID-19270745_T7", "type": "Protein", "text": [ "Asx" ], "offsets": [ [ 760, 763 ] ], "normalized": [] }, { "id": "PMID-19270745_T8", "type": "Protein", "text": [ "Asx-like 1" ], "offsets": [ [ 776, 786 ] ], "normalized": [] }, { "id": "PMID-19270745_T9", "type": "Protein", "text": [ "2" ], "offsets": [ [ 788, 789 ] ], "normalized": [] }, { "id": "PMID-19270745_T10", "type": "Protein", "text": [ "3" ], "offsets": [ [ 795, 796 ] ], "normalized": [] }, { "id": "PMID-19270745_T11", "type": "Protein", "text": [ "Asx" ], "offsets": [ [ 848, 851 ] ], "normalized": [] }, { "id": "PMID-19270745_T12", "type": "Protein", "text": [ "Asxl2" ], "offsets": [ [ 890, 895 ] ], "normalized": [] }, { "id": "PMID-19270745_T13", "type": "Protein", "text": [ "Asxl2" ], "offsets": [ [ 989, 994 ] ], "normalized": [] }, { "id": "PMID-19270745_T14", "type": "Protein", "text": [ "Asxl2" ], "offsets": [ [ 1386, 1391 ] ], "normalized": [] }, { "id": "PMID-19270745_T15", "type": "Protein", "text": [ "Asxl2" ], "offsets": [ [ 1520, 1525 ] ], "normalized": [] }, { "id": "PMID-19270745_T16", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1600, 1607 ] ], "normalized": [] }, { "id": "PMID-19270745_T17", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 1640, 1650 ] ], "normalized": [] }, { "id": "PMID-19270745_T18", "type": "Protein", "text": [ "Asxl2" ], "offsets": [ [ 1676, 1681 ] ], "normalized": [] }, { "id": "PMID-19270745_T19", "type": "Protein", "text": [ "Asxl2" ], "offsets": [ [ 1868, 1873 ] ], "normalized": [] }, { "id": "PMID-19270745_T20", "type": "Protein", "text": [ "Asxl2" ], "offsets": [ [ 2010, 2015 ] ], "normalized": [] }, { "id": "PMID-19270745_T23", "type": "Entity", "text": [ "lysine 27" ], "offsets": [ [ 1651, 1660 ] ], "normalized": [] } ]

[ { "id": "PMID-19270745_E1", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 208, 219 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19270745_T3" } ] }, { "id": "PMID-19270745_E2", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 1622, 1636 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19270745_T17" }, { "role": "Site", "ref_id": "PMID-19270745_T23" } ] } ]

[ { "id": "PMID-19270745_1", "entity_ids": [ "PMID-19270745_T4", "PMID-19270745_T5" ] } ]

[]

[ { "id": "PMID-19273841__text", "type": "abstract", "text": [ "A family of Salmonella virulence factors functions as a distinct class of autoregulated E3 ubiquitin ligases. \nProcesses as diverse as receptor binding and signaling, cytoskeletal dynamics, and programmed cell death are manipulated by mimics of host proteins encoded by pathogenic bacteria. We show here that the Salmonella virulence factor SspH2 belongs to a growing class of bacterial effector proteins that harness and subvert the eukaryotic ubiquitination pathway. This virulence protein possesses ubiquitination activity that depends on a conserved cysteine residue. A crystal structure of SspH2 reveals a canonical leucine-rich repeat (LRR) domain that interacts with a unique E3 ligase [which we have termed NEL for Novel E3 Ligase] C-terminal fold unrelated to previously observed HECT or RING-finger E3 ligases. Moreover, the LRR domain sequesters the catalytic cysteine residue contained in the NEL domain, and we suggest a mechanism for activation of the ligase requiring a substantial conformational change to release the catalytic domain for function. We also show that the N-terminal domain targets SspH2 to the apical plasma membrane of polarized epithelial cells and propose a model whereby binding of the LRR to proteins at the target site releases the ligase domain for site-specific function.\n" ], "offsets": [ [ 0, 1312 ] ] } ]

[ { "id": "PMID-19273841_T1", "type": "Protein", "text": [ "SspH2" ], "offsets": [ [ 341, 346 ] ], "normalized": [] }, { "id": "PMID-19273841_T2", "type": "Protein", "text": [ "SspH2" ], "offsets": [ [ 595, 600 ] ], "normalized": [] }, { "id": "PMID-19273841_T3", "type": "Protein", "text": [ "SspH2" ], "offsets": [ [ 1113, 1118 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-19276074__text", "type": "abstract", "text": [ "The cholinesterase-like domain, essential in thyroglobulin trafficking for thyroid hormone synthesis, is required for protein dimerization. \nThe carboxyl-terminal cholinesterase-like (ChEL) domain of thyroglobulin (Tg) has been identified as critically important in Tg export from the endoplasmic reticulum. In a number of human kindreds suffering from congenital hypothyroidism, and in the cog congenital goiter mouse and rdw rat dwarf models, thyroid hormone synthesis is inhibited because of mutations in the ChEL domain that block protein export from the endoplasmic reticulum. We hypothesize that Tg forms homodimers through noncovalent interactions involving two predicted alpha-helices in each ChEL domain that are homologous to the dimerization helices of acetylcholinesterase. This has been explored through selective epitope tagging of dimerization partners and by inserting an extra, unpaired Cys residue to create an opportunity for intermolecular disulfide pairing. We show that the ChEL domain is necessary and sufficient for Tg dimerization; specifically, the isolated ChEL domain can dimerize with full-length Tg or with itself. Insertion of an N-linked glycan into the putative upstream dimerization helix inhibits homodimerization of the isolated ChEL domain. However, interestingly, co-expression of upstream Tg domains, either in cis or in trans, overrides the dimerization defect of such a mutant. Thus, although the ChEL domain provides a nidus for Tg dimerization, interactions of upstream Tg regions with the ChEL domain actively stabilizes the Tg dimer complex for intracellular transport.\n" ], "offsets": [ [ 0, 1615 ] ] } ]

[ { "id": "PMID-19276074_T1", "type": "Protein", "text": [ "thyroglobulin" ], "offsets": [ [ 45, 58 ] ], "normalized": [] }, { "id": "PMID-19276074_T2", "type": "Protein", "text": [ "thyroglobulin" ], "offsets": [ [ 200, 213 ] ], "normalized": [] }, { "id": "PMID-19276074_T3", "type": "Protein", "text": [ "Tg" ], "offsets": [ [ 215, 217 ] ], "normalized": [] }, { "id": "PMID-19276074_T4", "type": "Protein", "text": [ "Tg" ], "offsets": [ [ 266, 268 ] ], "normalized": [] }, { "id": "PMID-19276074_T5", "type": "Protein", "text": [ "Tg" ], "offsets": [ [ 602, 604 ] ], "normalized": [] }, { "id": "PMID-19276074_T6", "type": "Protein", "text": [ "acetylcholinesterase" ], "offsets": [ [ 764, 784 ] ], "normalized": [] }, { "id": "PMID-19276074_T7", "type": "Protein", "text": [ "Tg" ], "offsets": [ [ 1040, 1042 ] ], "normalized": [] }, { "id": "PMID-19276074_T8", "type": "Protein", "text": [ "Tg" ], "offsets": [ [ 1126, 1128 ] ], "normalized": [] }, { "id": "PMID-19276074_T9", "type": "Protein", "text": [ "Tg" ], "offsets": [ [ 1328, 1330 ] ], "normalized": [] }, { "id": "PMID-19276074_T10", "type": "Protein", "text": [ "Tg" ], "offsets": [ [ 1471, 1473 ] ], "normalized": [] }, { "id": "PMID-19276074_T11", "type": "Protein", "text": [ "Tg" ], "offsets": [ [ 1513, 1515 ] ], "normalized": [] }, { "id": "PMID-19276074_T12", "type": "Protein", "text": [ "Tg" ], "offsets": [ [ 1569, 1571 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-19276074_1", "entity_ids": [ "PMID-19276074_T2", "PMID-19276074_T3" ] } ]

[]

[ { "id": "PMID-19279190__text", "type": "abstract", "text": [ "PCNA mono-ubiquitination and activation of translesion DNA polymerases by DNA polymerase {alpha}. \nTranslesion DNA synthesis (TLS) involves PCNA mono-ubiquitination and TLS DNA polymerases (pols). Recent evidence has shown that the mono-ubiquitination is induced not only by DNA damage but also by other factors that induce stalling of the DNA replication fork. We studied the effect of spontaneous DNA replication errors on PCNA mono-ubiquitination and TLS induction. In the pol1L868F strain, which expressed an error-prone pol alpha, PCNA was spontaneously mono-ubiquitinated. Pol alpha L868F had a rate-limiting step at the extension from mismatched primer termini. Electron microscopic observation showed the accumulation of a single-stranded region at the DNA replication fork in yeast cells. For pol alpha errors, pol zeta participated in a generation of +1 frameshifts. Furthermore, in the pol1L868F strain, UV-induced mutations were lower than in the wild-type and a pol delta mutant strain (pol3-5DV), and deletion of the RAD30 gene (pol eta) suppressed this defect. These data suggest that nucleotide misincorporation by pol alpha induces exposure of single-stranded DNA, PCNA mono-ubiquitination and activates TLS pols.\n" ], "offsets": [ [ 0, 1231 ] ] } ]

[ { "id": "PMID-19279190_T1", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-19279190_T2", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 140, 144 ] ], "normalized": [] }, { "id": "PMID-19279190_T3", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 425, 429 ] ], "normalized": [] }, { "id": "PMID-19279190_T4", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 536, 540 ] ], "normalized": [] }, { "id": "PMID-19279190_T5", "type": "Protein", "text": [ "RAD30" ], "offsets": [ [ 1031, 1036 ] ], "normalized": [] }, { "id": "PMID-19279190_T6", "type": "Protein", "text": [ "pol eta" ], "offsets": [ [ 1043, 1050 ] ], "normalized": [] }, { "id": "PMID-19279190_T7", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 1182, 1186 ] ], "normalized": [] } ]

[ { "id": "PMID-19279190_E1", "type": "Ubiquitination", "trigger": { "text": [ "mono-ubiquitination" ], "offsets": [ [ 5, 24 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19279190_T1" } ] }, { "id": "PMID-19279190_E2", "type": "Ubiquitination", "trigger": { "text": [ "mono-ubiquitination" ], "offsets": [ [ 145, 164 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19279190_T2" } ] }, { "id": "PMID-19279190_E3", "type": "Ubiquitination", "trigger": { "text": [ "mono-ubiquitination" ], "offsets": [ [ 430, 449 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19279190_T3" } ] }, { "id": "PMID-19279190_E4", "type": "Ubiquitination", "trigger": { "text": [ "mono-ubiquitinated" ], "offsets": [ [ 559, 577 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19279190_T4" } ] }, { "id": "PMID-19279190_E5", "type": "Ubiquitination", "trigger": { "text": [ "mono-ubiquitination" ], "offsets": [ [ 1187, 1206 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19279190_T7" } ] } ]

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[]

[ { "id": "PMID-19302814__text", "type": "abstract", "text": [ "Monohydroxylated polycyclic aromatic hydrocarbons inhibit both osteoclastic and osteoblastic activities in teleost scales. \nAIMS: We previously demonstrated that monohydroxylated polycyclic aromatic hydrocarbons (OHPAHs) bound to a human estrogen receptor (ER) by a yeast two-hybrid assay, but polycyclic aromatic hydrocarbons did not have a binding activity. Therefore, the direct effect of 3-hydroxybenz[a]anthracene (3-OHBaA) and 4-hydroxybenz[a]anthracene (4-OHBaA) on osteoclasts and osteoblasts in teleosts was examined. As a negative control, 1-hydroxypyrene (1-OHPy), which has no binding activity to human ER, was used. MAIN METHODS: The effect of OHPAHs on osteoclasts and osteoblasts was examined by an assay system using teleost scale as each marker: tartrate-resistant acid phosphatase for osteoclasts and alkaline phosphatase for osteoblasts. Changes in cathepsin K (an osteoclastic marker) and insulin-like growth factor-I (IGF-I) (an osteoblastic marker) mRNA expressions in 4-OHBaA-treated goldfish scales were examined by using a reverse transcription-polymerase chain reaction. KEY FINDINGS: In both goldfish (a freshwater teleost) and wrasse (a marine teleost), the osteoclastic activity in the scales was significantly suppressed by 3-OHBaA and 4-OHBaA, although 1-OHPy did not affect the osteoclastic activity. In reference to osteoblasts, the osteoblastic activity decreased with both 3-OHBaA and 4-OHBaA and did not change with the 1-OHPy treatment. However, 17beta-estradiol (E(2)) significantly increased both the osteoclastic and osteoblastic activities in the scales of both goldfish and wrasse. The mRNA expressions of both cathepsin K and IGF-I decreased in the 4-OHBaA-treated scales but increased in the E(2)-treated scales. SIGNIFICANCE: The current data are the first to demonstrate that 3-OHBaA and 4-OHBaA inhibited both osteoclasts and osteoblasts and disrupted the bone metabolism in teleosts.\n" ], "offsets": [ [ 0, 1932 ] ] } ]

[ { "id": "PMID-19302814_T1", "type": "Protein", "text": [ "estrogen receptor" ], "offsets": [ [ 238, 255 ] ], "normalized": [] }, { "id": "PMID-19302814_T2", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 257, 259 ] ], "normalized": [] }, { "id": "PMID-19302814_T3", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 615, 617 ] ], "normalized": [] }, { "id": "PMID-19302814_T4", "type": "Protein", "text": [ "cathepsin K" ], "offsets": [ [ 868, 879 ] ], "normalized": [] }, { "id": "PMID-19302814_T5", "type": "Protein", "text": [ "insulin-like growth factor-I" ], "offsets": [ [ 909, 937 ] ], "normalized": [] }, { "id": "PMID-19302814_T6", "type": "Protein", "text": [ "IGF-I" ], "offsets": [ [ 939, 944 ] ], "normalized": [] }, { "id": "PMID-19302814_T7", "type": "Protein", "text": [ "cathepsin K" ], "offsets": [ [ 1653, 1664 ] ], "normalized": [] }, { "id": "PMID-19302814_T8", "type": "Protein", "text": [ "IGF-I" ], "offsets": [ [ 1669, 1674 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-19302814_1", "entity_ids": [ "PMID-19302814_T1", "PMID-19302814_T2" ] }, { "id": "PMID-19302814_2", "entity_ids": [ "PMID-19302814_T5", "PMID-19302814_T6" ] } ]

[]

[ { "id": "PMID-19304754__text", "type": "abstract", "text": [ "The transcriptional coactivator MAML1 regulates p300 autoacetylation and HAT activity. \nMAML1 is a transcriptional coregulator originally identified as a Notch coactivator. MAML1 is also reported to interact with other coregulator proteins, such as CDK8 and p300, to modulate the activity of Notch. We, and others, previously showed that MAML1 recruits p300 to Notch-regulated genes through direct interactions with the DNA-CSL-Notch complex and p300. MAML1 interacts with the C/H3 domain of p300, and the p300-MAML1 complex specifically acetylates lysines of histone H3 and H4 tails in chromatin in vitro. In this report, we show that MAML1 potentiates p300 autoacetylation and p300 transcriptional activation. MAML1 directly enhances p300 HAT activity, and this coincides with the translocation of MAML1, p300 and acetylated histones to nuclear bodies.\n" ], "offsets": [ [ 0, 855 ] ] } ]

[ { "id": "PMID-19304754_T1", "type": "Protein", "text": [ "MAML1" ], "offsets": [ [ 32, 37 ] ], "normalized": [] }, { "id": "PMID-19304754_T2", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 48, 52 ] ], "normalized": [] }, { "id": "PMID-19304754_T3", "type": "Protein", "text": [ "MAML1" ], "offsets": [ [ 88, 93 ] ], "normalized": [] }, { "id": "PMID-19304754_T4", "type": "Protein", "text": [ "MAML1" ], "offsets": [ [ 173, 178 ] ], "normalized": [] }, { "id": "PMID-19304754_T5", "type": "Protein", "text": [ "CDK8" ], "offsets": [ [ 249, 253 ] ], "normalized": [] }, { "id": "PMID-19304754_T6", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 258, 262 ] ], "normalized": [] }, { "id": "PMID-19304754_T7", "type": "Protein", "text": [ "MAML1" ], "offsets": [ [ 338, 343 ] ], "normalized": [] }, { "id": "PMID-19304754_T8", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 353, 357 ] ], "normalized": [] }, { "id": "PMID-19304754_T9", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 446, 450 ] ], "normalized": [] }, { "id": "PMID-19304754_T10", "type": "Protein", "text": [ "MAML1" ], "offsets": [ [ 452, 457 ] ], "normalized": [] }, { "id": "PMID-19304754_T11", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 492, 496 ] ], "normalized": [] }, { "id": "PMID-19304754_T12", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 506, 510 ] ], "normalized": [] }, { "id": "PMID-19304754_T13", "type": "Protein", "text": [ "MAML1" ], "offsets": [ [ 511, 516 ] ], "normalized": [] }, { "id": "PMID-19304754_T14", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 560, 570 ] ], "normalized": [] }, { "id": "PMID-19304754_T15", "type": "Protein", "text": [ "H4" ], "offsets": [ [ 575, 577 ] ], "normalized": [] }, { "id": "PMID-19304754_T16", "type": "Protein", "text": [ "MAML1" ], "offsets": [ [ 636, 641 ] ], "normalized": [] }, { "id": "PMID-19304754_T17", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 654, 658 ] ], "normalized": [] }, { "id": "PMID-19304754_T18", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 679, 683 ] ], "normalized": [] }, { "id": "PMID-19304754_T19", "type": "Protein", "text": [ "MAML1" ], "offsets": [ [ 712, 717 ] ], "normalized": [] }, { "id": "PMID-19304754_T20", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 736, 740 ] ], "normalized": [] }, { "id": "PMID-19304754_T21", "type": "Protein", "text": [ "MAML1" ], "offsets": [ [ 800, 805 ] ], "normalized": [] }, { "id": "PMID-19304754_T22", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 807, 811 ] ], "normalized": [] }, { "id": "PMID-19304754_T23", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 827, 835 ] ], "normalized": [] }, { "id": "PMID-19304754_T27", "type": "Entity", "text": [ "lysines" ], "offsets": [ [ 549, 556 ] ], "normalized": [] } ]

[ { "id": "PMID-19304754_E1", "type": "Acetylation", "trigger": { "text": [ "autoacetylation" ], "offsets": [ [ 53, 68 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19304754_T2" } ] }, { "id": "PMID-19304754_E2", "type": "Catalysis", "trigger": { "text": [ "autoacetylation" ], "offsets": [ [ 53, 68 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19304754_E1" }, { "role": "Cause", "ref_id": "PMID-19304754_T2" } ] }, { "id": "PMID-19304754_E3", "type": "Acetylation", "trigger": { "text": [ "acetylates" ], "offsets": [ [ 538, 548 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19304754_T14" }, { "role": "Site", "ref_id": "PMID-19304754_T27" } ] }, { "id": "PMID-19304754_E4", "type": "Acetylation", "trigger": { "text": [ "acetylates" ], "offsets": [ [ 538, 548 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19304754_T15" }, { "role": "Site", "ref_id": "PMID-19304754_T27" } ] }, { "id": "PMID-19304754_E5", "type": "Acetylation", "trigger": { "text": [ "autoacetylation" ], "offsets": [ [ 659, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19304754_T17" } ] }, { "id": "PMID-19304754_E6", "type": "Catalysis", "trigger": { "text": [ "autoacetylation" ], "offsets": [ [ 659, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19304754_E5" }, { "role": "Cause", "ref_id": "PMID-19304754_T17" } ] }, { "id": "PMID-19304754_E7", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 816, 826 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19304754_T23" } ] } ]

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[]

[ { "id": "PMID-19309453__text", "type": "abstract", "text": [ "Auxin-induced, SCF(TIR1)-mediated poly-ubiquitination marks AUX/IAA proteins for degradation. \nThe plant hormone auxin (indole-3-acetic acid or IAA) regulates plant development by inducing rapid cellular responses and changes in gene expression. Auxin promotes the degradation of Aux/IAA transcriptional repressors, thereby allowing auxin response factors (ARFs) to activate the transcription of auxin-responsive genes. Auxin enhances the binding of Aux/IAA proteins to the receptor TIR1, which is an F-box protein that is part of the E3 ubiquitin ligase complex SCF(TIR1). Binding of Aux/IAA proteins leads to degradation via the 26S proteasome, but evidence for SCF(TIR1)-mediated poly-ubiquitination of Aux/IAA proteins is lacking. Here we used an Arabidopsis cell suspension-based protoplast system to find evidence for SCF(TIR1)-mediated ubiquitination of the Aux/IAA proteins SHY2/IAA3 and BDL/IAA12. Each of these proteins showed a distinct abundance and repressor activity when expressed in this cell system. Moreover, the amount of endogenous TIR1 protein appeared to be rate-limiting for a proper auxin response measured by the co-transfected DR5::GUS reporter construct. Co-transfection with 35S::TIR1 led to auxin-dependent degradation, and excess of 35S::TIR1 even led to degradation of Aux/IAAs in the absence of auxin treatment. Expression of the mutant tir1-1 protein or the related F-box protein COI1, which is involved in jasmonate signaling, had no effect on Aux/IAA degradation. Our results show that SHY2/IAA3 and BDL/IAA12 are poly-ubiquitinated and degraded in response to increased auxin or TIR1 levels. In conclusion, our data provide experimental support for the model that SCF(TIR1)-dependent poly-ubiquitination of Aux/IAA proteins marks these proteins for degradation by the 26S proteasome, leading to activation of auxin-responsive gene expression.\n" ], "offsets": [ [ 0, 1879 ] ] } ]

[ { "id": "PMID-19309453_T1", "type": "Protein", "text": [ "TIR1" ], "offsets": [ [ 19, 23 ] ], "normalized": [] }, { "id": "PMID-19309453_T2", "type": "Protein", "text": [ "TIR1" ], "offsets": [ [ 483, 487 ] ], "normalized": [] }, { "id": "PMID-19309453_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 538, 547 ] ], "normalized": [] }, { "id": "PMID-19309453_T4", "type": "Protein", "text": [ "TIR1" ], "offsets": [ [ 567, 571 ] ], "normalized": [] }, { "id": "PMID-19309453_T5", "type": "Protein", "text": [ "TIR1" ], "offsets": [ [ 668, 672 ] ], "normalized": [] }, { "id": "PMID-19309453_T6", "type": "Protein", "text": [ "TIR1" ], "offsets": [ [ 828, 832 ] ], "normalized": [] }, { "id": "PMID-19309453_T7", "type": "Protein", "text": [ "SHY2" ], "offsets": [ [ 882, 886 ] ], "normalized": [] }, { "id": "PMID-19309453_T8", "type": "Protein", "text": [ "IAA3" ], "offsets": [ [ 887, 891 ] ], "normalized": [] }, { "id": "PMID-19309453_T9", "type": "Protein", "text": [ "BDL" ], "offsets": [ [ 896, 899 ] ], "normalized": [] }, { "id": "PMID-19309453_T10", "type": "Protein", "text": [ "IAA12" ], "offsets": [ [ 900, 905 ] ], "normalized": [] }, { "id": "PMID-19309453_T11", "type": "Protein", "text": [ "TIR1" ], "offsets": [ [ 1052, 1056 ] ], "normalized": [] }, { "id": "PMID-19309453_T12", "type": "Protein", "text": [ "DR5" ], "offsets": [ [ 1153, 1156 ] ], "normalized": [] }, { "id": "PMID-19309453_T13", "type": "Protein", "text": [ "TIR1" ], "offsets": [ [ 1208, 1212 ] ], "normalized": [] }, { "id": "PMID-19309453_T14", "type": "Protein", "text": [ "TIR1" ], "offsets": [ [ 1268, 1272 ] ], "normalized": [] }, { "id": "PMID-19309453_T15", "type": "Protein", "text": [ "tir1-1" ], "offsets": [ [ 1369, 1375 ] ], "normalized": [] }, { "id": "PMID-19309453_T16", "type": "Protein", "text": [ "COI1" ], "offsets": [ [ 1413, 1417 ] ], "normalized": [] }, { "id": "PMID-19309453_T17", "type": "Protein", "text": [ "SHY2" ], "offsets": [ [ 1521, 1525 ] ], "normalized": [] }, { "id": "PMID-19309453_T18", "type": "Protein", "text": [ "IAA3" ], "offsets": [ [ 1526, 1530 ] ], "normalized": [] }, { "id": "PMID-19309453_T19", "type": "Protein", "text": [ "BDL" ], "offsets": [ [ 1535, 1538 ] ], "normalized": [] }, { "id": "PMID-19309453_T20", "type": "Protein", "text": [ "IAA12" ], "offsets": [ [ 1539, 1544 ] ], "normalized": [] }, { "id": "PMID-19309453_T21", "type": "Protein", "text": [ "TIR1" ], "offsets": [ [ 1615, 1619 ] ], "normalized": [] }, { "id": "PMID-19309453_T22", "type": "Protein", "text": [ "TIR1" ], "offsets": [ [ 1704, 1708 ] ], "normalized": [] } ]

[ { "id": "PMID-19309453_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 843, 857 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19309453_T7" } ] }, { "id": "PMID-19309453_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 843, 857 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19309453_T9" } ] }, { "id": "PMID-19309453_E3", "type": "Ubiquitination", "trigger": { "text": [ "poly-ubiquitinated" ], "offsets": [ [ 1549, 1567 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19309453_T17" } ] }, { "id": "PMID-19309453_E4", "type": "Ubiquitination", "trigger": { "text": [ "poly-ubiquitinated" ], "offsets": [ [ 1549, 1567 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19309453_T19" } ] } ]

[ { "id": "PMID-19309453_1", "entity_ids": [ "PMID-19309453_T7", "PMID-19309453_T8" ] }, { "id": "PMID-19309453_2", "entity_ids": [ "PMID-19309453_T9", "PMID-19309453_T10" ] }, { "id": "PMID-19309453_3", "entity_ids": [ "PMID-19309453_T17", "PMID-19309453_T18" ] }, { "id": "PMID-19309453_4", "entity_ids": [ "PMID-19309453_T19", "PMID-19309453_T20" ] } ]

[]

[ { "id": "PMID-19332566__text", "type": "abstract", "text": [ "Masking of a nuclear signal motif by monoubiquitination leads to mislocalization and degradation of the regulatory enzyme cytidylyltransferase. \nMonoubiquitination aids in the nuclear export and entrance of proteins into the lysosomal degradative pathway, although the mechanisms are unknown. Cytidylyltransferase (CCTalpha) is a proteolytically sensitive lipogenic enzyme containing an NH(2)-terminal nuclear localization signal (NLS). We show here that CCTalpha is monoubiquitinated at a molecular site (K(57)) juxtaposed near its NLS, resulting in disruption of its interaction with importin-alpha, nuclear exclusion, and subsequent degradation within the lysosome. Cellular expression of a CCTalpha-ubiquitin fusion protein that mimics the monoubiquitinated enzyme resulted in cytoplasmic retention. A CCTalpha K(57R) mutant exhibited an extended half-life, was retained in the nucleus, and displayed proteolytic resistance. Importantly, by using CCTalpha-ubiquitin hybrid constructs that vary in the intermolecular distance between ubiquitin and the NLS, we show that CCTalpha monoubiquitination masks its NLS, resulting in cytoplasmic retention. These results unravel a unique molecular mechanism whereby monoubiquitination governs the trafficking and life span of a critical regulatory enzyme in vivo.\n" ], "offsets": [ [ 0, 1309 ] ] } ]

[ { "id": "PMID-19332566_T1", "type": "Protein", "text": [ "CCTalpha" ], "offsets": [ [ 315, 323 ] ], "normalized": [] }, { "id": "PMID-19332566_T2", "type": "Protein", "text": [ "CCTalpha" ], "offsets": [ [ 455, 463 ] ], "normalized": [] }, { "id": "PMID-19332566_T3", "type": "Protein", "text": [ "CCTalpha" ], "offsets": [ [ 694, 702 ] ], "normalized": [] }, { "id": "PMID-19332566_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 703, 712 ] ], "normalized": [] }, { "id": "PMID-19332566_T5", "type": "Protein", "text": [ "CCTalpha" ], "offsets": [ [ 806, 814 ] ], "normalized": [] }, { "id": "PMID-19332566_T6", "type": "Protein", "text": [ "CCTalpha" ], "offsets": [ [ 951, 959 ] ], "normalized": [] }, { "id": "PMID-19332566_T7", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 960, 969 ] ], "normalized": [] }, { "id": "PMID-19332566_T8", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1037, 1046 ] ], "normalized": [] }, { "id": "PMID-19332566_T9", "type": "Protein", "text": [ "CCTalpha" ], "offsets": [ [ 1073, 1081 ] ], "normalized": [] }, { "id": "PMID-19332566_T11", "type": "Entity", "text": [ "K(57)" ], "offsets": [ [ 506, 511 ] ], "normalized": [] } ]

[ { "id": "PMID-19332566_E1", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitinated" ], "offsets": [ [ 467, 484 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19332566_T2" }, { "role": "Site", "ref_id": "PMID-19332566_T11" } ] }, { "id": "PMID-19332566_E2", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitination" ], "offsets": [ [ 1082, 1100 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19332566_T9" } ] } ]

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[ { "id": "PMID-19333736__text", "type": "abstract", "text": [ "The roles of the RAG1 and RAG2 \"non-core\" regions in V(D)J recombination and lymphocyte development. \nThe enormous repertoire of the vertebrate specific immune system relies on the rearrangement of discrete gene segments into intact antigen receptor genes during the early stages of B-and T-cell development. This V(D)J recombination is initiated by a lymphoid-specific recombinase comprising the RAG1 and RAG2 proteins, which introduces double-strand breaks in the DNA adjacent to the coding segments. Much of the biochemical research into V(D)J recombination has focused on truncated or \"core\" fragments of RAG1 and RAG2, which lack approximately one third of the amino acids from each. However, genetic analyses of SCID and Omenn syndrome patients indicate that residues outside the cores are essential to normal immune development. This is in agreement with the striking degree of conservation across all vertebrate classes in certain non-core domains. Work from multiple laboratories has shed light on activities resident within these domains, including ubiquitin ligase activity and KPNA1 binding by the RING finger domain of RAG1 and the recognition of specific chromatin modifications as well as phosphoinositide binding by the PHD module of RAG2. In addition, elements outside of the cores are necessary for regulated protein expression and turnover. Here the current state of knowledge is reviewed regarding the non-core regions of RAG1 and RAG2 and how these findings contribute to our broader understanding of recombination.\n" ], "offsets": [ [ 0, 1537 ] ] } ]

[ { "id": "PMID-19333736_T1", "type": "Protein", "text": [ "RAG1" ], "offsets": [ [ 17, 21 ] ], "normalized": [] }, { "id": "PMID-19333736_T2", "type": "Protein", "text": [ "RAG2" ], "offsets": [ [ 26, 30 ] ], "normalized": [] }, { "id": "PMID-19333736_T3", "type": "Protein", "text": [ "RAG1" ], "offsets": [ [ 397, 401 ] ], "normalized": [] }, { "id": "PMID-19333736_T4", "type": "Protein", "text": [ "RAG2" ], "offsets": [ [ 406, 410 ] ], "normalized": [] }, { "id": "PMID-19333736_T5", "type": "Protein", "text": [ "RAG1" ], "offsets": [ [ 609, 613 ] ], "normalized": [] }, { "id": "PMID-19333736_T6", "type": "Protein", "text": [ "RAG2" ], "offsets": [ [ 618, 622 ] ], "normalized": [] }, { "id": "PMID-19333736_T7", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1059, 1068 ] ], "normalized": [] }, { "id": "PMID-19333736_T8", "type": "Protein", "text": [ "KPNA1" ], "offsets": [ [ 1089, 1094 ] ], "normalized": [] }, { "id": "PMID-19333736_T9", "type": "Protein", "text": [ "RAG1" ], "offsets": [ [ 1132, 1136 ] ], "normalized": [] }, { "id": "PMID-19333736_T10", "type": "Protein", "text": [ "RAG2" ], "offsets": [ [ 1250, 1254 ] ], "normalized": [] }, { "id": "PMID-19333736_T11", "type": "Protein", "text": [ "RAG1" ], "offsets": [ [ 1442, 1446 ] ], "normalized": [] }, { "id": "PMID-19333736_T12", "type": "Protein", "text": [ "RAG2" ], "offsets": [ [ 1451, 1455 ] ], "normalized": [] } ]

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[ { "id": "PMID-19336759__text", "type": "abstract", "text": [ "Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells. \nThe molecular mechanism of autocrine regulation of vascular endothelial growth factor (VEGF) in chronic lymphocytic leukemia (CLL) B cells is unknown. Here, we report that CLL B cells express constitutive levels of HIF-1alpha under normoxia. We have examined the status of the von Hippel-Lindau gene product (pVHL) that is responsible for HIF-1alpha degradation and found it to be at a notably low level in CLL B cells compared with normal B cells. We demonstrate that the microRNA, miR-92-1, overexpressed in CLL B cells, can target the VHL transcript to repress its expression. We found that the stabilized HIF-1alpha can form an active complex with the transcriptional coactivator p300 and phosphorylated-STAT3 at the VEGF promoter and recruit RNA polymerase II. This is initial evidence that pVHL, without any genetic alteration, can be regulated by microRNA and explains the aberrant autocrine VEGF secretion in CLL.\n" ], "offsets": [ [ 0, 1013 ] ] } ]

[ { "id": "PMID-19336759_T1", "type": "Protein", "text": [ "pVHL" ], "offsets": [ [ 23, 27 ] ], "normalized": [] }, { "id": "PMID-19336759_T2", "type": "Protein", "text": [ "VEGF" ], "offsets": [ [ 64, 68 ] ], "normalized": [] }, { "id": "PMID-19336759_T3", "type": "Protein", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 142, 176 ] ], "normalized": [] }, { "id": "PMID-19336759_T4", "type": "Protein", "text": [ "VEGF" ], "offsets": [ [ 178, 182 ] ], "normalized": [] }, { "id": "PMID-19336759_T5", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 306, 316 ] ], "normalized": [] }, { "id": "PMID-19336759_T6", "type": "Protein", "text": [ "von Hippel-Lindau" ], "offsets": [ [ 368, 385 ] ], "normalized": [] }, { "id": "PMID-19336759_T7", "type": "Protein", "text": [ "pVHL" ], "offsets": [ [ 400, 404 ] ], "normalized": [] }, { "id": "PMID-19336759_T8", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 430, 440 ] ], "normalized": [] }, { "id": "PMID-19336759_T9", "type": "Protein", "text": [ "miR-92-1" ], "offsets": [ [ 574, 582 ] ], "normalized": [] }, { "id": "PMID-19336759_T10", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 629, 632 ] ], "normalized": [] }, { "id": "PMID-19336759_T11", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 700, 710 ] ], "normalized": [] }, { "id": "PMID-19336759_T12", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 775, 779 ] ], "normalized": [] }, { "id": "PMID-19336759_T13", "type": "Protein", "text": [ "STAT3" ], "offsets": [ [ 799, 804 ] ], "normalized": [] }, { "id": "PMID-19336759_T14", "type": "Protein", "text": [ "VEGF" ], "offsets": [ [ 812, 816 ] ], "normalized": [] }, { "id": "PMID-19336759_T15", "type": "Protein", "text": [ "pVHL" ], "offsets": [ [ 887, 891 ] ], "normalized": [] }, { "id": "PMID-19336759_T16", "type": "Protein", "text": [ "VEGF" ], "offsets": [ [ 990, 994 ] ], "normalized": [] } ]

[ { "id": "PMID-19336759_E1", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 784, 798 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19336759_T13" } ] } ]

[ { "id": "PMID-19336759_1", "entity_ids": [ "PMID-19336759_T3", "PMID-19336759_T4" ] }, { "id": "PMID-19336759_2", "entity_ids": [ "PMID-19336759_T6", "PMID-19336759_T7" ] } ]

[]

[ { "id": "PMID-19337321__text", "type": "abstract", "text": [ "Targeting protein ubiquitylation: DDB1 takes its RING off. \nUbiquitin E3 ligases of the RING and HECT families are distinct not only in their catalytic mechanisms but also in targeting substrates. Now it seems that one heterodimeric complex can target substrates to both types of E3 ligase.\n" ], "offsets": [ [ 0, 291 ] ] } ]

[ { "id": "PMID-19337321_T1", "type": "Protein", "text": [ "DDB1" ], "offsets": [ [ 34, 38 ] ], "normalized": [] }, { "id": "PMID-19337321_T2", "type": "Protein", "text": [ "Ubiquitin" ], "offsets": [ [ 60, 69 ] ], "normalized": [] } ]

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[ { "id": "PMID-19337370__text", "type": "abstract", "text": [ "Inefficient quality control of thermosensitive proteins on the plasma membrane. \nBACKGROUND: Misfolded proteins are generally recognised by cellular quality control machinery, which typically results in their ubiquitination and degradation. For soluble cytoplasmic proteins, degradation is mediated by the proteasome. Membrane proteins that fail to fold correctly are subject to ER associated degradation (ERAD), which involves their extraction from the membrane and subsequent proteasome-dependent destruction. Proteins with abnormal transmembrane domains can also be recognised in the Golgi or endosomal system and targeted for destruction in the vacuole/lysosome. It is much less clear what happens to membrane proteins that reach their destination, such as the cell surface, and then suffer damage. METHODOLOGY/PRINCIPAL FINDINGS: We have tested the ability of yeast cells to degrade membrane proteins to which temperature-sensitive cytoplasmic alleles of the Ura3 protein or of phage lambda repressor have been fused. In soluble form, these proteins are rapidly degraded upon temperature shift, in part due to the action of the Doa10 and San1 ubiquitin ligases and the proteasome. When tethered to the ER protein Use1, they are also degraded. However, when tethered to a plasma membrane protein such as Sso1 they escape degradation, either in the vacuole or by the proteasome. CONCLUSIONS/SIGNIFICANCE: Membrane proteins with a misfolded cytoplasmic domain appear not to be efficiently recognised and degraded once they have escaped the ER, even though their defective domains are exposed to the cytoplasm and potentially to cytoplasmic quality controls. Membrane tethering may provide a way to reduce degradation of unstable proteins.\n" ], "offsets": [ [ 0, 1741 ] ] } ]

[ { "id": "PMID-19337370_T1", "type": "Protein", "text": [ "Ura3" ], "offsets": [ [ 964, 968 ] ], "normalized": [] }, { "id": "PMID-19337370_T2", "type": "Protein", "text": [ "Doa10" ], "offsets": [ [ 1133, 1138 ] ], "normalized": [] }, { "id": "PMID-19337370_T3", "type": "Protein", "text": [ "San1" ], "offsets": [ [ 1143, 1147 ] ], "normalized": [] }, { "id": "PMID-19337370_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1148, 1157 ] ], "normalized": [] }, { "id": "PMID-19337370_T5", "type": "Protein", "text": [ "Use1" ], "offsets": [ [ 1218, 1222 ] ], "normalized": [] }, { "id": "PMID-19337370_T6", "type": "Protein", "text": [ "Sso1" ], "offsets": [ [ 1308, 1312 ] ], "normalized": [] } ]

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[ { "id": "PMID-19343071__text", "type": "abstract", "text": [ "Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle. \nIn eukaryotic cells, the cell-division cycle (CDC)-6 protein is essential to promote the assembly of pre-replicative complexes in the early G1 phase of the cell cycle, a process requiring tight regulation to ensure that proper origin licensing occurs once per cell cycle. Here we show that, in late G1 and early S phase, CDC6 is found in a complex also containing Cyclin A, cyclin-dependent kinase (CDK)-2 and the acetyltransferase general control nonderepressible 5 (GCN5). GCN5 specifically acetylates CDC6 at three lysine residues flanking its cyclin-docking motif, and this modification is crucial for the subsequent phosphorylation of the protein by Cyclin A-CDKs at a specific residue close to the acetylation site. GCN5-mediated acetylation and site-specific phosphorylation of CDC6 are both necessary for the relocalization of the protein to the cell cytoplasm in the S phase, as well as to regulate its stability. This two-step, intramolecular regulatory program by sequential modification of CDC6 seems to be essential for proper S-phase progression.\n" ], "offsets": [ [ 0, 1147 ] ] } ]

[ { "id": "PMID-19343071_T1", "type": "Protein", "text": [ "GCN5" ], "offsets": [ [ 15, 19 ] ], "normalized": [] }, { "id": "PMID-19343071_T2", "type": "Protein", "text": [ "CDC6" ], "offsets": [ [ 30, 34 ] ], "normalized": [] }, { "id": "PMID-19343071_T3", "type": "Protein", "text": [ "cell-division cycle (CDC)-6" ], "offsets": [ [ 111, 138 ] ], "normalized": [] }, { "id": "PMID-19343071_T4", "type": "Protein", "text": [ "CDC6" ], "offsets": [ [ 407, 411 ] ], "normalized": [] }, { "id": "PMID-19343071_T5", "type": "Protein", "text": [ "Cyclin A" ], "offsets": [ [ 450, 458 ] ], "normalized": [] }, { "id": "PMID-19343071_T6", "type": "Protein", "text": [ "cyclin-dependent kinase (CDK)-2" ], "offsets": [ [ 460, 491 ] ], "normalized": [] }, { "id": "PMID-19343071_T7", "type": "Protein", "text": [ "general control nonderepressible 5" ], "offsets": [ [ 518, 552 ] ], "normalized": [] }, { "id": "PMID-19343071_T8", "type": "Protein", "text": [ "GCN5" ], "offsets": [ [ 554, 558 ] ], "normalized": [] }, { "id": "PMID-19343071_T9", "type": "Protein", "text": [ "GCN5" ], "offsets": [ [ 561, 565 ] ], "normalized": [] }, { "id": "PMID-19343071_T10", "type": "Protein", "text": [ "CDC6" ], "offsets": [ [ 590, 594 ] ], "normalized": [] }, { "id": "PMID-19343071_T11", "type": "Protein", "text": [ "Cyclin A" ], "offsets": [ [ 741, 749 ] ], "normalized": [] }, { "id": "PMID-19343071_T12", "type": "Protein", "text": [ "GCN5" ], "offsets": [ [ 808, 812 ] ], "normalized": [] }, { "id": "PMID-19343071_T13", "type": "Protein", "text": [ "CDC6" ], "offsets": [ [ 871, 875 ] ], "normalized": [] }, { "id": "PMID-19343071_T14", "type": "Protein", "text": [ "CDC6" ], "offsets": [ [ 1088, 1092 ] ], "normalized": [] }, { "id": "PMID-19343071_T20", "type": "Entity", "text": [ "lysine residues" ], "offsets": [ [ 604, 619 ] ], "normalized": [] } ]

[ { "id": "PMID-19343071_E1", "type": "Acetylation", "trigger": { "text": [ "Acetylation" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19343071_T2" } ] }, { "id": "PMID-19343071_E2", "type": "Catalysis", "trigger": { "text": [ "Acetylation" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19343071_E1" }, { "role": "Cause", "ref_id": "PMID-19343071_T1" } ] }, { "id": "PMID-19343071_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 35, 50 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19343071_T2" } ] }, { "id": "PMID-19343071_E4", "type": "Acetylation", "trigger": { "text": [ "acetylates" ], "offsets": [ [ 579, 589 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19343071_T10" }, { "role": "Site", "ref_id": "PMID-19343071_T20" } ] }, { "id": "PMID-19343071_E5", "type": "Catalysis", "trigger": { "text": [ "acetylates" ], "offsets": [ [ 579, 589 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19343071_E4" }, { "role": "Cause", "ref_id": "PMID-19343071_T9" } ] }, { "id": "PMID-19343071_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 707, 722 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19343071_T10" } ] }, { "id": "PMID-19343071_E7", "type": "Catalysis", "trigger": { "text": [ "mediated" ], "offsets": [ [ 813, 821 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19343071_E8" }, { "role": "Cause", "ref_id": "PMID-19343071_T12" } ] }, { "id": "PMID-19343071_E8", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 822, 833 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19343071_T13" } ] }, { "id": "PMID-19343071_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 852, 867 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19343071_T13" } ] } ]

[ { "id": "PMID-19343071_1", "entity_ids": [ "PMID-19343071_T7", "PMID-19343071_T8" ] } ]

[]