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[ { "id": "PMID-16732293__text", "type": "abstract", "text": [ "The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. \nMethylation of lysine and arginine residues on histone tails affects chromatin structure and gene transcription. Tri- and dimethylation of lysine 9 on histone H3 (H3K9me3/me2) is required for the binding of the repressive protein HP1 and is associated with heterochromatin formation and transcriptional repression in a variety of species. H3K9me3 has long been regarded as a 'permanent' epigenetic mark. In a search for proteins and complexes interacting with H3K9me3, we identified the protein GASC1 (gene amplified in squamous cell carcinoma 1), which belongs to the JMJD2 (jumonji domain containing 2) subfamily of the jumonji family, and is also known as JMJD2C. Here we show that three members of this subfamily of proteins demethylate H3K9me3/me2 in vitro through a hydroxylation reaction requiring iron and alpha-ketoglutarate as cofactors. Furthermore, we demonstrate that ectopic expression of GASC1 or other JMJD2 members markedly decreases H3K9me3/me2 levels, increases H3K9me1 levels, delocalizes HP1 and reduces heterochromatin in vivo. Previously, GASC1 was found to be amplified in several cell lines derived from oesophageal squamous carcinomas, and in agreement with a contribution of GASC1 to tumour development, inhibition of GASC1 expression decreases cell proliferation. Thus, in addition to identifying GASC1 as a histone trimethyl demethylase, we suggest a model for how this enzyme might be involved in cancer development, and propose it as a target for anti-cancer therapy.\n" ], "offsets": [ [ 0, 1587 ] ] } ]

[ { "id": "PMID-16732293_T1", "type": "Protein", "text": [ "GASC1" ], "offsets": [ [ 22, 27 ] ], "normalized": [] }, { "id": "PMID-16732293_T2", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 75, 85 ] ], "normalized": [] }, { "id": "PMID-16732293_T3", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 135, 142 ] ], "normalized": [] }, { "id": "PMID-16732293_T4", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 239, 249 ] ], "normalized": [] }, { "id": "PMID-16732293_T5", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 251, 253 ] ], "normalized": [] }, { "id": "PMID-16732293_T6", "type": "Protein", "text": [ "HP1" ], "offsets": [ [ 318, 321 ] ], "normalized": [] }, { "id": "PMID-16732293_T7", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 427, 429 ] ], "normalized": [] }, { "id": "PMID-16732293_T8", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 548, 550 ] ], "normalized": [] }, { "id": "PMID-16732293_T9", "type": "Protein", "text": [ "GASC1" ], "offsets": [ [ 583, 588 ] ], "normalized": [] }, { "id": "PMID-16732293_T10", "type": "Protein", "text": [ "gene amplified in squamous cell carcinoma 1" ], "offsets": [ [ 590, 633 ] ], "normalized": [] }, { "id": "PMID-16732293_T11", "type": "Protein", "text": [ "JMJD2C" ], "offsets": [ [ 747, 753 ] ], "normalized": [] }, { "id": "PMID-16732293_T12", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 829, 831 ] ], "normalized": [] }, { "id": "PMID-16732293_T13", "type": "Protein", "text": [ "GASC1" ], "offsets": [ [ 991, 996 ] ], "normalized": [] }, { "id": "PMID-16732293_T14", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1039, 1041 ] ], "normalized": [] }, { "id": "PMID-16732293_T15", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1069, 1071 ] ], "normalized": [] }, { "id": "PMID-16732293_T16", "type": "Protein", "text": [ "HP1" ], "offsets": [ [ 1097, 1100 ] ], "normalized": [] }, { "id": "PMID-16732293_T17", "type": "Protein", "text": [ "GASC1" ], "offsets": [ [ 1150, 1155 ] ], "normalized": [] }, { "id": "PMID-16732293_T18", "type": "Protein", "text": [ "GASC1" ], "offsets": [ [ 1290, 1295 ] ], "normalized": [] }, { "id": "PMID-16732293_T19", "type": "Protein", "text": [ "GASC1" ], "offsets": [ [ 1333, 1338 ] ], "normalized": [] }, { "id": "PMID-16732293_T20", "type": "Protein", "text": [ "GASC1" ], "offsets": [ [ 1413, 1418 ] ], "normalized": [] }, { "id": "PMID-16732293_T21", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1424, 1431 ] ], "normalized": [] }, { "id": "PMID-16732293_T26", "type": "Entity", "text": [ "lysine 9" ], "offsets": [ [ 63, 71 ] ], "normalized": [] }, { "id": "PMID-16732293_T28", "type": "Entity", "text": [ "lysine" ], "offsets": [ [ 103, 109 ] ], "normalized": [] }, { "id": "PMID-16732293_T29", "type": "Entity", "text": [ "arginine residues" ], "offsets": [ [ 114, 131 ] ], "normalized": [] }, { "id": "PMID-16732293_T32", "type": "Entity", "text": [ "lysine 9" ], "offsets": [ [ 227, 235 ] ], "normalized": [] }, { "id": "PMID-16732293_T33", "type": "Entity", "text": [ "K9" ], "offsets": [ [ 253, 255 ] ], "normalized": [] }, { "id": "PMID-16732293_T35", "type": "Entity", "text": [ "K9" ], "offsets": [ [ 831, 833 ] ], "normalized": [] } ]

[ { "id": "PMID-16732293_E1", "type": "Demethylation", "trigger": { "text": [ "demethylates" ], "offsets": [ [ 28, 40 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16732293_T2" }, { "role": "Site", "ref_id": "PMID-16732293_T26" } ] }, { "id": "PMID-16732293_E2", "type": "Catalysis", "trigger": { "text": [ "demethylates" ], "offsets": [ [ 28, 40 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16732293_E1" }, { "role": "Cause", "ref_id": "PMID-16732293_T1" } ] }, { "id": "PMID-16732293_E3", "type": "Methylation", "trigger": { "text": [ "tri-" ], "offsets": [ [ 41, 45 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16732293_T2" }, { "role": "Site", "ref_id": "PMID-16732293_T26" } ] }, { "id": "PMID-16732293_E4", "type": "Methylation", "trigger": { "text": [ "dimethylated" ], "offsets": [ [ 50, 62 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16732293_T2" }, { "role": "Site", "ref_id": "PMID-16732293_T26" } ] }, { "id": "PMID-16732293_E5", "type": "Methylation", "trigger": { "text": [ "Methylation" ], "offsets": [ [ 88, 99 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16732293_T3" }, { "role": "Site", "ref_id": "PMID-16732293_T28" } ] }, { "id": "PMID-16732293_E6", "type": "Methylation", "trigger": { "text": [ "Methylation" ], "offsets": [ [ 88, 99 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16732293_T3" }, { "role": "Site", "ref_id": "PMID-16732293_T29" } ] }, { "id": "PMID-16732293_E7", "type": "Methylation", "trigger": { "text": [ "Tri-" ], "offsets": [ [ 201, 205 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16732293_T4" }, { "role": "Site", "ref_id": "PMID-16732293_T32" } ] }, { "id": "PMID-16732293_E8", "type": "Methylation", "trigger": { "text": [ "dimethylation" ], "offsets": [ [ 210, 223 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16732293_T4" }, { "role": "Site", "ref_id": "PMID-16732293_T32" } ] }, { "id": "PMID-16732293_E9", "type": "Demethylation", "trigger": { "text": [ "demethylate" ], "offsets": [ [ 817, 828 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16732293_T12" }, { "role": "Site", "ref_id": "PMID-16732293_T35" } ] } ]

[ { "id": "PMID-16732293_1", "entity_ids": [ "PMID-16732293_T32", "PMID-16732293_T33" ] }, { "id": "PMID-16732293_2", "entity_ids": [ "PMID-16732293_T4", "PMID-16732293_T5" ] }, { "id": "PMID-16732293_3", "entity_ids": [ "PMID-16732293_T9", "PMID-16732293_T10", "PMID-16732293_T11" ] } ]

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[ { "id": "PMID-16766075__text", "type": "abstract", "text": [ "Generation of hybrid transgenic silkworms that express Bombyx mori prolyl-hydroxylase alpha-subunits and human collagens in posterior silk glands: Production of cocoons that contained collagens with hydroxylated proline residues. \nProlyl 4-hydroxylase (P4H) is a heterotetramer enzyme consisting of alpha-subunits (P4Halpha) and beta-subunits (P4Hbeta), and is required for collagen biosynthesis. Previously, we generated transgenic silkworms that produced human type III collagen fragments (mini-collagens) in the posterior silk gland (PSG). However, prolyl 4-hydroxylation did not occur on the mini-collagens, because in spite of an abundant expression of P4Hbeta in PSGs, P4Halpha expression was quite low there, thus resulting in an insufficient activity of P4H. In this study we aimed at generating hybrid transgenic silkworms whose PSGs are capable of producing mini-collagens and enough P4H for their prolyl 4-hydroxylation. Isolated PSGs were bombarded with fibroin L-chain gene promoter-driven vectors containing Bombyx mori P4Halpha (BmP4Halpha) cDNAs and were transplanted into the hemolymphatic cavity. The P4H activity in the PSG cells significantly increased, indicating that the expressed BmP4Halpha formed active tetramers with endogenous BmP4Hbeta. Using germ-line transgenesis technology, silkworms were generated that synthesized BmP4Halpha in PSG cells. The P4H activity in the transgenic silkworms was 130-fold higher than that of wild-type counterparts. Finally, we generated hybrid transgenic silkworms that expressed cDNAs of both BmP4Halpha and mini-collagen in PSG cells. They spun cocoons that contained mini-collagens whose appropriate proline residues had been adequately hydroxylated.\n" ], "offsets": [ [ 0, 1715 ] ] } ]

[ { "id": "PMID-16766075_T1", "type": "Protein", "text": [ "prolyl-hydroxylase alpha-subunits" ], "offsets": [ [ 67, 100 ] ], "normalized": [] }, { "id": "PMID-16766075_T2", "type": "Protein", "text": [ "type III collagen" ], "offsets": [ [ 463, 480 ] ], "normalized": [] }, { "id": "PMID-16766075_T3", "type": "Protein", "text": [ "P4Hbeta" ], "offsets": [ [ 658, 665 ] ], "normalized": [] }, { "id": "PMID-16766075_T4", "type": "Protein", "text": [ "P4Halpha" ], "offsets": [ [ 675, 683 ] ], "normalized": [] }, { "id": "PMID-16766075_T5", "type": "Protein", "text": [ "fibroin L-chain" ], "offsets": [ [ 966, 981 ] ], "normalized": [] }, { "id": "PMID-16766075_T6", "type": "Protein", "text": [ "P4Halpha" ], "offsets": [ [ 1034, 1042 ] ], "normalized": [] }, { "id": "PMID-16766075_T7", "type": "Protein", "text": [ "P4Halpha" ], "offsets": [ [ 1046, 1054 ] ], "normalized": [] }, { "id": "PMID-16766075_T8", "type": "Protein", "text": [ "P4Halpha" ], "offsets": [ [ 1206, 1214 ] ], "normalized": [] }, { "id": "PMID-16766075_T9", "type": "Protein", "text": [ "P4Hbeta" ], "offsets": [ [ 1257, 1264 ] ], "normalized": [] }, { "id": "PMID-16766075_T10", "type": "Protein", "text": [ "P4Halpha" ], "offsets": [ [ 1351, 1359 ] ], "normalized": [] }, { "id": "PMID-16766075_T11", "type": "Protein", "text": [ "P4Halpha" ], "offsets": [ [ 1557, 1565 ] ], "normalized": [] } ]

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[ { "id": "PMID-16781830__text", "type": "abstract", "text": [ "A carotenoid synthesis gene cluster from a non-marine Brevundimonas that synthesizes hydroxylated astaxanthin. \nA Brevundimonas vesicularis strain DC263 isolated from surface soil was shown to produce hydroxylated astaxanthin. A carotenoid synthesis gene cluster containing ten genes was cloned from strain DC263, among which eight genes were involved in carotenoid synthesis. In addition to the crtW gene encoding the 4,4'-beta-ionone ring ketolase and the crtZ gene encoding the 3,3'-beta-ionone ring hydroxylase that were responsible for astaxanthin synthesis, the cluster also contained a novel gene crtG identified recently encoding the 2,2'-beta-ionone ring hydroxylase that further hydroxylate astaxanthin. The individual genes in the DC263 cluster showed the highest sequence similarities to the corresponding genes reported in Brevundimonas sp. strain SD212, a marine isolate that also produced hydroxylated astaxanthin. The genetic organization of the carotenoid synthesis gene clusters in the two Brevundimonas strains was identical. It is likely that the two Brevundimonas strains were evolved from the same ancestor and adapted later to growth in different environments. Expression of the crtW and crtZ from DC263 in a beta-carotene-accumulating E. coli produced astaxanthin as the predominant carotenoid. The crtG from DC263 and the crtG from another Brevundimonas aurantiaca strain were expressed in E. coli producing different carotenoid substrates. Both CrtG showed low activity on beta-carotene and high activity on zeaxanthin. The main difference was that the CrtG from B. aurantiaca worked well on canthaxanthin or astaxanthin, but the CrtG from DC263 did not work on either of the ketocarotenoids.\n" ], "offsets": [ [ 0, 1719 ] ] } ]

[ { "id": "PMID-16781830_T1", "type": "Protein", "text": [ "crtW" ], "offsets": [ [ 396, 400 ] ], "normalized": [] }, { "id": "PMID-16781830_T2", "type": "Protein", "text": [ "crtZ" ], "offsets": [ [ 458, 462 ] ], "normalized": [] }, { "id": "PMID-16781830_T3", "type": "Protein", "text": [ "crtG" ], "offsets": [ [ 604, 608 ] ], "normalized": [] }, { "id": "PMID-16781830_T4", "type": "Protein", "text": [ "crtW" ], "offsets": [ [ 1202, 1206 ] ], "normalized": [] }, { "id": "PMID-16781830_T5", "type": "Protein", "text": [ "crtZ" ], "offsets": [ [ 1211, 1215 ] ], "normalized": [] }, { "id": "PMID-16781830_T6", "type": "Protein", "text": [ "crtG" ], "offsets": [ [ 1323, 1327 ] ], "normalized": [] }, { "id": "PMID-16781830_T7", "type": "Protein", "text": [ "crtG" ], "offsets": [ [ 1347, 1351 ] ], "normalized": [] }, { "id": "PMID-16781830_T8", "type": "Protein", "text": [ "CrtG" ], "offsets": [ [ 1471, 1475 ] ], "normalized": [] }, { "id": "PMID-16781830_T9", "type": "Protein", "text": [ "CrtG" ], "offsets": [ [ 1579, 1583 ] ], "normalized": [] }, { "id": "PMID-16781830_T10", "type": "Protein", "text": [ "CrtG" ], "offsets": [ [ 1656, 1660 ] ], "normalized": [] } ]

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[ { "id": "PMID-16823379__text", "type": "abstract", "text": [ "Probing long-distance regulatory interactions in the Drosophila melanogaster bithorax complex using Dam identification. \nA cis-regulatory region of nearly 300 kb controls the expression of the three bithorax complex (BX-C) homeotic genes: Ubx, abd-A and Abd-B. Interspersed between the numerous enhancers and silencers within the complex are elements called domain boundaries. Recently, many pieces of evidence have suggested that boundaries function to create autonomous domains by interacting among themselves and forming chromatin loops. In order to test this hypothesis, we used Dam identification to probe for interactions between the Fab-7 boundary and other regions in the BX-C. We were surprised to find that the targeting of Dam methyltransferase (Dam) to the Fab-7 boundary results in a strong methylation signal at the Abd-Bm promoter, approximately 35 kb away. Moreover, this methylation pattern is found primarily in the tissues where Abd-B is not expressed and requires an intact Fab-7 boundary. Overall, our work provides the first documented example of a dynamic, long-distance physical interaction between distal regulatory elements within a living, multicellular organism.\n" ], "offsets": [ [ 0, 1191 ] ] } ]

[ { "id": "PMID-16823379_T1", "type": "Protein", "text": [ "Ubx" ], "offsets": [ [ 239, 242 ] ], "normalized": [] }, { "id": "PMID-16823379_T2", "type": "Protein", "text": [ "abd-A" ], "offsets": [ [ 244, 249 ] ], "normalized": [] }, { "id": "PMID-16823379_T3", "type": "Protein", "text": [ "Abd-B" ], "offsets": [ [ 254, 259 ] ], "normalized": [] }, { "id": "PMID-16823379_T4", "type": "Protein", "text": [ "Abd-Bm" ], "offsets": [ [ 830, 836 ] ], "normalized": [] }, { "id": "PMID-16823379_T5", "type": "Protein", "text": [ "Abd-B" ], "offsets": [ [ 948, 953 ] ], "normalized": [] }, { "id": "PMID-16823379_T7", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 837, 845 ] ], "normalized": [] } ]

[ { "id": "PMID-16823379_E1", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 804, 815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16823379_T4" }, { "role": "Site", "ref_id": "PMID-16823379_T7" } ] }, { "id": "PMID-16823379_E2", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 888, 899 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16823379_T4" }, { "role": "Site", "ref_id": "PMID-16823379_T7" } ] } ]

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[ { "id": "PMID-16861932__text", "type": "abstract", "text": [ "Activation of mitochondrial pathway is crucial for tumor selective induction of apoptosis by LAQ824. \nHDAC inhibitors are promising antitumor drugs with several HDAC inhibitors already in clinical trials. LAQ824, a potent pan-HDAC inhibitor, has been shown to induce cell cycle arrest and cell death. However, the mechanism of its antitumor effects and specially its tumor selectivity are still poorly understood. The focus of this study is to elucidate LAQ824 mediated anti-proliferative effects in lung carcinoma cells and the mechanism underlying the different sensitivity of LAQ824 to cancer and normal cells. In this study, LAQ824 mediated apoptosis was found to occur mainly via activation of the mitochondrial death pathway by inducing Apaf1 and caspase 9 and promoting mitochondrial release of key proapoptotic factors in lung cancer cells, but not in normal fibroblast cells. Using chromatin immunoprecipitation assay, we found that RNA Pol II binding and histone H3 acetylation levels at Apaf1 promoter were increased following LAQ824 treatment, explaining LAQ824 induced expression of Apaf1 in lung cancer cells. Furthermore, we showed that LAQ824 only triggered the release of mitochondrial proapoptotic factors such as cytochrome C (Cyto C) and apoptosis inducing factor (AIF) in lung cancer cells but not in normal blast cells. In addition, LAQ824 was found to induce Bax translocation in lung cancer cell, which may play important role in the induction of the release of mitochondrial proapoptotic factors. These data provide insight into the mechanism underlying the selective induction of apoptosis by LAQ824 in cancer cells.\n" ], "offsets": [ [ 0, 1643 ] ] } ]

[ { "id": "PMID-16861932_T1", "type": "Protein", "text": [ "Apaf1" ], "offsets": [ [ 743, 748 ] ], "normalized": [] }, { "id": "PMID-16861932_T2", "type": "Protein", "text": [ "caspase 9" ], "offsets": [ [ 753, 762 ] ], "normalized": [] }, { "id": "PMID-16861932_T3", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 965, 975 ] ], "normalized": [] }, { "id": "PMID-16861932_T4", "type": "Protein", "text": [ "Apaf1" ], "offsets": [ [ 998, 1003 ] ], "normalized": [] }, { "id": "PMID-16861932_T5", "type": "Protein", "text": [ "Apaf1" ], "offsets": [ [ 1096, 1101 ] ], "normalized": [] }, { "id": "PMID-16861932_T6", "type": "Protein", "text": [ "cytochrome C" ], "offsets": [ [ 1232, 1244 ] ], "normalized": [] }, { "id": "PMID-16861932_T7", "type": "Protein", "text": [ "Cyto C" ], "offsets": [ [ 1246, 1252 ] ], "normalized": [] }, { "id": "PMID-16861932_T8", "type": "Protein", "text": [ "Bax" ], "offsets": [ [ 1382, 1385 ] ], "normalized": [] } ]

[ { "id": "PMID-16861932_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 976, 987 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16861932_T3" }, { "role": "Contextgene", "ref_id": "PMID-16861932_T4" } ] } ]

[ { "id": "PMID-16861932_1", "entity_ids": [ "PMID-16861932_T6", "PMID-16861932_T7" ] } ]

[]

[ { "id": "PMID-16920952__text", "type": "abstract", "text": [ "Human cytomegalovirus-encoded UL16 discriminates MIC molecules by their alpha2 domains. \nHuman CMV infection results in MHC class I down-regulation and induction of NKG2D ligand expression favoring NK recognition of infected cells. However, human CMV-encoded UL16 counteracts surface expression of several NKG2D ligands by intracellular retention. Interestingly, UL16 interacts with MICB, but not with the closely related MICA, and with UL16-binding proteins (ULBP) ULBP1 and ULBP2, which are only distantly related to MICB, but not with ULPB3 or ULBP4, although all constitute ligands for NKG2D. Here, we dissected the molecular basis of MICA-MICB discrimination by UL16 to elucidate its puzzling binding behavior. We report that the UL16-MICB interaction is independent of glycosylation and demonstrate that selective MICB recognition by UL16 is governed by helical structures of the MICB alpha2 domain. Transplantation of the MICB alpha2 domain confers UL16 binding capacity to MICA, and thus, diversification of the MICA alpha2 domain may have been driven by the selective pressure exerted by UL16.\n" ], "offsets": [ [ 0, 1103 ] ] } ]

[ { "id": "PMID-16920952_T1", "type": "Protein", "text": [ "UL16" ], "offsets": [ [ 30, 34 ] ], "normalized": [] }, { "id": "PMID-16920952_T2", "type": "Protein", "text": [ "NKG2D" ], "offsets": [ [ 165, 170 ] ], "normalized": [] }, { "id": "PMID-16920952_T3", "type": "Protein", "text": [ "UL16" ], "offsets": [ [ 259, 263 ] ], "normalized": [] }, { "id": "PMID-16920952_T4", "type": "Protein", "text": [ "NKG2D" ], "offsets": [ [ 306, 311 ] ], "normalized": [] }, { "id": "PMID-16920952_T5", "type": "Protein", "text": [ "UL16" ], "offsets": [ [ 363, 367 ] ], "normalized": [] }, { "id": "PMID-16920952_T6", "type": "Protein", "text": [ "MICB" ], "offsets": [ [ 383, 387 ] ], "normalized": [] }, { "id": "PMID-16920952_T7", "type": "Protein", "text": [ "MICA" ], "offsets": [ [ 422, 426 ] ], "normalized": [] }, { "id": "PMID-16920952_T8", "type": "Protein", "text": [ "UL16" ], "offsets": [ [ 437, 441 ] ], "normalized": [] }, { "id": "PMID-16920952_T9", "type": "Protein", "text": [ "ULBP1" ], "offsets": [ [ 466, 471 ] ], "normalized": [] }, { "id": "PMID-16920952_T10", "type": "Protein", "text": [ "ULBP2" ], "offsets": [ [ 476, 481 ] ], "normalized": [] }, { "id": "PMID-16920952_T11", "type": "Protein", "text": [ "MICB" ], "offsets": [ [ 519, 523 ] ], "normalized": [] }, { "id": "PMID-16920952_T12", "type": "Protein", "text": [ "ULPB3" ], "offsets": [ [ 538, 543 ] ], "normalized": [] }, { "id": "PMID-16920952_T13", "type": "Protein", "text": [ "ULBP4" ], "offsets": [ [ 547, 552 ] ], "normalized": [] }, { "id": "PMID-16920952_T14", "type": "Protein", "text": [ "NKG2D" ], "offsets": [ [ 590, 595 ] ], "normalized": [] }, { "id": "PMID-16920952_T15", "type": "Protein", "text": [ "MICA" ], "offsets": [ [ 639, 643 ] ], "normalized": [] }, { "id": "PMID-16920952_T16", "type": "Protein", "text": [ "MICB" ], "offsets": [ [ 644, 648 ] ], "normalized": [] }, { "id": "PMID-16920952_T17", "type": "Protein", "text": [ "UL16" ], "offsets": [ [ 667, 671 ] ], "normalized": [] }, { "id": "PMID-16920952_T18", "type": "Protein", "text": [ "UL16" ], "offsets": [ [ 735, 739 ] ], "normalized": [] }, { "id": "PMID-16920952_T19", "type": "Protein", "text": [ "MICB" ], "offsets": [ [ 740, 744 ] ], "normalized": [] }, { "id": "PMID-16920952_T20", "type": "Protein", "text": [ "MICB" ], "offsets": [ [ 820, 824 ] ], "normalized": [] }, { "id": "PMID-16920952_T21", "type": "Protein", "text": [ "UL16" ], "offsets": [ [ 840, 844 ] ], "normalized": [] }, { "id": "PMID-16920952_T22", "type": "Protein", "text": [ "MICB" ], "offsets": [ [ 886, 890 ] ], "normalized": [] }, { "id": "PMID-16920952_T23", "type": "Protein", "text": [ "MICB" ], "offsets": [ [ 929, 933 ] ], "normalized": [] }, { "id": "PMID-16920952_T24", "type": "Protein", "text": [ "UL16" ], "offsets": [ [ 956, 960 ] ], "normalized": [] }, { "id": "PMID-16920952_T25", "type": "Protein", "text": [ "MICA" ], "offsets": [ [ 981, 985 ] ], "normalized": [] }, { "id": "PMID-16920952_T26", "type": "Protein", "text": [ "MICA" ], "offsets": [ [ 1020, 1024 ] ], "normalized": [] }, { "id": "PMID-16920952_T27", "type": "Protein", "text": [ "UL16" ], "offsets": [ [ 1097, 1101 ] ], "normalized": [] } ]

[ { "id": "PMID-16920952_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 775, 788 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16920952_T18" } ] }, { "id": "PMID-16920952_E2", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 775, 788 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16920952_T19" } ] } ]

[]

[]

[ { "id": "PMID-16958618__text", "type": "abstract", "text": [ "Hypoxia-induced assembly of prolyl hydroxylase PHD3 into complexes: implications for its activity and susceptibility for degradation by the E3 ligase Siah2. \nPHD1-3 (prolyl hydroxylases 1-3) catalyse the hydroxylation of HIF (hypoxia-inducible factor)-alpha subunit that triggers the substrate ubiquitination and subsequent degradation. The RING (really interesting new gene) finger E3 ligase Siah2 preferentially targets PHD3 for degradation. Here, we identify the requirements for such selective targeting. Firstly, PHD3 lacks an N-terminal extension found in PHD1 and PHD2; deletion of this domain from PHD1 and PHD2 renders them susceptible to degradation by Siah2. Secondly, PHD3 can homo- and hetero-multimerize with other PHDs. Consequently, PHD3 is found in high-molecular-mass fractions that were enriched in hypoxia. Interestingly, within the lower-molecular-mass complex, PHD3 exhibits higher specific activity towards hydroxylation of HIF-1alpha and co-localizes with Siah2, suggesting that Siah2 limits the availability of the more active form of PHD3. These findings provide new insight into the mechanism underlying the regulation of PHD3 availability and activity in hypoxia by the E3 ligase Siah2.\n" ], "offsets": [ [ 0, 1215 ] ] } ]

[ { "id": "PMID-16958618_T1", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 47, 51 ] ], "normalized": [] }, { "id": "PMID-16958618_T2", "type": "Protein", "text": [ "Siah2" ], "offsets": [ [ 150, 155 ] ], "normalized": [] }, { "id": "PMID-16958618_T3", "type": "Protein", "text": [ "PHD1" ], "offsets": [ [ 158, 162 ] ], "normalized": [] }, { "id": "PMID-16958618_T4", "type": "Protein", "text": [ "3" ], "offsets": [ [ 163, 164 ] ], "normalized": [] }, { "id": "PMID-16958618_T5", "type": "Protein", "text": [ "prolyl hydroxylases 1" ], "offsets": [ [ 166, 187 ] ], "normalized": [] }, { "id": "PMID-16958618_T6", "type": "Protein", "text": [ "3" ], "offsets": [ [ 188, 189 ] ], "normalized": [] }, { "id": "PMID-16958618_T7", "type": "Protein", "text": [ "Siah2" ], "offsets": [ [ 393, 398 ] ], "normalized": [] }, { "id": "PMID-16958618_T8", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 422, 426 ] ], "normalized": [] }, { "id": "PMID-16958618_T9", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 518, 522 ] ], "normalized": [] }, { "id": "PMID-16958618_T10", "type": "Protein", "text": [ "PHD1" ], "offsets": [ [ 562, 566 ] ], "normalized": [] }, { "id": "PMID-16958618_T11", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 571, 575 ] ], "normalized": [] }, { "id": "PMID-16958618_T12", "type": "Protein", "text": [ "PHD1" ], "offsets": [ [ 606, 610 ] ], "normalized": [] }, { "id": "PMID-16958618_T13", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 615, 619 ] ], "normalized": [] }, { "id": "PMID-16958618_T14", "type": "Protein", "text": [ "Siah2" ], "offsets": [ [ 663, 668 ] ], "normalized": [] }, { "id": "PMID-16958618_T15", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 680, 684 ] ], "normalized": [] }, { "id": "PMID-16958618_T16", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 749, 753 ] ], "normalized": [] }, { "id": "PMID-16958618_T17", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 883, 887 ] ], "normalized": [] }, { "id": "PMID-16958618_T18", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 947, 957 ] ], "normalized": [] }, { "id": "PMID-16958618_T19", "type": "Protein", "text": [ "Siah2" ], "offsets": [ [ 980, 985 ] ], "normalized": [] }, { "id": "PMID-16958618_T20", "type": "Protein", "text": [ "Siah2" ], "offsets": [ [ 1003, 1008 ] ], "normalized": [] }, { "id": "PMID-16958618_T21", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 1060, 1064 ] ], "normalized": [] }, { "id": "PMID-16958618_T22", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 1149, 1153 ] ], "normalized": [] }, { "id": "PMID-16958618_T23", "type": "Protein", "text": [ "Siah2" ], "offsets": [ [ 1208, 1213 ] ], "normalized": [] } ]

[ { "id": "PMID-16958618_E1", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 930, 943 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16958618_T18" } ] }, { "id": "PMID-16958618_E2", "type": "Catalysis", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 930, 943 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16958618_E1" }, { "role": "Cause", "ref_id": "PMID-16958618_T17" } ] } ]

[ { "id": "PMID-16958618_1", "entity_ids": [ "PMID-16958618_T3", "PMID-16958618_T5" ] }, { "id": "PMID-16958618_2", "entity_ids": [ "PMID-16958618_T4", "PMID-16958618_T6" ] } ]

[]

[ { "id": "PMID-16963356__text", "type": "abstract", "text": [ "Comparative analysis of the human angiotensin II type 1a receptor heterologously produced in insect cells and mammalian cells. \nAngiotensin II type 1a receptor (AT1aR) is a member of GPCR superfamily and it plays crucial roles in the regulation of blood pressure, hormone secretion and renal functions. Here, we report functional overexpression and characterization of the human AT1aR in insect cells using the baculovirus system and in mammalian cells using the Semliki Forest virus system. The recombinant receptor was expressed at a level of 29-32 pmol/mg and it binds to angiontensin II with high affinity (Kd=0.98-1.1 nM). Angiotensin II stimulated accumulation of inositol phosphate and phosphorylation of MAP kinase was also observed, which indicated that the recombinant AT1aR could couple to endogenous Galphaq protein. Confocal laser scanning microscopy revealed that the recombinant receptor was predominantly localized in the plasma membrane and agonist induced internalization of the recombinant AT1aR was also observed. The recombinant AT1aR was expressed in glycosylated form and in vivo inhibition of glycosylation suppressed its surface expression.\n" ], "offsets": [ [ 0, 1166 ] ] } ]

[ { "id": "PMID-16963356_T1", "type": "Protein", "text": [ "angiotensin II type 1a receptor" ], "offsets": [ [ 34, 65 ] ], "normalized": [] }, { "id": "PMID-16963356_T2", "type": "Protein", "text": [ "Angiotensin II type 1a receptor" ], "offsets": [ [ 128, 159 ] ], "normalized": [] }, { "id": "PMID-16963356_T3", "type": "Protein", "text": [ "AT1aR" ], "offsets": [ [ 161, 166 ] ], "normalized": [] }, { "id": "PMID-16963356_T4", "type": "Protein", "text": [ "AT1aR" ], "offsets": [ [ 379, 384 ] ], "normalized": [] }, { "id": "PMID-16963356_T5", "type": "Protein", "text": [ "angiontensin II" ], "offsets": [ [ 575, 590 ] ], "normalized": [] }, { "id": "PMID-16963356_T6", "type": "Protein", "text": [ "Angiotensin II" ], "offsets": [ [ 628, 642 ] ], "normalized": [] }, { "id": "PMID-16963356_T7", "type": "Protein", "text": [ "AT1aR" ], "offsets": [ [ 779, 784 ] ], "normalized": [] }, { "id": "PMID-16963356_T8", "type": "Protein", "text": [ "Galphaq" ], "offsets": [ [ 812, 819 ] ], "normalized": [] }, { "id": "PMID-16963356_T9", "type": "Protein", "text": [ "AT1aR" ], "offsets": [ [ 1009, 1014 ] ], "normalized": [] }, { "id": "PMID-16963356_T10", "type": "Protein", "text": [ "AT1aR" ], "offsets": [ [ 1050, 1055 ] ], "normalized": [] } ]

[ { "id": "PMID-16963356_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylated" ], "offsets": [ [ 1073, 1085 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16963356_T10" } ] } ]

[ { "id": "PMID-16963356_1", "entity_ids": [ "PMID-16963356_T2", "PMID-16963356_T3" ] } ]

[]

[ { "id": "PMID-16989963__text", "type": "abstract", "text": [ "Control of human cytomegalovirus gene expression by differential histone modifications during lytic and latent infection of a monocytic cell line. \nNon-differentiated THP-1 cells can be infected by human cytomegalovirus (HCMV) Towne strain, which persists in these cells in a non-active (latent) form without undergoing a productive cycle. The same cells become permissive for HCMV lytic infection after induction of cell differentiation by treatment with 12-O-tetradecanoylphorbol-13-acetate. We used this cellular model to study the possible role of histone modifications in the control of HCMV latency. Using chromatin immunoprecipitation with antibodies against histone H3 acetylated or dimethylated in position K9, we demonstrated that in lytically infected cells the HCMV enhancer was associated with heavy acetylated but not dimethylated H3. In the case of latent infection, the HCMV enhancer was associated with neither acetylated nor dimethylated H3. HCMV genes encoding DNA polymerase (early), pp65 (early-late) and pp150 (late) proteins were associated preferentially with acetylated H3 in lytically infected cells and with dimethylated H3 in latently infected cells. These data strongly suggest that K9 methylation of H3 is involved in HCMV gene repression, while association of the above genes with acetylated histones is likely to be necessary for active transcription. It can be postulated that the same histone modifications are used to mark active and repressed genes in both cellular and viral chromatin.\n" ], "offsets": [ [ 0, 1523 ] ] } ]

[ { "id": "PMID-16989963_T1", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 65, 72 ] ], "normalized": [] }, { "id": "PMID-16989963_T2", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 552, 559 ] ], "normalized": [] }, { "id": "PMID-16989963_T3", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 666, 676 ] ], "normalized": [] }, { "id": "PMID-16989963_T4", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 845, 847 ] ], "normalized": [] }, { "id": "PMID-16989963_T5", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 956, 958 ] ], "normalized": [] }, { "id": "PMID-16989963_T6", "type": "Protein", "text": [ "DNA polymerase" ], "offsets": [ [ 980, 994 ] ], "normalized": [] }, { "id": "PMID-16989963_T7", "type": "Protein", "text": [ "pp65" ], "offsets": [ [ 1004, 1008 ] ], "normalized": [] }, { "id": "PMID-16989963_T8", "type": "Protein", "text": [ "pp150" ], "offsets": [ [ 1026, 1031 ] ], "normalized": [] }, { "id": "PMID-16989963_T9", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1095, 1097 ] ], "normalized": [] }, { "id": "PMID-16989963_T10", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1148, 1150 ] ], "normalized": [] }, { "id": "PMID-16989963_T11", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1230, 1232 ] ], "normalized": [] }, { "id": "PMID-16989963_T12", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 1323, 1331 ] ], "normalized": [] }, { "id": "PMID-16989963_T15", "type": "Entity", "text": [ "K9" ], "offsets": [ [ 716, 718 ] ], "normalized": [] }, { "id": "PMID-16989963_T22", "type": "Entity", "text": [ "K9" ], "offsets": [ [ 1212, 1214 ] ], "normalized": [] } ]

[ { "id": "PMID-16989963_E1", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 677, 687 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T3" }, { "role": "Site", "ref_id": "PMID-16989963_T15" } ] }, { "id": "PMID-16989963_E2", "type": "Methylation", "trigger": { "text": [ "dimethylated" ], "offsets": [ [ 691, 703 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T3" }, { "role": "Site", "ref_id": "PMID-16989963_T15" } ] }, { "id": "PMID-16989963_E3", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 813, 823 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T4" }, { "role": "Site", "ref_id": "PMID-16989963_T15" } ] }, { "id": "PMID-16989963_E4", "type": "Methylation", "trigger": { "text": [ "dimethylated" ], "offsets": [ [ 832, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T4" }, { "role": "Site", "ref_id": "PMID-16989963_T15" } ] }, { "id": "PMID-16989963_E5", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 928, 938 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T5" } ] }, { "id": "PMID-16989963_E6", "type": "Methylation", "trigger": { "text": [ "dimethylated" ], "offsets": [ [ 943, 955 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T5" } ] }, { "id": "PMID-16989963_E7", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 1084, 1094 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T9" }, { "role": "Contextgene", "ref_id": "PMID-16989963_T7" } ] }, { "id": "PMID-16989963_E8", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 1084, 1094 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T9" }, { "role": "Contextgene", "ref_id": "PMID-16989963_T8" } ] }, { "id": "PMID-16989963_E9", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 1084, 1094 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T9" }, { "role": "Contextgene", "ref_id": "PMID-16989963_T6" } ] }, { "id": "PMID-16989963_E10", "type": "Methylation", "trigger": { "text": [ "dimethylated" ], "offsets": [ [ 1135, 1147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T10" }, { "role": "Contextgene", "ref_id": "PMID-16989963_T7" } ] }, { "id": "PMID-16989963_E11", "type": "Methylation", "trigger": { "text": [ "dimethylated" ], "offsets": [ [ 1135, 1147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T10" }, { "role": "Contextgene", "ref_id": "PMID-16989963_T8" } ] }, { "id": "PMID-16989963_E12", "type": "Methylation", "trigger": { "text": [ "dimethylated" ], "offsets": [ [ 1135, 1147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T10" }, { "role": "Contextgene", "ref_id": "PMID-16989963_T6" } ] }, { "id": "PMID-16989963_E13", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1215, 1226 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T11" }, { "role": "Site", "ref_id": "PMID-16989963_T22" } ] }, { "id": "PMID-16989963_E14", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 1312, 1322 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-16989963_T12" } ] } ]

[]

[]

[ { "id": "PMID-17003112__text", "type": "abstract", "text": [ "Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). \nStudies on hypoxia-sensitive pathways have revealed a series of Fe(II)-dependent dioxygenases that regulate hypoxia-inducible factor (HIF) by prolyl and asparaginyl hydroxylation. The recognition of these unprecedented signaling processes has led to a search for other substrates of the HIF hydroxylases. Here we show that the human HIF asparaginyl hydroxylase, factor inhibiting HIF (FIH), also efficiently hydroxylates specific asparaginyl (Asn)-residues within proteins of the IkappaB family. After the identification of a series of ankyrin repeat domain (ARD)-containing proteins in a screen for proteins interacting with FIH, the ARDs of p105 (NFKB1) and IkappaBalpha were shown to be efficiently hydroxylated by FIH at specific Asn residues in the hairpin loops linking particular ankyrin repeats. The target Asn residue is highly conserved as part of the ankyrin consensus, and peptides derived from a diverse range of ARD-containing proteins supported FIH enzyme activity. These findings demonstrate that this type of protein hydroxylation is not restricted to HIF and strongly suggest that FIH-dependent ARD hydroxylation is a common occurrence, potentially providing an oxygen-sensitive signal to a diverse range of processes.\n" ], "offsets": [ [ 0, 1401 ] ] } ]

[ { "id": "PMID-17003112_T1", "type": "Protein", "text": [ "hypoxia-inducible factor (HIF) asparaginyl hydroxylase" ], "offsets": [ [ 78, 132 ] ], "normalized": [] }, { "id": "PMID-17003112_T2", "type": "Protein", "text": [ "factor inhibiting HIF" ], "offsets": [ [ 134, 155 ] ], "normalized": [] }, { "id": "PMID-17003112_T3", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 157, 160 ] ], "normalized": [] }, { "id": "PMID-17003112_T4", "type": "Protein", "text": [ "HIF asparaginyl hydroxylase" ], "offsets": [ [ 497, 524 ] ], "normalized": [] }, { "id": "PMID-17003112_T5", "type": "Protein", "text": [ "factor inhibiting HIF" ], "offsets": [ [ 526, 547 ] ], "normalized": [] }, { "id": "PMID-17003112_T6", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 549, 552 ] ], "normalized": [] }, { "id": "PMID-17003112_T7", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 790, 793 ] ], "normalized": [] }, { "id": "PMID-17003112_T8", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 807, 811 ] ], "normalized": [] }, { "id": "PMID-17003112_T9", "type": "Protein", "text": [ "NFKB1" ], "offsets": [ [ 813, 818 ] ], "normalized": [] }, { "id": "PMID-17003112_T10", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 824, 836 ] ], "normalized": [] }, { "id": "PMID-17003112_T11", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 882, 885 ] ], "normalized": [] }, { "id": "PMID-17003112_T12", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1124, 1127 ] ], "normalized": [] }, { "id": "PMID-17003112_T13", "type": "Protein", "text": [ "FIH" ], "offsets": [ [ 1263, 1266 ] ], "normalized": [] }, { "id": "PMID-17003112_T16", "type": "Entity", "text": [ "Asn residues" ], "offsets": [ [ 898, 910 ] ], "normalized": [] } ]

[ { "id": "PMID-17003112_E1", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylated" ], "offsets": [ [ 866, 878 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17003112_T8" }, { "role": "Site", "ref_id": "PMID-17003112_T16" } ] }, { "id": "PMID-17003112_E2", "type": "Catalysis", "trigger": { "text": [ "hydroxylated" ], "offsets": [ [ 866, 878 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17003112_E1" }, { "role": "Cause", "ref_id": "PMID-17003112_T11" } ] }, { "id": "PMID-17003112_E3", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylated" ], "offsets": [ [ 866, 878 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17003112_T10" }, { "role": "Site", "ref_id": "PMID-17003112_T16" } ] }, { "id": "PMID-17003112_E4", "type": "Catalysis", "trigger": { "text": [ "hydroxylated" ], "offsets": [ [ 866, 878 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17003112_E3" }, { "role": "Cause", "ref_id": "PMID-17003112_T11" } ] } ]

[ { "id": "PMID-17003112_1", "entity_ids": [ "PMID-17003112_T1", "PMID-17003112_T2", "PMID-17003112_T3" ] }, { "id": "PMID-17003112_2", "entity_ids": [ "PMID-17003112_T4", "PMID-17003112_T5", "PMID-17003112_T6" ] }, { "id": "PMID-17003112_3", "entity_ids": [ "PMID-17003112_T8", "PMID-17003112_T9" ] } ]

[]

[ { "id": "PMID-17005254__text", "type": "abstract", "text": [ "Protein arginine methyltransferases: evolution and assessment of their pharmacological and therapeutic potential. \nProtein arginine N-methylation is a post-translational modification whose influence on cell function is becoming widely appreciated. Protein arginine methyltransferases (PRMT) catalyze the methylation of terminal nitrogen atoms of guanidinium side chains within arginine residues of proteins. Recently, several new members of the PRMT family have been cloned and their catalytic function determined. In this report, we present a review and phylogenetic analysis of the PRMT found so far in genomes. PRMT are found in nearly all groups of eukaryotes. Many human PRMT originated early in eukaryote evolution. Homologs of PRMT1 and PRMT5 are found in nearly every eukaryote studied. The gene structure of PRMT vary: most introns appear to be inserted randomly into the open reading frame. The change in catalytic specificity of some PRMT occurred with changes in the arginine binding pocket within the active site. Because of the high degree of conservation of sequence among the family throughout evolution, creation of specific PRMT inhibitors in pathogenic organisms may be difficult, but could be very effective if developed. Furthermore, because of the intricate involvement of several PRMT in cellular physiology, their inhibition may be fraught with unwanted side effects. Nevertheless, development of pharmaceutical agents to control PRMT functions could lead to significant new targets.\n" ], "offsets": [ [ 0, 1508 ] ] } ]

[ { "id": "PMID-17005254_T1", "type": "Protein", "text": [ "PRMT1" ], "offsets": [ [ 734, 739 ] ], "normalized": [] }, { "id": "PMID-17005254_T2", "type": "Protein", "text": [ "PRMT5" ], "offsets": [ [ 744, 749 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-17013932__text", "type": "abstract", "text": [ "Glycosylation of an immunoglobulin produced from a murine hybridoma cell line: the effect of culture mode and the anti-apoptotic gene, bcl-2. \nThe impact of bcl-2 over-expression on the glycosylation pattern of an antibody produced by a bcl-2 transfected hybridoma cell line (TB/C3.bcl-2) was investigated in suspension batch, continuous and high cell density culture (Flat hollow fibre, Tecnomouse system). In all culture modes bcl-2 over-expression resulted in higher cell viability. Analysis of the glycans from the IgG of batch cultures showed that >95% of the structures were neutral core fucosylated asialo biantennary oligosaccharides with variable terminal galactosylation (G0f, G1f and G2f) consistent with previous analysis of glycans from the conserved site at Asn-297 of the IgG protein. The galactosylation index (GI) was determined as an indicator of the glycan profile (=(G2 + 0.5* G1)/(G0 + G1 + G2)). GI values in control cultures were comparable to bcl-2 cultures during exponential growth (0.53) but declined toward the end of the culture when there was a loss in cell viability. Low dilution rates in chemostat culture were associated with reduced galactosylation of the IgG glycans in both cell lines. However, at the higher dilution rates the GI for IgG was consistently higher in the TB/C3.bcl-2 cultures. In the hollow fibre bioreactor the galactosylation of the IgG glycans was considerably lower than in suspension batch or continuous cultures with GI values averaging 0.38. Similar low galactosylation values have been found previously for high density cell cultures and these are consistent with the low values obtained when the dissolved oxygen level is maintained at a low value (10%) in controlled suspension cultures of hybridomas.\n" ], "offsets": [ [ 0, 1764 ] ] } ]

[ { "id": "PMID-17013932_T1", "type": "Protein", "text": [ "bcl-2" ], "offsets": [ [ 135, 140 ] ], "normalized": [] }, { "id": "PMID-17013932_T2", "type": "Protein", "text": [ "bcl-2" ], "offsets": [ [ 157, 162 ] ], "normalized": [] }, { "id": "PMID-17013932_T3", "type": "Protein", "text": [ "bcl-2" ], "offsets": [ [ 237, 242 ] ], "normalized": [] }, { "id": "PMID-17013932_T4", "type": "Protein", "text": [ "bcl-2" ], "offsets": [ [ 429, 434 ] ], "normalized": [] }, { "id": "PMID-17013932_T5", "type": "Protein", "text": [ "bcl-2" ], "offsets": [ [ 967, 972 ] ], "normalized": [] }, { "id": "PMID-17013932_T6", "type": "Protein", "text": [ "bcl-2" ], "offsets": [ [ 1313, 1318 ] ], "normalized": [] } ]

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[ { "id": "PMID-17015441__text", "type": "abstract", "text": [ "The cold and menthol receptor TRPM8 contains a functionally important double cysteine motif. \nWe have investigated the glycosylation, disulfide bonding, and subunit structure of mouse TRPM8. To do this, amino-terminal c-myc or hemagglutinin epitope-tagged proteins were incorporated and expressed in Chinese hamster ovary cells. These modifications had no obvious effects on channel function in intracellular calcium imaging assays upon application of agonists, icilin or menthol, and cold temperatures. Unmodified TRPM8 migrates with an apparent mass of 129 kDa and can be glycosylated in Chinese hamster ovary cells to give glycoproteins with apparent masses of 136 and 147 kDa. We identified two potential N-linked glycosylation sites in TRPM8 (Asn-821 and Asn-934) and mutated them to show that only the site in the putative pore region at position 934 is modified and that glycosylation of this site is not absolutely necessary for cell surface expression or responsiveness to icilin, menthol, and cool temperatures. Enzymatic cleavage of the carbohydrate chains indicated that they are complex carbohydrate. The glycosylation site is flanked in the pore by two cysteine residues that we mutated, to prove that they are involved in a conserved double cysteine motif, which is essential for channel function. Mutation of either of these cysteines abolishes function and forces the formation of a non-functional complex of the size of a homodimer. The double cysteine mutant is also non-functional. Finally, we showed in Perfluoro-octanoic acid-polyacrylamide gels that TRPM8 can form a tetramer (in addition to dimer and trimer forms), consistent with current thinking that functional TRP ion channels are tetrameric.\n" ], "offsets": [ [ 0, 1722 ] ] } ]

[ { "id": "PMID-17015441_T1", "type": "Protein", "text": [ "TRPM8" ], "offsets": [ [ 30, 35 ] ], "normalized": [] }, { "id": "PMID-17015441_T2", "type": "Protein", "text": [ "TRPM8" ], "offsets": [ [ 184, 189 ] ], "normalized": [] }, { "id": "PMID-17015441_T3", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 218, 223 ] ], "normalized": [] }, { "id": "PMID-17015441_T4", "type": "Protein", "text": [ "hemagglutinin" ], "offsets": [ [ 227, 240 ] ], "normalized": [] }, { "id": "PMID-17015441_T5", "type": "Protein", "text": [ "TRPM8" ], "offsets": [ [ 515, 520 ] ], "normalized": [] }, { "id": "PMID-17015441_T6", "type": "Protein", "text": [ "TRPM8" ], "offsets": [ [ 741, 746 ] ], "normalized": [] }, { "id": "PMID-17015441_T7", "type": "Protein", "text": [ "TRPM8" ], "offsets": [ [ 1573, 1578 ] ], "normalized": [] }, { "id": "PMID-17015441_T10", "type": "Entity", "text": [ "position 934" ], "offsets": [ [ 844, 856 ] ], "normalized": [] } ]

[ { "id": "PMID-17015441_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 119, 132 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17015441_T2" } ] }, { "id": "PMID-17015441_E2", "type": "Glycosylation", "trigger": { "text": [ "glycosylated" ], "offsets": [ [ 574, 586 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17015441_T5" } ] }, { "id": "PMID-17015441_E3", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 878, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17015441_T6" }, { "role": "Site", "ref_id": "PMID-17015441_T10" } ] } ]

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[ { "id": "PMID-17028180__text", "type": "abstract", "text": [ "Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation. \nRegulatory T cells (T(reg)) express Foxp3, a forkhead family member that is necessary and sufficient for T(reg) lineage choice and function. Ectopic expression of Foxp3 in non-T(reg) leads to repression of the interleukin 2 (IL-2) and interferon gamma (IFNgamma) genes, gain of suppressor function, and induction of genes such as CD25, GITR, and CTLA-4, but the mode by which Foxp3 enforces this program is unclear. Using chromatin immunoprecipitation, we have demonstrated that Foxp3 binds to the endogenous IL-2 and IFNgamma loci in T cells, but only after T cell receptor stimulation. This activation-induced Foxp3 binding was abrogated by cyclosporin A, suggesting a role for the phosphatase calcineurin in Foxp3 function. We have also shown that binding of Foxp3 to the IL-2 and IFNgamma genes induces active deacetylation of histone H3, a process that inhibits chromatin remodeling and opposes gene transcription. Conversely, binding of Foxp3 to the GITR, CD25, and CTLA-4 genes results in increased histone acetylation. These data indicate that Foxp3 may regulate transcription through direct chromatin remodeling and show that Foxp3 function is influenced by signals from the TCR.\n" ], "offsets": [ [ 0, 1310 ] ] } ]

[ { "id": "PMID-17028180_T1", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 30, 35 ] ], "normalized": [] }, { "id": "PMID-17028180_T2", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 99, 106 ] ], "normalized": [] }, { "id": "PMID-17028180_T3", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 157, 162 ] ], "normalized": [] }, { "id": "PMID-17028180_T4", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 284, 289 ] ], "normalized": [] }, { "id": "PMID-17028180_T5", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 331, 344 ] ], "normalized": [] }, { "id": "PMID-17028180_T6", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 346, 350 ] ], "normalized": [] }, { "id": "PMID-17028180_T7", "type": "Protein", "text": [ "interferon gamma" ], "offsets": [ [ 356, 372 ] ], "normalized": [] }, { "id": "PMID-17028180_T8", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 374, 382 ] ], "normalized": [] }, { "id": "PMID-17028180_T9", "type": "Protein", "text": [ "CD25" ], "offsets": [ [ 451, 455 ] ], "normalized": [] }, { "id": "PMID-17028180_T10", "type": "Protein", "text": [ "GITR" ], "offsets": [ [ 457, 461 ] ], "normalized": [] }, { "id": "PMID-17028180_T11", "type": "Protein", "text": [ "CTLA-4" ], "offsets": [ [ 467, 473 ] ], "normalized": [] }, { "id": "PMID-17028180_T12", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 497, 502 ] ], "normalized": [] }, { "id": "PMID-17028180_T13", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 600, 605 ] ], "normalized": [] }, { "id": "PMID-17028180_T14", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 630, 634 ] ], "normalized": [] }, { "id": "PMID-17028180_T15", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 639, 647 ] ], "normalized": [] }, { "id": "PMID-17028180_T16", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 733, 738 ] ], "normalized": [] }, { "id": "PMID-17028180_T17", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 832, 837 ] ], "normalized": [] }, { "id": "PMID-17028180_T18", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 883, 888 ] ], "normalized": [] }, { "id": "PMID-17028180_T19", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 896, 900 ] ], "normalized": [] }, { "id": "PMID-17028180_T20", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 905, 913 ] ], "normalized": [] }, { "id": "PMID-17028180_T21", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 952, 962 ] ], "normalized": [] }, { "id": "PMID-17028180_T22", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 1064, 1069 ] ], "normalized": [] }, { "id": "PMID-17028180_T23", "type": "Protein", "text": [ "GITR" ], "offsets": [ [ 1077, 1081 ] ], "normalized": [] }, { "id": "PMID-17028180_T24", "type": "Protein", "text": [ "CD25" ], "offsets": [ [ 1083, 1087 ] ], "normalized": [] }, { "id": "PMID-17028180_T25", "type": "Protein", "text": [ "CTLA-4" ], "offsets": [ [ 1093, 1099 ] ], "normalized": [] }, { "id": "PMID-17028180_T26", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1127, 1134 ] ], "normalized": [] }, { "id": "PMID-17028180_T27", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 1173, 1178 ] ], "normalized": [] }, { "id": "PMID-17028180_T28", "type": "Protein", "text": [ "Foxp3" ], "offsets": [ [ 1256, 1261 ] ], "normalized": [] } ]

[ { "id": "PMID-17028180_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 107, 118 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17028180_T2" } ] }, { "id": "PMID-17028180_E2", "type": "Deacetylation", "trigger": { "text": [ "deacetylation" ], "offsets": [ [ 935, 948 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17028180_T21" }, { "role": "Contextgene", "ref_id": "PMID-17028180_T19" } ] }, { "id": "PMID-17028180_E3", "type": "Deacetylation", "trigger": { "text": [ "deacetylation" ], "offsets": [ [ 935, 948 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17028180_T21" }, { "role": "Contextgene", "ref_id": "PMID-17028180_T20" } ] }, { "id": "PMID-17028180_E4", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1135, 1146 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17028180_T26" }, { "role": "Contextgene", "ref_id": "PMID-17028180_T23" } ] }, { "id": "PMID-17028180_E5", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1135, 1146 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17028180_T26" }, { "role": "Contextgene", "ref_id": "PMID-17028180_T24" } ] }, { "id": "PMID-17028180_E6", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1135, 1146 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17028180_T26" }, { "role": "Contextgene", "ref_id": "PMID-17028180_T25" } ] } ]

[ { "id": "PMID-17028180_1", "entity_ids": [ "PMID-17028180_T5", "PMID-17028180_T6" ] }, { "id": "PMID-17028180_2", "entity_ids": [ "PMID-17028180_T7", "PMID-17028180_T8" ] } ]

[]

[ { "id": "PMID-17045735__text", "type": "abstract", "text": [ "Assembly and structural characterization of an authentic complex between human follicle stimulating hormone and a hormone-binding ectodomain of its receptor. \nFollicle stimulating hormone (FSH) is secreted from the pituitary gland to regulate reproduction in vertebrates. FSH signals through a G-protein coupled receptor (FSHR) on the target cell surface. We describe here the strategy to produce a soluble FSH-FSHR complex that involves the co-secretion of a truncated FSHR ectodomain (FSHR(HB)) and a covalently linked FSHalphabeta heterodimer from baculovirus-infected insect cells. FSH binds to FSHR(HB) with a high affinity comparable to that for the full-length receptor. The crystal structure of the FSH-FSHR(HB) complex provides explanations for the high affinity and specificity of FSH interaction with FSHR, and it shows an unexpected dimerization of these complexes. Here we also compare the crystal structure with theoretical models of the FSH-FSHR-binding mode. We conclude that the FSH-FSHR(HB) structure gives an authentic representation of FSH binding to intact FSHR.\n" ], "offsets": [ [ 0, 1084 ] ] } ]

[ { "id": "PMID-17045735_T1", "type": "Protein", "text": [ "FSHR" ], "offsets": [ [ 322, 326 ] ], "normalized": [] }, { "id": "PMID-17045735_T2", "type": "Protein", "text": [ "FSHR" ], "offsets": [ [ 411, 415 ] ], "normalized": [] }, { "id": "PMID-17045735_T3", "type": "Protein", "text": [ "FSHR" ], "offsets": [ [ 470, 474 ] ], "normalized": [] }, { "id": "PMID-17045735_T4", "type": "Protein", "text": [ "FSHR" ], "offsets": [ [ 487, 491 ] ], "normalized": [] }, { "id": "PMID-17045735_T5", "type": "Protein", "text": [ "FSHalpha" ], "offsets": [ [ 521, 529 ] ], "normalized": [] }, { "id": "PMID-17045735_T6", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 529, 533 ] ], "normalized": [] }, { "id": "PMID-17045735_T7", "type": "Protein", "text": [ "FSHR" ], "offsets": [ [ 599, 603 ] ], "normalized": [] }, { "id": "PMID-17045735_T8", "type": "Protein", "text": [ "FSHR" ], "offsets": [ [ 711, 715 ] ], "normalized": [] }, { "id": "PMID-17045735_T9", "type": "Protein", "text": [ "FSHR" ], "offsets": [ [ 812, 816 ] ], "normalized": [] }, { "id": "PMID-17045735_T10", "type": "Protein", "text": [ "FSH" ], "offsets": [ [ 952, 955 ] ], "normalized": [] }, { "id": "PMID-17045735_T11", "type": "Protein", "text": [ "FSH" ], "offsets": [ [ 996, 999 ] ], "normalized": [] }, { "id": "PMID-17045735_T12", "type": "Protein", "text": [ "FSHR" ], "offsets": [ [ 1000, 1004 ] ], "normalized": [] }, { "id": "PMID-17045735_T13", "type": "Protein", "text": [ "FSHR" ], "offsets": [ [ 1078, 1082 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-17054082__text", "type": "abstract", "text": [ "Assessing the instability of the isoelectric focusing patterns of erythropoietin in urine. \nIEF can be used to differentiate human urinary erythropoietin (uEPO), recombinant human erythropoietin or epoetin (rEPO) and darbepoetin (novel erythropoiesis stimulating protein (NESP)). This is the basis of the method currently used to detect misuse of rEPO and NESP by elite athletes. Recently, an unknown activity has been attributed to some urine samples (denominated 'unstable' urine by the World Anti-Doping Agency; WADA). This activity has shown to give rise to artefactual profiles for both rEPO and NESP when incubated with such urine and, thus, raised concerns with respect to doping control. We have evaluated which charges produce the characteristic IEF profiles of uEPO, rEPO and NESP and how these profiles respond to distinct enzymatic reactions. From sialidase digestions it became evident that only uEPO contains charges different from sialic acid, and a comparison of all substances after complete de-N-glycosylation localized these charges in the carbohydrate moiety. Partial desialylation, or digestion with arylsulfatase from Helix pomatia yielded profiles for recombinants species similar to those observed for unstable urine samples. The contributions from our studies to the anti-doping problem include: (i) protocols that may corroborate the potential misuse of rEPO or NESP based on the particular enzymatic activity of an arylsulfatase preparation, or a broad-specificity sialidase; (ii) assurance that the instability observed in some urine samples may only result from false-negatives, but not from false-positive testing; and (iii) a simple remedy to prevent an unstable urine from altering the IEF profile by adding selective competitive substrates.\n" ], "offsets": [ [ 0, 1774 ] ] } ]

[ { "id": "PMID-17054082_T1", "type": "Protein", "text": [ "erythropoietin" ], "offsets": [ [ 66, 80 ] ], "normalized": [] }, { "id": "PMID-17054082_T2", "type": "Protein", "text": [ "erythropoietin" ], "offsets": [ [ 139, 153 ] ], "normalized": [] }, { "id": "PMID-17054082_T3", "type": "Protein", "text": [ "EPO" ], "offsets": [ [ 156, 159 ] ], "normalized": [] }, { "id": "PMID-17054082_T4", "type": "Protein", "text": [ "erythropoietin" ], "offsets": [ [ 180, 194 ] ], "normalized": [] }, { "id": "PMID-17054082_T5", "type": "Protein", "text": [ "epoetin" ], "offsets": [ [ 198, 205 ] ], "normalized": [] }, { "id": "PMID-17054082_T6", "type": "Protein", "text": [ "EPO" ], "offsets": [ [ 208, 211 ] ], "normalized": [] }, { "id": "PMID-17054082_T7", "type": "Protein", "text": [ "EPO" ], "offsets": [ [ 348, 351 ] ], "normalized": [] }, { "id": "PMID-17054082_T8", "type": "Protein", "text": [ "EPO" ], "offsets": [ [ 593, 596 ] ], "normalized": [] }, { "id": "PMID-17054082_T9", "type": "Protein", "text": [ "EPO" ], "offsets": [ [ 772, 775 ] ], "normalized": [] }, { "id": "PMID-17054082_T10", "type": "Protein", "text": [ "EPO" ], "offsets": [ [ 778, 781 ] ], "normalized": [] }, { "id": "PMID-17054082_T11", "type": "Protein", "text": [ "EPO" ], "offsets": [ [ 910, 913 ] ], "normalized": [] }, { "id": "PMID-17054082_T12", "type": "Protein", "text": [ "EPO" ], "offsets": [ [ 1381, 1384 ] ], "normalized": [] } ]

[ { "id": "PMID-17054082_E1", "type": "Deglycosylation", "trigger": { "text": [ "de-N-glycosylation" ], "offsets": [ [ 1009, 1027 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17054082_T11" } ] } ]

[ { "id": "PMID-17054082_1", "entity_ids": [ "PMID-17054082_T2", "PMID-17054082_T3" ] }, { "id": "PMID-17054082_2", "entity_ids": [ "PMID-17054082_T4", "PMID-17054082_T5", "PMID-17054082_T6" ] } ]

[]

[ { "id": "PMID-17054391__text", "type": "abstract", "text": [ "The transcriptional regulator CBP has defined spatial associations within interphase nuclei. \nIt is becoming increasingly clear that nuclear macromolecules and macromolecular complexes are compartmentalized through binding interactions into an apparent three-dimensionally ordered structure. This ordering, however, does not appear to be deterministic to the extent that chromatin and nonchromatin structures maintain a strict 3-D arrangement. Rather, spatial ordering within the cell nucleus appears to conform to stochastic rather than deterministic spatial relationships. The stochastic nature of organization becomes particularly problematic when any attempt is made to describe the spatial relationship between proteins involved in the regulation of the genome. The CREB-binding protein (CBP) is one such transcriptional regulator that, when visualised by confocal microscopy, reveals a highly punctate staining pattern comprising several hundred individual foci distributed within the nuclear volume. Markers for euchromatic sequences have similar patterns. Surprisingly, in most cases, the predicted one-to-one relationship between transcription factor and chromatin sequence is not observed. Consequently, to understand whether spatial relationships that are not coincident are nonrandom and potentially biologically important, it is necessary to develop statistical approaches. In this study, we report on the development of such an approach and apply it to understanding the role of CBP in mediating chromatin modification and transcriptional regulation. We have used nearest-neighbor distance measurements and probability analyses to study the spatial relationship between CBP and other nuclear subcompartments enriched in transcription factors, chromatin, and splicing factors. Our results demonstrate that CBP has an order of spatial association with other nuclear subcompartments. We observe closer associations between CBP and RNA polymerase II-enriched foci and SC35 speckles than nascent RNA or specific acetylated histones. Furthermore, we find that CBP has a significantly higher probability of being close to its known in vivo substrate histone H4 lysine 5 compared with the closely related H4 lysine 12. This study demonstrates that complex relationships not described by colocalization exist in the interphase nucleus and can be characterized and quantified. The subnuclear distribution of CBP is difficult to reconcile with a model where chromatin organization is the sole determinant of the nuclear organization of proteins that regulate transcription but is consistent with a close link between spatial associations and nuclear functions.\n" ], "offsets": [ [ 0, 2664 ] ] } ]

[ { "id": "PMID-17054391_T1", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 30, 33 ] ], "normalized": [] }, { "id": "PMID-17054391_T2", "type": "Protein", "text": [ "CREB-binding protein" ], "offsets": [ [ 771, 791 ] ], "normalized": [] }, { "id": "PMID-17054391_T3", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 793, 796 ] ], "normalized": [] }, { "id": "PMID-17054391_T4", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 1493, 1496 ] ], "normalized": [] }, { "id": "PMID-17054391_T5", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 1684, 1687 ] ], "normalized": [] }, { "id": "PMID-17054391_T6", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 1819, 1822 ] ], "normalized": [] }, { "id": "PMID-17054391_T7", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 1934, 1937 ] ], "normalized": [] }, { "id": "PMID-17054391_T8", "type": "Protein", "text": [ "SC35" ], "offsets": [ [ 1978, 1982 ] ], "normalized": [] }, { "id": "PMID-17054391_T9", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 2032, 2040 ] ], "normalized": [] }, { "id": "PMID-17054391_T10", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 2068, 2071 ] ], "normalized": [] }, { "id": "PMID-17054391_T11", "type": "Protein", "text": [ "histone H4" ], "offsets": [ [ 2157, 2167 ] ], "normalized": [] }, { "id": "PMID-17054391_T12", "type": "Protein", "text": [ "H4" ], "offsets": [ [ 2211, 2213 ] ], "normalized": [] }, { "id": "PMID-17054391_T13", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 2412, 2415 ] ], "normalized": [] } ]

[ { "id": "PMID-17054391_E1", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 2021, 2031 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17054391_T9" } ] } ]

[ { "id": "PMID-17054391_1", "entity_ids": [ "PMID-17054391_T2", "PMID-17054391_T3" ] } ]

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[ { "id": "PMID-17099721__text", "type": "abstract", "text": [ "Characterization of promoter regulatory elements involved in downexpression of the DNA polymerase kappa in colorectal cancer. \nThe low-fidelity DNA polymerases thought to be specialized in DNA damage processing are frequently misregulated in cancers. We show here that DNA polymerase kappa (polkappa), prone to replicate across oxidative and aromatic adducts and known to function in nucleotide excision repair (NER), is downregulated in colorectal tumour biopsies. Contrary to the replicative poldelta and polalpha, for which only activating domains were described, we identified an upstream 465-bp-long repressor region in the promoter of POLK. We also found an activating 237-bp region that includes stimulating protein-1 (SP1) and cyclic AMP-responsive element (CRE)-binding sites. Mutations at one CRE-binding site led to a dramatic 80% decrease in promoter activity. Alterations of the SP1-binding site also affected, to a lesser extent, the transcription. Gel shift assays confirmed the role played by CRE/SP1 recognition sequences. Moreover, ectopic expression of SP1 or CRE-binding protein (CREB) protein favoured polkappa transcription. Finally, we found that polkappa downexpression in colorectal biopsies correlated with a decreased level of CREB and SP1 transcripts. This work shows that the promoter of POLK is cis-controlled and suggests that silencing of CREB and SP1 proteins could contribute to downregulation of this repair polymerase in colorectal tumours.\n" ], "offsets": [ [ 0, 1477 ] ] } ]

[ { "id": "PMID-17099721_T1", "type": "Protein", "text": [ "DNA polymerase kappa" ], "offsets": [ [ 83, 103 ] ], "normalized": [] }, { "id": "PMID-17099721_T2", "type": "Protein", "text": [ "DNA polymerase kappa" ], "offsets": [ [ 269, 289 ] ], "normalized": [] }, { "id": "PMID-17099721_T3", "type": "Protein", "text": [ "polkappa" ], "offsets": [ [ 291, 299 ] ], "normalized": [] }, { "id": "PMID-17099721_T4", "type": "Protein", "text": [ "POLK" ], "offsets": [ [ 641, 645 ] ], "normalized": [] }, { "id": "PMID-17099721_T5", "type": "Protein", "text": [ "stimulating protein-1" ], "offsets": [ [ 703, 724 ] ], "normalized": [] }, { "id": "PMID-17099721_T6", "type": "Protein", "text": [ "SP1" ], "offsets": [ [ 726, 729 ] ], "normalized": [] }, { "id": "PMID-17099721_T7", "type": "Protein", "text": [ "SP1" ], "offsets": [ [ 892, 895 ] ], "normalized": [] }, { "id": "PMID-17099721_T8", "type": "Protein", "text": [ "SP1" ], "offsets": [ [ 1013, 1016 ] ], "normalized": [] }, { "id": "PMID-17099721_T9", "type": "Protein", "text": [ "SP1" ], "offsets": [ [ 1072, 1075 ] ], "normalized": [] }, { "id": "PMID-17099721_T10", "type": "Protein", "text": [ "SP1" ], "offsets": [ [ 1263, 1266 ] ], "normalized": [] }, { "id": "PMID-17099721_T11", "type": "Protein", "text": [ "POLK" ], "offsets": [ [ 1317, 1321 ] ], "normalized": [] }, { "id": "PMID-17099721_T12", "type": "Protein", "text": [ "SP1" ], "offsets": [ [ 1380, 1383 ] ], "normalized": [] } ]

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[ { "id": "PMID-17099721_1", "entity_ids": [ "PMID-17099721_T2", "PMID-17099721_T3" ] }, { "id": "PMID-17099721_2", "entity_ids": [ "PMID-17099721_T5", "PMID-17099721_T6" ] } ]

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[ { "id": "PMID-17119870__text", "type": "abstract", "text": [ "Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression. \nApelin interacts with the APJ receptor to enhance inotropy. In heart failure, apelin-APJ coupling may provide a means of enhancing myocardial function. The alterations in apelin and APJ receptor concentrations with ischemic cardiomyopathy are poorly understood. We investigated the compensatory changes in endogenous apelin and APJ levels in the setting of ischemic cardiomyopathy. Male, Lewis rats underwent LAD ligation and progressed into heart failure over 6 weeks. Corresponding animals underwent sham thoracotomy as control. Six weeks after initial surgery, the animals underwent hemodynamic functional analysis in the presence of exogenous apelin-13 infusion and the hearts were explanted for western blot and enzyme immunoassay analysis. Western blot analysis of myocardial APJ concentration demonstrated increased APJ receptor protein levels with heart failure (1890750+/-133500 vs. 901600+/-143120 intensity units, n=8, p=0.00001). Total apelin protein levels increased with ischemic heart failure as demonstrated by enzyme immunoassay (12.0+/-4.6 vs. 1.0+/-1.2 ng/ml, n=5, p=0.006) and western blot (1579400+/-477733 vs. 943000+/-157600 intensity units, n=10, p=0.008). Infusion of apelin-13 significantly enhanced myocardial function in sham and failing hearts. We conclude that total myocardial apelin and APJ receptor levels increase in compensation for ischemic cardiomyopathy.\n" ], "offsets": [ [ 0, 1484 ] ] } ]

[ { "id": "PMID-17119870_T1", "type": "Protein", "text": [ "apelin" ], "offsets": [ [ 54, 60 ] ], "normalized": [] }, { "id": "PMID-17119870_T2", "type": "Protein", "text": [ "APJ" ], "offsets": [ [ 65, 68 ] ], "normalized": [] }, { "id": "PMID-17119870_T3", "type": "Protein", "text": [ "Apelin" ], "offsets": [ [ 91, 97 ] ], "normalized": [] }, { "id": "PMID-17119870_T4", "type": "Protein", "text": [ "APJ" ], "offsets": [ [ 117, 120 ] ], "normalized": [] }, { "id": "PMID-17119870_T5", "type": "Protein", "text": [ "apelin" ], "offsets": [ [ 169, 175 ] ], "normalized": [] }, { "id": "PMID-17119870_T6", "type": "Protein", "text": [ "APJ" ], "offsets": [ [ 176, 179 ] ], "normalized": [] }, { "id": "PMID-17119870_T7", "type": "Protein", "text": [ "apelin" ], "offsets": [ [ 262, 268 ] ], "normalized": [] }, { "id": "PMID-17119870_T8", "type": "Protein", "text": [ "APJ" ], "offsets": [ [ 273, 276 ] ], "normalized": [] }, { "id": "PMID-17119870_T9", "type": "Protein", "text": [ "apelin" ], "offsets": [ [ 408, 414 ] ], "normalized": [] }, { "id": "PMID-17119870_T10", "type": "Protein", "text": [ "APJ" ], "offsets": [ [ 419, 422 ] ], "normalized": [] }, { "id": "PMID-17119870_T11", "type": "Protein", "text": [ "apelin-13" ], "offsets": [ [ 738, 747 ] ], "normalized": [] }, { "id": "PMID-17119870_T12", "type": "Protein", "text": [ "APJ" ], "offsets": [ [ 873, 876 ] ], "normalized": [] }, { "id": "PMID-17119870_T13", "type": "Protein", "text": [ "APJ" ], "offsets": [ [ 914, 917 ] ], "normalized": [] }, { "id": "PMID-17119870_T14", "type": "Protein", "text": [ "apelin" ], "offsets": [ [ 1039, 1045 ] ], "normalized": [] }, { "id": "PMID-17119870_T15", "type": "Protein", "text": [ "apelin-13" ], "offsets": [ [ 1284, 1293 ] ], "normalized": [] }, { "id": "PMID-17119870_T16", "type": "Protein", "text": [ "apelin" ], "offsets": [ [ 1399, 1405 ] ], "normalized": [] }, { "id": "PMID-17119870_T17", "type": "Protein", "text": [ "APJ" ], "offsets": [ [ 1410, 1413 ] ], "normalized": [] } ]

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[ { "id": "PMID-17121856__text", "type": "abstract", "text": [ "Site-specific acetylation of p53 directs selective transcription complex assembly. \nHistone deacetylase (HDAC) inhibitors are being investigated as possible adjuvant therapies for a number of diseases, including cancer. In addition to stabilization of acetylated histones, HDAC inhibitors stabilize the acetylation of a number of transcription factors, including p53. This study investigates the action of two HDAC inhibitors, CG-1521 and trichostatin A, which stabilize Ac-Lys-373 p53 and Ac-Lys-382 p53, respectively, in LNCaP prostate cancer cells. Real-time PCR demonstrates that CG-1521 induces p21 transcription whereas trichostatin A does not alter the steady state level of p21 mRNA. Co-immunoprecipitation demonstrates that the selective acetylation of p53 directs the recruitment of mutually exclusive coactivator complexes on the p53 response elements in the p21 promoter. Furthermore, the co-activator complexes initiate the recruitment of the components of the basal transcription apparatus to the basal promoter with markedly different outcomes because only Ac-Lys-373 p53 promotes the assembly of the basal transcriptional apparatus on the p21 promoter. These data highlight the profound effects of post-translational modification, including acetylation, on the function of p53. The data also suggest a novel and critically important role for protein acetylation/deacetylation in the assembly of active transcription processes that may be as important as classical phosphorylation/dephosphorylation.\n" ], "offsets": [ [ 0, 1515 ] ] } ]

[ { "id": "PMID-17121856_T1", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 29, 32 ] ], "normalized": [] }, { "id": "PMID-17121856_T2", "type": "Protein", "text": [ "Histone" ], "offsets": [ [ 84, 91 ] ], "normalized": [] }, { "id": "PMID-17121856_T3", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 263, 271 ] ], "normalized": [] }, { "id": "PMID-17121856_T4", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 363, 366 ] ], "normalized": [] }, { "id": "PMID-17121856_T5", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 482, 485 ] ], "normalized": [] }, { "id": "PMID-17121856_T6", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 501, 504 ] ], "normalized": [] }, { "id": "PMID-17121856_T7", "type": "Protein", "text": [ "p21" ], "offsets": [ [ 600, 603 ] ], "normalized": [] }, { "id": "PMID-17121856_T8", "type": "Protein", "text": [ "p21" ], "offsets": [ [ 682, 685 ] ], "normalized": [] }, { "id": "PMID-17121856_T9", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 762, 765 ] ], "normalized": [] }, { "id": "PMID-17121856_T10", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 841, 844 ] ], "normalized": [] }, { "id": "PMID-17121856_T11", "type": "Protein", "text": [ "p21" ], "offsets": [ [ 870, 873 ] ], "normalized": [] }, { "id": "PMID-17121856_T12", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1083, 1086 ] ], "normalized": [] }, { "id": "PMID-17121856_T13", "type": "Protein", "text": [ "p21" ], "offsets": [ [ 1155, 1158 ] ], "normalized": [] }, { "id": "PMID-17121856_T14", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1289, 1292 ] ], "normalized": [] } ]

[ { "id": "PMID-17121856_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 14, 25 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17121856_T1" } ] }, { "id": "PMID-17121856_E2", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 252, 262 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17121856_T3" } ] }, { "id": "PMID-17121856_E3", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 303, 314 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17121856_T4" } ] }, { "id": "PMID-17121856_E4", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 747, 758 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17121856_T9" } ] }, { "id": "PMID-17121856_E5", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1257, 1268 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17121856_T14" } ] } ]

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[ { "id": "PMID-1712781__text", "type": "abstract", "text": [ "Cell-free translation and characterization of corneal keratan sulfate proteoglycan core proteins. \nBovine corneal keratan sulfate proteoglycan (KSPG) contains two core proteins, 37 and 25 kDa, if fully deglycosylated, but 47 and 35 kDa, respectively, after endo-beta-galactosidase (Funderburgh, J. L., and Conrad, G. W. (1990) J. Biol Chem. 265, 8297-8303). Chicken corneal KSPG released a single core protein of 47 kDa after endo-beta-galactosidase, and of 35 and 36 kDa, if deglycosylated with N-glycanase or trifluoromethanesulfonic acid. Affinity purified rabbit antibodies against each KSPG recognized only the intact proteoglycan or its core proteins in immunoblots of unfractionated guanidine-HCl extracts of whole cornea after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Affinity purified antibody to a synthetic peptide duplicating the NH2-terminal sequence of the 37-kDa bovine core protein showed little reactivity with untreated corneal extract but reacted with the 47-kDa bovine protein in endo-beta-galactosidase-treated extracts. RNA was isolated from bovine and chick corneal stromas and used for in vitro translation. Antibody against bovine KSPG immunoprecipitated two proteins of 56-53 kDa and a protein of 41 kDa after translation of bovine RNA. Translation of chick RNA produced a double band of 38-39 kDa and a single band of 25 kDa precipitating with antibody against chicken KSPG. Homologous unlabeled KSPG competed for binding of antibodies to these translation products. These data suggest that in vertebrate corneas, the multiple KSPG core protein isoforms may arise as products of separate mRNAs, rather than from proteolytic processing of a large polypeptide precursor.\n" ], "offsets": [ [ 0, 1714 ] ] } ]

[ { "id": "PMID-1712781_T1", "type": "Protein", "text": [ "N-glycanase" ], "offsets": [ [ 496, 507 ] ], "normalized": [] } ]

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[]

[ { "id": "PMID-17129494__text", "type": "abstract", "text": [ "[Reciprocal regulation between hypoxia-inducible factor-1alpha and its prolyl hydroxylases in hypoxic pulmonary hypertension rats] \nOBJECTIVE: To investigate the interaction between hypoxia-inducible factors-1alpha subunit (HIF-1alpha) and its three prolyl hydroxylases (PHD1, PHD2 and PHD3) during the development of rat hypoxic pulmonary hypertension. METHODS: Forty male SD rats were randomly divided into 5 groups and exposed to normoxia (C group) or exposed to hypoxia for 3, 7, 14 or 21 d (H(3), H(7), H(14), H(21) group), respectively. Mean pulmonary arterial pressure (mPAP), vessel morphometry and right ventricle hypertrophy index (RVHI) were measured. Reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization were used to determine the expression of mRNA. Immunohistochemistry and Western blot were used to determine the expression of mRNA. RESULTS: The level of mPAP [(21.7 +/- 2.4) mm Hg, 1 mm Hg = 0.133 kPa], the ratio of vascular wall thickness to external diameter [WA%, (43.9 +/- 5.3)%] and pulmonary artery media thickness [PAMT, (10.0 +/- 0.7) microm] were significantly higher in H(7) group than those in C group [(16.6 +/- 1.6) mm Hg, (36.3 +/- 4.8)% and (8.5 +/- 1.3) microm respectively, q value were 5.591, 4.082, 2.929, respectively, all P < 0.05]. These parameters reached a high level and remained stable on H(14) group, and RVHI was significantly higher in H(14) group [(27.6 +/- 1.4)%] than in C group [(23.6 +/- 2.9)%, q = 5.817, P < 0.05]. HIF-1alpha protein was barely positive in C group (0.080 +/- 0.009), but markedly up-regulated in H(3) group (0.196 +/- 0.018, compared with C group q = 18.864, P < 0.05), reaching its peak in H(7) group (0.203 +/- 0.022), and then declined slightly in H(14) and H(21) group. HIF-1alpha mRNA increased marginally in H(14) group (0.176 +/- 0.019, compared with C group q = 5.401, P < 0.05, 0.139 +/- 0.017). PHD1 and PHD2 mRNA (0.260 +/- 0.031, 0.196 +/- 0.023) and protein (0.244 +/- 0.030, 0.205 +/- 0.025) were positive in C group. PHD2 mRNA and protein were up-regulated in H(3) group (0.246 +/- 0.023, 0.235 +/- 0.025, compared with C group q value was 5.268, 3.046, respectively, all P < 0.05), reaching its peak in H(14) group whereas PHD1 protein declined in H(14) group (0.210 +/- 0.023, compared with C group q = 3.885, P < 0.05) without significant mRNA change. PHD3 mRNA and protein were detected at low level in C group (0.110 +/- 0.013, 0.153 +/- 0.019), but markedly up-regulated in H(3) group (0.259 +/- 0.024, compared with C group q = 15.831, P < 0.05), and then PHD3 mRNA remained at high level while PHD3 protein declined in H(14) and H(21) group (0.206 +/- 0.025, 0.189 +/- 0.019, compared with H(7) group q value was 6.441, 8.526, respectively, all P < 0.05). Linear correlation analysis showed that HIF-1alpha mRNA and protein were positively correlated with mPAP. There was a positive correlation between HIF-1alpha protein and PHD2, PHD3 mRNA (r value was 0.580, 0.690, respectively, all P value was 0.000) but a negative correlation between HIF-1alpha protein and PHD2 protein (r = -0.704, P < 0.05). CONCLUSIONS: HIF-1alpha was regulated mainly at the protein level during the development of hypoxic pulmonary hypertension. PHD2 and PHD3 are inducible by hypoxia, possibly via elevated HIF-1alpha, suggesting that a hypoxic up-regulation of PHD acts via feedback mechanism to attenuate hypoxia induced responses. PHD may also be regulated by posttranscriptional mechanisms.\n" ], "offsets": [ [ 0, 3498 ] ] } ]

[ { "id": "PMID-17129494_T1", "type": "Protein", "text": [ "hypoxia-inducible factor-1alpha" ], "offsets": [ [ 31, 62 ] ], "normalized": [] }, { "id": "PMID-17129494_T2", "type": "Protein", "text": [ "hypoxia-inducible factors-1alpha" ], "offsets": [ [ 182, 214 ] ], "normalized": [] }, { "id": "PMID-17129494_T3", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 224, 234 ] ], "normalized": [] }, { "id": "PMID-17129494_T4", "type": "Protein", "text": [ "PHD1" ], "offsets": [ [ 271, 275 ] ], "normalized": [] }, { "id": "PMID-17129494_T5", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 277, 281 ] ], "normalized": [] }, { "id": "PMID-17129494_T6", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 286, 290 ] ], "normalized": [] }, { "id": "PMID-17129494_T7", "type": "Protein", "text": [ "Reverse transcriptase" ], "offsets": [ [ 663, 684 ] ], "normalized": [] }, { "id": "PMID-17129494_T8", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 1498, 1508 ] ], "normalized": [] }, { "id": "PMID-17129494_T9", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 1774, 1784 ] ], "normalized": [] }, { "id": "PMID-17129494_T10", "type": "Protein", "text": [ "PHD1" ], "offsets": [ [ 1905, 1909 ] ], "normalized": [] }, { "id": "PMID-17129494_T11", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 1914, 1918 ] ], "normalized": [] }, { "id": "PMID-17129494_T12", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 2032, 2036 ] ], "normalized": [] }, { "id": "PMID-17129494_T13", "type": "Protein", "text": [ "PHD1" ], "offsets": [ [ 2239, 2243 ] ], "normalized": [] }, { "id": "PMID-17129494_T14", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 2370, 2374 ] ], "normalized": [] }, { "id": "PMID-17129494_T15", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 2578, 2582 ] ], "normalized": [] }, { "id": "PMID-17129494_T16", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 2617, 2621 ] ], "normalized": [] }, { "id": "PMID-17129494_T17", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 2819, 2829 ] ], "normalized": [] }, { "id": "PMID-17129494_T18", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 2926, 2936 ] ], "normalized": [] }, { "id": "PMID-17129494_T19", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 2949, 2953 ] ], "normalized": [] }, { "id": "PMID-17129494_T20", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 2955, 2959 ] ], "normalized": [] }, { "id": "PMID-17129494_T21", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 3064, 3074 ] ], "normalized": [] }, { "id": "PMID-17129494_T22", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 3087, 3091 ] ], "normalized": [] }, { "id": "PMID-17129494_T23", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 3137, 3147 ] ], "normalized": [] }, { "id": "PMID-17129494_T24", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 3248, 3252 ] ], "normalized": [] }, { "id": "PMID-17129494_T25", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 3257, 3261 ] ], "normalized": [] }, { "id": "PMID-17129494_T26", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 3310, 3320 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-17129494_1", "entity_ids": [ "PMID-17129494_T2", "PMID-17129494_T3" ] } ]

[]

[ { "id": "PMID-17144668__text", "type": "abstract", "text": [ "Identification of the N-linked glycosylation sites of vitamin K-dependent carboxylase and effect of glycosylation on carboxylase function. \nThe vitamin K-dependent carboxylase is an integral membrane protein which is required for the post-translational modification of a variety of vitamin K-dependent proteins. Previous studies have suggested carboxylase is a glycoprotein with N-linked glycosylation sites. In this study, we identify the N-glycosylation sites of carboxylase by mass spectrometric peptide mapping analyses combined with site-directed mutagenesis. Our mass spectrometric results show that the N-linked glycosylation in carboxylase occurs at positions N459, N550, N605, and N627. Eliminating these glycosylation sites by changing asparagine to glutamine caused the mutant carboxylase to migrate faster on SDS-PAGE gels, adding further evidence that these sites are glycosylated. In addition, the mutation studies identified N525, a site that cannot be recovered by mass spectroscopy analysis, as a glycosylation site. Furthermore, the potential glycosylation site at N570 is glycosylated only if all five natural glycosylation sites are simultaneously mutated. Removal of the oligosaccharides by glycosidase from wild-type carboxylase or by elimination of the functional glycosylation sites by site-directed mutagenesis did not affect either the carboxylation or epoxidation activity when the small FLEEL pentapeptide was used as a substrate, suggesting that N-linked glycosylation is not required for the enzymatic function of carboxylase. In contrast, when site N570 and the five natural glycosylation sites were mutated simultaneously, the resulting carboxylase protein was degraded. Our results suggest that N-linked glycosylation is not essential for carboxylase enzymatic activity but is important for protein folding and stability.\n" ], "offsets": [ [ 0, 1855 ] ] } ]

[ { "id": "PMID-17144668_T1", "type": "Protein", "text": [ "vitamin K-dependent carboxylase" ], "offsets": [ [ 54, 85 ] ], "normalized": [] }, { "id": "PMID-17144668_T2", "type": "Protein", "text": [ "vitamin K-dependent carboxylase" ], "offsets": [ [ 144, 175 ] ], "normalized": [] }, { "id": "PMID-17144668_T5", "type": "Entity", "text": [ "N459" ], "offsets": [ [ 668, 672 ] ], "normalized": [] }, { "id": "PMID-17144668_T6", "type": "Entity", "text": [ "N550" ], "offsets": [ [ 674, 678 ] ], "normalized": [] }, { "id": "PMID-17144668_T7", "type": "Entity", "text": [ "N605" ], "offsets": [ [ 680, 684 ] ], "normalized": [] }, { "id": "PMID-17144668_T8", "type": "Entity", "text": [ "N627" ], "offsets": [ [ 690, 694 ] ], "normalized": [] }, { "id": "PMID-17144668_T10", "type": "Entity", "text": [ "N570" ], "offsets": [ [ 1083, 1087 ] ], "normalized": [] }, { "id": "PMID-17144668_T13", "type": "Entity", "text": [ "oligosaccharides" ], "offsets": [ [ 1192, 1208 ] ], "normalized": [] } ]

[ { "id": "PMID-17144668_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 100, 113 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17144668_T1" } ] }, { "id": "PMID-17144668_E2", "type": "Glycosylation", "trigger": { "text": [ "N-linked glycosylation" ], "offsets": [ [ 610, 632 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17144668_T2" }, { "role": "Site", "ref_id": "PMID-17144668_T5" } ] }, { "id": "PMID-17144668_E3", "type": "Glycosylation", "trigger": { "text": [ "N-linked glycosylation" ], "offsets": [ [ 610, 632 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17144668_T2" }, { "role": "Site", "ref_id": "PMID-17144668_T6" } ] }, { "id": "PMID-17144668_E4", "type": "Glycosylation", "trigger": { "text": [ "N-linked glycosylation" ], "offsets": [ [ 610, 632 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17144668_T2" }, { "role": "Site", "ref_id": "PMID-17144668_T7" } ] }, { "id": "PMID-17144668_E5", "type": "Glycosylation", "trigger": { "text": [ "N-linked glycosylation" ], "offsets": [ [ 610, 632 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17144668_T2" }, { "role": "Site", "ref_id": "PMID-17144668_T8" } ] }, { "id": "PMID-17144668_E6", "type": "Glycosylation", "trigger": { "text": [ "glycosylated" ], "offsets": [ [ 881, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17144668_T2" } ] }, { "id": "PMID-17144668_E7", "type": "Glycosylation", "trigger": { "text": [ "glycosylated" ], "offsets": [ [ 1091, 1103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17144668_T2" }, { "role": "Site", "ref_id": "PMID-17144668_T10" } ] }, { "id": "PMID-17144668_E8", "type": "Deglycosylation", "trigger": { "text": [ "Removal" ], "offsets": [ [ 1177, 1184 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17144668_T2" }, { "role": "Sidechain", "ref_id": "PMID-17144668_T13" } ] }, { "id": "PMID-17144668_E9", "type": "Glycosylation", "trigger": { "text": [ "N-linked glycosylation" ], "offsets": [ [ 1475, 1497 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17144668_T2" } ] }, { "id": "PMID-17144668_E10", "type": "Glycosylation", "trigger": { "text": [ "N-linked glycosylation" ], "offsets": [ [ 1728, 1750 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17144668_T2" } ] } ]

[]

[]

[ { "id": "PMID-17172825__text", "type": "abstract", "text": [ "Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. \nOur previous studies demonstrated that inhibition of histone deacetylases (HDACs) by trichostatin A reactivates estrogen receptor alpha (ER) gene expression in ER-negative breast cancer cells. Here, we use the clinically relevant HDAC inhibitor, LBH589 (LBH) to explore the roles of HDAC in ER gene silencing. In the ER-negative human breast cancer lines, MDA-MB-231 and MDA-MB-435, treatment with LBH for 24 hours restored ER mRNA and protein expression without a concomitant demethylation of the CpG island at the ER promoter. The expression of ER mRNA was sustained at least 96 hours after withdrawal of LBH treatment. Restoration of ER expression by LBH enhanced 4-hydroxy-tamoxifen sensitivity in MDA-MB-231 cells. The molecular mechanisms by which LBH reactivated silenced ER gene in MDA-MB-231 cells were examined with emphasis on chromatin structure reorganization. By chromatin immunoprecipitation analysis, LBH treatment released DNMT1, HDAC1, and the H3 lysine 9 (H3-K9) methyltransferase SUV39H 1 from the ER promoter. Such changes were associated with an active chromatin formation manifested as accumulation of acetylated histones H3 and H4, a decrease in methylated H3-K9, and an impaired binding of heterochromatin protein 1 (HP1 alpha) at the promoter. Our findings suggest that HDAC inhibitors could restore expression of the silenced ER gene by reorganizing the heterochromatin-associated proteins without alteration in promoter DNA hypermethylation.\n" ], "offsets": [ [ 0, 1612 ] ] } ]

[ { "id": "PMID-17172825_T1", "type": "Protein", "text": [ "Histone" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "PMID-17172825_T2", "type": "Protein", "text": [ "estrogen receptor alpha" ], "offsets": [ [ 58, 81 ] ], "normalized": [] }, { "id": "PMID-17172825_T3", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 83, 85 ] ], "normalized": [] }, { "id": "PMID-17172825_T4", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 195, 202 ] ], "normalized": [] }, { "id": "PMID-17172825_T5", "type": "Protein", "text": [ "estrogen receptor alpha" ], "offsets": [ [ 254, 277 ] ], "normalized": [] }, { "id": "PMID-17172825_T6", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 279, 281 ] ], "normalized": [] }, { "id": "PMID-17172825_T7", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 302, 304 ] ], "normalized": [] }, { "id": "PMID-17172825_T8", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 433, 435 ] ], "normalized": [] }, { "id": "PMID-17172825_T9", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 459, 461 ] ], "normalized": [] }, { "id": "PMID-17172825_T10", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 566, 568 ] ], "normalized": [] }, { "id": "PMID-17172825_T11", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 658, 660 ] ], "normalized": [] }, { "id": "PMID-17172825_T12", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 689, 691 ] ], "normalized": [] }, { "id": "PMID-17172825_T13", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 779, 781 ] ], "normalized": [] }, { "id": "PMID-17172825_T14", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 921, 923 ] ], "normalized": [] }, { "id": "PMID-17172825_T15", "type": "Protein", "text": [ "DNMT1" ], "offsets": [ [ 1082, 1087 ] ], "normalized": [] }, { "id": "PMID-17172825_T16", "type": "Protein", "text": [ "HDAC1" ], "offsets": [ [ 1089, 1094 ] ], "normalized": [] }, { "id": "PMID-17172825_T17", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1104, 1106 ] ], "normalized": [] }, { "id": "PMID-17172825_T18", "type": "Protein", "text": [ "SUV39H 1" ], "offsets": [ [ 1142, 1150 ] ], "normalized": [] }, { "id": "PMID-17172825_T19", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 1160, 1162 ] ], "normalized": [] }, { "id": "PMID-17172825_T20", "type": "Protein", "text": [ "histones H3" ], "offsets": [ [ 1278, 1289 ] ], "normalized": [] }, { "id": "PMID-17172825_T21", "type": "Protein", "text": [ "H4" ], "offsets": [ [ 1294, 1296 ] ], "normalized": [] }, { "id": "PMID-17172825_T22", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1323, 1325 ] ], "normalized": [] }, { "id": "PMID-17172825_T23", "type": "Protein", "text": [ "HP1 alpha" ], "offsets": [ [ 1384, 1393 ] ], "normalized": [] }, { "id": "PMID-17172825_T24", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 1495, 1497 ] ], "normalized": [] }, { "id": "PMID-17172825_T26", "type": "Entity", "text": [ "CpG island" ], "offsets": [ [ 640, 650 ] ], "normalized": [] }, { "id": "PMID-17172825_T29", "type": "Entity", "text": [ "K9" ], "offsets": [ [ 1326, 1328 ] ], "normalized": [] }, { "id": "PMID-17172825_T30", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1581, 1589 ] ], "normalized": [] } ]

[ { "id": "PMID-17172825_E1", "type": "DNA_demethylation", "trigger": { "text": [ "demethylation" ], "offsets": [ [ 619, 632 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17172825_T11" }, { "role": "Site", "ref_id": "PMID-17172825_T26" } ] }, { "id": "PMID-17172825_E2", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 1267, 1277 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17172825_T20" }, { "role": "Contextgene", "ref_id": "PMID-17172825_T19" } ] }, { "id": "PMID-17172825_E3", "type": "Acetylation", "trigger": { "text": [ "acetylated" ], "offsets": [ [ 1267, 1277 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17172825_T21" }, { "role": "Contextgene", "ref_id": "PMID-17172825_T19" } ] }, { "id": "PMID-17172825_E4", "type": "Methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 1312, 1322 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17172825_T22" }, { "role": "Site", "ref_id": "PMID-17172825_T29" }, { "role": "Contextgene", "ref_id": "PMID-17172825_T19" } ] }, { "id": "PMID-17172825_E5", "type": "DNA_methylation", "trigger": { "text": [ "DNA hypermethylation" ], "offsets": [ [ 1590, 1610 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17172825_T24" }, { "role": "Site", "ref_id": "PMID-17172825_T30" } ] } ]

[ { "id": "PMID-17172825_1", "entity_ids": [ "PMID-17172825_T2", "PMID-17172825_T3" ] }, { "id": "PMID-17172825_2", "entity_ids": [ "PMID-17172825_T5", "PMID-17172825_T6" ] } ]

[]

[ { "id": "PMID-17189173__text", "type": "abstract", "text": [ "Glycosylation variant analysis of recombinant human tissue plasminogen activator produced in urea-cycle-enzyme-expressing Chinese hamster ovary (CHO) cell line. \nTissue plasminogen activator (tPA) was produced in ornithine transcarbamoylase (OTC) cells by introducing the tPA gene into OTC cells. OTC cells were originally derived from Chinese hamster ovary (CHO) cells and express the first two enzymes of the urea cycle, carbamoyl phosphate synthetase I (CPS I) and OTC. To investigate glycosylation variants, tPA variants produced in serum-supplemented culture medium of OTC-tPA cells were separated by lysine-Sepharose 4B chromatography. Unlike in previous studies that used lysine-Sepharose chromatography, two peaks were identified to correspond to eluted glycosylation variants type I and II and type II and the percentages of the type I and type II variants were found to be 23% and 77%, respectively. The biological activities of the type I and II and type II variants were twofold that of the Third International tPA Standard (98/714) produced in the CHO cell line, and the activity of type II variant was 12.6% higher than that of the type I and II variants. These results demonstrate that tPA produced in urea-cycle-enzyme-producing OTC cells have a very high biological activity and the percentage of type II variant which is very valuable for the biopharmaceutical industry is higher than that of any report using CHO cells.\n" ], "offsets": [ [ 0, 1439 ] ] } ]

[ { "id": "PMID-17189173_T1", "type": "Protein", "text": [ "tissue plasminogen activator" ], "offsets": [ [ 52, 80 ] ], "normalized": [] }, { "id": "PMID-17189173_T2", "type": "Protein", "text": [ "Tissue plasminogen activator" ], "offsets": [ [ 162, 190 ] ], "normalized": [] }, { "id": "PMID-17189173_T3", "type": "Protein", "text": [ "tPA" ], "offsets": [ [ 192, 195 ] ], "normalized": [] }, { "id": "PMID-17189173_T4", "type": "Protein", "text": [ "ornithine transcarbamoylase" ], "offsets": [ [ 213, 240 ] ], "normalized": [] }, { "id": "PMID-17189173_T5", "type": "Protein", "text": [ "OTC" ], "offsets": [ [ 242, 245 ] ], "normalized": [] }, { "id": "PMID-17189173_T6", "type": "Protein", "text": [ "tPA" ], "offsets": [ [ 272, 275 ] ], "normalized": [] }, { "id": "PMID-17189173_T7", "type": "Protein", "text": [ "OTC" ], "offsets": [ [ 286, 289 ] ], "normalized": [] }, { "id": "PMID-17189173_T8", "type": "Protein", "text": [ "OTC" ], "offsets": [ [ 297, 300 ] ], "normalized": [] }, { "id": "PMID-17189173_T9", "type": "Protein", "text": [ "carbamoyl phosphate synthetase I" ], "offsets": [ [ 423, 455 ] ], "normalized": [] }, { "id": "PMID-17189173_T10", "type": "Protein", "text": [ "CPS I" ], "offsets": [ [ 457, 462 ] ], "normalized": [] }, { "id": "PMID-17189173_T11", "type": "Protein", "text": [ "OTC" ], "offsets": [ [ 468, 471 ] ], "normalized": [] }, { "id": "PMID-17189173_T12", "type": "Protein", "text": [ "tPA" ], "offsets": [ [ 512, 515 ] ], "normalized": [] }, { "id": "PMID-17189173_T13", "type": "Protein", "text": [ "OTC" ], "offsets": [ [ 574, 577 ] ], "normalized": [] }, { "id": "PMID-17189173_T14", "type": "Protein", "text": [ "tPA" ], "offsets": [ [ 578, 581 ] ], "normalized": [] }, { "id": "PMID-17189173_T15", "type": "Protein", "text": [ "tPA" ], "offsets": [ [ 1023, 1026 ] ], "normalized": [] }, { "id": "PMID-17189173_T16", "type": "Protein", "text": [ "tPA" ], "offsets": [ [ 1201, 1204 ] ], "normalized": [] }, { "id": "PMID-17189173_T17", "type": "Protein", "text": [ "OTC" ], "offsets": [ [ 1245, 1248 ] ], "normalized": [] } ]

[ { "id": "PMID-17189173_E1", "type": "Glycosylation", "trigger": { "text": [ "Glycosylation" ], "offsets": [ [ 0, 13 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189173_T1" } ] }, { "id": "PMID-17189173_E2", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 488, 501 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189173_T12" } ] } ]

[ { "id": "PMID-17189173_1", "entity_ids": [ "PMID-17189173_T2", "PMID-17189173_T3" ] }, { "id": "PMID-17189173_2", "entity_ids": [ "PMID-17189173_T4", "PMID-17189173_T5" ] }, { "id": "PMID-17189173_3", "entity_ids": [ "PMID-17189173_T9", "PMID-17189173_T10" ] } ]

[]

[ { "id": "PMID-17189186__text", "type": "abstract", "text": [ "Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. \nUpon DNA damage and other types of stress, p53 induces either cell-cycle arrest or apoptosis depending on the cellular context. However, the molecular mechanisms that govern the choice between cell-cycle arrest and apoptosis are not well understood. Here, we show that Tip60 is required for both cell growth arrest and apoptosis mediated by p53 and also induces its acetylation specifically at lysine 120 (K120) within the DNA-binding domain. Interestingly, this modification is crucial for p53-dependent apoptosis but is dispensable for its mediated growth arrest. K120 is a recurrent site for p53 mutation in human cancer, and the corresponding acetylation-defective tumor mutant (K120R) abrogates p53-mediated apoptosis, but not growth arrest. Thus, our study demonstrates that Tip60-dependent acetylation of p53 at K120 modulates the decision between cell-cycle arrest and apoptosis, and it reveals that the DNA-binding core domain is an important target for p53 regulation by posttranslational modifications.\n" ], "offsets": [ [ 0, 1114 ] ] } ]

[ { "id": "PMID-17189186_T1", "type": "Protein", "text": [ "Tip60" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-17189186_T2", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 31, 34 ] ], "normalized": [] }, { "id": "PMID-17189186_T3", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 143, 146 ] ], "normalized": [] }, { "id": "PMID-17189186_T4", "type": "Protein", "text": [ "Tip60" ], "offsets": [ [ 369, 374 ] ], "normalized": [] }, { "id": "PMID-17189186_T5", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 441, 444 ] ], "normalized": [] }, { "id": "PMID-17189186_T6", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 591, 594 ] ], "normalized": [] }, { "id": "PMID-17189186_T7", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 695, 698 ] ], "normalized": [] }, { "id": "PMID-17189186_T8", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 800, 803 ] ], "normalized": [] }, { "id": "PMID-17189186_T9", "type": "Protein", "text": [ "Tip60" ], "offsets": [ [ 881, 886 ] ], "normalized": [] }, { "id": "PMID-17189186_T10", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 912, 915 ] ], "normalized": [] }, { "id": "PMID-17189186_T11", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1063, 1066 ] ], "normalized": [] }, { "id": "PMID-17189186_T16", "type": "Entity", "text": [ "lysine 120" ], "offsets": [ [ 494, 504 ] ], "normalized": [] }, { "id": "PMID-17189186_T17", "type": "Entity", "text": [ "K120" ], "offsets": [ [ 506, 510 ] ], "normalized": [] }, { "id": "PMID-17189186_T20", "type": "Entity", "text": [ "K120" ], "offsets": [ [ 919, 923 ] ], "normalized": [] } ]

[ { "id": "PMID-17189186_E1", "type": "Catalysis", "trigger": { "text": [ "dependent" ], "offsets": [ [ 6, 15 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189186_E2" }, { "role": "Cause", "ref_id": "PMID-17189186_T1" } ] }, { "id": "PMID-17189186_E2", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 16, 27 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189186_T2" } ] }, { "id": "PMID-17189186_E3", "type": "Catalysis", "trigger": { "text": [ "induces" ], "offsets": [ [ 454, 461 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189186_E4" }, { "role": "Cause", "ref_id": "PMID-17189186_T4" } ] }, { "id": "PMID-17189186_E4", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 466, 477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189186_T5" }, { "role": "Site", "ref_id": "PMID-17189186_T16" } ] }, { "id": "PMID-17189186_E5", "type": "Catalysis", "trigger": { "text": [ "dependent" ], "offsets": [ [ 887, 896 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189186_E6" }, { "role": "Cause", "ref_id": "PMID-17189186_T9" } ] }, { "id": "PMID-17189186_E6", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 897, 908 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17189186_T10" }, { "role": "Site", "ref_id": "PMID-17189186_T20" } ] } ]

[ { "id": "PMID-17189186_1", "entity_ids": [ "PMID-17189186_T16", "PMID-17189186_T17" ] } ]

[]

[ { "id": "PMID-17200555__text", "type": "abstract", "text": [ "An in vivo assay to quantify stable protein phosphatase 2A (PP2A) heterotrimeric species. \nProtein phosphatase 2A (PP2A) regulates a broad spectrum of cellular processes. The enzyme is, in fact, largely a collection of varied heterotrimeric species composed of a catalytic (C) subunit and regulatory (B-type) subunit bound together by a structural (A) subunit. One important feature of the C subunit is that its carboxy-terminus can be modified by phosphorylation and methylation. The mechanisms that trigger such posttranslational modifications, as well as their consequences, are still under investigation. However, data collected thus far indicate that these modifications alter the binding to B subunits for an AC dimer, thereby affecting the makeup of the PP2A species in the cell. In this chapter, we describe an in vivo assay for assessing stable PP2A heterotrimer formation that is based on specific subcellular localizations of PP2A heterotrimers. This assay can be used to study the impact of a wide variety of alterations (such as mutations and covalent modifications) on PP2A heterotrimer formation. We specifically describe the use of this assay to quantify the effects of methylation on the stable formation of PP2ARts1p and PP2ACdc55p heterotrimers.\n" ], "offsets": [ [ 0, 1265 ] ] } ]

[ { "id": "PMID-17200555_T1", "type": "Protein", "text": [ "Rts1p" ], "offsets": [ [ 1229, 1234 ] ], "normalized": [] }, { "id": "PMID-17200555_T2", "type": "Protein", "text": [ "Cdc55p" ], "offsets": [ [ 1243, 1249 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-17208043__text", "type": "abstract", "text": [ "Secretion and lysophospholipase D activity of autotaxin by adipocytes are controlled by N-glycosylation and signal peptidase. \nAutotaxin (ATX) is a lysophospholipase D involved in synthesis of lysophosphatidic acid (LPA). ATX is secreted by adipocytes and is associated with adipogenesis and obesity-associated diabetes. Here we have studied the mechanisms involved in biosynthesis and secretion of ATX by mouse 3T3-F442A adipocytes. We found that inhibition of N-glycosylation with tunicamycin or by double point deletion of the amino-acids N53 and N410 of ATX inhibit its secretion. In addition, N-glycosidase treatment and point deletion of the amino-acid N410 inhibits the lysophospholipase D activity of ATX. Analysis of the amino-acid sequence of mouse ATX shows the presence of a N-terminal signal peptide. Treatment with the signal peptidase inhibitor globomycin inhibits ATX secretion by adipocytes. Transfection in Cos-7 cells of site-directed deleted ATX shows that ATX secretion is dependent on the hydrophobic core sequence of the signal peptide, not on the putative signal peptidase cleavage site sequence. Analysis of the amino-acid sequence of mouse ATX also reveals the presence of a putative cleavage site by the protein convertase furin. Treatment of adipocytes with the furin inhibitor decanoyl-Arg-Val-Lys-Arg-chloromethylketone does not modified secretion or lysophospholipase D activity of ATX. Transfection in Cos-7 cells of site-directed deleted ATX shows that the furin recognition site is not required for secretion or lysophospholipase D activity of ATX. In conclusion, the present work demonstrates the crucial role of N-glycosylation in secretion and activity of ATX. The present work also confirms the crucial role signal peptidase in secretion of ATX by adipocytes.\n" ], "offsets": [ [ 0, 1798 ] ] } ]

[ { "id": "PMID-17208043_T1", "type": "Protein", "text": [ "autotaxin" ], "offsets": [ [ 46, 55 ] ], "normalized": [] }, { "id": "PMID-17208043_T2", "type": "Protein", "text": [ "Autotaxin" ], "offsets": [ [ 127, 136 ] ], "normalized": [] }, { "id": "PMID-17208043_T3", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 138, 141 ] ], "normalized": [] }, { "id": "PMID-17208043_T4", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 222, 225 ] ], "normalized": [] }, { "id": "PMID-17208043_T5", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 399, 402 ] ], "normalized": [] }, { "id": "PMID-17208043_T6", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 558, 561 ] ], "normalized": [] }, { "id": "PMID-17208043_T7", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 709, 712 ] ], "normalized": [] }, { "id": "PMID-17208043_T8", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 759, 762 ] ], "normalized": [] }, { "id": "PMID-17208043_T9", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 880, 883 ] ], "normalized": [] }, { "id": "PMID-17208043_T10", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 962, 965 ] ], "normalized": [] }, { "id": "PMID-17208043_T11", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 977, 980 ] ], "normalized": [] }, { "id": "PMID-17208043_T12", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 1166, 1169 ] ], "normalized": [] }, { "id": "PMID-17208043_T13", "type": "Protein", "text": [ "furin" ], "offsets": [ [ 1250, 1255 ] ], "normalized": [] }, { "id": "PMID-17208043_T14", "type": "Protein", "text": [ "furin" ], "offsets": [ [ 1290, 1295 ] ], "normalized": [] }, { "id": "PMID-17208043_T15", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 1413, 1416 ] ], "normalized": [] }, { "id": "PMID-17208043_T16", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 1471, 1474 ] ], "normalized": [] }, { "id": "PMID-17208043_T17", "type": "Protein", "text": [ "furin" ], "offsets": [ [ 1490, 1495 ] ], "normalized": [] }, { "id": "PMID-17208043_T18", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 1578, 1581 ] ], "normalized": [] }, { "id": "PMID-17208043_T19", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 1693, 1696 ] ], "normalized": [] }, { "id": "PMID-17208043_T20", "type": "Protein", "text": [ "ATX" ], "offsets": [ [ 1779, 1782 ] ], "normalized": [] } ]

[ { "id": "PMID-17208043_E1", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 88, 103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17208043_T1" } ] }, { "id": "PMID-17208043_E2", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 1648, 1663 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17208043_T19" } ] } ]

[ { "id": "PMID-17208043_1", "entity_ids": [ "PMID-17208043_T2", "PMID-17208043_T3" ] } ]

[]

[ { "id": "PMID-17267293__text", "type": "abstract", "text": [ "Methylation of histone H3 lysine-79 by Dot1p plays multiple roles in the response to UV damage in Saccharomyces cerevisiae. \nVarious proteins have been found to play roles in both the repair of UV damaged DNA and heterochromatin-mediated silencing in the yeast Saccharomyces cerevisiae. In particular, factors that are involved in the methylation of lysine-79 of histone H3 by Dot1p have been implicated in both processes, suggesting a bipartite function for this modification. We find that a dot1 null mutation and a histone H3 point mutation at lysine-79 cause increased sensitivity to UV radiation, suggesting that lysine-79 methylation is important for efficient repair of UV damage. Epistasis analysis between dot1 and various UV repair genes indicates that lysine-79 methylation plays overlapping roles within the nucleotide excision, post-replication and recombination repair pathways, as well as RAD9-mediated checkpoint function. In contrast, epistasis analysis with the H3 lysine-79 point mutation indicates that the lysine-to-glutamic acid substitution exerts specific effects within the nucleotide excision repair and post-replication repair pathways, suggesting that this allele only disrupts a subset of the functions of lysine-79 methylation. The overall results indicate the existence of distinct and separable roles of histone H3 lysine-79 methylation in the response to UV damage, potentially serving to coordinate the various repair processes.\n" ], "offsets": [ [ 0, 1463 ] ] } ]

[ { "id": "PMID-17267293_T1", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 15, 25 ] ], "normalized": [] }, { "id": "PMID-17267293_T2", "type": "Protein", "text": [ "Dot1p" ], "offsets": [ [ 39, 44 ] ], "normalized": [] }, { "id": "PMID-17267293_T3", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 363, 373 ] ], "normalized": [] }, { "id": "PMID-17267293_T4", "type": "Protein", "text": [ "Dot1p" ], "offsets": [ [ 377, 382 ] ], "normalized": [] }, { "id": "PMID-17267293_T5", "type": "Protein", "text": [ "dot1" ], "offsets": [ [ 493, 497 ] ], "normalized": [] }, { "id": "PMID-17267293_T6", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 518, 528 ] ], "normalized": [] }, { "id": "PMID-17267293_T7", "type": "Protein", "text": [ "dot1" ], "offsets": [ [ 715, 719 ] ], "normalized": [] }, { "id": "PMID-17267293_T8", "type": "Protein", "text": [ "RAD9" ], "offsets": [ [ 904, 908 ] ], "normalized": [] }, { "id": "PMID-17267293_T9", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 980, 982 ] ], "normalized": [] }, { "id": "PMID-17267293_T10", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 1336, 1346 ] ], "normalized": [] }, { "id": "PMID-17267293_T13", "type": "Entity", "text": [ "lysine-79" ], "offsets": [ [ 26, 35 ] ], "normalized": [] }, { "id": "PMID-17267293_T16", "type": "Entity", "text": [ "lysine-79" ], "offsets": [ [ 350, 359 ] ], "normalized": [] }, { "id": "PMID-17267293_T17", "type": "Entity", "text": [ "lysine-79" ], "offsets": [ [ 618, 627 ] ], "normalized": [] }, { "id": "PMID-17267293_T19", "type": "Entity", "text": [ "lysine-79" ], "offsets": [ [ 763, 772 ] ], "normalized": [] }, { "id": "PMID-17267293_T21", "type": "Entity", "text": [ "lysine-79" ], "offsets": [ [ 1235, 1244 ] ], "normalized": [] }, { "id": "PMID-17267293_T23", "type": "Entity", "text": [ "lysine-79" ], "offsets": [ [ 1347, 1356 ] ], "normalized": [] } ]

[ { "id": "PMID-17267293_E1", "type": "Methylation", "trigger": { "text": [ "Methylation" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17267293_T1" }, { "role": "Site", "ref_id": "PMID-17267293_T13" } ] }, { "id": "PMID-17267293_E2", "type": "Catalysis", "trigger": { "text": [ "Methylation" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17267293_E1" }, { "role": "Cause", "ref_id": "PMID-17267293_T2" } ] }, { "id": "PMID-17267293_E3", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 335, 346 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17267293_T3" }, { "role": "Site", "ref_id": "PMID-17267293_T16" } ] }, { "id": "PMID-17267293_E4", "type": "Catalysis", "trigger": { "text": [ "methylation" ], "offsets": [ [ 335, 346 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17267293_E3" }, { "role": "Cause", "ref_id": "PMID-17267293_T4" } ] }, { "id": "PMID-17267293_E5", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 628, 639 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17267293_T6" }, { "role": "Site", "ref_id": "PMID-17267293_T17" } ] }, { "id": "PMID-17267293_E6", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 773, 784 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17267293_T6" }, { "role": "Site", "ref_id": "PMID-17267293_T19" } ] }, { "id": "PMID-17267293_E7", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1245, 1256 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17267293_T9" }, { "role": "Site", "ref_id": "PMID-17267293_T21" } ] }, { "id": "PMID-17267293_E8", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1357, 1368 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17267293_T10" }, { "role": "Site", "ref_id": "PMID-17267293_T23" } ] } ]

[]

[]

[ { "id": "PMID-17295238__text", "type": "abstract", "text": [ "2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine-induced DNA adducts and genotoxicity in chinese hamster ovary (CHO) cells expressing human CYP1A2 and rapid or slow acetylator N-acetyltransferase 2. \nHeterocyclic amine carcinogens such as 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) are present in diet and cigarette smoke. Bioactivation in humans includes N-hydroxylation catalyzed by cytochrome P4501A2 possibly followed by O-acetylation catalyzed by N-acetyltransferase 2 (NAT2). Nucleotide excision repair-deficient Chinese hamster ovary (CHO) cells were stably transfected with human CYP1A2 and either NAT2*4 (rapid acetylator) or NAT2*5B (slow acetylator) alleles. CYP1A2 and NAT2 catalytic activities were undetectable in untransfected CHO cell lines. CYP1A2 catalytic activity levels did not differ significantly (P > 0.05) among the CYP1A2-transfected cell lines. Cells transfected with NAT2*4 had significantly higher levels of N-acetyltransferase (P = 0.0001) and N-hydroxy-PhIP O-acetyltransferase (P = 0.0170) catalytic activity than cells transfected with NAT2*5B. PhIP caused dose-dependent decreases in cell survival and significant (P < 0.001) increases in mutagenesis measured at the hypoxanthine phosphoribosyl transferase (hprt) locus in all the CYP1A2-transfected cell lines. Transfection with NAT2*4 or NAT2*5B did not further increase hprt mutagenesis. PhIP-induced hprt mutant cDNAs were sequenced, and 80% of the mutations were single base substitutions at G:C base pairs. dG-C8-PhIP DNA adduct levels were dose-dependent in the order: untransfected < transfected with CYP1A2 < transfected with CYP1A2 and NAT2*5B < transfected with CYP1A2 and NAT2*4. Following incubation with 1.2 microM PhIP, DNA adduct levels were significantly (P < 0.05) higher in CHO cells transfected with CYP1A2/NAT2*4 versus CYP1A2/NAT2*5B. These results strongly support an activation role for CYP1A2 in PhIP-induced mutagenesis and DNA damage and suggest a modest effect of human NAT2 and its genetic polymorphism on PhIP DNA adduct levels.\n" ], "offsets": [ [ 0, 2058 ] ] } ]

[ { "id": "PMID-17295238_T1", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 141, 147 ] ], "normalized": [] }, { "id": "PMID-17295238_T2", "type": "Protein", "text": [ "N-acetyltransferase 2" ], "offsets": [ [ 177, 198 ] ], "normalized": [] }, { "id": "PMID-17295238_T3", "type": "Protein", "text": [ "cytochrome P4501A2" ], "offsets": [ [ 400, 418 ] ], "normalized": [] }, { "id": "PMID-17295238_T4", "type": "Protein", "text": [ "N-acetyltransferase 2" ], "offsets": [ [ 467, 488 ] ], "normalized": [] }, { "id": "PMID-17295238_T5", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 490, 494 ] ], "normalized": [] }, { "id": "PMID-17295238_T6", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 603, 609 ] ], "normalized": [] }, { "id": "PMID-17295238_T7", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 621, 625 ] ], "normalized": [] }, { "id": "PMID-17295238_T8", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 650, 654 ] ], "normalized": [] }, { "id": "PMID-17295238_T9", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 685, 691 ] ], "normalized": [] }, { "id": "PMID-17295238_T10", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 696, 700 ] ], "normalized": [] }, { "id": "PMID-17295238_T11", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 773, 779 ] ], "normalized": [] }, { "id": "PMID-17295238_T12", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 856, 862 ] ], "normalized": [] }, { "id": "PMID-17295238_T13", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 910, 914 ] ], "normalized": [] }, { "id": "PMID-17295238_T14", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 1084, 1088 ] ], "normalized": [] }, { "id": "PMID-17295238_T15", "type": "Protein", "text": [ "hypoxanthine phosphoribosyl transferase" ], "offsets": [ [ 1216, 1255 ] ], "normalized": [] }, { "id": "PMID-17295238_T16", "type": "Protein", "text": [ "hprt" ], "offsets": [ [ 1257, 1261 ] ], "normalized": [] }, { "id": "PMID-17295238_T17", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 1280, 1286 ] ], "normalized": [] }, { "id": "PMID-17295238_T18", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 1329, 1333 ] ], "normalized": [] }, { "id": "PMID-17295238_T19", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 1339, 1343 ] ], "normalized": [] }, { "id": "PMID-17295238_T20", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 1608, 1614 ] ], "normalized": [] }, { "id": "PMID-17295238_T21", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 1634, 1640 ] ], "normalized": [] }, { "id": "PMID-17295238_T22", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 1645, 1649 ] ], "normalized": [] }, { "id": "PMID-17295238_T23", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 1672, 1678 ] ], "normalized": [] }, { "id": "PMID-17295238_T24", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 1683, 1687 ] ], "normalized": [] }, { "id": "PMID-17295238_T25", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 1819, 1825 ] ], "normalized": [] }, { "id": "PMID-17295238_T26", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 1826, 1830 ] ], "normalized": [] }, { "id": "PMID-17295238_T27", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 1840, 1846 ] ], "normalized": [] }, { "id": "PMID-17295238_T28", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 1847, 1851 ] ], "normalized": [] }, { "id": "PMID-17295238_T29", "type": "Protein", "text": [ "CYP1A2" ], "offsets": [ [ 1910, 1916 ] ], "normalized": [] }, { "id": "PMID-17295238_T30", "type": "Protein", "text": [ "NAT2" ], "offsets": [ [ 1997, 2001 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-17295238_1", "entity_ids": [ "PMID-17295238_T4", "PMID-17295238_T5" ] }, { "id": "PMID-17295238_2", "entity_ids": [ "PMID-17295238_T15", "PMID-17295238_T16" ] } ]

[]

[ { "id": "PMID-17309836__text", "type": "abstract", "text": [ "Expression and purification of recombinant yeast Ada2/Ada3/Gcn5 and Piccolo NuA4 histone acetyltransferase complexes. \nAcetylation of histone tails by histone acetyltransferase (HAT) enzymes is a key post-translational modification of histones associated with transcriptionally active genes. Acetylation of the physiological nucleosome substrate is performed in cells by megadalton complexes such as SAGA and NuA4. To understand how HAT enzymes specifically recognize their nucleosome and not just histone tail substrates, we have identified the catalytic SAGA and NuA4 subcomplexes sufficient to act on nucleosomes. We describe here expression and purification procedures to prepare recombinant yeast Ada2/Ada3/Gcn5 subcomplex of SAGA which acetylates histones H3 and H2B on nucleosomes, and the Piccolo NuA4 complex which acetylates histones H4 and H2A on nucleosomes. We demonstrate an unexpected benefit of using the BL21-CodonPlus strain to enhance the purity of metal affinity purified Ada2/Ada3/Gcn5 complex. We also identify Escherichia coli EF-Tu as a contaminant that copurifies with both complexes over multiple chromatographic steps and use of hydrophobic interaction chromatography to remove the contaminant from the Piccolo NuA4 complex. The methods described here will be useful for studies into the molecular mechanism of these enzymes and for preparing the enzymes as reagents to study the interplay of nucleosome acetylation with other chromatin modification and remodeling enzymes.\n" ], "offsets": [ [ 0, 1501 ] ] } ]

[ { "id": "PMID-17309836_T1", "type": "Protein", "text": [ "Ada2" ], "offsets": [ [ 49, 53 ] ], "normalized": [] }, { "id": "PMID-17309836_T2", "type": "Protein", "text": [ "Ada3" ], "offsets": [ [ 54, 58 ] ], "normalized": [] }, { "id": "PMID-17309836_T3", "type": "Protein", "text": [ "Gcn5" ], "offsets": [ [ 59, 63 ] ], "normalized": [] }, { "id": "PMID-17309836_T4", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 134, 141 ] ], "normalized": [] }, { "id": "PMID-17309836_T5", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 151, 158 ] ], "normalized": [] }, { "id": "PMID-17309836_T6", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 498, 505 ] ], "normalized": [] }, { "id": "PMID-17309836_T7", "type": "Protein", "text": [ "Ada2" ], "offsets": [ [ 702, 706 ] ], "normalized": [] }, { "id": "PMID-17309836_T8", "type": "Protein", "text": [ "Ada3" ], "offsets": [ [ 707, 711 ] ], "normalized": [] }, { "id": "PMID-17309836_T9", "type": "Protein", "text": [ "Gcn5" ], "offsets": [ [ 712, 716 ] ], "normalized": [] }, { "id": "PMID-17309836_T10", "type": "Protein", "text": [ "histones H3" ], "offsets": [ [ 753, 764 ] ], "normalized": [] }, { "id": "PMID-17309836_T11", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 769, 772 ] ], "normalized": [] }, { "id": "PMID-17309836_T12", "type": "Protein", "text": [ "histones H4" ], "offsets": [ [ 835, 846 ] ], "normalized": [] }, { "id": "PMID-17309836_T13", "type": "Protein", "text": [ "H2A" ], "offsets": [ [ 851, 854 ] ], "normalized": [] }, { "id": "PMID-17309836_T14", "type": "Protein", "text": [ "Ada2" ], "offsets": [ [ 992, 996 ] ], "normalized": [] }, { "id": "PMID-17309836_T15", "type": "Protein", "text": [ "Ada3" ], "offsets": [ [ 997, 1001 ] ], "normalized": [] }, { "id": "PMID-17309836_T16", "type": "Protein", "text": [ "Gcn5" ], "offsets": [ [ 1002, 1006 ] ], "normalized": [] }, { "id": "PMID-17309836_T18", "type": "Entity", "text": [ "tails" ], "offsets": [ [ 142, 147 ] ], "normalized": [] } ]

[ { "id": "PMID-17309836_E1", "type": "Acetylation", "trigger": { "text": [ "Acetylation" ], "offsets": [ [ 119, 130 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17309836_T4" }, { "role": "Site", "ref_id": "PMID-17309836_T18" } ] }, { "id": "PMID-17309836_E2", "type": "Acetylation", "trigger": { "text": [ "acetylates" ], "offsets": [ [ 742, 752 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17309836_T10" } ] }, { "id": "PMID-17309836_E3", "type": "Acetylation", "trigger": { "text": [ "acetylates" ], "offsets": [ [ 742, 752 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17309836_T11" } ] }, { "id": "PMID-17309836_E4", "type": "Acetylation", "trigger": { "text": [ "acetylates" ], "offsets": [ [ 824, 834 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17309836_T12" } ] }, { "id": "PMID-17309836_E5", "type": "Acetylation", "trigger": { "text": [ "acetylates" ], "offsets": [ [ 824, 834 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17309836_T13" } ] } ]

[]

[]

[ { "id": "PMID-17337388__text", "type": "abstract", "text": [ "[Aberrant methylation of tumor suppressor genes in head and neck squamous cell carcinoma: is it clinically relevant?] \nDuring malignant transformation, the malignant cell accumulates epigenetic abnormalities that do not alter the DNA sequence but are transmissible during divisions and modify genes expression. The methylation of CpG islands in the tumor suppressor genes (TS genes) promoters inhibits their transcription ; it is a mecanism of gene inactivation as frequent as allelic deletions. The methylation profile (or panel of methylated genes in a tumor), similarly to allelic deletions, varies with the tumor histology. Within head and neck squamous cell carcinoma (oral cavity, larynx and oropharynx), 19 genes have been analysed, among them 5 are frequently methylated, i.e. : p16, ECAD, DAPK, MGMT et TIMP3. The method of methylation analysis, based on a bisulfite treatment followed by a PCR amplification, is sensitive and specific enough to allow the detection of abnormalities in biological fluid that drain the tumor or in circulating tumoral DNA. In the head and neck squamous cell carcinoma, correlation between the methylation profile in tumor and paired saliva is excellent ; thus methylation analysis in saliva is a very promising approach for early cancer detection in high risk patients or for the post treatment follow up and rapid diagnosis of relapse. The methylation signature might also reflect the tumor prognosis and complete the histology to define the diagnosis. Finally, DNA methylation is reversible with demethylating agents, a new avenue for cancer therapy in association with conventional chemotherapy.\n" ], "offsets": [ [ 0, 1640 ] ] } ]

[ { "id": "PMID-17337388_T1", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 787, 790 ] ], "normalized": [] }, { "id": "PMID-17337388_T2", "type": "Protein", "text": [ "ECAD" ], "offsets": [ [ 792, 796 ] ], "normalized": [] }, { "id": "PMID-17337388_T3", "type": "Protein", "text": [ "DAPK" ], "offsets": [ [ 798, 802 ] ], "normalized": [] }, { "id": "PMID-17337388_T4", "type": "Protein", "text": [ "MGMT" ], "offsets": [ [ 804, 808 ] ], "normalized": [] }, { "id": "PMID-17337388_T5", "type": "Protein", "text": [ "TIMP3" ], "offsets": [ [ 812, 817 ] ], "normalized": [] } ]

[ { "id": "PMID-17337388_E1", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 768, 778 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17337388_T1" } ] }, { "id": "PMID-17337388_E2", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 768, 778 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17337388_T2" } ] }, { "id": "PMID-17337388_E3", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 768, 778 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17337388_T3" } ] }, { "id": "PMID-17337388_E4", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 768, 778 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17337388_T4" } ] }, { "id": "PMID-17337388_E5", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 768, 778 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17337388_T5" } ] } ]

[]

[]

[ { "id": "PMID-17382325__text", "type": "abstract", "text": [ "Modulation of p300 binding by posttranslational modifications of the C-terminal activation domain of hypoxia-inducible factor-1alpha. \nPosttranslational modifications of hypoxia-inducible factor-1alpha (HIF-1alpha) influence HIF-mediated transcription, likely by affecting binding to p300/cAMP-response element-binding protein (CBP). To systematically analyze the HIF-1alpha-p300/CBP interaction, we developed a fluorescence polarization-based binding assay, employing fluorescein-labeled peptides derived from the C-terminal transactivation domain (C-TAD) of HIF-1alpha. After optimized for effectively capturing p300/CBP, the assay was utilized for evaluating direct effects of posttranslational modifications of the HIF-1alpha C-TAD on p300 binding. The results demonstrated that asparagine hydroxylation and S-nitrosylation of HIF-1alpha decrease p300 binding, while its phosphorylation does not affect p300 binding, which was reconfirmed by competitive inhibition analyses using mutant peptides.\n" ], "offsets": [ [ 0, 1001 ] ] } ]

[ { "id": "PMID-17382325_T1", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 14, 18 ] ], "normalized": [] }, { "id": "PMID-17382325_T2", "type": "Protein", "text": [ "hypoxia-inducible factor-1alpha" ], "offsets": [ [ 101, 132 ] ], "normalized": [] }, { "id": "PMID-17382325_T3", "type": "Protein", "text": [ "hypoxia-inducible factor-1alpha" ], "offsets": [ [ 170, 201 ] ], "normalized": [] }, { "id": "PMID-17382325_T4", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 203, 213 ] ], "normalized": [] }, { "id": "PMID-17382325_T5", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 284, 288 ] ], "normalized": [] }, { "id": "PMID-17382325_T6", "type": "Protein", "text": [ "cAMP-response element-binding protein" ], "offsets": [ [ 289, 326 ] ], "normalized": [] }, { "id": "PMID-17382325_T7", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 328, 331 ] ], "normalized": [] }, { "id": "PMID-17382325_T8", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 364, 374 ] ], "normalized": [] }, { "id": "PMID-17382325_T9", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 375, 379 ] ], "normalized": [] }, { "id": "PMID-17382325_T10", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 380, 383 ] ], "normalized": [] }, { "id": "PMID-17382325_T11", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 560, 570 ] ], "normalized": [] }, { "id": "PMID-17382325_T12", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 614, 618 ] ], "normalized": [] }, { "id": "PMID-17382325_T13", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 619, 622 ] ], "normalized": [] }, { "id": "PMID-17382325_T14", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 719, 729 ] ], "normalized": [] }, { "id": "PMID-17382325_T15", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 739, 743 ] ], "normalized": [] }, { "id": "PMID-17382325_T16", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 831, 841 ] ], "normalized": [] }, { "id": "PMID-17382325_T17", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 851, 855 ] ], "normalized": [] }, { "id": "PMID-17382325_T18", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 907, 911 ] ], "normalized": [] }, { "id": "PMID-17382325_T19", "type": "Entity", "text": [ "asparagine" ], "offsets": [ [ 783, 793 ] ], "normalized": [] } ]

[ { "id": "PMID-17382325_E1", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 794, 807 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17382325_T16" }, { "role": "Site", "ref_id": "PMID-17382325_T19" } ] }, { "id": "PMID-17382325_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 875, 890 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17382325_T16" } ] } ]

[ { "id": "PMID-17382325_1", "entity_ids": [ "PMID-17382325_T3", "PMID-17382325_T4" ] }, { "id": "PMID-17382325_2", "entity_ids": [ "PMID-17382325_T6", "PMID-17382325_T7" ] } ]

[]

[ { "id": "PMID-17389396__text", "type": "abstract", "text": [ "CCR4/NOT complex associates with the proteasome and regulates histone methylation. \nThe proteasome regulates histone lysine methylation and gene transcription, but how it does so is poorly understood. To better understand this process, we used the epistatic miniarray profile (E-MAP) approach to identify factors that genetically interact with proteasomal subunits. In addition to members of the Set1 complex that mediate histone H3 lysine 4 methylation (H3K4me), we found that deleting members of the CCR4/NOT mRNA processing complex exhibit synthetic phenotypes when combined with proteasome mutants. Further biochemical analyses revealed physical associations between CCR4/NOT and the proteasome in vivo. Consistent with the genetic and biochemical interactions linking CCR4/NOT with proteasome and Set1-mediated methylation, we find that loss of Not4 decreases global and gene-specific H3K4 trimethylation (H3K4me3) and decreases 19S proteasome recruitment to the PMA1 gene. Similar to proteasome regulation of histone methylation, loss of CCR4/NOT members does not affect ubiquitinated H2B. Mapping of Not4 identified the RING finger domain as essential for H3K4me3, suggesting a role for ubiquitin in this process. Consistent with this idea, loss of the Not4-interacting protein Ubc4, a known ubiquitin-conjugating enzyme, decreases H3K4me3. These studies implicate CCR4/NOT in the regulation of H3K4me3 through a ubiquitin-dependent pathway that likely involves the proteasome.\n" ], "offsets": [ [ 0, 1485 ] ] } ]

[ { "id": "PMID-17389396_T1", "type": "Protein", "text": [ "CCR4" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-17389396_T2", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 62, 69 ] ], "normalized": [] }, { "id": "PMID-17389396_T3", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 109, 116 ] ], "normalized": [] }, { "id": "PMID-17389396_T4", "type": "Protein", "text": [ "Set1" ], "offsets": [ [ 396, 400 ] ], "normalized": [] }, { "id": "PMID-17389396_T5", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 422, 432 ] ], "normalized": [] }, { "id": "PMID-17389396_T6", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 455, 457 ] ], "normalized": [] }, { "id": "PMID-17389396_T7", "type": "Protein", "text": [ "CCR4" ], "offsets": [ [ 502, 506 ] ], "normalized": [] }, { "id": "PMID-17389396_T8", "type": "Protein", "text": [ "CCR4" ], "offsets": [ [ 671, 675 ] ], "normalized": [] }, { "id": "PMID-17389396_T9", "type": "Protein", "text": [ "CCR4" ], "offsets": [ [ 773, 777 ] ], "normalized": [] }, { "id": "PMID-17389396_T10", "type": "Protein", "text": [ "Set1" ], "offsets": [ [ 802, 806 ] ], "normalized": [] }, { "id": "PMID-17389396_T11", "type": "Protein", "text": [ "Not4" ], "offsets": [ [ 850, 854 ] ], "normalized": [] }, { "id": "PMID-17389396_T12", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 890, 892 ] ], "normalized": [] }, { "id": "PMID-17389396_T13", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 911, 913 ] ], "normalized": [] }, { "id": "PMID-17389396_T14", "type": "Protein", "text": [ "PMA1" ], "offsets": [ [ 968, 972 ] ], "normalized": [] }, { "id": "PMID-17389396_T15", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1015, 1022 ] ], "normalized": [] }, { "id": "PMID-17389396_T16", "type": "Protein", "text": [ "CCR4" ], "offsets": [ [ 1044, 1048 ] ], "normalized": [] }, { "id": "PMID-17389396_T17", "type": "Protein", "text": [ "H2B" ], "offsets": [ [ 1091, 1094 ] ], "normalized": [] }, { "id": "PMID-17389396_T18", "type": "Protein", "text": [ "Not4" ], "offsets": [ [ 1107, 1111 ] ], "normalized": [] }, { "id": "PMID-17389396_T19", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1163, 1165 ] ], "normalized": [] }, { "id": "PMID-17389396_T20", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1194, 1203 ] ], "normalized": [] }, { "id": "PMID-17389396_T21", "type": "Protein", "text": [ "Not4" ], "offsets": [ [ 1260, 1264 ] ], "normalized": [] }, { "id": "PMID-17389396_T22", "type": "Protein", "text": [ "Ubc4" ], "offsets": [ [ 1285, 1289 ] ], "normalized": [] }, { "id": "PMID-17389396_T23", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1339, 1341 ] ], "normalized": [] }, { "id": "PMID-17389396_T24", "type": "Protein", "text": [ "CCR4" ], "offsets": [ [ 1372, 1376 ] ], "normalized": [] }, { "id": "PMID-17389396_T25", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1402, 1404 ] ], "normalized": [] }, { "id": "PMID-17389396_T26", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1420, 1429 ] ], "normalized": [] }, { "id": "PMID-17389396_T28", "type": "Entity", "text": [ "lysine" ], "offsets": [ [ 117, 123 ] ], "normalized": [] }, { "id": "PMID-17389396_T30", "type": "Entity", "text": [ "lysine 4" ], "offsets": [ [ 433, 441 ] ], "normalized": [] }, { "id": "PMID-17389396_T32", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 457, 459 ] ], "normalized": [] }, { "id": "PMID-17389396_T33", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 892, 894 ] ], "normalized": [] }, { "id": "PMID-17389396_T35", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 913, 915 ] ], "normalized": [] } ]

[ { "id": "PMID-17389396_E1", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 70, 81 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17389396_T2" } ] }, { "id": "PMID-17389396_E2", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 124, 135 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17389396_T3" }, { "role": "Site", "ref_id": "PMID-17389396_T28" } ] }, { "id": "PMID-17389396_E3", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 442, 453 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17389396_T5" }, { "role": "Site", "ref_id": "PMID-17389396_T30" } ] }, { "id": "PMID-17389396_E4", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 895, 909 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17389396_T12" }, { "role": "Site", "ref_id": "PMID-17389396_T33" }, { "role": "Contextgene", "ref_id": "PMID-17389396_T14" } ] }, { "id": "PMID-17389396_E5", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1023, 1034 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17389396_T15" } ] }, { "id": "PMID-17389396_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 1077, 1090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17389396_T17" } ] } ]

[ { "id": "PMID-17389396_1", "entity_ids": [ "PMID-17389396_T5", "PMID-17389396_T6" ] }, { "id": "PMID-17389396_2", "entity_ids": [ "PMID-17389396_T30", "PMID-17389396_T32" ] }, { "id": "PMID-17389396_3", "entity_ids": [ "PMID-17389396_T12", "PMID-17389396_T13" ] }, { "id": "PMID-17389396_4", "entity_ids": [ "PMID-17389396_T33", "PMID-17389396_T35" ] } ]

[]

[ { "id": "PMID-17446684__text", "type": "abstract", "text": [ "Increased inhibitory capacity of an anti-C5a complementary peptide following acetylation of N-terminal alanine. \nAmino acids 37 to 53 (RAARISLGPRCIKAFTE) of C5a anaphylatoxin form an essential region for C5a function. To target this sequence, we generated a complementary peptide (ASGAPAPGPAGPLRPMF) designated PepA which has a potent inhibitory effect on C5a activity. By introducing an acetyl group at the N-terminal alanine of PepA, an acetylated form was generated which was designated AcPepA. The acetylation resulted in increased inhibition of C5a stimulation of neutrophils as determined by Ca influx. Furthermore, AcPepA partially inhibited the lethal shock induced in mice by intravenous administration of Candida albicans water-soluble mannoprotein-beta-glucan complex. In addition, local skin inflammation in rats caused by an anti-Crry monoclonal antibody was suppressed when AcPepA and the antibody were injected together, while PepA had little inhibitory capacity. The potent inhibitory capacity of AcPepA was also confirmed by a skin reaction of guinea pigs inoculated with recombinant human C5a together with AcPepA.\n" ], "offsets": [ [ 0, 1133 ] ] } ]

[ { "id": "PMID-17446684_T1", "type": "Protein", "text": [ "C5a" ], "offsets": [ [ 41, 44 ] ], "normalized": [] }, { "id": "PMID-17446684_T2", "type": "Protein", "text": [ "C5a" ], "offsets": [ [ 157, 160 ] ], "normalized": [] }, { "id": "PMID-17446684_T3", "type": "Protein", "text": [ "C5a" ], "offsets": [ [ 204, 207 ] ], "normalized": [] }, { "id": "PMID-17446684_T4", "type": "Protein", "text": [ "C5a" ], "offsets": [ [ 356, 359 ] ], "normalized": [] }, { "id": "PMID-17446684_T5", "type": "Protein", "text": [ "C5a" ], "offsets": [ [ 550, 553 ] ], "normalized": [] }, { "id": "PMID-17446684_T6", "type": "Protein", "text": [ "Crry" ], "offsets": [ [ 843, 847 ] ], "normalized": [] }, { "id": "PMID-17446684_T7", "type": "Protein", "text": [ "C5a" ], "offsets": [ [ 1107, 1110 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-17451637__text", "type": "abstract", "text": [ "Down-regulation of N-acetylglucosaminyltransferase-V induces ER stress by changing glycosylation and function of GLUT1. \nN-Acetylglucosaminyltransferase-V (GnT-V) is a key enzyme in the processing of N-glycans during synthesis of glycoproteins. We have reported that down-regulating GnT-V could induce endoplasmic reticulum stress (ER stress) in 7721 cells, a human hepatocarcinoma cell line. In a search for mechanisms of ER stress, we found that there was a prominent decline of glucose uptake in antisense GnT-V transfectant, furthermore, a decrease of tri- or tetra-antannary sugar chain of glucose transporter 1 (GLUT1). However, distribution of GLUT1 in antisense GnT-V transfectant was not affected. Glucose deprivation has been known to activate ER stress in tumor cells. Therefore, the data presented in this study indicate that the glycosylation change and decrease of transport activity of GLUT1 may be one possible mechanism of ER stress induced by down-regulating GnT-V, and GnT-V may contribute to the regulation of glucose uptake by modifying glycosylation of GLUT1 in some tumor cells.\n" ], "offsets": [ [ 0, 1102 ] ] } ]

[ { "id": "PMID-17451637_T1", "type": "Protein", "text": [ "N-acetylglucosaminyltransferase-V" ], "offsets": [ [ 19, 52 ] ], "normalized": [] }, { "id": "PMID-17451637_T2", "type": "Protein", "text": [ "GLUT1" ], "offsets": [ [ 113, 118 ] ], "normalized": [] }, { "id": "PMID-17451637_T3", "type": "Protein", "text": [ "N-Acetylglucosaminyltransferase-V" ], "offsets": [ [ 121, 154 ] ], "normalized": [] }, { "id": "PMID-17451637_T4", "type": "Protein", "text": [ "GnT-V" ], "offsets": [ [ 156, 161 ] ], "normalized": [] }, { "id": "PMID-17451637_T5", "type": "Protein", "text": [ "GnT-V" ], "offsets": [ [ 283, 288 ] ], "normalized": [] }, { "id": "PMID-17451637_T6", "type": "Protein", "text": [ "GnT-V" ], "offsets": [ [ 509, 514 ] ], "normalized": [] }, { "id": "PMID-17451637_T7", "type": "Protein", "text": [ "glucose transporter 1" ], "offsets": [ [ 595, 616 ] ], "normalized": [] }, { "id": "PMID-17451637_T8", "type": "Protein", "text": [ "GLUT1" ], "offsets": [ [ 618, 623 ] ], "normalized": [] }, { "id": "PMID-17451637_T9", "type": "Protein", "text": [ "GLUT1" ], "offsets": [ [ 651, 656 ] ], "normalized": [] }, { "id": "PMID-17451637_T10", "type": "Protein", "text": [ "GnT-V" ], "offsets": [ [ 670, 675 ] ], "normalized": [] }, { "id": "PMID-17451637_T11", "type": "Protein", "text": [ "GLUT1" ], "offsets": [ [ 901, 906 ] ], "normalized": [] }, { "id": "PMID-17451637_T12", "type": "Protein", "text": [ "GnT-V" ], "offsets": [ [ 977, 982 ] ], "normalized": [] }, { "id": "PMID-17451637_T13", "type": "Protein", "text": [ "GnT-V" ], "offsets": [ [ 988, 993 ] ], "normalized": [] }, { "id": "PMID-17451637_T14", "type": "Protein", "text": [ "GLUT1" ], "offsets": [ [ 1075, 1080 ] ], "normalized": [] } ]

[ { "id": "PMID-17451637_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 83, 96 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17451637_T2" } ] }, { "id": "PMID-17451637_E2", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 842, 855 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17451637_T11" } ] }, { "id": "PMID-17451637_E3", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 1058, 1071 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17451637_T14" } ] } ]

[ { "id": "PMID-17451637_1", "entity_ids": [ "PMID-17451637_T3", "PMID-17451637_T4" ] }, { "id": "PMID-17451637_2", "entity_ids": [ "PMID-17451637_T7", "PMID-17451637_T8" ] } ]

[]

[ { "id": "PMID-17451959__text", "type": "abstract", "text": [ "Probing the receptor interactions of an H5 avian influenza virus using a baculovirus expression system and functionalised poly(acrylic acid) ligands. \nInfluenza viruses attach to host cells by binding to terminal sialic acid (Neu5Ac) on glycoproteins or glycolipids. Both the linkage of Neu5Ac and the identity of other carbohydrates within the oligosaccharide are thought to play roles in restricting the host range of the virus. In this study, the receptor specificity of an H5 avian influenza virus haemagglutinin protein that has recently infected man (influenza strain A/Vietnam/1194/04) has been probed using carbohydrate functionalised poly(acrylic acid) polymers. A baculovirus expression system that allows facile and safe analysis of the Neu5Ac binding specificity of mutants of H5 HA engineered at sites that are predicted to effect a switch in host range has also been developed.\n" ], "offsets": [ [ 0, 892 ] ] } ]

[ { "id": "PMID-17451959_T1", "type": "Protein", "text": [ "haemagglutinin" ], "offsets": [ [ 502, 516 ] ], "normalized": [] }, { "id": "PMID-17451959_T2", "type": "Protein", "text": [ "H5 HA" ], "offsets": [ [ 789, 794 ] ], "normalized": [] } ]

[]

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[]

[ { "id": "PMID-17478518__text", "type": "abstract", "text": [ "Transcription-coupled deposition of histone modifications during MHC class II gene activation. \nPosttranslational histone modifications associated with actively expressed genes are generally believed to be introduced primarily by histone-modifying enzymes that are recruited by transcription factors or their associated co-activators. We have performed a comprehensive spatial and temporal analyses of the histone modifications that are deposited upon activation of the MHC class II gene HLA-DRA by the co-activator CIITA. We find that transcription-associated histone modifications are introduced during two sequential phases. The first phase precedes transcription initiation and is characterized exclusively by a rapid increase in histone H4 acetylation over a large upstream domain. All other modifications examined, including the acetylation and methylation of several residues in histone H3, are restricted to short regions situated at or within the 5' end of the gene and are established during a second phase that is concomitant with ongoing transcription. This second phase is completely abrogated when elongation by RNA polymerase II is blocked. These results provide strong evidence that transcription elongation can play a decisive role in the deposition of histone modification patterns associated with inducible gene activation.\n" ], "offsets": [ [ 0, 1343 ] ] } ]

[ { "id": "PMID-17478518_T1", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 36, 43 ] ], "normalized": [] }, { "id": "PMID-17478518_T2", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 114, 121 ] ], "normalized": [] }, { "id": "PMID-17478518_T3", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 230, 237 ] ], "normalized": [] }, { "id": "PMID-17478518_T4", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 406, 413 ] ], "normalized": [] }, { "id": "PMID-17478518_T5", "type": "Protein", "text": [ "HLA-DRA" ], "offsets": [ [ 488, 495 ] ], "normalized": [] }, { "id": "PMID-17478518_T6", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 516, 521 ] ], "normalized": [] }, { "id": "PMID-17478518_T7", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 561, 568 ] ], "normalized": [] }, { "id": "PMID-17478518_T8", "type": "Protein", "text": [ "histone H4" ], "offsets": [ [ 734, 744 ] ], "normalized": [] }, { "id": "PMID-17478518_T9", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 886, 896 ] ], "normalized": [] }, { "id": "PMID-17478518_T10", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1270, 1277 ] ], "normalized": [] } ]

[ { "id": "PMID-17478518_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 745, 756 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17478518_T8" }, { "role": "Contextgene", "ref_id": "PMID-17478518_T5" } ] }, { "id": "PMID-17478518_E2", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 835, 846 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17478518_T9" }, { "role": "Contextgene", "ref_id": "PMID-17478518_T5" } ] }, { "id": "PMID-17478518_E3", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 851, 862 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17478518_T9" }, { "role": "Contextgene", "ref_id": "PMID-17478518_T5" } ] } ]

[]

[]

[ { "id": "PMID-17486068__text", "type": "abstract", "text": [ "Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling. \nSeveral distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.\n" ], "offsets": [ [ 0, 882 ] ] } ]

[ { "id": "PMID-17486068_T1", "type": "Protein", "text": [ "EGFR" ], "offsets": [ [ 30, 34 ] ], "normalized": [] }, { "id": "PMID-17486068_T2", "type": "Protein", "text": [ "epidermal growth factor receptor" ], "offsets": [ [ 147, 179 ] ], "normalized": [] }, { "id": "PMID-17486068_T3", "type": "Protein", "text": [ "EGFR" ], "offsets": [ [ 181, 185 ] ], "normalized": [] }, { "id": "PMID-17486068_T4", "type": "Protein", "text": [ "EGFR" ], "offsets": [ [ 375, 379 ] ], "normalized": [] }, { "id": "PMID-17486068_T5", "type": "Protein", "text": [ "Cbl" ], "offsets": [ [ 383, 386 ] ], "normalized": [] }, { "id": "PMID-17486068_T6", "type": "Protein", "text": [ "EGFR" ], "offsets": [ [ 486, 490 ] ], "normalized": [] }, { "id": "PMID-17486068_T7", "type": "Protein", "text": [ "EGFR" ], "offsets": [ [ 580, 584 ] ], "normalized": [] }, { "id": "PMID-17486068_T8", "type": "Protein", "text": [ "EGFR" ], "offsets": [ [ 619, 623 ] ], "normalized": [] }, { "id": "PMID-17486068_T9", "type": "Protein", "text": [ "c-Cbl" ], "offsets": [ [ 649, 654 ] ], "normalized": [] }, { "id": "PMID-17486068_T10", "type": "Protein", "text": [ "EGFR" ], "offsets": [ [ 750, 754 ] ], "normalized": [] }, { "id": "PMID-17486068_T11", "type": "Protein", "text": [ "HER2" ], "offsets": [ [ 837, 841 ] ], "normalized": [] } ]

[ { "id": "PMID-17486068_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinylation" ], "offsets": [ [ 10, 26 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17486068_T1" } ] }, { "id": "PMID-17486068_E2", "type": "Catalysis", "trigger": { "text": [ "mediated" ], "offsets": [ [ 387, 395 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17486068_E3" }, { "role": "Cause", "ref_id": "PMID-17486068_T5" } ] }, { "id": "PMID-17486068_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinylation" ], "offsets": [ [ 405, 421 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17486068_T4" } ] }, { "id": "PMID-17486068_E4", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinylation" ], "offsets": [ [ 659, 675 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17486068_T7" } ] }, { "id": "PMID-17486068_E5", "type": "Catalysis", "trigger": { "text": [ "ubiquitinylation" ], "offsets": [ [ 659, 675 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17486068_E4" }, { "role": "Cause", "ref_id": "PMID-17486068_T9" } ] }, { "id": "PMID-17486068_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinylation" ], "offsets": [ [ 659, 675 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17486068_T8" } ] }, { "id": "PMID-17486068_E7", "type": "Catalysis", "trigger": { "text": [ "ubiquitinylation" ], "offsets": [ [ 659, 675 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17486068_E6" }, { "role": "Cause", "ref_id": "PMID-17486068_T9" } ] } ]

[ { "id": "PMID-17486068_1", "entity_ids": [ "PMID-17486068_T2", "PMID-17486068_T3" ] } ]

[]

[ { "id": "PMID-17516511__text", "type": "abstract", "text": [ "Increased expression and altered subunit composition of proteasomes induced by continuous proteasome inhibition establish apoptosis resistance and hyperproliferation of Burkitt lymphoma cells. \nThe proteasome is the main protease for extralysosomal protein degradation in eukaryotic cells, and constitutes a sophisticated high molecular mass proteinase complex underlying a tightly coordinated expression and assembly of multiple subunits and subcomplexes. Here we show that continuous inhibition of proteasomal chymotrypsin-like peptidase activity by the proteasome inhibitor bortezomib induces in human Namalwa Burkitt lymphoma cells increased de novo biogenesis of proteasomes accompanied by increased expression of the proteasome maturation protein POMP, increased expression of 19S-20S-19S proteasomes, and abrogation of expression of beta 1i, beta 2i and beta 5i immunosubunits and PA28 in favor of increased expression of constitutive proteolytic beta1, beta2 and beta 5 subunits and 19S regulatory complexes. These alterations of proteasome expression and subunit composition are accompanied by an increase in proteasomal caspase-like, trypsin-like and chymotrypsin-like peptidase activities, not inhibitable by high doses of bortezomib. Cells harboring these proteasomal alterations display rapid proliferation and cell cycle progression, and acquire resistance to apoptosis induced by proteasome inhibitors, gamma-irradiation and staurosporine. This acquired apoptosis resistance is accompanied by de novo expression of anti-apoptotic Hsp27 protein and the loss of ability to accumulate and stabilize pro-apoptotic p53 protein. Thus, increased expression, altered subunit composition and increased activity of proteasomes constitute a hitherto unknown adaptive and autoregulatory feedback mechanism to allow cells to survive the lethal challenge of proteasome inhibition and to establish a hyperproliferative and apoptosis-resistant phenotype.\n" ], "offsets": [ [ 0, 1954 ] ] } ]

[ { "id": "PMID-17516511_T1", "type": "Protein", "text": [ "POMP" ], "offsets": [ [ 753, 757 ] ], "normalized": [] }, { "id": "PMID-17516511_T2", "type": "Protein", "text": [ "PA28" ], "offsets": [ [ 888, 892 ] ], "normalized": [] }, { "id": "PMID-17516511_T3", "type": "Protein", "text": [ "Hsp27" ], "offsets": [ [ 1545, 1550 ] ], "normalized": [] }, { "id": "PMID-17516511_T4", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1625, 1628 ] ], "normalized": [] } ]

[]

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[]

[ { "id": "PMID-17524393__text", "type": "abstract", "text": [ "Cell shape regulates global histone acetylation in human mammary epithelial cells. \nExtracellular matrix (ECM) regulates cell morphology and gene expression in vivo; these relationships are maintained in three-dimensional (3D) cultures of mammary epithelial cells. In the presence of laminin-rich ECM (lrECM), mammary epithelial cells round up and undergo global histone deacetylation, a process critical for their functional differentiation. However, it remains unclear whether lrECM-dependent cell rounding and global histone deacetylation are indeed part of a common physical-biochemical pathway. Using 3D cultures as well as nonadhesive and micropatterned substrata, here we showed that the cell 'rounding' caused by lrECM was sufficient to induce deacetylation of histones H3 and H4 in the absence of biochemical cues. Microarray and confocal analysis demonstrated that this deacetylation in 3D culture is associated with a global increase in chromatin condensation and a reduction in gene expression. Whereas cells cultured on plastic substrata formed prominent stress fibers, cells grown in 3D lrECM or on micropatterns lacked these structures. Disruption of the actin cytoskeleton with cytochalasin D phenocopied the lrECM-induced cell rounding and histone deacetylation. These results reveal a novel link between ECM-controlled cell shape and chromatin structure and suggest that this link is mediated by changes in the actin cytoskeleton.\n" ], "offsets": [ [ 0, 1449 ] ] } ]

[ { "id": "PMID-17524393_T1", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 28, 35 ] ], "normalized": [] }, { "id": "PMID-17524393_T2", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 363, 370 ] ], "normalized": [] }, { "id": "PMID-17524393_T3", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 520, 527 ] ], "normalized": [] }, { "id": "PMID-17524393_T4", "type": "Protein", "text": [ "histones H3" ], "offsets": [ [ 769, 780 ] ], "normalized": [] }, { "id": "PMID-17524393_T5", "type": "Protein", "text": [ "H4" ], "offsets": [ [ 785, 787 ] ], "normalized": [] }, { "id": "PMID-17524393_T6", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1257, 1264 ] ], "normalized": [] } ]

[ { "id": "PMID-17524393_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 36, 47 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17524393_T1" } ] }, { "id": "PMID-17524393_E2", "type": "Deacetylation", "trigger": { "text": [ "deacetylation" ], "offsets": [ [ 371, 384 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17524393_T2" } ] }, { "id": "PMID-17524393_E3", "type": "Deacetylation", "trigger": { "text": [ "deacetylation" ], "offsets": [ [ 528, 541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17524393_T3" } ] }, { "id": "PMID-17524393_E4", "type": "Deacetylation", "trigger": { "text": [ "deacetylation" ], "offsets": [ [ 752, 765 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17524393_T4" } ] }, { "id": "PMID-17524393_E5", "type": "Deacetylation", "trigger": { "text": [ "deacetylation" ], "offsets": [ [ 752, 765 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17524393_T5" } ] }, { "id": "PMID-17524393_E6", "type": "Deacetylation", "trigger": { "text": [ "deacetylation" ], "offsets": [ [ 880, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17524393_T4" } ] }, { "id": "PMID-17524393_E7", "type": "Deacetylation", "trigger": { "text": [ "deacetylation" ], "offsets": [ [ 880, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17524393_T5" } ] }, { "id": "PMID-17524393_E8", "type": "Deacetylation", "trigger": { "text": [ "deacetylation" ], "offsets": [ [ 1265, 1278 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17524393_T6" } ] } ]

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[ { "id": "PMID-17541304__text", "type": "abstract", "text": [ "EZH2 polycomb transcriptional repressor expression correlates with methylation of the APAF-1 gene in superficial transitional cell carcinoma of the bladder. \nThe EZH2 gene controls methylation of various EZH2 target promoters. The APAF-1, DAPK-1 und IGFBP-3 genes are frequently methylated in bladder cancer, and methylation of these genes is found in more aggressive tumor types. The aim of our study was to investigate a potential link between EZH2 mRNA expression and the extent of APAF-1, DAPK-1 and IGFBP-3 methylation in urothelial transitional cell carcinoma (TCC) and to correlate the data with histopathological parameters and follow-up data. EZH2 mRNA expression was measured by real-time reverse transcription polymerase chain reaction, and the methylation analysis was performed using methylation-specific real-time polymerase chain reaction. Tissue specimens were obtained from 35 patients with TCC. EZH2 mRNA expression was detected in all tumor specimens investigated. The EZH2 expression levels correlated well with the differentiation grade of the tumor specimens (p = 0.03), and the APAF-1 methylation correlated with tumor stage (p = 0.0001) and grade (p = 0.004). Matched pair analysis demonstrated a statistically significant correlation between elevated EZH2 mRNA expression and higher methylation levels of APAF-1 in superficial (p = 0.024) and well- differentiated (p = 0.04) TCC. In patients with recurrent TCC, APAF-1 and IGFBP-3 methylation levels were significantly higher (p = 0.03 and p = 0.01, respectively), which was not observed when EZH2 mRNA expression or DAPK-1 methylation levels were related to the clinical outcome. In conclusion, our data show that EZH2 expression and APAF-1 methylation are related to tumor progression and invasiveness. Moreover, these data present first evidence that APAF-1 methylation is related to transcriptional activity of EZH2 expression in early-stage tumor disease of the bladder.\n" ], "offsets": [ [ 0, 1951 ] ] } ]

[ { "id": "PMID-17541304_T1", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-17541304_T2", "type": "Protein", "text": [ "APAF-1" ], "offsets": [ [ 86, 92 ] ], "normalized": [] }, { "id": "PMID-17541304_T3", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 162, 166 ] ], "normalized": [] }, { "id": "PMID-17541304_T4", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 204, 208 ] ], "normalized": [] }, { "id": "PMID-17541304_T5", "type": "Protein", "text": [ "APAF-1" ], "offsets": [ [ 231, 237 ] ], "normalized": [] }, { "id": "PMID-17541304_T6", "type": "Protein", "text": [ "DAPK-1" ], "offsets": [ [ 239, 245 ] ], "normalized": [] }, { "id": "PMID-17541304_T7", "type": "Protein", "text": [ "IGFBP-3" ], "offsets": [ [ 250, 257 ] ], "normalized": [] }, { "id": "PMID-17541304_T8", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 446, 450 ] ], "normalized": [] }, { "id": "PMID-17541304_T9", "type": "Protein", "text": [ "APAF-1" ], "offsets": [ [ 485, 491 ] ], "normalized": [] }, { "id": "PMID-17541304_T10", "type": "Protein", "text": [ "DAPK-1" ], "offsets": [ [ 493, 499 ] ], "normalized": [] }, { "id": "PMID-17541304_T11", "type": "Protein", "text": [ "IGFBP-3" ], "offsets": [ [ 504, 511 ] ], "normalized": [] }, { "id": "PMID-17541304_T12", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 652, 656 ] ], "normalized": [] }, { "id": "PMID-17541304_T13", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 913, 917 ] ], "normalized": [] }, { "id": "PMID-17541304_T14", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 988, 992 ] ], "normalized": [] }, { "id": "PMID-17541304_T15", "type": "Protein", "text": [ "APAF-1" ], "offsets": [ [ 1101, 1107 ] ], "normalized": [] }, { "id": "PMID-17541304_T16", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 1276, 1280 ] ], "normalized": [] }, { "id": "PMID-17541304_T17", "type": "Protein", "text": [ "APAF-1" ], "offsets": [ [ 1330, 1336 ] ], "normalized": [] }, { "id": "PMID-17541304_T18", "type": "Protein", "text": [ "APAF-1" ], "offsets": [ [ 1437, 1443 ] ], "normalized": [] }, { "id": "PMID-17541304_T19", "type": "Protein", "text": [ "IGFBP-3" ], "offsets": [ [ 1448, 1455 ] ], "normalized": [] }, { "id": "PMID-17541304_T20", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 1568, 1572 ] ], "normalized": [] }, { "id": "PMID-17541304_T21", "type": "Protein", "text": [ "DAPK-1" ], "offsets": [ [ 1592, 1598 ] ], "normalized": [] }, { "id": "PMID-17541304_T22", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 1690, 1694 ] ], "normalized": [] }, { "id": "PMID-17541304_T23", "type": "Protein", "text": [ "APAF-1" ], "offsets": [ [ 1710, 1716 ] ], "normalized": [] }, { "id": "PMID-17541304_T24", "type": "Protein", "text": [ "APAF-1" ], "offsets": [ [ 1829, 1835 ] ], "normalized": [] }, { "id": "PMID-17541304_T25", "type": "Protein", "text": [ "EZH2" ], "offsets": [ [ 1890, 1894 ] ], "normalized": [] } ]

[ { "id": "PMID-17541304_E1", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 67, 78 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T2" } ] }, { "id": "PMID-17541304_E2", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 279, 289 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T5" } ] }, { "id": "PMID-17541304_E3", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 279, 289 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T6" } ] }, { "id": "PMID-17541304_E4", "type": "DNA_methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 279, 289 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T7" } ] }, { "id": "PMID-17541304_E5", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 313, 324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T5" } ] }, { "id": "PMID-17541304_E6", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 313, 324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T6" } ] }, { "id": "PMID-17541304_E7", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 313, 324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T7" } ] }, { "id": "PMID-17541304_E8", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 512, 523 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T9" } ] }, { "id": "PMID-17541304_E9", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 512, 523 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T10" } ] }, { "id": "PMID-17541304_E10", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 512, 523 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T11" } ] }, { "id": "PMID-17541304_E11", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1108, 1119 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T15" } ] }, { "id": "PMID-17541304_E12", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1308, 1319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T17" } ] }, { "id": "PMID-17541304_E13", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1456, 1467 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T18" } ] }, { "id": "PMID-17541304_E14", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1456, 1467 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T19" } ] }, { "id": "PMID-17541304_E15", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1599, 1610 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T21" } ] }, { "id": "PMID-17541304_E16", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1717, 1728 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T23" } ] }, { "id": "PMID-17541304_E17", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1836, 1847 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17541304_T24" } ] } ]

[]

[]

[ { "id": "PMID-17548520__text", "type": "abstract", "text": [ "Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. \nThe deubiquitinating enzyme CYLD has recently been implicated in the regulation of signal transduction, but its physiological function and mechanism of action are still elusive. In this study, we show that CYLD plays a pivotal role in regulating T cell activation and homeostasis. T cells derived from Cyld knockout mice display a hyperresponsive phenotype and mediate the spontaneous development of intestinal inflammation. Interestingly, CYLD targets a ubiquitin-dependent kinase, transforming growth factor-beta-activated kinase 1 (Tak1), and inhibits its ubiquitination and autoactivation. Cyld-deficient T cells exhibit constitutively active Tak1 and its downstream kinases c-Jun N-terminal kinase and IkappaB kinase beta. These results emphasize a critical role for CYLD in preventing spontaneous activation of the Tak1 axis of T cell signaling and, thereby, maintaining normal T cell function.\n" ], "offsets": [ [ 0, 1028 ] ] } ]

[ { "id": "PMID-17548520_T1", "type": "Protein", "text": [ "CYLD" ], "offsets": [ [ 24, 28 ] ], "normalized": [] }, { "id": "PMID-17548520_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 54, 63 ] ], "normalized": [] }, { "id": "PMID-17548520_T3", "type": "Protein", "text": [ "Tak1" ], "offsets": [ [ 81, 85 ] ], "normalized": [] }, { "id": "PMID-17548520_T4", "type": "Protein", "text": [ "CYLD" ], "offsets": [ [ 155, 159 ] ], "normalized": [] }, { "id": "PMID-17548520_T5", "type": "Protein", "text": [ "CYLD" ], "offsets": [ [ 333, 337 ] ], "normalized": [] }, { "id": "PMID-17548520_T6", "type": "Protein", "text": [ "Cyld" ], "offsets": [ [ 429, 433 ] ], "normalized": [] }, { "id": "PMID-17548520_T7", "type": "Protein", "text": [ "CYLD" ], "offsets": [ [ 567, 571 ] ], "normalized": [] }, { "id": "PMID-17548520_T8", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 582, 591 ] ], "normalized": [] }, { "id": "PMID-17548520_T9", "type": "Protein", "text": [ "transforming growth factor-beta-activated kinase 1" ], "offsets": [ [ 610, 660 ] ], "normalized": [] }, { "id": "PMID-17548520_T10", "type": "Protein", "text": [ "Tak1" ], "offsets": [ [ 662, 666 ] ], "normalized": [] }, { "id": "PMID-17548520_T11", "type": "Protein", "text": [ "Cyld" ], "offsets": [ [ 721, 725 ] ], "normalized": [] }, { "id": "PMID-17548520_T12", "type": "Protein", "text": [ "Tak1" ], "offsets": [ [ 774, 778 ] ], "normalized": [] }, { "id": "PMID-17548520_T13", "type": "Protein", "text": [ "c-Jun N-terminal kinase" ], "offsets": [ [ 806, 829 ] ], "normalized": [] }, { "id": "PMID-17548520_T14", "type": "Protein", "text": [ "IkappaB kinase beta" ], "offsets": [ [ 834, 853 ] ], "normalized": [] }, { "id": "PMID-17548520_T15", "type": "Protein", "text": [ "CYLD" ], "offsets": [ [ 899, 903 ] ], "normalized": [] }, { "id": "PMID-17548520_T16", "type": "Protein", "text": [ "Tak1" ], "offsets": [ [ 948, 952 ] ], "normalized": [] } ]

[ { "id": "PMID-17548520_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 686, 700 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17548520_T9" } ] } ]

[ { "id": "PMID-17548520_1", "entity_ids": [ "PMID-17548520_T9", "PMID-17548520_T10" ] } ]

[]

[ { "id": "PMID-17573539__text", "type": "abstract", "text": [ "Mutations in the Type II protein arginine methyltransferase AtPRMT5 result in pleiotropic developmental defects in Arabidopsis. \nHuman PROTEIN ARGININE METHYLTRANSFERASE5 (PRMT5) encodes a type II protein arginine (Arg) methyltransferase and its homologs in animals and yeast (Saccharomyces cerevisiae and Schizosaccharomyces pombe) are known to regulate RNA processing, signal transduction, and gene expression. However, PRMT5 homologs in higher plants have not yet been reported and the biological roles of these proteins in plant development remain elusive. Here, using conventional biochemical approaches, we purified a plant histone Arg methyltransferase from cauliflower (Brassica oleracea) that was nearly identical to AtPRMT5, an Arabidopsis (Arabidopsis thaliana) homolog of human PRMT5. AtPRMT5 methylated histone H4, H2A, and myelin basic protein in vitro. Western blot using symmetric dimethyl histone H4 Arg 3-specific antibody and thin-layer chromatography analysis demonstrated that AtPRMT5 is a type II enzyme. Mutations in AtPRMT5 caused pleiotropic developmental defects, including growth retardation, dark green and curled leaves, and FlOWERING LOCUS C (FLC)-dependent delayed flowering. Therefore, the type II protein Arg methyltransferase AtPRMT5 is involved in promotion of vegetative growth and FLC-dependent flowering time regulation in Arabidopsis.\n" ], "offsets": [ [ 0, 1374 ] ] } ]

[ { "id": "PMID-17573539_T1", "type": "Protein", "text": [ "AtPRMT5" ], "offsets": [ [ 60, 67 ] ], "normalized": [] }, { "id": "PMID-17573539_T2", "type": "Protein", "text": [ "PROTEIN ARGININE METHYLTRANSFERASE5" ], "offsets": [ [ 135, 170 ] ], "normalized": [] }, { "id": "PMID-17573539_T3", "type": "Protein", "text": [ "PRMT5" ], "offsets": [ [ 172, 177 ] ], "normalized": [] }, { "id": "PMID-17573539_T4", "type": "Protein", "text": [ "PRMT5" ], "offsets": [ [ 422, 427 ] ], "normalized": [] }, { "id": "PMID-17573539_T5", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 630, 637 ] ], "normalized": [] }, { "id": "PMID-17573539_T6", "type": "Protein", "text": [ "AtPRMT5" ], "offsets": [ [ 726, 733 ] ], "normalized": [] }, { "id": "PMID-17573539_T7", "type": "Protein", "text": [ "PRMT5" ], "offsets": [ [ 790, 795 ] ], "normalized": [] }, { "id": "PMID-17573539_T8", "type": "Protein", "text": [ "AtPRMT5" ], "offsets": [ [ 797, 804 ] ], "normalized": [] }, { "id": "PMID-17573539_T9", "type": "Protein", "text": [ "histone H4" ], "offsets": [ [ 816, 826 ] ], "normalized": [] }, { "id": "PMID-17573539_T10", "type": "Protein", "text": [ "H2A" ], "offsets": [ [ 828, 831 ] ], "normalized": [] }, { "id": "PMID-17573539_T11", "type": "Protein", "text": [ "myelin basic protein" ], "offsets": [ [ 837, 857 ] ], "normalized": [] }, { "id": "PMID-17573539_T12", "type": "Protein", "text": [ "histone H4" ], "offsets": [ [ 906, 916 ] ], "normalized": [] }, { "id": "PMID-17573539_T13", "type": "Protein", "text": [ "AtPRMT5" ], "offsets": [ [ 998, 1005 ] ], "normalized": [] }, { "id": "PMID-17573539_T14", "type": "Protein", "text": [ "AtPRMT5" ], "offsets": [ [ 1040, 1047 ] ], "normalized": [] }, { "id": "PMID-17573539_T15", "type": "Protein", "text": [ "FlOWERING LOCUS C" ], "offsets": [ [ 1154, 1171 ] ], "normalized": [] }, { "id": "PMID-17573539_T16", "type": "Protein", "text": [ "FLC" ], "offsets": [ [ 1173, 1176 ] ], "normalized": [] }, { "id": "PMID-17573539_T17", "type": "Protein", "text": [ "AtPRMT5" ], "offsets": [ [ 1260, 1267 ] ], "normalized": [] }, { "id": "PMID-17573539_T18", "type": "Protein", "text": [ "FLC" ], "offsets": [ [ 1318, 1321 ] ], "normalized": [] } ]

[ { "id": "PMID-17573539_E1", "type": "Methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 805, 815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17573539_T9" } ] }, { "id": "PMID-17573539_E2", "type": "Catalysis", "trigger": { "text": [ "methylated" ], "offsets": [ [ 805, 815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17573539_E1" }, { "role": "Cause", "ref_id": "PMID-17573539_T8" } ] }, { "id": "PMID-17573539_E3", "type": "Methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 805, 815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17573539_T10" } ] }, { "id": "PMID-17573539_E4", "type": "Catalysis", "trigger": { "text": [ "methylated" ], "offsets": [ [ 805, 815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17573539_E3" }, { "role": "Cause", "ref_id": "PMID-17573539_T8" } ] }, { "id": "PMID-17573539_E5", "type": "Methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 805, 815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17573539_T11" } ] }, { "id": "PMID-17573539_E6", "type": "Catalysis", "trigger": { "text": [ "methylated" ], "offsets": [ [ 805, 815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17573539_E5" }, { "role": "Cause", "ref_id": "PMID-17573539_T8" } ] } ]

[ { "id": "PMID-17573539_1", "entity_ids": [ "PMID-17573539_T2", "PMID-17573539_T3" ] }, { "id": "PMID-17573539_2", "entity_ids": [ "PMID-17573539_T15", "PMID-17573539_T16" ] } ]

[]

[ { "id": "PMID-17585950__text", "type": "abstract", "text": [ "HAUSP-regulated switch from auto- to p53 ubiquitination by Mdm2 (in silico discovery). \nStability of the 'guardian of the genome' tumor suppressor protein p53 is regulated predominantly through its ubiquitination. The ubiquitin-specific protease HAUSP plays an important role in this process. Recent experiments showed that p53 demonstrates a differential response to changes in HAUSP which nature and significance are not understood yet. Here a data-driven mathematical model of the Mdm2-mediated p53 ubiquitination network is presented which offers an explanation for the cause of such a response. The model predicts existence of the HAUSP-regulated switch from auto- to p53 ubiquitination by Mdm2. This switch suggests a potential role of HAUSP as a downstream target of stress signals in cells. The model accounts for a significant amount of experimental data, makes predictions for some rate constants, and can serve as a building block for the larger model describing a complex dynamic response of p53 to cellular stresses.\n" ], "offsets": [ [ 0, 1030 ] ] } ]

[ { "id": "PMID-17585950_T1", "type": "Protein", "text": [ "HAUSP" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-17585950_T2", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 37, 40 ] ], "normalized": [] }, { "id": "PMID-17585950_T3", "type": "Protein", "text": [ "Mdm2" ], "offsets": [ [ 59, 63 ] ], "normalized": [] }, { "id": "PMID-17585950_T4", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 155, 158 ] ], "normalized": [] }, { "id": "PMID-17585950_T5", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 218, 227 ] ], "normalized": [] }, { "id": "PMID-17585950_T6", "type": "Protein", "text": [ "HAUSP" ], "offsets": [ [ 246, 251 ] ], "normalized": [] }, { "id": "PMID-17585950_T7", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 324, 327 ] ], "normalized": [] }, { "id": "PMID-17585950_T8", "type": "Protein", "text": [ "HAUSP" ], "offsets": [ [ 379, 384 ] ], "normalized": [] }, { "id": "PMID-17585950_T9", "type": "Protein", "text": [ "Mdm2" ], "offsets": [ [ 484, 488 ] ], "normalized": [] }, { "id": "PMID-17585950_T10", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 498, 501 ] ], "normalized": [] }, { "id": "PMID-17585950_T11", "type": "Protein", "text": [ "HAUSP" ], "offsets": [ [ 636, 641 ] ], "normalized": [] }, { "id": "PMID-17585950_T12", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 673, 676 ] ], "normalized": [] }, { "id": "PMID-17585950_T13", "type": "Protein", "text": [ "Mdm2" ], "offsets": [ [ 695, 699 ] ], "normalized": [] }, { "id": "PMID-17585950_T14", "type": "Protein", "text": [ "HAUSP" ], "offsets": [ [ 742, 747 ] ], "normalized": [] }, { "id": "PMID-17585950_T15", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1004, 1007 ] ], "normalized": [] } ]

[ { "id": "PMID-17585950_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 41, 55 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17585950_T2" } ] }, { "id": "PMID-17585950_E2", "type": "Catalysis", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 41, 55 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17585950_E1" }, { "role": "Cause", "ref_id": "PMID-17585950_T3" } ] }, { "id": "PMID-17585950_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 198, 212 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17585950_T4" } ] }, { "id": "PMID-17585950_E4", "type": "Catalysis", "trigger": { "text": [ "mediated" ], "offsets": [ [ 489, 497 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17585950_E5" }, { "role": "Cause", "ref_id": "PMID-17585950_T9" } ] }, { "id": "PMID-17585950_E5", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 502, 516 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17585950_T10" } ] }, { "id": "PMID-17585950_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 677, 691 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17585950_T12" } ] }, { "id": "PMID-17585950_E7", "type": "Catalysis", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 677, 691 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17585950_E6" }, { "role": "Cause", "ref_id": "PMID-17585950_T13" } ] } ]

[]

[]

[ { "id": "PMID-17601874__text", "type": "abstract", "text": [ "Evolutionarily divergent type II protein arginine methyltransferase in Trypanosoma brucei. \nProtein arginine methylation is a posttranslational modification that impacts cellular functions, such as RNA processing, transcription, DNA repair, and signal transduction. The majority of our knowledge regarding arginine methylation derives from studies of yeast and mammals. Here, we describe a protein arginine N-methyltransferase (PRMT), TbPRMT5, from the early-branching eukaryote Trypanosoma brucei. TbPRMT5 shares the greatest sequence similarity with PRMT5 and Skb1 type II enzymes from humans and Schizosaccharomyces pombe, respectively, although it is significantly divergent at the amino acid level from its mammalian and yeast counterparts. Recombinant TbPRMT5 displays broad substrate specificity in vitro, including methylation of a mitochondrial-gene-regulatory protein, RBP16. TbPRMT5 catalyzes the formation of omega-N(G)-monomethylarginine and symmetric omega-N(G),N(G')-dimethylarginine and does not require trypanosome cofactors for this activity. These data establish that type II PRMTs evolved early in the eukaryotic lineage. In vivo, TbPRMT5 is constitutively expressed in the bloodstream form and procyclic-form (insect host) life stages of the parasite and localizes to the cytoplasm. Genetic disruption via RNA interference in procyclic-form trypanosomes indicates that TbPRMT5 is not essential for growth in this life cycle stage. TbPRMT5-TAP ectopically expressed in procyclic-form trypanosomes is present in high-molecular-weight complexes and associates with an RG domain-containing DEAD box protein related to yeast Ded1 and two kinetoplastid-specific proteins. Thus, TbPRMT5 is likely to be involved in novel methylation-regulated functions in trypanosomes, some of which may include RNA processing and/or translation.\n" ], "offsets": [ [ 0, 1845 ] ] } ]

[ { "id": "PMID-17601874_T1", "type": "Protein", "text": [ "TbPRMT5" ], "offsets": [ [ 435, 442 ] ], "normalized": [] }, { "id": "PMID-17601874_T2", "type": "Protein", "text": [ "TbPRMT5" ], "offsets": [ [ 499, 506 ] ], "normalized": [] }, { "id": "PMID-17601874_T3", "type": "Protein", "text": [ "PRMT5" ], "offsets": [ [ 552, 557 ] ], "normalized": [] }, { "id": "PMID-17601874_T4", "type": "Protein", "text": [ "Skb1" ], "offsets": [ [ 562, 566 ] ], "normalized": [] }, { "id": "PMID-17601874_T5", "type": "Protein", "text": [ "TbPRMT5" ], "offsets": [ [ 758, 765 ] ], "normalized": [] }, { "id": "PMID-17601874_T6", "type": "Protein", "text": [ "RBP16" ], "offsets": [ [ 879, 884 ] ], "normalized": [] }, { "id": "PMID-17601874_T7", "type": "Protein", "text": [ "TbPRMT5" ], "offsets": [ [ 886, 893 ] ], "normalized": [] }, { "id": "PMID-17601874_T8", "type": "Protein", "text": [ "TbPRMT5" ], "offsets": [ [ 1151, 1158 ] ], "normalized": [] }, { "id": "PMID-17601874_T9", "type": "Protein", "text": [ "TbPRMT5" ], "offsets": [ [ 1390, 1397 ] ], "normalized": [] }, { "id": "PMID-17601874_T10", "type": "Protein", "text": [ "TbPRMT5" ], "offsets": [ [ 1452, 1459 ] ], "normalized": [] }, { "id": "PMID-17601874_T11", "type": "Protein", "text": [ "Ded1" ], "offsets": [ [ 1641, 1645 ] ], "normalized": [] }, { "id": "PMID-17601874_T12", "type": "Protein", "text": [ "TbPRMT5" ], "offsets": [ [ 1693, 1700 ] ], "normalized": [] } ]

[ { "id": "PMID-17601874_E1", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 823, 834 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17601874_T6" } ] }, { "id": "PMID-17601874_E2", "type": "Catalysis", "trigger": { "text": [ "methylation" ], "offsets": [ [ 823, 834 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17601874_E1" }, { "role": "Cause", "ref_id": "PMID-17601874_T5" } ] } ]

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[ { "id": "PMID-17624450__text", "type": "abstract", "text": [ "Activity of compounds from Chinese herbal medicine Rhodiola kirilowii (Regel) Maxim against HCV NS3 serine protease. \nTreatment of the chronic hepatitis C virus (HCV) infection is an unmet medical need, and the HCV NS3 serine protease (NS3-SP) has been used as an attractive target of antiviral screening against HCV. To find naturally chemical entities as lead compounds from which novel anti-HCV agents could be developed, bioassay-guided fractionation and isolation were performed on a crude ethanol extract from rhizomes of the Chinese medicinal herb Rhodiola kirilowii (Regel) Maxim using column chromatography (CC) techniques and in vitro inhibitory activity against HCV NS3-SP. The partition of the extract between water and different organic solvents led to the isolation and identification of 12 compounds in the ethyl acetate part which proved to be the most active. These compounds were tested for in vitro activity against HCV NS3-SP, among which four (-)-Epicatechin derivatives: 3,3'-Digalloylproprodelphinidin B2 (Rhodisin, 1); 3,3'-Digalloylprocyanidin B2 (2); (-)-Epigallocatechin-3-O-gallate (EGCG, 3); and (-)-Epicatechin-3-O-gallate (4, ECG) represented the most potent ones with IC(50) of 0.77, 0.91, 8.51, and 18.55 microM, respectively. Salidroside, the commonly known compounds, together with the other compounds showed no activity up to 100.0 microM. Methylation and acylation of the hydroxyl groups of 1-4 caused a decrease of activity. Cell viability and secreted alkaline phosphatase (SEAP) activity assays with 1-4 revealed little if any toxicity. These nonpeptide inhibitors of HCV NS3-SP might serve as potential candidate anti-HCV agents.\n" ], "offsets": [ [ 0, 1671 ] ] } ]

[ { "id": "PMID-17624450_T1", "type": "Protein", "text": [ "NS3" ], "offsets": [ [ 96, 99 ] ], "normalized": [] }, { "id": "PMID-17624450_T2", "type": "Protein", "text": [ "NS3" ], "offsets": [ [ 215, 218 ] ], "normalized": [] }, { "id": "PMID-17624450_T3", "type": "Protein", "text": [ "NS3" ], "offsets": [ [ 236, 239 ] ], "normalized": [] }, { "id": "PMID-17624450_T4", "type": "Protein", "text": [ "NS3" ], "offsets": [ [ 677, 680 ] ], "normalized": [] }, { "id": "PMID-17624450_T5", "type": "Protein", "text": [ "NS3" ], "offsets": [ [ 939, 942 ] ], "normalized": [] }, { "id": "PMID-17624450_T6", "type": "Protein", "text": [ "NS3" ], "offsets": [ [ 1612, 1615 ] ], "normalized": [] } ]

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[ { "id": "PMID-17628003__text", "type": "abstract", "text": [ "Activation of endoproteolytic processing of insulin-like growth factor-II in fetal, early postnatal, and pregnant rats and persistence of circulating levels in postnatal life. \nThe process of posttranslational modifications of IGF-II likely has important physiological consequences. In addition to mature IGF-II, glycosylated proIGF-II(156-amino acid peptide) and two glycosylated big IGF-II forms, IGF-II(1-104) and IGF-II(1-87), have been identified in the human circulation. Due to lack of an appropriate methodology, different IGF-II isoforms have not been demonstrated and characterized in the rat circulation, thus preventing a better understanding of the physiological and pathological roles of IGF-II. In the present study, we characterized each IGF-II form and assessed its content in the rat circulation throughout life time by using a highly sensitive Western blot analysis, which is void of the IGF binding protein interference and distinguished all IGF-II forms. For the first time, we demonstrated the presence of IGF-II variants, including proIGF-II, IGF-II(1-87), and mature IGF-II, in the rat circulation during postnatal life, challenging the current impression that IGF-II is absent from sera of adult rats. ProIGF-II is glycosylated and is the predominant form in the rat circulation. Endoproteolytic processing of proIGF-II was clearly activated in fetal, neonatal, and pregnant rats, likely reflecting its involvement in fetal development through the generation of specific forms of IGF-II (e.g. mature IGF-II) that are required for their distinct biological functions. Taken together, our data also suggest that serum IGF-II profiles may reflect underlying physiological conditions.\n" ], "offsets": [ [ 0, 1706 ] ] } ]

[ { "id": "PMID-17628003_T1", "type": "Protein", "text": [ "insulin-like growth factor-II" ], "offsets": [ [ 44, 73 ] ], "normalized": [] }, { "id": "PMID-17628003_T2", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 227, 233 ] ], "normalized": [] }, { "id": "PMID-17628003_T3", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 305, 311 ] ], "normalized": [] }, { "id": "PMID-17628003_T4", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 329, 335 ] ], "normalized": [] }, { "id": "PMID-17628003_T5", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 385, 391 ] ], "normalized": [] }, { "id": "PMID-17628003_T6", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 399, 405 ] ], "normalized": [] }, { "id": "PMID-17628003_T7", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 417, 423 ] ], "normalized": [] }, { "id": "PMID-17628003_T8", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 531, 537 ] ], "normalized": [] }, { "id": "PMID-17628003_T9", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 702, 708 ] ], "normalized": [] }, { "id": "PMID-17628003_T10", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 754, 760 ] ], "normalized": [] }, { "id": "PMID-17628003_T11", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 962, 968 ] ], "normalized": [] }, { "id": "PMID-17628003_T12", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 1028, 1034 ] ], "normalized": [] }, { "id": "PMID-17628003_T13", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 1058, 1064 ] ], "normalized": [] }, { "id": "PMID-17628003_T14", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 1066, 1072 ] ], "normalized": [] }, { "id": "PMID-17628003_T15", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 1091, 1097 ] ], "normalized": [] }, { "id": "PMID-17628003_T16", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 1185, 1191 ] ], "normalized": [] }, { "id": "PMID-17628003_T17", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 1230, 1236 ] ], "normalized": [] }, { "id": "PMID-17628003_T18", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 1338, 1344 ] ], "normalized": [] }, { "id": "PMID-17628003_T19", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 1505, 1511 ] ], "normalized": [] }, { "id": "PMID-17628003_T20", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 1525, 1531 ] ], "normalized": [] }, { "id": "PMID-17628003_T21", "type": "Protein", "text": [ "IGF-II" ], "offsets": [ [ 1641, 1647 ] ], "normalized": [] } ]

[ { "id": "PMID-17628003_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylated" ], "offsets": [ [ 313, 325 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17628003_T4" } ] }, { "id": "PMID-17628003_E2", "type": "Glycosylation", "trigger": { "text": [ "glycosylated" ], "offsets": [ [ 368, 380 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17628003_T6" } ] }, { "id": "PMID-17628003_E3", "type": "Glycosylation", "trigger": { "text": [ "glycosylated" ], "offsets": [ [ 368, 380 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17628003_T7" } ] }, { "id": "PMID-17628003_E4", "type": "Glycosylation", "trigger": { "text": [ "glycosylated" ], "offsets": [ [ 1240, 1252 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17628003_T17" } ] } ]

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[ { "id": "PMID-17630273__text", "type": "abstract", "text": [ "A unique beta1,3-galactosyltransferase is indispensable for the biosynthesis of N-glycans containing Lewis a structures in Arabidopsis thaliana. \nIn plants, the only known outer-chain elongation of complex N-glycans is the formation of Lewis a [Fuc alpha1-4(Gal beta1-3)GlcNAc-R] structures. This process involves the sequential attachment of beta1,3-galactose and alpha1,4-fucose residues by beta1,3-galactosyltransferase and alpha1,4-fucosyltransferase. However, the exact mechanism underlying the formation of Lewis a epitopes in plants is poorly understood, largely because one of the involved enzymes, beta1,3-galactosyltransferase, has not yet been identified and characterized. Here, we report the identification of an Arabidopsis thaliana beta1,3-galactosyltransferase involved in the biosynthesis of the Lewis a epitope using an expression cloning strategy. Overexpression of various candidates led to the identification of a single gene (named GALACTOSYLTRANSFERASE1 [GALT1]) that increased the originally very low Lewis a epitope levels in planta. Recombinant GALT1 protein produced in insect cells was capable of transferring beta1,3-linked galactose residues to various N-glycan acceptor substrates, and subsequent treatment of the reaction products with alpha1,4-fucosyltransferase resulted in the generation of Lewis a structures. Furthermore, transgenic Arabidopsis plants lacking a functional GALT1 mRNA did not show any detectable amounts of Lewis a epitopes on endogenous glycoproteins. Taken together, our results demonstrate that GALT1 is both sufficient and essential for the addition of beta1,3-linked galactose residues to N-glycans and thus is required for the biosynthesis of Lewis a structures in Arabidopsis. Moreover, cell biological characterization of a transiently expressed GALT1-fluorescent protein fusion using confocal laser scanning microscopy revealed the exclusive location of GALT1 within the Golgi apparatus, which is in good agreement with the proposed physiological action of the enzyme.\n" ], "offsets": [ [ 0, 2031 ] ] } ]

[ { "id": "PMID-17630273_T1", "type": "Protein", "text": [ "alpha1,4-fucosyltransferase" ], "offsets": [ [ 427, 454 ] ], "normalized": [] }, { "id": "PMID-17630273_T2", "type": "Protein", "text": [ "GALACTOSYLTRANSFERASE1" ], "offsets": [ [ 954, 976 ] ], "normalized": [] }, { "id": "PMID-17630273_T3", "type": "Protein", "text": [ "GALT1" ], "offsets": [ [ 978, 983 ] ], "normalized": [] }, { "id": "PMID-17630273_T4", "type": "Protein", "text": [ "GALT1" ], "offsets": [ [ 1071, 1076 ] ], "normalized": [] }, { "id": "PMID-17630273_T5", "type": "Protein", "text": [ "alpha1,4-fucosyltransferase" ], "offsets": [ [ 1268, 1295 ] ], "normalized": [] }, { "id": "PMID-17630273_T6", "type": "Protein", "text": [ "GALT1" ], "offsets": [ [ 1410, 1415 ] ], "normalized": [] }, { "id": "PMID-17630273_T7", "type": "Protein", "text": [ "GALT1" ], "offsets": [ [ 1551, 1556 ] ], "normalized": [] }, { "id": "PMID-17630273_T8", "type": "Protein", "text": [ "GALT1" ], "offsets": [ [ 1807, 1812 ] ], "normalized": [] }, { "id": "PMID-17630273_T9", "type": "Protein", "text": [ "GALT1" ], "offsets": [ [ 1916, 1921 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-17630273_1", "entity_ids": [ "PMID-17630273_T2", "PMID-17630273_T3" ] } ]

[]

[ { "id": "PMID-17638879__text", "type": "abstract", "text": [ "The PAX3-FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence. \nRhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with a histologic variant of rhabdomyosarcoma known as alveolar rhabdomyosarcoma (ARMS) have a 5-year survival of <30%. ARMS is characterized by a chromosomal translocation generating the PAX3-FKHR fusion gene. However, ectopic expression of PAX3-FKHR often induces inhibition of cell proliferation, or cell death, when expressed in nonmuscle cells. This prompted us to explore the effect of expressing PAX3-FKHR in more relevant cells, specifically primary human skeletal muscle cells because these cells can be converted to a tumorigenic state that mimics rhabdomyosarcoma. PAX3-FKHR expression promoted both fetal and postnatal primary human skeletal muscle cell precursors to bypass the senescence growth arrest checkpoint. This bypass was accompanied by epigenetic DNA methylation of the p16(INK4A) promoter and correspondingly a loss of expression of this tumor suppressor. Knockdown of p16(INK4A) cooperated with PAX3-FKHR to drive proliferation past senescence, whereas reintroduction of wild-type p16(INK4A) in post-senescent cells caused growth arrest. Thus, PAX3-FKHR acts in concert with loss of p16(INK4A) to promote inappropriate proliferation of skeletal muscle cells. This association between PAX3-FKHR expression and p16(INK4A) loss was seen in human ARMS tumor tissue, as both human rhabdomyosarcoma cell lines and tissue microarrays showed a trend toward down-regulation of p16(INK4A) protein in alveolar subsets. We surmise that the generation of the PAX3-FKHR fusion protein may require loss of p16(INK4A) to promote malignant proliferation of skeletal muscle cells as an early step in ARMS tumorigenesis.\n" ], "offsets": [ [ 0, 1873 ] ] } ]

[ { "id": "PMID-17638879_T1", "type": "Protein", "text": [ "PAX3" ], "offsets": [ [ 4, 8 ] ], "normalized": [] }, { "id": "PMID-17638879_T2", "type": "Protein", "text": [ "FKHR" ], "offsets": [ [ 9, 13 ] ], "normalized": [] }, { "id": "PMID-17638879_T3", "type": "Protein", "text": [ "p16INK4A" ], "offsets": [ [ 70, 78 ] ], "normalized": [] }, { "id": "PMID-17638879_T4", "type": "Protein", "text": [ "PAX3" ], "offsets": [ [ 434, 438 ] ], "normalized": [] }, { "id": "PMID-17638879_T5", "type": "Protein", "text": [ "FKHR" ], "offsets": [ [ 439, 443 ] ], "normalized": [] }, { "id": "PMID-17638879_T6", "type": "Protein", "text": [ "PAX3" ], "offsets": [ [ 488, 492 ] ], "normalized": [] }, { "id": "PMID-17638879_T7", "type": "Protein", "text": [ "FKHR" ], "offsets": [ [ 493, 497 ] ], "normalized": [] }, { "id": "PMID-17638879_T8", "type": "Protein", "text": [ "PAX3" ], "offsets": [ [ 649, 653 ] ], "normalized": [] }, { "id": "PMID-17638879_T9", "type": "Protein", "text": [ "FKHR" ], "offsets": [ [ 654, 658 ] ], "normalized": [] }, { "id": "PMID-17638879_T10", "type": "Protein", "text": [ "PAX3" ], "offsets": [ [ 822, 826 ] ], "normalized": [] }, { "id": "PMID-17638879_T11", "type": "Protein", "text": [ "FKHR" ], "offsets": [ [ 827, 831 ] ], "normalized": [] }, { "id": "PMID-17638879_T12", "type": "Protein", "text": [ "p16(INK4A)" ], "offsets": [ [ 1039, 1049 ] ], "normalized": [] }, { "id": "PMID-17638879_T13", "type": "Protein", "text": [ "p16(INK4A)" ], "offsets": [ [ 1139, 1149 ] ], "normalized": [] }, { "id": "PMID-17638879_T14", "type": "Protein", "text": [ "PAX3" ], "offsets": [ [ 1166, 1170 ] ], "normalized": [] }, { "id": "PMID-17638879_T15", "type": "Protein", "text": [ "FKHR" ], "offsets": [ [ 1171, 1175 ] ], "normalized": [] }, { "id": "PMID-17638879_T16", "type": "Protein", "text": [ "p16(INK4A)" ], "offsets": [ [ 1252, 1262 ] ], "normalized": [] }, { "id": "PMID-17638879_T17", "type": "Protein", "text": [ "PAX3" ], "offsets": [ [ 1315, 1319 ] ], "normalized": [] }, { "id": "PMID-17638879_T18", "type": "Protein", "text": [ "FKHR" ], "offsets": [ [ 1320, 1324 ] ], "normalized": [] }, { "id": "PMID-17638879_T19", "type": "Protein", "text": [ "p16(INK4A)" ], "offsets": [ [ 1354, 1364 ] ], "normalized": [] }, { "id": "PMID-17638879_T20", "type": "Protein", "text": [ "PAX3" ], "offsets": [ [ 1455, 1459 ] ], "normalized": [] }, { "id": "PMID-17638879_T21", "type": "Protein", "text": [ "FKHR" ], "offsets": [ [ 1460, 1464 ] ], "normalized": [] }, { "id": "PMID-17638879_T22", "type": "Protein", "text": [ "p16(INK4A)" ], "offsets": [ [ 1480, 1490 ] ], "normalized": [] }, { "id": "PMID-17638879_T23", "type": "Protein", "text": [ "p16(INK4A)" ], "offsets": [ [ 1639, 1649 ] ], "normalized": [] }, { "id": "PMID-17638879_T24", "type": "Protein", "text": [ "PAX3" ], "offsets": [ [ 1717, 1721 ] ], "normalized": [] }, { "id": "PMID-17638879_T25", "type": "Protein", "text": [ "FKHR" ], "offsets": [ [ 1722, 1726 ] ], "normalized": [] }, { "id": "PMID-17638879_T26", "type": "Protein", "text": [ "p16(INK4A)" ], "offsets": [ [ 1762, 1772 ] ], "normalized": [] }, { "id": "PMID-17638879_T28", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1050, 1058 ] ], "normalized": [] } ]

[ { "id": "PMID-17638879_E1", "type": "DNA_methylation", "trigger": { "text": [ "DNA methylation" ], "offsets": [ [ 1016, 1031 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17638879_T12" }, { "role": "Site", "ref_id": "PMID-17638879_T28" } ] } ]

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[ { "id": "PMID-17644761__text", "type": "abstract", "text": [ "Analysis of dynamic changes in post-translational modifications of human histones during cell cycle by mass spectrometry. \nThe N-terminal tails of the four core histones are subject to several types of covalent post-translational modifications that have specific roles in regulating chromatin structure and function. Here we present an extensive analysis of the core histone modifications occurring through the cell cycle. Our MS experiments characterized the modification patterns of histones from HeLa cells arrested in phase G1, S, and G2/M. For all core histones, the modifications in the G1 and S phases were largely identical but drastically different during mitosis. Modification changes between S and G2/M phases were quantified using the SILAC (stable isotope labeling by amino acids in cell culture) approach. Most striking was the mitotic phosphorylation on histone H3 and H4, whereas phosphorylation on H2A was constant during the cell cycle. A loss of acetylation was observed on all histones in G2/M-arrested cells. The pattern of cycle-dependent methylation was more complex: during G2/M, H3 Lys27 and Lys36 were decreased, whereas H4 Lys20 was increased. Our results show that mitosis was the period of the cell cycle during which many modifications exhibit dynamic changes.\n" ], "offsets": [ [ 0, 1291 ] ] } ]

[ { "id": "PMID-17644761_T1", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 73, 81 ] ], "normalized": [] }, { "id": "PMID-17644761_T2", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 161, 169 ] ], "normalized": [] }, { "id": "PMID-17644761_T3", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 367, 374 ] ], "normalized": [] }, { "id": "PMID-17644761_T4", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 558, 566 ] ], "normalized": [] }, { "id": "PMID-17644761_T5", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 869, 879 ] ], "normalized": [] }, { "id": "PMID-17644761_T6", "type": "Protein", "text": [ "H4" ], "offsets": [ [ 884, 886 ] ], "normalized": [] }, { "id": "PMID-17644761_T7", "type": "Protein", "text": [ "H2A" ], "offsets": [ [ 915, 918 ] ], "normalized": [] }, { "id": "PMID-17644761_T8", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 997, 1005 ] ], "normalized": [] }, { "id": "PMID-17644761_T9", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1104, 1106 ] ], "normalized": [] }, { "id": "PMID-17644761_T10", "type": "Protein", "text": [ "H4" ], "offsets": [ [ 1147, 1149 ] ], "normalized": [] }, { "id": "PMID-17644761_T15", "type": "Entity", "text": [ "Lys27" ], "offsets": [ [ 1107, 1112 ] ], "normalized": [] }, { "id": "PMID-17644761_T16", "type": "Entity", "text": [ "Lys36" ], "offsets": [ [ 1117, 1122 ] ], "normalized": [] }, { "id": "PMID-17644761_T17", "type": "Entity", "text": [ "Lys20" ], "offsets": [ [ 1150, 1155 ] ], "normalized": [] } ]

[ { "id": "PMID-17644761_E1", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 850, 865 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17644761_T5" } ] }, { "id": "PMID-17644761_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 850, 865 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17644761_T6" } ] }, { "id": "PMID-17644761_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 896, 911 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17644761_T7" } ] }, { "id": "PMID-17644761_E4", "type": "Deacetylation", "trigger": { "text": [ "loss of acetylation" ], "offsets": [ [ 957, 976 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17644761_T8" } ] }, { "id": "PMID-17644761_E5", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1061, 1072 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17644761_T9" }, { "role": "Site", "ref_id": "PMID-17644761_T15" } ] }, { "id": "PMID-17644761_E6", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1061, 1072 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17644761_T9" }, { "role": "Site", "ref_id": "PMID-17644761_T16" } ] }, { "id": "PMID-17644761_E7", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1061, 1072 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17644761_T10" }, { "role": "Site", "ref_id": "PMID-17644761_T17" } ] } ]

[]

[]

[ { "id": "PMID-17658575__text", "type": "abstract", "text": [ "High-mannose-specific deglycosylation of HIV-1 gp120 induced by resistance to cyanovirin-N and the impact on antibody neutralization. \nHIV-1 uses glycans on gp120 to occlude its highly immunogenic epitopes. To better elucidate escape mechanisms of HIV-1 from carbohydrate-binding agents (CBA) and to understand the impact of CBA-escape on viral immune evasion, we generated and examined the biological properties of HIV-1 resistant to cyanovirin-N (CV-N) or cross-resistant to additional CBAs. Genotypic and phenotypic characterization of resistant env clones indicated that 3-5 high-mannose residues from 289 to 448 in the C2-C4 region of gp120 were mutated and correlated with the resistance levels. The specificity and minimal requirements of deglycosylation for CV-N resistance were further assessed by mutagenesis study. The sensitivity of resistant variants to a range of CBAs, immunoglobulins, sera and monoclonal antibodies (MAb) were investigated. For the first time, our data have collectively defined the high-mannose residues on gp120 affecting CV-N activity, and demonstrated that CBA-escape HIV-1 has increased sensitivity to immunoglobulins and sera from HIV patients, and particularly to V3 loop-directed MAbs. Our study provides a proof-of-concept that targeting HIV-1 glycan shields may represent a novel antiviral strategy.\n" ], "offsets": [ [ 0, 1343 ] ] } ]

[ { "id": "PMID-17658575_T1", "type": "Protein", "text": [ "gp120" ], "offsets": [ [ 47, 52 ] ], "normalized": [] }, { "id": "PMID-17658575_T2", "type": "Protein", "text": [ "gp120" ], "offsets": [ [ 157, 162 ] ], "normalized": [] }, { "id": "PMID-17658575_T3", "type": "Protein", "text": [ "gp120" ], "offsets": [ [ 640, 645 ] ], "normalized": [] }, { "id": "PMID-17658575_T4", "type": "Entity", "text": [ "High-mannose" ], "offsets": [ [ 0, 12 ] ], "normalized": [] } ]

[ { "id": "PMID-17658575_E1", "type": "Deglycosylation", "trigger": { "text": [ "deglycosylation" ], "offsets": [ [ 22, 37 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17658575_T1" }, { "role": "Sidechain", "ref_id": "PMID-17658575_T4" } ] }, { "id": "PMID-17658575_E2", "type": "Deglycosylation", "trigger": { "text": [ "deglycosylation" ], "offsets": [ [ 746, 761 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17658575_T3" } ] } ]

[]

[]

[ { "id": "PMID-17690039__text", "type": "abstract", "text": [ "Promoter hypermethylation of death-associated protein kinase gene in cholangiocarcinoma. \nBACKGROUND: Death-associated protein kinase (DAPK) is a Ca2+/calmodulin-regulated Ser/Thr kinase which is involved in apoptosis. The aberrant methylation of its promoter region CpG islands may be one of the important mechanisms of carcinogenesis. We studied the relationship of methylation status and expression of the DAPK gene with the clinical findings in cholangiocarcinoma. METHODS: Target DNA was modified by sodium bisulfite, coverting all unmethylated, but not methylated, cytosines to uracil, and subsequently detected by methylation-specific PCR. Moreover, mRNA expression of the DAPK gene was assessed by RT-PCR. RESULTS: Aberrant methylation of the DAPK gene was detected in 11 (30.6%) of 36 tissue specimens of cholangiocarcinoma, and in 2 (5.6%) of 36 specimens of adjacent normal tissues. DAPK mRNA was not expressed in tumor and adjacent tissues with hypermethylation of the DAPK promoter. There were no statistical differences in the extent of differentiation and invasion, lymph node metastasis or pathologic type between the methylated and unmethylated tissues. CONCLUSIONS: The frequency of DAPK gene methylation in cholangiocarcinoma is high and it may offer an effective means for earlier auxiliary diagnosis of the malignancy. The DAPK gene is probably suppressed by methylation, and it could become resistant to apoptosis and immunological surveillance. The DAPK gene epigenetically affected by methylation may be associated with the carcinogenesis of cholangiocarcinoma.\n" ], "offsets": [ [ 0, 1586 ] ] } ]

[ { "id": "PMID-17690039_T1", "type": "Protein", "text": [ "death-associated protein kinase" ], "offsets": [ [ 29, 60 ] ], "normalized": [] }, { "id": "PMID-17690039_T2", "type": "Protein", "text": [ "Death-associated protein kinase" ], "offsets": [ [ 102, 133 ] ], "normalized": [] }, { "id": "PMID-17690039_T3", "type": "Protein", "text": [ "DAPK" ], "offsets": [ [ 135, 139 ] ], "normalized": [] }, { "id": "PMID-17690039_T4", "type": "Protein", "text": [ "calmodulin" ], "offsets": [ [ 151, 161 ] ], "normalized": [] }, { "id": "PMID-17690039_T5", "type": "Protein", "text": [ "DAPK" ], "offsets": [ [ 409, 413 ] ], "normalized": [] }, { "id": "PMID-17690039_T6", "type": "Protein", "text": [ "DAPK" ], "offsets": [ [ 680, 684 ] ], "normalized": [] }, { "id": "PMID-17690039_T7", "type": "Protein", "text": [ "DAPK" ], "offsets": [ [ 751, 755 ] ], "normalized": [] }, { "id": "PMID-17690039_T8", "type": "Protein", "text": [ "DAPK" ], "offsets": [ [ 894, 898 ] ], "normalized": [] }, { "id": "PMID-17690039_T9", "type": "Protein", "text": [ "DAPK" ], "offsets": [ [ 981, 985 ] ], "normalized": [] }, { "id": "PMID-17690039_T10", "type": "Protein", "text": [ "DAPK" ], "offsets": [ [ 1201, 1205 ] ], "normalized": [] }, { "id": "PMID-17690039_T11", "type": "Protein", "text": [ "DAPK" ], "offsets": [ [ 1344, 1348 ] ], "normalized": [] }, { "id": "PMID-17690039_T12", "type": "Protein", "text": [ "DAPK" ], "offsets": [ [ 1472, 1476 ] ], "normalized": [] }, { "id": "PMID-17690039_T13", "type": "Entity", "text": [ "Promoter" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-17690039_T16", "type": "Entity", "text": [ "CpG islands" ], "offsets": [ [ 267, 278 ] ], "normalized": [] }, { "id": "PMID-17690039_T20", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 986, 994 ] ], "normalized": [] } ]

[ { "id": "PMID-17690039_E1", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 9, 25 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690039_T1" }, { "role": "Site", "ref_id": "PMID-17690039_T13" } ] }, { "id": "PMID-17690039_E2", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 232, 243 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690039_T2" }, { "role": "Site", "ref_id": "PMID-17690039_T16" } ] }, { "id": "PMID-17690039_E3", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 368, 379 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690039_T5" } ] }, { "id": "PMID-17690039_E4", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 732, 743 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690039_T7" } ] }, { "id": "PMID-17690039_E5", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 957, 973 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690039_T9" }, { "role": "Site", "ref_id": "PMID-17690039_T20" } ] }, { "id": "PMID-17690039_E6", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1211, 1222 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690039_T10" } ] }, { "id": "PMID-17690039_E7", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1380, 1391 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690039_T11" } ] }, { "id": "PMID-17690039_E8", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1509, 1520 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17690039_T12" } ] } ]

[ { "id": "PMID-17690039_1", "entity_ids": [ "PMID-17690039_T2", "PMID-17690039_T3" ] } ]

[]

[ { "id": "PMID-17694077__text", "type": "abstract", "text": [ "Distinct GCN5/PCAF-containing complexes function as co-activators and are involved in transcription factor and global histone acetylation. \nTranscription in eukaryotes is a tightly regulated, multistep process. Gene-specific transcriptional activators, several different co-activators and general transcription factors are necessary to access specific loci to allow precise initiation of RNA polymerase II transcription. As the dense chromatin folding of the genome does not allow the access of these sites by the huge multiprotein transcription machinery, remodelling is required to loosen up the chromatin structure for successful transcription initiation. In the present review, we summarize the recent evolution of our understanding of the function of two histone acetyl transferases (ATs) from metazoan organisms: GCN5 and PCAF. Their overall structure and the multiprotein complexes in which they are carrying out their activities are discussed. Metazoan GCN5 and PCAF are subunits of at least two types of multiprotein complexes, one having a molecular weight of 2 MDa (SPT3-TAF9-GCN5 acetyl transferase/TATA binding protein (TBP)-free-TAF complex/PCAF complexes) and a second type with about a size of 700 kDa (ATAC complex). These complexes possess global histone acetylation activity and locus-specific co-activator functions together with AT activity on non-histone substrates. Thus, their biological functions cover a wide range of tasks and render them indispensable for the normal function of cells. That deregulation of the global and/or specific AT activities of these complexes leads to the cancerous transformation of the cells highlights their importance in cellular processes. The possible effects of GCN5 and PCAF in tumorigenesis are also discussed.\n" ], "offsets": [ [ 0, 1772 ] ] } ]

[ { "id": "PMID-17694077_T1", "type": "Protein", "text": [ "GCN5" ], "offsets": [ [ 9, 13 ] ], "normalized": [] }, { "id": "PMID-17694077_T2", "type": "Protein", "text": [ "PCAF" ], "offsets": [ [ 14, 18 ] ], "normalized": [] }, { "id": "PMID-17694077_T3", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 118, 125 ] ], "normalized": [] }, { "id": "PMID-17694077_T4", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 760, 767 ] ], "normalized": [] }, { "id": "PMID-17694077_T5", "type": "Protein", "text": [ "GCN5" ], "offsets": [ [ 819, 823 ] ], "normalized": [] }, { "id": "PMID-17694077_T6", "type": "Protein", "text": [ "PCAF" ], "offsets": [ [ 828, 832 ] ], "normalized": [] }, { "id": "PMID-17694077_T7", "type": "Protein", "text": [ "GCN5" ], "offsets": [ [ 961, 965 ] ], "normalized": [] }, { "id": "PMID-17694077_T8", "type": "Protein", "text": [ "PCAF" ], "offsets": [ [ 970, 974 ] ], "normalized": [] }, { "id": "PMID-17694077_T9", "type": "Protein", "text": [ "SPT3" ], "offsets": [ [ 1077, 1081 ] ], "normalized": [] }, { "id": "PMID-17694077_T10", "type": "Protein", "text": [ "TAF9" ], "offsets": [ [ 1082, 1086 ] ], "normalized": [] }, { "id": "PMID-17694077_T11", "type": "Protein", "text": [ "GCN5" ], "offsets": [ [ 1087, 1091 ] ], "normalized": [] }, { "id": "PMID-17694077_T12", "type": "Protein", "text": [ "TATA binding protein" ], "offsets": [ [ 1111, 1131 ] ], "normalized": [] }, { "id": "PMID-17694077_T13", "type": "Protein", "text": [ "TBP" ], "offsets": [ [ 1133, 1136 ] ], "normalized": [] }, { "id": "PMID-17694077_T14", "type": "Protein", "text": [ "PCAF" ], "offsets": [ [ 1155, 1159 ] ], "normalized": [] }, { "id": "PMID-17694077_T15", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1265, 1272 ] ], "normalized": [] }, { "id": "PMID-17694077_T16", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1369, 1376 ] ], "normalized": [] }, { "id": "PMID-17694077_T17", "type": "Protein", "text": [ "GCN5" ], "offsets": [ [ 1721, 1725 ] ], "normalized": [] }, { "id": "PMID-17694077_T18", "type": "Protein", "text": [ "PCAF" ], "offsets": [ [ 1730, 1734 ] ], "normalized": [] } ]

[ { "id": "PMID-17694077_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 126, 137 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17694077_T3" } ] }, { "id": "PMID-17694077_E2", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1273, 1284 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17694077_T15" } ] } ]

[ { "id": "PMID-17694077_1", "entity_ids": [ "PMID-17694077_T12", "PMID-17694077_T13" ] } ]

[]

[ { "id": "PMID-17700531__text", "type": "abstract", "text": [ "Collagen matrix assembly is driven by the interaction of von Hippel-Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2. \nInactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes to vascular tumor formation in several organs. VHL regulates two evolutionary conserved pathways: the targeting of hydroxylated hypoxia-inducible factor-alpha (HIF-alpha) for proteasomal degradation and the remodeling of extracellular matrix (ECM). The biochemical mechanisms of the ECM assembly pathway remain poorly defined. Here, we provide evidence supporting a biochemical role for VHL in ECM assembly. We show that VHL directly binds to the collagen IV alpha 2 (COL4A2) chain and that this interaction is necessary for its assembly into the ECM. The VHL-COL4A2 interaction is dependent on endoplasmic reticulum (ER)-mediated COL4A2 hydroxylation and independent of cytosolic, hypoxia regulated HIF-alpha-modifying enzymes. We find that the N-terminal tail of COL4A2 protrudes from the ER lumen into the cytosol where it is bound by VHL. Failure of VHL to interact with COL4A2 correlates with loss of collagen IV network formation in vitro and collagen IV remodeling in vivo. Our data suggest a HIF-alpha-independent role for the VHL-COL4A2 interaction in suppression of angiogenic tumor formation through collagen IV network assembly.\n" ], "offsets": [ [ 0, 1359 ] ] } ]

[ { "id": "PMID-17700531_T1", "type": "Protein", "text": [ "von Hippel-Lindau tumor suppressor" ], "offsets": [ [ 57, 91 ] ], "normalized": [] }, { "id": "PMID-17700531_T2", "type": "Protein", "text": [ "collagen IV alpha 2" ], "offsets": [ [ 118, 137 ] ], "normalized": [] }, { "id": "PMID-17700531_T3", "type": "Protein", "text": [ "von Hippel-Lindau (VHL) tumor suppressor" ], "offsets": [ [ 160, 200 ] ], "normalized": [] }, { "id": "PMID-17700531_T4", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 265, 268 ] ], "normalized": [] }, { "id": "PMID-17700531_T5", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 605, 608 ] ], "normalized": [] }, { "id": "PMID-17700531_T6", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 639, 642 ] ], "normalized": [] }, { "id": "PMID-17700531_T7", "type": "Protein", "text": [ "collagen IV alpha 2" ], "offsets": [ [ 665, 684 ] ], "normalized": [] }, { "id": "PMID-17700531_T8", "type": "Protein", "text": [ "COL4A2" ], "offsets": [ [ 686, 692 ] ], "normalized": [] }, { "id": "PMID-17700531_T9", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 774, 777 ] ], "normalized": [] }, { "id": "PMID-17700531_T10", "type": "Protein", "text": [ "COL4A2" ], "offsets": [ [ 778, 784 ] ], "normalized": [] }, { "id": "PMID-17700531_T11", "type": "Protein", "text": [ "COL4A2" ], "offsets": [ [ 849, 855 ] ], "normalized": [] }, { "id": "PMID-17700531_T12", "type": "Protein", "text": [ "COL4A2" ], "offsets": [ [ 983, 989 ] ], "normalized": [] }, { "id": "PMID-17700531_T13", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 1056, 1059 ] ], "normalized": [] }, { "id": "PMID-17700531_T14", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 1072, 1075 ] ], "normalized": [] }, { "id": "PMID-17700531_T15", "type": "Protein", "text": [ "COL4A2" ], "offsets": [ [ 1093, 1099 ] ], "normalized": [] }, { "id": "PMID-17700531_T16", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 1253, 1256 ] ], "normalized": [] }, { "id": "PMID-17700531_T17", "type": "Protein", "text": [ "COL4A2" ], "offsets": [ [ 1257, 1263 ] ], "normalized": [] } ]

[ { "id": "PMID-17700531_E1", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylated" ], "offsets": [ [ 105, 117 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17700531_T2" } ] }, { "id": "PMID-17700531_E2", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 856, 869 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17700531_T11" } ] } ]

[ { "id": "PMID-17700531_1", "entity_ids": [ "PMID-17700531_T7", "PMID-17700531_T8" ] } ]

[]

[ { "id": "PMID-17709377__text", "type": "abstract", "text": [ "T-cell ubiquitin ligand affects cell death through a functional interaction with apoptosis-inducing factor, a key factor of caspase-independent apoptosis. \nThe lymphoid protein T-cell ubiquitin ligand (TULA)/suppressor of T-cell receptor signaling (Sts)-2 is associated with c-Cbl and ubiquitylated proteins and has been implicated in the regulation of signaling mediated by protein-tyrosine kinases. The results presented in this report indicate that TULA facilitates T-cell apoptosis independent of either T-cell receptor/CD3-mediated signaling or caspase activity. Mass spectrometry-based analysis of protein-protein interactions of TULA demonstrates that TULA binds to the apoptosis-inducing protein AIF, which has previously been shown to function as a key factor of caspase-independent apoptosis. Using RNA interference, we demonstrate that AIF is essential for the apoptotic effect of TULA. Analysis of the subcellular localization of TULA and AIF together with the functional analysis of TULA mutants is consistent with the idea that TULA enhances the apoptotic effect of AIF by facilitating the interactions of AIF with its apoptotic co-factors, which remain to be identified. Overall, our results shed new light on the biological functions of TULA, a recently discovered protein, describing its role as one of very few known functional interactors of AIF.\n" ], "offsets": [ [ 0, 1366 ] ] } ]

[ { "id": "PMID-17709377_T1", "type": "Protein", "text": [ "T-cell ubiquitin ligand" ], "offsets": [ [ 0, 23 ] ], "normalized": [] }, { "id": "PMID-17709377_T2", "type": "Protein", "text": [ "T-cell ubiquitin ligand" ], "offsets": [ [ 177, 200 ] ], "normalized": [] }, { "id": "PMID-17709377_T3", "type": "Protein", "text": [ "TULA" ], "offsets": [ [ 202, 206 ] ], "normalized": [] }, { "id": "PMID-17709377_T4", "type": "Protein", "text": [ "suppressor of T-cell receptor signaling (Sts)-2" ], "offsets": [ [ 208, 255 ] ], "normalized": [] }, { "id": "PMID-17709377_T5", "type": "Protein", "text": [ "c-Cbl" ], "offsets": [ [ 275, 280 ] ], "normalized": [] }, { "id": "PMID-17709377_T6", "type": "Protein", "text": [ "TULA" ], "offsets": [ [ 452, 456 ] ], "normalized": [] }, { "id": "PMID-17709377_T7", "type": "Protein", "text": [ "TULA" ], "offsets": [ [ 636, 640 ] ], "normalized": [] }, { "id": "PMID-17709377_T8", "type": "Protein", "text": [ "TULA" ], "offsets": [ [ 659, 663 ] ], "normalized": [] }, { "id": "PMID-17709377_T9", "type": "Protein", "text": [ "AIF" ], "offsets": [ [ 704, 707 ] ], "normalized": [] }, { "id": "PMID-17709377_T10", "type": "Protein", "text": [ "AIF" ], "offsets": [ [ 847, 850 ] ], "normalized": [] }, { "id": "PMID-17709377_T11", "type": "Protein", "text": [ "TULA" ], "offsets": [ [ 892, 896 ] ], "normalized": [] }, { "id": "PMID-17709377_T12", "type": "Protein", "text": [ "TULA" ], "offsets": [ [ 942, 946 ] ], "normalized": [] }, { "id": "PMID-17709377_T13", "type": "Protein", "text": [ "AIF" ], "offsets": [ [ 951, 954 ] ], "normalized": [] }, { "id": "PMID-17709377_T14", "type": "Protein", "text": [ "TULA" ], "offsets": [ [ 996, 1000 ] ], "normalized": [] }, { "id": "PMID-17709377_T15", "type": "Protein", "text": [ "TULA" ], "offsets": [ [ 1042, 1046 ] ], "normalized": [] }, { "id": "PMID-17709377_T16", "type": "Protein", "text": [ "AIF" ], "offsets": [ [ 1080, 1083 ] ], "normalized": [] }, { "id": "PMID-17709377_T17", "type": "Protein", "text": [ "AIF" ], "offsets": [ [ 1120, 1123 ] ], "normalized": [] }, { "id": "PMID-17709377_T18", "type": "Protein", "text": [ "TULA" ], "offsets": [ [ 1253, 1257 ] ], "normalized": [] }, { "id": "PMID-17709377_T19", "type": "Protein", "text": [ "AIF" ], "offsets": [ [ 1361, 1364 ] ], "normalized": [] } ]

[ { "id": "PMID-17709377_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylated" ], "offsets": [ [ 285, 298 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17709377_T2" } ] } ]

[ { "id": "PMID-17709377_1", "entity_ids": [ "PMID-17709377_T2", "PMID-17709377_T3", "PMID-17709377_T4" ] } ]

[]

[ { "id": "PMID-17726030__text", "type": "abstract", "text": [ "Ubiquitination of mammalian Pex5p, the peroxisomal import receptor. \nProtein translocation across the peroxisomal membrane requires the concerted action of numerous peroxins. One central component of this machinery is Pex5p, the cycling receptor for matrix proteins. Pex5p recognizes newly synthesized proteins in the cytosol and promotes their translocation across the peroxisomal membrane. After this translocation step, Pex5p is recycled back into the cytosol to start a new protein transport cycle. Here, we show that mammalian Pex5p is ubiquitinated at the peroxisomal membrane. Two different types of ubiquitination were detected, one of which is thiol-sensitive, involves Cys(11) of Pex5p, and is necessary for the export of the receptor back into the cytosol. Together with mechanistic data recently described for yeast Pex5p, these findings provide strong evidence for the existence of Pex4p- and Pex22p-like proteins in mammals.\n" ], "offsets": [ [ 0, 939 ] ] } ]

[ { "id": "PMID-17726030_T1", "type": "Protein", "text": [ "Pex5p" ], "offsets": [ [ 28, 33 ] ], "normalized": [] }, { "id": "PMID-17726030_T2", "type": "Protein", "text": [ "Pex5p" ], "offsets": [ [ 218, 223 ] ], "normalized": [] }, { "id": "PMID-17726030_T3", "type": "Protein", "text": [ "Pex5p" ], "offsets": [ [ 267, 272 ] ], "normalized": [] }, { "id": "PMID-17726030_T4", "type": "Protein", "text": [ "Pex5p" ], "offsets": [ [ 423, 428 ] ], "normalized": [] }, { "id": "PMID-17726030_T5", "type": "Protein", "text": [ "Pex5p" ], "offsets": [ [ 532, 537 ] ], "normalized": [] }, { "id": "PMID-17726030_T6", "type": "Protein", "text": [ "Pex5p" ], "offsets": [ [ 690, 695 ] ], "normalized": [] }, { "id": "PMID-17726030_T7", "type": "Protein", "text": [ "Pex5p" ], "offsets": [ [ 828, 833 ] ], "normalized": [] }, { "id": "PMID-17726030_T8", "type": "Protein", "text": [ "Pex4p" ], "offsets": [ [ 895, 900 ] ], "normalized": [] }, { "id": "PMID-17726030_T9", "type": "Protein", "text": [ "Pex22p" ], "offsets": [ [ 906, 912 ] ], "normalized": [] }, { "id": "PMID-17726030_T13", "type": "Entity", "text": [ "Cys(11)" ], "offsets": [ [ 679, 686 ] ], "normalized": [] } ]

[ { "id": "PMID-17726030_E1", "type": "Ubiquitination", "trigger": { "text": [ "Ubiquitination" ], "offsets": [ [ 0, 14 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17726030_T1" } ] }, { "id": "PMID-17726030_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 541, 554 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17726030_T5" } ] }, { "id": "PMID-17726030_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 607, 621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17726030_T6" }, { "role": "Site", "ref_id": "PMID-17726030_T13" } ] } ]

[]

[]

[ { "id": "PMID-17728323__text", "type": "abstract", "text": [ "Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmenti. \nThe regulatory subunit NEMO is involved in the mechanism of activation of IkappaB kinase (IKK), the kinase complex that controls the NF-kappaB signaling pathway. During this process, NEMO is modified post-translationally through K63-linked polyubiquitination. We report the molecular characterization of a new missense mutation of NEMO (A323P) which causes a severe form of incontinentia pigmenti (OMIM#308300), an inherited disease characterized predominantly by skin inflammation. The A323P mutation was found to impair TNF-, IL-1-, LPS- and PMA/ionomycin-induced NF-kappaB activation, as well as to disrupt TRAF6-dependent NEMO polyubiquitination, due to a defective NEMO/TRAF6 interaction. Mutagenesis identified the affected ubiquitination sites as three lysine residues located in the vicinity of A323. Unexpectedly, these lysines were ubiquitinated together with two previously identified lysines not connected to TRAF6. Mutation of all these ubiquitination sites severely impaired NF-kappaB activation induced by stimulation with IL-1, LPS, Nod2/RICK or serum/LPA. In contrast, mutation at all of these sites had only a limited effect on stimulation by TNF. These findings indicate that post-translational modification of NEMO through K63-linked polyubiquitination is a key event in IKK activation and that perturbation of this step may cause human pathophysiology.\n" ], "offsets": [ [ 0, 1511 ] ] } ]

[ { "id": "PMID-17728323_T1", "type": "Protein", "text": [ "TRAF6" ], "offsets": [ [ 18, 23 ] ], "normalized": [] }, { "id": "PMID-17728323_T2", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 34, 38 ] ], "normalized": [] }, { "id": "PMID-17728323_T3", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 90, 94 ] ], "normalized": [] }, { "id": "PMID-17728323_T4", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 160, 164 ] ], "normalized": [] }, { "id": "PMID-17728323_T5", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 320, 324 ] ], "normalized": [] }, { "id": "PMID-17728323_T6", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 468, 472 ] ], "normalized": [] }, { "id": "PMID-17728323_T7", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 659, 662 ] ], "normalized": [] }, { "id": "PMID-17728323_T8", "type": "Protein", "text": [ "TRAF6" ], "offsets": [ [ 747, 752 ] ], "normalized": [] }, { "id": "PMID-17728323_T9", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 763, 767 ] ], "normalized": [] }, { "id": "PMID-17728323_T10", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 807, 811 ] ], "normalized": [] }, { "id": "PMID-17728323_T11", "type": "Protein", "text": [ "TRAF6" ], "offsets": [ [ 812, 817 ] ], "normalized": [] }, { "id": "PMID-17728323_T12", "type": "Protein", "text": [ "TRAF6" ], "offsets": [ [ 1058, 1063 ] ], "normalized": [] }, { "id": "PMID-17728323_T13", "type": "Protein", "text": [ "Nod2" ], "offsets": [ [ 1186, 1190 ] ], "normalized": [] }, { "id": "PMID-17728323_T14", "type": "Protein", "text": [ "RICK" ], "offsets": [ [ 1191, 1195 ] ], "normalized": [] }, { "id": "PMID-17728323_T15", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 1298, 1301 ] ], "normalized": [] }, { "id": "PMID-17728323_T16", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 1367, 1371 ] ], "normalized": [] }, { "id": "PMID-17728323_T23", "type": "Entity", "text": [ "lysine residues" ], "offsets": [ [ 897, 912 ] ], "normalized": [] }, { "id": "PMID-17728323_T24", "type": "Entity", "text": [ "lysines" ], "offsets": [ [ 966, 973 ] ], "normalized": [] }, { "id": "PMID-17728323_T26", "type": "Entity", "text": [ "lysines" ], "offsets": [ [ 1033, 1040 ] ], "normalized": [] } ]

[ { "id": "PMID-17728323_E1", "type": "Catalysis", "trigger": { "text": [ "dependent" ], "offsets": [ [ 24, 33 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17728323_E2" }, { "role": "Cause", "ref_id": "PMID-17728323_T1" } ] }, { "id": "PMID-17728323_E2", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 39, 57 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17728323_T2" } ] }, { "id": "PMID-17728323_E3", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 377, 395 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17728323_T5" } ] }, { "id": "PMID-17728323_E4", "type": "Catalysis", "trigger": { "text": [ "dependent" ], "offsets": [ [ 753, 762 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17728323_E5" }, { "role": "Cause", "ref_id": "PMID-17728323_T8" } ] }, { "id": "PMID-17728323_E5", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 768, 786 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17728323_T9" } ] }, { "id": "PMID-17728323_E6", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 867, 881 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17728323_T9" }, { "role": "Site", "ref_id": "PMID-17728323_T23" } ] }, { "id": "PMID-17728323_E7", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 979, 992 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17728323_T9" }, { "role": "Site", "ref_id": "PMID-17728323_T24" } ] }, { "id": "PMID-17728323_E8", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 979, 992 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17728323_T9" }, { "role": "Site", "ref_id": "PMID-17728323_T26" } ] }, { "id": "PMID-17728323_E9", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1087, 1101 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17728323_T9" } ] }, { "id": "PMID-17728323_E10", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 1391, 1409 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17728323_T16" } ] } ]

[]

[]

[ { "id": "PMID-1777991__text", "type": "abstract", "text": [ "Glycosylation of alpha 1-acid glycoprotein in relation to duration of disease in acute and chronic infection and inflammation. \nMicroheterogeneity of acute phase proteins frequently differs in acute and chronic types of inflammation. However, it is unknown whether these changes depend on the duration of the inflammation in a given disease. We therefore investigated the microheterogeneity of alpha 1-acid glycoprotein (AGP) in sera from patients with acute and chronic bacterial infection in comparison to rheumatoid arthritis and ankylosing spondylitis. In acute bacterial infection Con A-reactivity of AGP was significantly elevated. By contrast, AGP in chronic bacterial infection showed the same glycosylation pattern as rheumatoid arthritis and ankylosing spondylitis being characterized by a decreased reactivity to Con A. Serial measurements in individual patients with bacterial infections showed a transition from the initially elevated to decreased reactivity to Con A as the disease became chronic.\n" ], "offsets": [ [ 0, 1012 ] ] } ]

[ { "id": "PMID-1777991_T1", "type": "Protein", "text": [ "Con A" ], "offsets": [ [ 586, 591 ] ], "normalized": [] }, { "id": "PMID-1777991_T2", "type": "Protein", "text": [ "Con A" ], "offsets": [ [ 824, 829 ] ], "normalized": [] }, { "id": "PMID-1777991_T3", "type": "Protein", "text": [ "Con A" ], "offsets": [ [ 975, 980 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-17823124__text", "type": "abstract", "text": [ "Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF. \nType I interferon gene induction relies on IKK-related kinase TBK1 and IKKepsilon-mediated phosphorylations of IRF3/7 through the Toll-like receptor-dependent signaling pathways. The scaffold proteins that assemble these kinase complexes are poorly characterized. We show here that TANK/ITRAF is required for the TBK1- and IKKepsilon-mediated IRF3/7 phosphorylations through some Toll-like receptor-dependent pathways and is part of a TRAF3-containing complex. Moreover, TANK is dispensable for the early phase of double-stranded RNA-mediated IRF3 phosphorylation. Interestingly, TANK is heavily phosphorylated by TBK1-IKKepsilon upon lipopolysaccharide stimulation and is also subject to lipopolysaccharide- and TBK1-IKKepsilon-mediated Lys(63)-linked polyubiquitination, a mechanism that does not require TBK1-IKKepsilon kinase activity. Thus, we have identified TANK as a scaffold protein that assembles some but not all IRF3/7-phosphorylating TBK1-IKKepsilon complexes and demonstrated that these kinases possess two functions, namely the phosphorylation of both IRF3/7 and TANK as well as the recruitment of an E3 ligase for Lys(63)-linked polyubiquitination of their scaffold protein, TANK.\n" ], "offsets": [ [ 0, 1371 ] ] } ]

[ { "id": "PMID-17823124_T1", "type": "Protein", "text": [ "TBK1" ], "offsets": [ [ 77, 81 ] ], "normalized": [] }, { "id": "PMID-17823124_T2", "type": "Protein", "text": [ "IKKepsilon" ], "offsets": [ [ 82, 92 ] ], "normalized": [] }, { "id": "PMID-17823124_T3", "type": "Protein", "text": [ "TANK" ], "offsets": [ [ 160, 164 ] ], "normalized": [] }, { "id": "PMID-17823124_T4", "type": "Protein", "text": [ "I-TRAF" ], "offsets": [ [ 165, 171 ] ], "normalized": [] }, { "id": "PMID-17823124_T5", "type": "Protein", "text": [ "TBK1" ], "offsets": [ [ 236, 240 ] ], "normalized": [] }, { "id": "PMID-17823124_T6", "type": "Protein", "text": [ "IKKepsilon" ], "offsets": [ [ 245, 255 ] ], "normalized": [] }, { "id": "PMID-17823124_T7", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 285, 289 ] ], "normalized": [] }, { "id": "PMID-17823124_T8", "type": "Protein", "text": [ "7" ], "offsets": [ [ 290, 291 ] ], "normalized": [] }, { "id": "PMID-17823124_T9", "type": "Protein", "text": [ "TANK" ], "offsets": [ [ 456, 460 ] ], "normalized": [] }, { "id": "PMID-17823124_T10", "type": "Protein", "text": [ "ITRAF" ], "offsets": [ [ 461, 466 ] ], "normalized": [] }, { "id": "PMID-17823124_T11", "type": "Protein", "text": [ "TBK1" ], "offsets": [ [ 487, 491 ] ], "normalized": [] }, { "id": "PMID-17823124_T12", "type": "Protein", "text": [ "IKKepsilon" ], "offsets": [ [ 497, 507 ] ], "normalized": [] }, { "id": "PMID-17823124_T13", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 517, 521 ] ], "normalized": [] }, { "id": "PMID-17823124_T14", "type": "Protein", "text": [ "7" ], "offsets": [ [ 522, 523 ] ], "normalized": [] }, { "id": "PMID-17823124_T15", "type": "Protein", "text": [ "TRAF3" ], "offsets": [ [ 609, 614 ] ], "normalized": [] }, { "id": "PMID-17823124_T16", "type": "Protein", "text": [ "TANK" ], "offsets": [ [ 645, 649 ] ], "normalized": [] }, { "id": "PMID-17823124_T17", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 717, 721 ] ], "normalized": [] }, { "id": "PMID-17823124_T18", "type": "Protein", "text": [ "TANK" ], "offsets": [ [ 754, 758 ] ], "normalized": [] }, { "id": "PMID-17823124_T19", "type": "Protein", "text": [ "TBK1" ], "offsets": [ [ 788, 792 ] ], "normalized": [] }, { "id": "PMID-17823124_T20", "type": "Protein", "text": [ "IKKepsilon" ], "offsets": [ [ 793, 803 ] ], "normalized": [] }, { "id": "PMID-17823124_T21", "type": "Protein", "text": [ "TBK1" ], "offsets": [ [ 887, 891 ] ], "normalized": [] }, { "id": "PMID-17823124_T22", "type": "Protein", "text": [ "IKKepsilon" ], "offsets": [ [ 892, 902 ] ], "normalized": [] }, { "id": "PMID-17823124_T23", "type": "Protein", "text": [ "TBK1" ], "offsets": [ [ 981, 985 ] ], "normalized": [] }, { "id": "PMID-17823124_T24", "type": "Protein", "text": [ "IKKepsilon" ], "offsets": [ [ 986, 996 ] ], "normalized": [] }, { "id": "PMID-17823124_T25", "type": "Protein", "text": [ "TANK" ], "offsets": [ [ 1039, 1043 ] ], "normalized": [] }, { "id": "PMID-17823124_T26", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 1098, 1102 ] ], "normalized": [] }, { "id": "PMID-17823124_T27", "type": "Protein", "text": [ "7" ], "offsets": [ [ 1103, 1104 ] ], "normalized": [] }, { "id": "PMID-17823124_T28", "type": "Protein", "text": [ "TBK1" ], "offsets": [ [ 1121, 1125 ] ], "normalized": [] }, { "id": "PMID-17823124_T29", "type": "Protein", "text": [ "IKKepsilon" ], "offsets": [ [ 1126, 1136 ] ], "normalized": [] }, { "id": "PMID-17823124_T30", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 1241, 1245 ] ], "normalized": [] }, { "id": "PMID-17823124_T31", "type": "Protein", "text": [ "7" ], "offsets": [ [ 1246, 1247 ] ], "normalized": [] }, { "id": "PMID-17823124_T32", "type": "Protein", "text": [ "TANK" ], "offsets": [ [ 1252, 1256 ] ], "normalized": [] }, { "id": "PMID-17823124_T33", "type": "Protein", "text": [ "TANK" ], "offsets": [ [ 1365, 1369 ] ], "normalized": [] } ]

[ { "id": "PMID-17823124_E1", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 118, 136 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T3" } ] }, { "id": "PMID-17823124_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 141, 156 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T3" } ] }, { "id": "PMID-17823124_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylations" ], "offsets": [ [ 265, 281 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T7" } ] }, { "id": "PMID-17823124_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylations" ], "offsets": [ [ 265, 281 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T8" } ] }, { "id": "PMID-17823124_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylations" ], "offsets": [ [ 524, 540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T13" } ] }, { "id": "PMID-17823124_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylations" ], "offsets": [ [ 524, 540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T14" } ] }, { "id": "PMID-17823124_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 722, 737 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T17" } ] }, { "id": "PMID-17823124_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 770, 784 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T18" } ] }, { "id": "PMID-17823124_E9", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 927, 945 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T18" } ] }, { "id": "PMID-17823124_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylating" ], "offsets": [ [ 1105, 1120 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T26" } ] }, { "id": "PMID-17823124_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylating" ], "offsets": [ [ 1105, 1120 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T27" } ] }, { "id": "PMID-17823124_E12", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1217, 1232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T30" } ] }, { "id": "PMID-17823124_E13", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1217, 1232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T31" } ] }, { "id": "PMID-17823124_E14", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1217, 1232 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T32" } ] }, { "id": "PMID-17823124_E15", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 1319, 1337 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17823124_T33" } ] } ]

[ { "id": "PMID-17823124_1", "entity_ids": [ "PMID-17823124_T3", "PMID-17823124_T4" ] }, { "id": "PMID-17823124_2", "entity_ids": [ "PMID-17823124_T9", "PMID-17823124_T10" ] } ]

[]

[ { "id": "PMID-17823202__text", "type": "abstract", "text": [ "Paraquat induces dopaminergic dysfunction and proteasome impairment in DJ-1-deficient mice. \nParkinson's disease (PD) may be caused by a complex interaction of environmental insults and genetic susceptibilities. Previous studies of DJ-1-deficient mice have noted dopaminergic dysfunction mainly in older mice. To simulate the interaction of genetic factors and environmental factors, we treated DJ-1-deficient mice with paraquat. Even in relatively young mice, this combination produced dopamine loss and motor dysfunction. To determine the potential mechanism for the dopaminergic dysfunction, we investigated the proteasome function and ubiquitinated protein levels. DJ-1-deficient mice treated with paraquat showed decreased proteasome activities and increased ubiquitinated protein levels. To further investigate the mechanism of proteasome dysfunction, ATP levels and subunit protein levels of 19S ATPase Rpt6 and 20S beta5 were measured and noted to be decreased in the ventral midbrain, but not in the striatum. Finally, a transcription factor, Nrf2 that has been previously shown to be regulated by DJ-1 and to regulate 20S beta5 levels was decreased. These pathologies were not observed in brain regions of normal mice treated with paraquat. In conclusion, this study raises the possibility that environmental and genetic factors might cooperatively involve the mechanisms underlying proteasome impairment in PD brains.\n" ], "offsets": [ [ 0, 1429 ] ] } ]

[ { "id": "PMID-17823202_T1", "type": "Protein", "text": [ "DJ-1" ], "offsets": [ [ 71, 75 ] ], "normalized": [] }, { "id": "PMID-17823202_T2", "type": "Protein", "text": [ "DJ-1" ], "offsets": [ [ 232, 236 ] ], "normalized": [] }, { "id": "PMID-17823202_T3", "type": "Protein", "text": [ "DJ-1" ], "offsets": [ [ 395, 399 ] ], "normalized": [] }, { "id": "PMID-17823202_T4", "type": "Protein", "text": [ "DJ-1" ], "offsets": [ [ 669, 673 ] ], "normalized": [] }, { "id": "PMID-17823202_T5", "type": "Protein", "text": [ "Rpt6" ], "offsets": [ [ 910, 914 ] ], "normalized": [] }, { "id": "PMID-17823202_T6", "type": "Protein", "text": [ "20S beta5" ], "offsets": [ [ 919, 928 ] ], "normalized": [] }, { "id": "PMID-17823202_T7", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 1052, 1056 ] ], "normalized": [] }, { "id": "PMID-17823202_T8", "type": "Protein", "text": [ "DJ-1" ], "offsets": [ [ 1107, 1111 ] ], "normalized": [] }, { "id": "PMID-17823202_T9", "type": "Protein", "text": [ "20S beta5" ], "offsets": [ [ 1128, 1137 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-17848550__text", "type": "abstract", "text": [ "The yeast Hex3.Slx8 heterodimer is a ubiquitin ligase stimulated by substrate sumoylation. \nHex3 and Slx8 are Saccharomyces cerevisiae proteins with important functions in DNA damage control and maintenance of genomic stability. Both proteins have RING domains at their C termini. Such domains are common in ubiquitin and ubiquitin-like protein ligases (E3s), but little was known about the molecular functions of either protein. In this study we identified HEX3 as a high-copy suppressor of a temperature-sensitive small ubiquitin-related modifier (SUMO) protease mutant, ulp1ts, suggesting that it may affect cellular SUMO dynamics. Remarkably, even a complete deletion of ULP1 is strongly suppressed. Hex3 forms a heterodimer with Slx8. We found that the Hex3.Slx8 complex has a robust substrate-specific E3 ubiquitin ligase activity. In this E3 complex, Slx8 appears to bear the core ligase function, with Hex3 strongly enhancing its activity. Notably, SUMO attachment to a substrate stimulates its Hex3.Slx8-dependent ubiquitination, primarily through direct noncovalent interactions between SUMO and Hex3. Our data reveal a novel mechanism of substrate targeting in which sumoylation of a protein can help trigger its subsequent ubiquitination by recruiting a SUMO-binding ubiquitin ligase.\n" ], "offsets": [ [ 0, 1297 ] ] } ]

[ { "id": "PMID-17848550_T1", "type": "Protein", "text": [ "Hex3" ], "offsets": [ [ 10, 14 ] ], "normalized": [] }, { "id": "PMID-17848550_T2", "type": "Protein", "text": [ "Slx8" ], "offsets": [ [ 15, 19 ] ], "normalized": [] }, { "id": "PMID-17848550_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 37, 46 ] ], "normalized": [] }, { "id": "PMID-17848550_T4", "type": "Protein", "text": [ "Hex3" ], "offsets": [ [ 92, 96 ] ], "normalized": [] }, { "id": "PMID-17848550_T5", "type": "Protein", "text": [ "Slx8" ], "offsets": [ [ 101, 105 ] ], "normalized": [] }, { "id": "PMID-17848550_T6", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 308, 317 ] ], "normalized": [] }, { "id": "PMID-17848550_T7", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 322, 331 ] ], "normalized": [] }, { "id": "PMID-17848550_T8", "type": "Protein", "text": [ "HEX3" ], "offsets": [ [ 458, 462 ] ], "normalized": [] }, { "id": "PMID-17848550_T9", "type": "Protein", "text": [ "small ubiquitin-related modifier" ], "offsets": [ [ 516, 548 ] ], "normalized": [] }, { "id": "PMID-17848550_T10", "type": "Protein", "text": [ "SUMO" ], "offsets": [ [ 550, 554 ] ], "normalized": [] }, { "id": "PMID-17848550_T11", "type": "Protein", "text": [ "ulp1" ], "offsets": [ [ 573, 577 ] ], "normalized": [] }, { "id": "PMID-17848550_T12", "type": "Protein", "text": [ "SUMO" ], "offsets": [ [ 620, 624 ] ], "normalized": [] }, { "id": "PMID-17848550_T13", "type": "Protein", "text": [ "ULP1" ], "offsets": [ [ 675, 679 ] ], "normalized": [] }, { "id": "PMID-17848550_T14", "type": "Protein", "text": [ "Hex3" ], "offsets": [ [ 704, 708 ] ], "normalized": [] }, { "id": "PMID-17848550_T15", "type": "Protein", "text": [ "Slx8" ], "offsets": [ [ 734, 738 ] ], "normalized": [] }, { "id": "PMID-17848550_T16", "type": "Protein", "text": [ "Hex3" ], "offsets": [ [ 758, 762 ] ], "normalized": [] }, { "id": "PMID-17848550_T17", "type": "Protein", "text": [ "Slx8" ], "offsets": [ [ 763, 767 ] ], "normalized": [] }, { "id": "PMID-17848550_T18", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 811, 820 ] ], "normalized": [] }, { "id": "PMID-17848550_T19", "type": "Protein", "text": [ "Slx8" ], "offsets": [ [ 858, 862 ] ], "normalized": [] }, { "id": "PMID-17848550_T20", "type": "Protein", "text": [ "Hex3" ], "offsets": [ [ 910, 914 ] ], "normalized": [] }, { "id": "PMID-17848550_T21", "type": "Protein", "text": [ "SUMO" ], "offsets": [ [ 957, 961 ] ], "normalized": [] }, { "id": "PMID-17848550_T22", "type": "Protein", "text": [ "Hex3" ], "offsets": [ [ 1003, 1007 ] ], "normalized": [] }, { "id": "PMID-17848550_T23", "type": "Protein", "text": [ "Slx8" ], "offsets": [ [ 1008, 1012 ] ], "normalized": [] }, { "id": "PMID-17848550_T24", "type": "Protein", "text": [ "SUMO" ], "offsets": [ [ 1097, 1101 ] ], "normalized": [] }, { "id": "PMID-17848550_T25", "type": "Protein", "text": [ "Hex3" ], "offsets": [ [ 1106, 1110 ] ], "normalized": [] }, { "id": "PMID-17848550_T26", "type": "Protein", "text": [ "SUMO" ], "offsets": [ [ 1266, 1270 ] ], "normalized": [] }, { "id": "PMID-17848550_T27", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1279, 1288 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-17848550_1", "entity_ids": [ "PMID-17848550_T9", "PMID-17848550_T10" ] } ]

[]

[ { "id": "PMID-17875808__text", "type": "abstract", "text": [ "A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin. \nThe oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and up-regulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.\n" ], "offsets": [ [ 0, 1323 ] ] } ]

[ { "id": "PMID-17875808_T1", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 67, 72 ] ], "normalized": [] }, { "id": "PMID-17875808_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 151, 160 ] ], "normalized": [] }, { "id": "PMID-17875808_T3", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 176, 181 ] ], "normalized": [] }, { "id": "PMID-17875808_T4", "type": "Protein", "text": [ "cyclin D2" ], "offsets": [ [ 333, 342 ] ], "normalized": [] }, { "id": "PMID-17875808_T5", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 381, 386 ] ], "normalized": [] }, { "id": "PMID-17875808_T6", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 457, 462 ] ], "normalized": [] }, { "id": "PMID-17875808_T7", "type": "Protein", "text": [ "cyclin D2" ], "offsets": [ [ 471, 480 ] ], "normalized": [] }, { "id": "PMID-17875808_T8", "type": "Protein", "text": [ "luciferase" ], "offsets": [ [ 498, 508 ] ], "normalized": [] }, { "id": "PMID-17875808_T9", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 597, 602 ] ], "normalized": [] }, { "id": "PMID-17875808_T10", "type": "Protein", "text": [ "cyclin D2" ], "offsets": [ [ 627, 636 ] ], "normalized": [] }, { "id": "PMID-17875808_T11", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 720, 725 ] ], "normalized": [] }, { "id": "PMID-17875808_T12", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 884, 889 ] ], "normalized": [] }, { "id": "PMID-17875808_T13", "type": "Protein", "text": [ "ubiquitin C" ], "offsets": [ [ 907, 918 ] ], "normalized": [] }, { "id": "PMID-17875808_T14", "type": "Protein", "text": [ "ubiquitin C" ], "offsets": [ [ 957, 968 ] ], "normalized": [] }, { "id": "PMID-17875808_T15", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 1043, 1048 ] ], "normalized": [] }, { "id": "PMID-17875808_T16", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1086, 1095 ] ], "normalized": [] }, { "id": "PMID-17875808_T17", "type": "Protein", "text": [ "c-maf" ], "offsets": [ [ 1250, 1255 ] ], "normalized": [] }, { "id": "PMID-17875808_T18", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1302, 1311 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-17884155__text", "type": "abstract", "text": [ "Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. \nTrimethylation of histone H3 at lysine 4 (H3K4me3) is regarded as a hallmark of active human promoters, but it remains unclear how this posttranslational modification links to transcriptional activation. Using a stable isotope labeling by amino acids in cell culture (SILAC)-based proteomic screening we show that the basal transcription factor TFIID directly binds to the H3K4me3 mark via the plant homeodomain (PHD) finger of TAF3. Selective loss of H3K4me3 reduces transcription from and TFIID binding to a subset of promoters in vivo. Equilibrium binding assays and competition experiments show that the TAF3 PHD finger is highly selective for H3K4me3. In transient assays, TAF3 can act as a transcriptional coactivator in a PHD finger-dependent manner. Interestingly, asymmetric dimethylation of H3R2 selectively inhibits TFIID binding to H3K4me3, whereas acetylation of H3K9 and H3K14 potentiates TFIID interaction. Our experiments reveal crosstalk between histone modifications and the transcription factor TFIID. This has important implications for regulation of RNA polymerase II-mediated transcription in higher eukaryotes.\n" ], "offsets": [ [ 0, 1221 ] ] } ]

[ { "id": "PMID-17884155_T1", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 65, 75 ] ], "normalized": [] }, { "id": "PMID-17884155_T2", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 105, 115 ] ], "normalized": [] }, { "id": "PMID-17884155_T3", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 129, 131 ] ], "normalized": [] }, { "id": "PMID-17884155_T4", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 460, 462 ] ], "normalized": [] }, { "id": "PMID-17884155_T5", "type": "Protein", "text": [ "TAF3" ], "offsets": [ [ 515, 519 ] ], "normalized": [] }, { "id": "PMID-17884155_T6", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 539, 541 ] ], "normalized": [] }, { "id": "PMID-17884155_T7", "type": "Protein", "text": [ "TAF3" ], "offsets": [ [ 695, 699 ] ], "normalized": [] }, { "id": "PMID-17884155_T8", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 735, 737 ] ], "normalized": [] }, { "id": "PMID-17884155_T9", "type": "Protein", "text": [ "TAF3" ], "offsets": [ [ 765, 769 ] ], "normalized": [] }, { "id": "PMID-17884155_T10", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 888, 890 ] ], "normalized": [] }, { "id": "PMID-17884155_T11", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 931, 933 ] ], "normalized": [] }, { "id": "PMID-17884155_T12", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 963, 965 ] ], "normalized": [] }, { "id": "PMID-17884155_T13", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 972, 974 ] ], "normalized": [] }, { "id": "PMID-17884155_T14", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1050, 1057 ] ], "normalized": [] }, { "id": "PMID-17884155_T16", "type": "Entity", "text": [ "lysine 4" ], "offsets": [ [ 76, 84 ] ], "normalized": [] }, { "id": "PMID-17884155_T18", "type": "Entity", "text": [ "lysine 4" ], "offsets": [ [ 119, 127 ] ], "normalized": [] }, { "id": "PMID-17884155_T19", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 131, 133 ] ], "normalized": [] }, { "id": "PMID-17884155_T21", "type": "Entity", "text": [ "R2" ], "offsets": [ [ 890, 892 ] ], "normalized": [] }, { "id": "PMID-17884155_T23", "type": "Entity", "text": [ "K9" ], "offsets": [ [ 965, 967 ] ], "normalized": [] }, { "id": "PMID-17884155_T24", "type": "Entity", "text": [ "K14" ], "offsets": [ [ 974, 977 ] ], "normalized": [] } ]

[ { "id": "PMID-17884155_E1", "type": "Methylation", "trigger": { "text": [ "trimethylation" ], "offsets": [ [ 47, 61 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17884155_T1" }, { "role": "Site", "ref_id": "PMID-17884155_T16" } ] }, { "id": "PMID-17884155_E2", "type": "Methylation", "trigger": { "text": [ "Trimethylation" ], "offsets": [ [ 87, 101 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17884155_T2" }, { "role": "Site", "ref_id": "PMID-17884155_T18" } ] }, { "id": "PMID-17884155_E3", "type": "Methylation", "trigger": { "text": [ "dimethylation" ], "offsets": [ [ 871, 884 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17884155_T10" }, { "role": "Site", "ref_id": "PMID-17884155_T21" } ] }, { "id": "PMID-17884155_E4", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 948, 959 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17884155_T12" }, { "role": "Site", "ref_id": "PMID-17884155_T23" } ] }, { "id": "PMID-17884155_E5", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 948, 959 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17884155_T13" }, { "role": "Site", "ref_id": "PMID-17884155_T24" } ] } ]

[ { "id": "PMID-17884155_1", "entity_ids": [ "PMID-17884155_T2", "PMID-17884155_T3" ] }, { "id": "PMID-17884155_2", "entity_ids": [ "PMID-17884155_T18", "PMID-17884155_T19" ] } ]

[]

[ { "id": "PMID-17894824__text", "type": "abstract", "text": [ "Recombinant bovine zona pellucida glycoproteins ZP3 and ZP4 coexpressed in Sf9 cells form a sperm-binding active hetero-complex. \nThe zona pellucida (ZP) is a transparent envelope that surrounds the mammalian oocyte and mediates species-selective sperm-egg interactions. Porcine and bovine ZPs are composed of the glycoproteins ZP2, ZP3, and ZP4. We previously established an expression system for porcine ZP glycoproteins (ZPGs) using baculovirus in insect Sf9 cells. Here we established a similar method for expression of bovine ZPGs. The recombinant ZPGs were secreted into the medium and purified by metal-chelating column chromatography. A mixture of bovine recombinant ZP3 (rZP3) and rZP4 coexpressed in Sf9 cells exhibited inhibitory activity for bovine sperm-ZP binding similar to that of a native bovine ZPG mixture, whereas neither bovine rZP3 nor rZP4 inhibited binding. An immunoprecipitation assay revealed that the coexpressed rZP3/rZP4 formed a hetero-complex. We examined the functional domain structure of bovine rZP4 by constructing ZP4 mutants lacking the N-terminal domain or lacking both the N-terminal and trefoil domains. When either of these mutant proteins was coexpressed with bovine rZP3, the resulting mixtures exhibited inhibitory activity comparable to that of the bovine rZP3/rZP4 complex. Hetero-complexes of bovine rZP3 and porcine rZP4, or porcine rZP3 and bovine rZP4, also inhibited bovine sperm-ZP binding. Our results demonstrate that the N-terminal and trefoil domains of bovine rZP4 are dispensable for formation of the sperm-binding active bovine rZP3/rZP4 complex and, furthermore, that the molecular interactions between rZP3 and rZP4 are conserved in the bovine and porcine systems.\n" ], "offsets": [ [ 0, 1727 ] ] } ]

[ { "id": "PMID-17894824_T1", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 48, 51 ] ], "normalized": [] }, { "id": "PMID-17894824_T2", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 56, 59 ] ], "normalized": [] }, { "id": "PMID-17894824_T3", "type": "Protein", "text": [ "ZP2" ], "offsets": [ [ 328, 331 ] ], "normalized": [] }, { "id": "PMID-17894824_T4", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 333, 336 ] ], "normalized": [] }, { "id": "PMID-17894824_T5", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 342, 345 ] ], "normalized": [] }, { "id": "PMID-17894824_T6", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 675, 678 ] ], "normalized": [] }, { "id": "PMID-17894824_T7", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 681, 684 ] ], "normalized": [] }, { "id": "PMID-17894824_T8", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 691, 694 ] ], "normalized": [] }, { "id": "PMID-17894824_T9", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 850, 853 ] ], "normalized": [] }, { "id": "PMID-17894824_T10", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 859, 862 ] ], "normalized": [] }, { "id": "PMID-17894824_T11", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 942, 945 ] ], "normalized": [] }, { "id": "PMID-17894824_T12", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 947, 950 ] ], "normalized": [] }, { "id": "PMID-17894824_T13", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 1031, 1034 ] ], "normalized": [] }, { "id": "PMID-17894824_T14", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 1051, 1054 ] ], "normalized": [] }, { "id": "PMID-17894824_T15", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 1211, 1214 ] ], "normalized": [] }, { "id": "PMID-17894824_T16", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 1303, 1306 ] ], "normalized": [] }, { "id": "PMID-17894824_T17", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 1308, 1311 ] ], "normalized": [] }, { "id": "PMID-17894824_T18", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 1349, 1352 ] ], "normalized": [] }, { "id": "PMID-17894824_T19", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 1366, 1369 ] ], "normalized": [] }, { "id": "PMID-17894824_T20", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 1383, 1386 ] ], "normalized": [] }, { "id": "PMID-17894824_T21", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 1399, 1402 ] ], "normalized": [] }, { "id": "PMID-17894824_T22", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 1519, 1522 ] ], "normalized": [] }, { "id": "PMID-17894824_T23", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 1589, 1592 ] ], "normalized": [] }, { "id": "PMID-17894824_T24", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 1594, 1597 ] ], "normalized": [] }, { "id": "PMID-17894824_T25", "type": "Protein", "text": [ "ZP3" ], "offsets": [ [ 1665, 1668 ] ], "normalized": [] }, { "id": "PMID-17894824_T26", "type": "Protein", "text": [ "ZP4" ], "offsets": [ [ 1674, 1677 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-17925579__text", "type": "abstract", "text": [ "Hypoxia-inducible factor 1 (HIF-1) pathway. \nHypoxia-inducible factor 1 (HIF-1) is a basic helix-loop-helix-PAS domain transcription factor that is expressed in all metazoan organisms and is composed of HIF-1alpha and HIF-1beta subunits. Under hypoxic conditions, HIF-1 regulates the transcription of hundreds of genes in a cell type-specific manner. The HIF-1alpha subunit is regulated by O2-dependent hydroxylation of proline residue 402, 564, or both, by prolyl hydroxylase domain protein 2 (PHD2), which promotes binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation; and O2-dependent hydroxylation of asparagine residue 803 by factor inhibiting HIF-1 (FIH-1), which blocks the binding of the 300-kilodalton coactivator protein (p300) and CREB binding protein (CBP). The hydroxylation reactions, which utilize O2 and alpha-ketoglutarate as substrates and generate CO2 and succinate as by-products, provide a mechanism by which changes in cellular oxygenation are transduced to the nucleus as changes in HIF-1 activity. Hydroxylase activity is inhibited in the presence of low concentrations of O2, high concentrations of tricarboxylic acid cycle intermediates (isocitrate, oxaloacetate, succinate, or fumarate), or chelators of Fe(II). Receptor for activated C kinase 1 (RACK1) competes with heat shock protein 90 (HSP90) for binding to HIF-1alpha and mediates O2-independent ubiquitination and proteasomal degradation. A growing number of proteins and small molecules have been identified that regulate HIF-1 activity by modulating the physical or functional interaction of PHD2, VHL, FIH-1, RACK1, or HSP90 with HIF-1alpha.\n" ], "offsets": [ [ 0, 1678 ] ] } ]

[ { "id": "PMID-17925579_T1", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 203, 213 ] ], "normalized": [] }, { "id": "PMID-17925579_T2", "type": "Protein", "text": [ "HIF-1beta" ], "offsets": [ [ 218, 227 ] ], "normalized": [] }, { "id": "PMID-17925579_T3", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 355, 365 ] ], "normalized": [] }, { "id": "PMID-17925579_T4", "type": "Protein", "text": [ "prolyl hydroxylase domain protein 2" ], "offsets": [ [ 458, 493 ] ], "normalized": [] }, { "id": "PMID-17925579_T5", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 495, 499 ] ], "normalized": [] }, { "id": "PMID-17925579_T6", "type": "Protein", "text": [ "von Hippel-Lindau" ], "offsets": [ [ 532, 549 ] ], "normalized": [] }, { "id": "PMID-17925579_T7", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 559, 562 ] ], "normalized": [] }, { "id": "PMID-17925579_T8", "type": "Protein", "text": [ "factor inhibiting HIF-1" ], "offsets": [ [ 680, 703 ] ], "normalized": [] }, { "id": "PMID-17925579_T9", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 705, 710 ] ], "normalized": [] }, { "id": "PMID-17925579_T10", "type": "Protein", "text": [ "p300" ], "offsets": [ [ 781, 785 ] ], "normalized": [] }, { "id": "PMID-17925579_T11", "type": "Protein", "text": [ "CREB binding protein" ], "offsets": [ [ 791, 811 ] ], "normalized": [] }, { "id": "PMID-17925579_T12", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 813, 816 ] ], "normalized": [] }, { "id": "PMID-17925579_T13", "type": "Protein", "text": [ "Receptor for activated C kinase 1" ], "offsets": [ [ 1288, 1321 ] ], "normalized": [] }, { "id": "PMID-17925579_T14", "type": "Protein", "text": [ "RACK1" ], "offsets": [ [ 1323, 1328 ] ], "normalized": [] }, { "id": "PMID-17925579_T15", "type": "Protein", "text": [ "heat shock protein 90" ], "offsets": [ [ 1344, 1365 ] ], "normalized": [] }, { "id": "PMID-17925579_T16", "type": "Protein", "text": [ "HSP90" ], "offsets": [ [ 1367, 1372 ] ], "normalized": [] }, { "id": "PMID-17925579_T17", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 1389, 1399 ] ], "normalized": [] }, { "id": "PMID-17925579_T18", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 1627, 1631 ] ], "normalized": [] }, { "id": "PMID-17925579_T19", "type": "Protein", "text": [ "VHL" ], "offsets": [ [ 1633, 1636 ] ], "normalized": [] }, { "id": "PMID-17925579_T20", "type": "Protein", "text": [ "FIH-1" ], "offsets": [ [ 1638, 1643 ] ], "normalized": [] }, { "id": "PMID-17925579_T21", "type": "Protein", "text": [ "RACK1" ], "offsets": [ [ 1645, 1650 ] ], "normalized": [] }, { "id": "PMID-17925579_T22", "type": "Protein", "text": [ "HSP90" ], "offsets": [ [ 1655, 1660 ] ], "normalized": [] }, { "id": "PMID-17925579_T23", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 1666, 1676 ] ], "normalized": [] }, { "id": "PMID-17925579_T26", "type": "Entity", "text": [ "proline residue 402" ], "offsets": [ [ 420, 439 ] ], "normalized": [] }, { "id": "PMID-17925579_T27", "type": "Entity", "text": [ "564" ], "offsets": [ [ 441, 444 ] ], "normalized": [] }, { "id": "PMID-17925579_T31", "type": "Entity", "text": [ "asparagine residue 803" ], "offsets": [ [ 654, 676 ] ], "normalized": [] } ]

[ { "id": "PMID-17925579_E1", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 403, 416 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17925579_T3" }, { "role": "Site", "ref_id": "PMID-17925579_T26" } ] }, { "id": "PMID-17925579_E2", "type": "Catalysis", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 403, 416 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17925579_E1" }, { "role": "Cause", "ref_id": "PMID-17925579_T4" } ] }, { "id": "PMID-17925579_E3", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 403, 416 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17925579_T3" }, { "role": "Site", "ref_id": "PMID-17925579_T27" } ] }, { "id": "PMID-17925579_E4", "type": "Catalysis", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 403, 416 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17925579_E3" }, { "role": "Cause", "ref_id": "PMID-17925579_T4" } ] }, { "id": "PMID-17925579_E5", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 576, 590 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17925579_T3" } ] }, { "id": "PMID-17925579_E6", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 637, 650 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17925579_T3" }, { "role": "Site", "ref_id": "PMID-17925579_T31" } ] }, { "id": "PMID-17925579_E7", "type": "Catalysis", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 637, 650 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17925579_E6" }, { "role": "Cause", "ref_id": "PMID-17925579_T8" } ] }, { "id": "PMID-17925579_E8", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 823, 836 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17925579_T3" } ] }, { "id": "PMID-17925579_E9", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1428, 1442 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17925579_T17" } ] } ]

[ { "id": "PMID-17925579_1", "entity_ids": [ "PMID-17925579_T4", "PMID-17925579_T5" ] }, { "id": "PMID-17925579_2", "entity_ids": [ "PMID-17925579_T6", "PMID-17925579_T7" ] }, { "id": "PMID-17925579_3", "entity_ids": [ "PMID-17925579_T8", "PMID-17925579_T9" ] }, { "id": "PMID-17925579_4", "entity_ids": [ "PMID-17925579_T11", "PMID-17925579_T12" ] }, { "id": "PMID-17925579_5", "entity_ids": [ "PMID-17925579_T13", "PMID-17925579_T14" ] }, { "id": "PMID-17925579_6", "entity_ids": [ "PMID-17925579_T15", "PMID-17925579_T16" ] } ]

[]

[ { "id": "PMID-17934516__text", "type": "abstract", "text": [ "The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. \nInverted CCAAT box-binding protein of 90 kDa (ICBP90) is over-expressed in several types of cancer, including breast, prostate and lung cancers. In search for proteins that interact with the set and ring-associated (SRA) domain of ICBP90, we used the two-hybrid system and screened a placental cDNA library. Several clones coding for a new domain of DNMT1 were found. The interaction, between the ICBP90 SRA domain and the DNMT1 domain, has been confirmed with purified proteins by glutathione-S-transferase pull-down experiments. We checked whether ICBP90 and DNMT1 are present in the same macro-molecular complexes in Jurkat cells and immortalized human vascular smooth muscle cells (HVTs-SM1). Co-immunoprecipitation experiments showed that ICBP90 and DNMT1 are present in the same molecular complex, which was further confirmed by co-localization experiments as assessed by immunocytochemistry. Downregulation of ICBP90 and DNMT1 decreased VEGF gene expression, a major pro-angiogenic factor, whereas those of p16(INK4A) gene and RB1 gene were significantly enhanced. Together, these results indicate that DNMT1 and ICBP90 are involved in VEGF gene expression, possibly via an interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 and an upregulation of p16(INK4A). They further suggest a new role of ICBP90 in the relationship between histone ubiquitination and DNA methylation in the context of tumoral angiogenesis and tumour suppressor genes silencing.\n" ], "offsets": [ [ 0, 1605 ] ] } ]

[ { "id": "PMID-17934516_T1", "type": "Protein", "text": [ "ICBP90" ], "offsets": [ [ 37, 43 ] ], "normalized": [] }, { "id": "PMID-17934516_T2", "type": "Protein", "text": [ "DNMT1" ], "offsets": [ [ 67, 72 ] ], "normalized": [] }, { "id": "PMID-17934516_T3", "type": "Protein", "text": [ "VEGF" ], "offsets": [ [ 106, 110 ] ], "normalized": [] }, { "id": "PMID-17934516_T4", "type": "Protein", "text": [ "Inverted CCAAT box-binding protein of 90 kDa" ], "offsets": [ [ 129, 173 ] ], "normalized": [] }, { "id": "PMID-17934516_T5", "type": "Protein", "text": [ "ICBP90" ], "offsets": [ [ 175, 181 ] ], "normalized": [] }, { "id": "PMID-17934516_T6", "type": "Protein", "text": [ "ICBP90" ], "offsets": [ [ 360, 366 ] ], "normalized": [] }, { "id": "PMID-17934516_T7", "type": "Protein", "text": [ "DNMT1" ], "offsets": [ [ 479, 484 ] ], "normalized": [] }, { "id": "PMID-17934516_T8", "type": "Protein", "text": [ "ICBP90" ], "offsets": [ [ 526, 532 ] ], "normalized": [] }, { "id": "PMID-17934516_T9", "type": "Protein", "text": [ "DNMT1" ], "offsets": [ [ 552, 557 ] ], "normalized": [] }, { "id": "PMID-17934516_T10", "type": "Protein", "text": [ "glutathione-S-transferase" ], "offsets": [ [ 611, 636 ] ], "normalized": [] }, { "id": "PMID-17934516_T11", "type": "Protein", "text": [ "ICBP90" ], "offsets": [ [ 679, 685 ] ], "normalized": [] }, { "id": "PMID-17934516_T12", "type": "Protein", "text": [ "DNMT1" ], "offsets": [ [ 690, 695 ] ], "normalized": [] }, { "id": "PMID-17934516_T13", "type": "Protein", "text": [ "ICBP90" ], "offsets": [ [ 873, 879 ] ], "normalized": [] }, { "id": "PMID-17934516_T14", "type": "Protein", "text": [ "DNMT1" ], "offsets": [ [ 884, 889 ] ], "normalized": [] }, { "id": "PMID-17934516_T15", "type": "Protein", "text": [ "ICBP90" ], "offsets": [ [ 1046, 1052 ] ], "normalized": [] }, { "id": "PMID-17934516_T16", "type": "Protein", "text": [ "DNMT1" ], "offsets": [ [ 1057, 1062 ] ], "normalized": [] }, { "id": "PMID-17934516_T17", "type": "Protein", "text": [ "VEGF" ], "offsets": [ [ 1073, 1077 ] ], "normalized": [] }, { "id": "PMID-17934516_T18", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 1143, 1146 ] ], "normalized": [] }, { "id": "PMID-17934516_T19", "type": "Protein", "text": [ "INK4A" ], "offsets": [ [ 1147, 1152 ] ], "normalized": [] }, { "id": "PMID-17934516_T20", "type": "Protein", "text": [ "RB1" ], "offsets": [ [ 1163, 1166 ] ], "normalized": [] }, { "id": "PMID-17934516_T21", "type": "Protein", "text": [ "DNMT1" ], "offsets": [ [ 1239, 1244 ] ], "normalized": [] }, { "id": "PMID-17934516_T22", "type": "Protein", "text": [ "ICBP90" ], "offsets": [ [ 1249, 1255 ] ], "normalized": [] }, { "id": "PMID-17934516_T23", "type": "Protein", "text": [ "VEGF" ], "offsets": [ [ 1272, 1276 ] ], "normalized": [] }, { "id": "PMID-17934516_T24", "type": "Protein", "text": [ "ICBP90" ], "offsets": [ [ 1343, 1349 ] ], "normalized": [] }, { "id": "PMID-17934516_T25", "type": "Protein", "text": [ "DNMT1" ], "offsets": [ [ 1373, 1378 ] ], "normalized": [] }, { "id": "PMID-17934516_T26", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 1402, 1405 ] ], "normalized": [] }, { "id": "PMID-17934516_T27", "type": "Protein", "text": [ "INK4A" ], "offsets": [ [ 1406, 1411 ] ], "normalized": [] }, { "id": "PMID-17934516_T28", "type": "Protein", "text": [ "ICBP90" ], "offsets": [ [ 1449, 1455 ] ], "normalized": [] }, { "id": "PMID-17934516_T29", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1484, 1491 ] ], "normalized": [] } ]

[ { "id": "PMID-17934516_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1492, 1506 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17934516_T29" } ] } ]

[ { "id": "PMID-17934516_1", "entity_ids": [ "PMID-17934516_T4", "PMID-17934516_T5" ] }, { "id": "PMID-17934516_2", "entity_ids": [ "PMID-17934516_T18", "PMID-17934516_T19" ] }, { "id": "PMID-17934516_3", "entity_ids": [ "PMID-17934516_T26", "PMID-17934516_T27" ] } ]

[]

[ { "id": "PMID-17962312__text", "type": "abstract", "text": [ "Automethylation of G9a and its implication in wider substrate specificity and HP1 binding. \nMethylation of lysine residues on histones participates in transcriptional gene regulation. Lysine 9 methylation of histone H3 is a transcriptional repression signal, mediated by a family of SET domain containing AdoMet-dependent enzymes. G9a methyltransferase is a euchromatic histone H3 lysine 9 methyltransferase. Here, G9a is shown to methylate other cellular proteins, apart from histone H3, including automethylation of K239 residue. Automethylation of G9a did not impair or activate the enzymatic activity in vitro. The automethylation motif of G9a flanking target K239 (ARKT) has similarity with histone H3 lysine 9 regions (ARKS), and is identical to amino acids residues in EuHMT (ARKT) and mAM (ARKT). Under steady-state kinetic assay conditions, full-length G9a methylates peptides representing ARKS/T motif of H3, G9a, mAM and EuHMT efficiently. Automethylation of G9a at ARKT motif creates a binding site for HP1 class of protein and mutation of lysine in the motif impairs this binding. In COS-7 cells GFP fusion of the wild-type G9a co-localized with HP1alpha and HP1gamma isoforms whereas the G9a mutant with K239A displayed poor co-localization. Thus, apart from transcriptional repression and regulatory roles of lysine methylation, the non-histone protein methylation may create binding sites for cellular protein-protein interactions.\n" ], "offsets": [ [ 0, 1448 ] ] } ]

[ { "id": "PMID-17962312_T1", "type": "Protein", "text": [ "G9a" ], "offsets": [ [ 19, 22 ] ], "normalized": [] }, { "id": "PMID-17962312_T2", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 126, 134 ] ], "normalized": [] }, { "id": "PMID-17962312_T3", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 208, 218 ] ], "normalized": [] }, { "id": "PMID-17962312_T4", "type": "Protein", "text": [ "G9a" ], "offsets": [ [ 331, 334 ] ], "normalized": [] }, { "id": "PMID-17962312_T5", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 370, 380 ] ], "normalized": [] }, { "id": "PMID-17962312_T6", "type": "Protein", "text": [ "G9a" ], "offsets": [ [ 415, 418 ] ], "normalized": [] }, { "id": "PMID-17962312_T7", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 477, 487 ] ], "normalized": [] }, { "id": "PMID-17962312_T8", "type": "Protein", "text": [ "G9a" ], "offsets": [ [ 551, 554 ] ], "normalized": [] }, { "id": "PMID-17962312_T9", "type": "Protein", "text": [ "G9a" ], "offsets": [ [ 644, 647 ] ], "normalized": [] }, { "id": "PMID-17962312_T10", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 696, 706 ] ], "normalized": [] }, { "id": "PMID-17962312_T11", "type": "Protein", "text": [ "EuHMT" ], "offsets": [ [ 776, 781 ] ], "normalized": [] }, { "id": "PMID-17962312_T12", "type": "Protein", "text": [ "mAM" ], "offsets": [ [ 793, 796 ] ], "normalized": [] }, { "id": "PMID-17962312_T13", "type": "Protein", "text": [ "G9a" ], "offsets": [ [ 862, 865 ] ], "normalized": [] }, { "id": "PMID-17962312_T14", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 915, 917 ] ], "normalized": [] }, { "id": "PMID-17962312_T15", "type": "Protein", "text": [ "G9a" ], "offsets": [ [ 919, 922 ] ], "normalized": [] }, { "id": "PMID-17962312_T16", "type": "Protein", "text": [ "mAM" ], "offsets": [ [ 924, 927 ] ], "normalized": [] }, { "id": "PMID-17962312_T17", "type": "Protein", "text": [ "EuHMT" ], "offsets": [ [ 932, 937 ] ], "normalized": [] }, { "id": "PMID-17962312_T18", "type": "Protein", "text": [ "G9a" ], "offsets": [ [ 970, 973 ] ], "normalized": [] }, { "id": "PMID-17962312_T19", "type": "Protein", "text": [ "G9a" ], "offsets": [ [ 1137, 1140 ] ], "normalized": [] }, { "id": "PMID-17962312_T20", "type": "Protein", "text": [ "HP1alpha" ], "offsets": [ [ 1159, 1167 ] ], "normalized": [] }, { "id": "PMID-17962312_T21", "type": "Protein", "text": [ "HP1gamma" ], "offsets": [ [ 1172, 1180 ] ], "normalized": [] }, { "id": "PMID-17962312_T22", "type": "Protein", "text": [ "G9a" ], "offsets": [ [ 1202, 1205 ] ], "normalized": [] }, { "id": "PMID-17962312_T23", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1352, 1359 ] ], "normalized": [] }, { "id": "PMID-17962312_T27", "type": "Entity", "text": [ "lysine residues" ], "offsets": [ [ 107, 122 ] ], "normalized": [] }, { "id": "PMID-17962312_T28", "type": "Entity", "text": [ "Lysine 9" ], "offsets": [ [ 184, 192 ] ], "normalized": [] }, { "id": "PMID-17962312_T32", "type": "Entity", "text": [ "K239 residue" ], "offsets": [ [ 518, 530 ] ], "normalized": [] } ]

[ { "id": "PMID-17962312_E1", "type": "Methylation", "trigger": { "text": [ "Automethylation" ], "offsets": [ [ 0, 15 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17962312_T1" } ] }, { "id": "PMID-17962312_E2", "type": "Catalysis", "trigger": { "text": [ "Automethylation" ], "offsets": [ [ 0, 15 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17962312_E1" }, { "role": "Cause", "ref_id": "PMID-17962312_T1" } ] }, { "id": "PMID-17962312_E3", "type": "Methylation", "trigger": { "text": [ "Methylation" ], "offsets": [ [ 92, 103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17962312_T2" }, { "role": "Site", "ref_id": "PMID-17962312_T27" } ] }, { "id": "PMID-17962312_E4", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 193, 204 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17962312_T3" }, { "role": "Site", "ref_id": "PMID-17962312_T28" } ] }, { "id": "PMID-17962312_E5", "type": "Methylation", "trigger": { "text": [ "automethylation" ], "offsets": [ [ 499, 514 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17962312_T6" }, { "role": "Site", "ref_id": "PMID-17962312_T32" } ] }, { "id": "PMID-17962312_E6", "type": "Catalysis", "trigger": { "text": [ "automethylation" ], "offsets": [ [ 499, 514 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17962312_E5" }, { "role": "Cause", "ref_id": "PMID-17962312_T6" } ] }, { "id": "PMID-17962312_E7", "type": "Methylation", "trigger": { "text": [ "Automethylation" ], "offsets": [ [ 532, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17962312_T8" } ] }, { "id": "PMID-17962312_E8", "type": "Catalysis", "trigger": { "text": [ "Automethylation" ], "offsets": [ [ 532, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17962312_E7" }, { "role": "Cause", "ref_id": "PMID-17962312_T8" } ] }, { "id": "PMID-17962312_E9", "type": "Catalysis", "trigger": { "text": [ "Automethylation" ], "offsets": [ [ 951, 966 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17962312_E10" }, { "role": "Cause", "ref_id": "PMID-17962312_T18" } ] }, { "id": "PMID-17962312_E10", "type": "Methylation", "trigger": { "text": [ "Automethylation" ], "offsets": [ [ 951, 966 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17962312_T18" } ] } ]

[]

[]

[ { "id": "PMID-17967422__text", "type": "abstract", "text": [ "CSF-1 and TPA stimulate independent pathways leading to lysosomal degradation or regulated intramembrane proteolysis of the CSF-1 receptor. \nThe CSF-1 receptor is a protein-tyrosine kinase that has been shown to undergo regulated intramembrane proteolysis, or RIPping. Here, we have compared receptor downregulation and RIPping in response to CSF-1 and TPA. Our studies show that CSF-1 is a relatively poor inducer of RIPping and that CSF-1-induced receptor downregulation is largely independent of RIPping. TPA is a strong inducer of RIPping and TPA-induced receptor downregulation is mediated by RIPping. We further found that RIPping is dependent on TACE or a TACE-like protease, that CSF-1 and TPA use independent pathways to initiate RIPping, and that the intracellular domain is targeted for degradation through ubiquitination.\n" ], "offsets": [ [ 0, 834 ] ] } ]

[ { "id": "PMID-17967422_T1", "type": "Protein", "text": [ "CSF-1" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "PMID-17967422_T2", "type": "Protein", "text": [ "CSF-1 receptor" ], "offsets": [ [ 124, 138 ] ], "normalized": [] }, { "id": "PMID-17967422_T3", "type": "Protein", "text": [ "CSF-1 receptor" ], "offsets": [ [ 145, 159 ] ], "normalized": [] }, { "id": "PMID-17967422_T4", "type": "Protein", "text": [ "CSF-1" ], "offsets": [ [ 343, 348 ] ], "normalized": [] }, { "id": "PMID-17967422_T5", "type": "Protein", "text": [ "CSF-1" ], "offsets": [ [ 380, 385 ] ], "normalized": [] }, { "id": "PMID-17967422_T6", "type": "Protein", "text": [ "CSF-1" ], "offsets": [ [ 435, 440 ] ], "normalized": [] }, { "id": "PMID-17967422_T7", "type": "Protein", "text": [ "TACE" ], "offsets": [ [ 653, 657 ] ], "normalized": [] }, { "id": "PMID-17967422_T8", "type": "Protein", "text": [ "TACE" ], "offsets": [ [ 663, 667 ] ], "normalized": [] }, { "id": "PMID-17967422_T9", "type": "Protein", "text": [ "CSF-1" ], "offsets": [ [ 688, 693 ] ], "normalized": [] } ]

[ { "id": "PMID-17967422_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 818, 832 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967422_T3" } ] } ]

[]

[]

[ { "id": "PMID-17967882__text", "type": "abstract", "text": [ "Certain and progressive methylation of histone H4 at lysine 20 during the cell cycle. \nMethylation of histone H4 at lysine 20 (K20) has been implicated in transcriptional activation, gene silencing, heterochromatin formation, mitosis, and DNA repair. However, little is known about how this modification is regulated or how it contributes to these diverse processes. Metabolic labeling and top-down mass spectrometry reveal that newly synthesized H4 is progressively methylated at K20 during the G(2), M, and G(1) phases of the cell cycle in a process that is largely inescapable and irreversible. Approximately 98% of new H4 becomes dimethylated within two to three cell cycles, and K20 methylation turnover in vivo is undetectable. New H4 is methylated regardless of prior acetylation, and acetylation occurs predominantly on K20-dimethylated H4, refuting the hypothesis that K20 methylation antagonizes H4 acetylation and represses transcription epigenetically. Despite suggestions that it is required for normal mitosis and cell cycle progression, K20 methylation proceeds normally during colchicine treatment. Moreover, delays in PR-Set7 synthesis and K20 methylation which accompany altered cell cycle progression during sodium butyrate treatment appear to be secondary to histone hyperacetylation or other effects of butyrate since depletion of PR-Set7 did not affect cell cycle progression. Together, our data provide an unbiased perspective of the regulation and function of K20 methylation.\n" ], "offsets": [ [ 0, 1501 ] ] } ]

[ { "id": "PMID-17967882_T1", "type": "Protein", "text": [ "histone H4" ], "offsets": [ [ 39, 49 ] ], "normalized": [] }, { "id": "PMID-17967882_T2", "type": "Protein", "text": [ "histone H4" ], "offsets": [ [ 102, 112 ] ], "normalized": [] }, { "id": "PMID-17967882_T3", "type": "Protein", "text": [ "H4" ], "offsets": [ [ 447, 449 ] ], "normalized": [] }, { "id": "PMID-17967882_T4", "type": "Protein", "text": [ "H4" ], "offsets": [ [ 623, 625 ] ], "normalized": [] }, { "id": "PMID-17967882_T5", "type": "Protein", "text": [ "H4" ], "offsets": [ [ 738, 740 ] ], "normalized": [] }, { "id": "PMID-17967882_T6", "type": "Protein", "text": [ "H4" ], "offsets": [ [ 845, 847 ] ], "normalized": [] }, { "id": "PMID-17967882_T7", "type": "Protein", "text": [ "H4" ], "offsets": [ [ 906, 908 ] ], "normalized": [] }, { "id": "PMID-17967882_T8", "type": "Protein", "text": [ "PR-Set7" ], "offsets": [ [ 1135, 1142 ] ], "normalized": [] }, { "id": "PMID-17967882_T9", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1279, 1286 ] ], "normalized": [] }, { "id": "PMID-17967882_T10", "type": "Protein", "text": [ "PR-Set7" ], "offsets": [ [ 1352, 1359 ] ], "normalized": [] }, { "id": "PMID-17967882_T12", "type": "Entity", "text": [ "lysine 20" ], "offsets": [ [ 53, 62 ] ], "normalized": [] }, { "id": "PMID-17967882_T14", "type": "Entity", "text": [ "lysine 20" ], "offsets": [ [ 116, 125 ] ], "normalized": [] }, { "id": "PMID-17967882_T16", "type": "Entity", "text": [ "K20" ], "offsets": [ [ 481, 484 ] ], "normalized": [] }, { "id": "PMID-17967882_T18", "type": "Entity", "text": [ "K20" ], "offsets": [ [ 684, 687 ] ], "normalized": [] }, { "id": "PMID-17967882_T22", "type": "Entity", "text": [ "K20" ], "offsets": [ [ 828, 831 ] ], "normalized": [] }, { "id": "PMID-17967882_T24", "type": "Entity", "text": [ "K20" ], "offsets": [ [ 878, 881 ] ], "normalized": [] }, { "id": "PMID-17967882_T27", "type": "Entity", "text": [ "K20" ], "offsets": [ [ 1052, 1055 ] ], "normalized": [] }, { "id": "PMID-17967882_T29", "type": "Entity", "text": [ "K20" ], "offsets": [ [ 1157, 1160 ] ], "normalized": [] }, { "id": "PMID-17967882_T32", "type": "Entity", "text": [ "K20" ], "offsets": [ [ 1484, 1487 ] ], "normalized": [] } ]

[ { "id": "PMID-17967882_E1", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 24, 35 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T1" }, { "role": "Site", "ref_id": "PMID-17967882_T12" } ] }, { "id": "PMID-17967882_E2", "type": "Methylation", "trigger": { "text": [ "Methylation" ], "offsets": [ [ 87, 98 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T2" }, { "role": "Site", "ref_id": "PMID-17967882_T14" } ] }, { "id": "PMID-17967882_E3", "type": "Methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 467, 477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T3" }, { "role": "Site", "ref_id": "PMID-17967882_T16" } ] }, { "id": "PMID-17967882_E4", "type": "Methylation", "trigger": { "text": [ "dimethylated" ], "offsets": [ [ 634, 646 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T4" } ] }, { "id": "PMID-17967882_E5", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 688, 699 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T4" }, { "role": "Site", "ref_id": "PMID-17967882_T18" } ] }, { "id": "PMID-17967882_E6", "type": "Methylation", "trigger": { "text": [ "methylated" ], "offsets": [ [ 744, 754 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T5" } ] }, { "id": "PMID-17967882_E7", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 792, 803 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T6" } ] }, { "id": "PMID-17967882_E8", "type": "Methylation", "trigger": { "text": [ "dimethylated" ], "offsets": [ [ 832, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T6" }, { "role": "Site", "ref_id": "PMID-17967882_T22" } ] }, { "id": "PMID-17967882_E9", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 882, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T7" }, { "role": "Site", "ref_id": "PMID-17967882_T24" } ] }, { "id": "PMID-17967882_E10", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 909, 920 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T7" } ] }, { "id": "PMID-17967882_E11", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1056, 1067 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T5" }, { "role": "Site", "ref_id": "PMID-17967882_T27" } ] }, { "id": "PMID-17967882_E12", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1161, 1172 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T5" }, { "role": "Site", "ref_id": "PMID-17967882_T29" } ] }, { "id": "PMID-17967882_E13", "type": "Acetylation", "trigger": { "text": [ "hyperacetylation" ], "offsets": [ [ 1287, 1303 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T9" } ] }, { "id": "PMID-17967882_E14", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1488, 1499 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17967882_T5" }, { "role": "Site", "ref_id": "PMID-17967882_T32" } ] } ]

[]

[]

[ { "id": "PMID-17970082__text", "type": "abstract", "text": [ "P16 methylation in serum as a potential marker for the malignancy of colorectal carcinoma. \nThe aim of the present study was to determine if p16 methylation in the serum can serve as a candidate marker for the malignancy of colorectal carcinoma, real-time quantitative methylation-specific PCR (RTQ-MSP) was performed for p16 methylation in serum and the relationship between p16 methylation levels and clinicopathological findings of colorectal carcinoma was evaluated. RESULTS: The p16 methylation score significantly increased with tumor stage (stage I=0.94+/-0.47, stage 11=2.33+/-0.90, stage 111=8.49+/-2.37, stage IV=10.03+/-4.30) (p=0.021; ANOVA). The p16 methylation score was significantly higher in patients with lymph node metastasis (p=0.001) and tumor invasion to the veins (p=0.020). The cumulative survival of patient groups according to the p16 methylation score (more or less than 1) was examined. Interestingly, the group with a high p16 methylation score showed significantly worse survival rates than the group with a low p16 expression score (p= 0.006). CONCLUSION: The p16 methylation score might serve as a new parameter for the prognosis of colorectal carcinoma. Moreover, p16 methylation was found in the serum of patients in all clinical stages, suggesting that early colorectal carcinoma could be detected using the RTQ-MSP method.\n" ], "offsets": [ [ 0, 1359 ] ] } ]

[ { "id": "PMID-17970082_T1", "type": "Protein", "text": [ "P16" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "PMID-17970082_T2", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 141, 144 ] ], "normalized": [] }, { "id": "PMID-17970082_T3", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 322, 325 ] ], "normalized": [] }, { "id": "PMID-17970082_T4", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 376, 379 ] ], "normalized": [] }, { "id": "PMID-17970082_T5", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 484, 487 ] ], "normalized": [] }, { "id": "PMID-17970082_T6", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 659, 662 ] ], "normalized": [] }, { "id": "PMID-17970082_T7", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 857, 860 ] ], "normalized": [] }, { "id": "PMID-17970082_T8", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 952, 955 ] ], "normalized": [] }, { "id": "PMID-17970082_T9", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 1042, 1045 ] ], "normalized": [] }, { "id": "PMID-17970082_T10", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 1091, 1094 ] ], "normalized": [] }, { "id": "PMID-17970082_T11", "type": "Protein", "text": [ "p16" ], "offsets": [ [ 1197, 1200 ] ], "normalized": [] } ]

[ { "id": "PMID-17970082_E1", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 4, 15 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17970082_T1" } ] }, { "id": "PMID-17970082_E2", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 145, 156 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17970082_T2" } ] }, { "id": "PMID-17970082_E3", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 326, 337 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17970082_T3" } ] }, { "id": "PMID-17970082_E4", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 380, 391 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17970082_T4" } ] }, { "id": "PMID-17970082_E5", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 488, 499 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17970082_T5" } ] }, { "id": "PMID-17970082_E6", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 663, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17970082_T6" } ] }, { "id": "PMID-17970082_E7", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 861, 872 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17970082_T7" } ] }, { "id": "PMID-17970082_E8", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 956, 967 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17970082_T8" } ] }, { "id": "PMID-17970082_E9", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1095, 1106 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17970082_T10" } ] }, { "id": "PMID-17970082_E10", "type": "DNA_methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1201, 1212 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17970082_T11" } ] } ]

[]

[]

[ { "id": "PMID-17971410__text", "type": "abstract", "text": [ "NCAM is ubiquitylated, endocytosed and recycled in neurons. \nThe neural cell adhesion molecule NCAM plays an important role during neural development and in the adult brain. To study the intracellular trafficking of NCAM in neurons, two major isoforms, NCAM140 or NCAM180, were expressed in primary cortical neurons and in the rat B35 neuroblastoma cell line. NCAM was endocytosed and subsequently recycled to the plasma membrane, whereas only a minor fraction was degraded in lysosomes. In cortical neurons, endocytosis of NCAM was detected in the soma, neurites and growth cones in a developmentally regulated fashion. Furthermore, we found that NCAM is mono-ubiquitylated at the plasma membrane and endocytosis was significantly increased in cells overexpressing ubiquitin. Therefore, we propose that ubiquitylation represents an endocytosis signal for NCAM.\n" ], "offsets": [ [ 0, 862 ] ] } ]

[ { "id": "PMID-17971410_T1", "type": "Protein", "text": [ "NCAM" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-17971410_T2", "type": "Protein", "text": [ "NCAM" ], "offsets": [ [ 95, 99 ] ], "normalized": [] }, { "id": "PMID-17971410_T3", "type": "Protein", "text": [ "NCAM" ], "offsets": [ [ 216, 220 ] ], "normalized": [] }, { "id": "PMID-17971410_T4", "type": "Protein", "text": [ "NCAM140" ], "offsets": [ [ 253, 260 ] ], "normalized": [] }, { "id": "PMID-17971410_T5", "type": "Protein", "text": [ "NCAM180" ], "offsets": [ [ 264, 271 ] ], "normalized": [] }, { "id": "PMID-17971410_T6", "type": "Protein", "text": [ "NCAM" ], "offsets": [ [ 360, 364 ] ], "normalized": [] }, { "id": "PMID-17971410_T7", "type": "Protein", "text": [ "NCAM" ], "offsets": [ [ 524, 528 ] ], "normalized": [] }, { "id": "PMID-17971410_T8", "type": "Protein", "text": [ "NCAM" ], "offsets": [ [ 648, 652 ] ], "normalized": [] }, { "id": "PMID-17971410_T9", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 766, 775 ] ], "normalized": [] }, { "id": "PMID-17971410_T10", "type": "Protein", "text": [ "NCAM" ], "offsets": [ [ 856, 860 ] ], "normalized": [] } ]

[ { "id": "PMID-17971410_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylated" ], "offsets": [ [ 8, 21 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17971410_T1" } ] }, { "id": "PMID-17971410_E2", "type": "Ubiquitination", "trigger": { "text": [ "mono-ubiquitylated" ], "offsets": [ [ 656, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17971410_T8" } ] }, { "id": "PMID-17971410_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitylation" ], "offsets": [ [ 804, 818 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17971410_T10" } ] } ]

[]

[]

[ { "id": "PMID-17980170__text", "type": "abstract", "text": [ "Proteolytic activation and glycosylation of N-acylethanolamine-hydrolyzing acid amidase, a lysosomal enzyme involved in the endocannabinoid metabolism. \nN-acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme hydrolyzing bioactive N-acylethanolamines, including anandamide and N-palmitoylethanolamine. Previously, we suggested that NAAA is glycosylated and proteolytically cleaved. Here, we investigated the mechanism and significance of the cleavage of human NAAA overexpressed in human embryonic kidney 293 cells. Western blotting with anti-NAAA antibody revealed that most of NAAA in the cell homogenate was the cleaved 30-kDa form. However, some of NAAA were released outside the cells and the extracellular enzyme was mostly the uncleaved 48-kDa form. When incubated at pH 4.5, the 48-kDa form was time-dependently converted to the 30-kDa form with concomitant increase in the N-palmitoylethanolamine-hydrolyzing activity. The purified 48-kDa form was also cleaved and activated. However, the cleavage did not proceed at pH 7.4 or in the presence of p-chloromercuribenzoic acid. The mutant C126S was resistant to the cleavage and remained inactive. These results suggested that this specific proteolysis is a self-catalyzed activation step. We next determined N-glycosylation sites of human NAAA by site-directed mutagenesis addressed to asparagine residues in six potential N-glycosylation sites. The results exhibited that Asn-37, Asn-107, Asn-309, and Asn-333 are actual N-glycosylation sites. The glycosylation appeared to play an important role in stabilizing the enzyme protein.\n" ], "offsets": [ [ 0, 1607 ] ] } ]

[ { "id": "PMID-17980170_T1", "type": "Protein", "text": [ "N-acylethanolamine-hydrolyzing acid amidase" ], "offsets": [ [ 44, 87 ] ], "normalized": [] }, { "id": "PMID-17980170_T2", "type": "Protein", "text": [ "N-acylethanolamine-hydrolyzing acid amidase" ], "offsets": [ [ 153, 196 ] ], "normalized": [] }, { "id": "PMID-17980170_T3", "type": "Protein", "text": [ "NAAA" ], "offsets": [ [ 198, 202 ] ], "normalized": [] }, { "id": "PMID-17980170_T4", "type": "Protein", "text": [ "NAAA" ], "offsets": [ [ 349, 353 ] ], "normalized": [] }, { "id": "PMID-17980170_T5", "type": "Protein", "text": [ "NAAA" ], "offsets": [ [ 477, 481 ] ], "normalized": [] }, { "id": "PMID-17980170_T6", "type": "Protein", "text": [ "NAAA" ], "offsets": [ [ 560, 564 ] ], "normalized": [] }, { "id": "PMID-17980170_T7", "type": "Protein", "text": [ "NAAA" ], "offsets": [ [ 596, 600 ] ], "normalized": [] }, { "id": "PMID-17980170_T8", "type": "Protein", "text": [ "NAAA" ], "offsets": [ [ 670, 674 ] ], "normalized": [] }, { "id": "PMID-17980170_T9", "type": "Protein", "text": [ "NAAA" ], "offsets": [ [ 1313, 1317 ] ], "normalized": [] }, { "id": "PMID-17980170_T12", "type": "Entity", "text": [ "Asn-37" ], "offsets": [ [ 1447, 1453 ] ], "normalized": [] }, { "id": "PMID-17980170_T13", "type": "Entity", "text": [ "Asn-107" ], "offsets": [ [ 1455, 1462 ] ], "normalized": [] }, { "id": "PMID-17980170_T14", "type": "Entity", "text": [ "Asn-309" ], "offsets": [ [ 1464, 1471 ] ], "normalized": [] }, { "id": "PMID-17980170_T15", "type": "Entity", "text": [ "Asn-333" ], "offsets": [ [ 1477, 1484 ] ], "normalized": [] } ]

[ { "id": "PMID-17980170_E1", "type": "Glycosylation", "trigger": { "text": [ "glycosylation" ], "offsets": [ [ 27, 40 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17980170_T1" } ] }, { "id": "PMID-17980170_E2", "type": "Glycosylation", "trigger": { "text": [ "glycosylated" ], "offsets": [ [ 357, 369 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17980170_T4" } ] }, { "id": "PMID-17980170_E3", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 1496, 1511 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17980170_T9" }, { "role": "Site", "ref_id": "PMID-17980170_T12" } ] }, { "id": "PMID-17980170_E4", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 1496, 1511 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17980170_T9" }, { "role": "Site", "ref_id": "PMID-17980170_T13" } ] }, { "id": "PMID-17980170_E5", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 1496, 1511 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17980170_T9" }, { "role": "Site", "ref_id": "PMID-17980170_T14" } ] }, { "id": "PMID-17980170_E6", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 1496, 1511 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17980170_T9" }, { "role": "Site", "ref_id": "PMID-17980170_T15" } ] } ]

[ { "id": "PMID-17980170_1", "entity_ids": [ "PMID-17980170_T2", "PMID-17980170_T3" ] } ]

[]

[ { "id": "PMID-17981811__text", "type": "abstract", "text": [ "Lysine 63-linked ubiquitination promotes the formation and autophagic clearance of protein inclusions associated with neurodegenerative diseases. \nAlthough ubiquitin-enriched protein inclusions represent an almost invariant feature of neurodegenerative diseases, the mechanism underlying their biogenesis remains unclear. In particular, whether the topology of ubiquitin linkages influences the dynamics of inclusions is not well explored. Here, we report that lysine 48 (K48)- and lysine 63 (K63)-linked polyubiquitination, as well as monoubiquitin modification contribute to the biogenesis of inclusions. K63-linked polyubiquitin is the most consistent enhancer of inclusions formation. Under basal conditions, ectopic expression of K63 mutant ubiquitin in cultured cells promotes the accumulation of proteins and the formation of intracellular inclusions in the apparent absence of proteasome impairment. When co-expressed with disease-associated tau and SOD1 mutants, K63 ubiquitin mutant facilitates the formation of tau- and SOD-1-positive inclusions. Moreover, K63-linked ubiquitination was found to selectively facilitate the clearance of inclusions via autophagy. These data indicate that K63-linked ubiquitin chains may represent a common denominator underlying inclusions biogenesis, as well as a general cellular strategy for defining cargo destined for the autophagic system. Collectively, our results provide a novel mechanistic route that underlies the life cycle of an inclusion body. Harnessing this pathway may offer innovative approaches in the treatment of neurodegenerative disorders.\n" ], "offsets": [ [ 0, 1606 ] ] } ]

[ { "id": "PMID-17981811_T1", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 156, 165 ] ], "normalized": [] }, { "id": "PMID-17981811_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 361, 370 ] ], "normalized": [] }, { "id": "PMID-17981811_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 540, 549 ] ], "normalized": [] }, { "id": "PMID-17981811_T4", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 622, 631 ] ], "normalized": [] }, { "id": "PMID-17981811_T5", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 746, 755 ] ], "normalized": [] }, { "id": "PMID-17981811_T6", "type": "Protein", "text": [ "tau" ], "offsets": [ [ 950, 953 ] ], "normalized": [] }, { "id": "PMID-17981811_T7", "type": "Protein", "text": [ "SOD1" ], "offsets": [ [ 958, 962 ] ], "normalized": [] }, { "id": "PMID-17981811_T8", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 976, 985 ] ], "normalized": [] }, { "id": "PMID-17981811_T9", "type": "Protein", "text": [ "tau" ], "offsets": [ [ 1022, 1025 ] ], "normalized": [] }, { "id": "PMID-17981811_T10", "type": "Protein", "text": [ "SOD-1" ], "offsets": [ [ 1031, 1036 ] ], "normalized": [] }, { "id": "PMID-17981811_T11", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1209, 1218 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-17983583__text", "type": "abstract", "text": [ "The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle. \nSkeletal muscle atrophy occurs as a side effect of treatment with synthetic glucocorticoids such as dexamethasone (DEX) and is a hallmark of cachectic syndromes associated with increased cortisol levels. The E3 ubiquitin ligase MuRF1 (muscle RING finger protein 1) is transcriptionally upregulated by DEX treatment. Differentiated myotubes treated with DEX undergo depletion of myosin heavy chain protein (MYH), which physically associates with MuRF1. This loss of MYH can be blocked by inhibition of MuRF1 expression. When wild-type and MuRF1(-/-) mice are treated with DEX, the MuRF1(-/-) animals exhibit a relative sparing of MYH. In vitro, MuRF1 is shown to function as an E3 ubiquitin ligase for MYH. These data identify the mechanism by which MYH is depleted under atrophy conditions and demonstrate that inhibition of a single E3 ligase, MuRF1, is sufficient to maintain this important sarcomeric protein.\n" ], "offsets": [ [ 0, 1012 ] ] } ]

[ { "id": "PMID-17983583_T1", "type": "Protein", "text": [ "MuRF1" ], "offsets": [ [ 14, 19 ] ], "normalized": [] }, { "id": "PMID-17983583_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 310, 319 ] ], "normalized": [] }, { "id": "PMID-17983583_T3", "type": "Protein", "text": [ "MuRF1" ], "offsets": [ [ 327, 332 ] ], "normalized": [] }, { "id": "PMID-17983583_T4", "type": "Protein", "text": [ "muscle RING finger protein 1" ], "offsets": [ [ 334, 362 ] ], "normalized": [] }, { "id": "PMID-17983583_T5", "type": "Protein", "text": [ "MuRF1" ], "offsets": [ [ 544, 549 ] ], "normalized": [] }, { "id": "PMID-17983583_T6", "type": "Protein", "text": [ "MuRF1" ], "offsets": [ [ 600, 605 ] ], "normalized": [] }, { "id": "PMID-17983583_T7", "type": "Protein", "text": [ "MuRF1" ], "offsets": [ [ 637, 642 ] ], "normalized": [] }, { "id": "PMID-17983583_T8", "type": "Protein", "text": [ "MuRF1" ], "offsets": [ [ 679, 684 ] ], "normalized": [] }, { "id": "PMID-17983583_T9", "type": "Protein", "text": [ "MuRF1" ], "offsets": [ [ 743, 748 ] ], "normalized": [] }, { "id": "PMID-17983583_T10", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 779, 788 ] ], "normalized": [] }, { "id": "PMID-17983583_T11", "type": "Protein", "text": [ "MuRF1" ], "offsets": [ [ 944, 949 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-17983583_1", "entity_ids": [ "PMID-17983583_T3", "PMID-17983583_T4" ] } ]

[]

[ { "id": "PMID-17989425__text", "type": "abstract", "text": [ "A high-throughput screen measuring ubiquitination of p53 by human mdm2. \nTumor suppressor p53 is typically maintained at low levels in normal cells. In response to cellular stresses, such as DNA damage, p53 is stabilized and can stimulate responses leading to cell cycle arrest or apoptosis. Corresponding to its central role in preventing propagation of damaged cells, mutation or deletion of p53 is found in nearly 50% of all human tumors. Mdm2 (mouse-d-minute 2) and its human ortholog (hmdm2 or hdm2) catalyze the ubiquitination of p53, targeting it for degradation via the proteosome. Thus, the activity of mdm2 is inversely correlated with p53 levels. Based on this, inhibition of human mdm2 activity by a small-molecule therapeutic will lead to net stabilization of p53 and be the basis for development of a novel cancer therapeutic. Previous high-throughput screening assays of mdm2 measured the autoubiquitination activity of mdm2, which occurs in the absence of an acceptor substrate such as p53. The major drawback to this approach is that inhibitors of mdm2 autoubiquitination may lead to a net stabilization of mdm2 and thus have the opposite effect of inhibitors that interfere with p53 ubiquitination. The authors describe the development, validation, and execution of a high-throughput screening measuring the ubiquitination of p53 by mdm2, with p53 labeled with europium and the other substrate (Ub-UbcH5b) labeled with a Cy5 on the ubiquitin. After confirming that known inhibitors are detected with this assay, it was successfully automated and used to query >600,000 compounds from the GlaxoSmithKline collection for mdm2 inhibitors.\n" ], "offsets": [ [ 0, 1654 ] ] } ]

[ { "id": "PMID-17989425_T1", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 53, 56 ] ], "normalized": [] }, { "id": "PMID-17989425_T2", "type": "Protein", "text": [ "mdm2" ], "offsets": [ [ 66, 70 ] ], "normalized": [] }, { "id": "PMID-17989425_T3", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 90, 93 ] ], "normalized": [] }, { "id": "PMID-17989425_T4", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 203, 206 ] ], "normalized": [] }, { "id": "PMID-17989425_T5", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 394, 397 ] ], "normalized": [] }, { "id": "PMID-17989425_T6", "type": "Protein", "text": [ "Mdm2" ], "offsets": [ [ 442, 446 ] ], "normalized": [] }, { "id": "PMID-17989425_T7", "type": "Protein", "text": [ "mouse-d-minute 2" ], "offsets": [ [ 448, 464 ] ], "normalized": [] }, { "id": "PMID-17989425_T8", "type": "Protein", "text": [ "mdm2" ], "offsets": [ [ 491, 495 ] ], "normalized": [] }, { "id": "PMID-17989425_T9", "type": "Protein", "text": [ "hdm2" ], "offsets": [ [ 499, 503 ] ], "normalized": [] }, { "id": "PMID-17989425_T10", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 536, 539 ] ], "normalized": [] }, { "id": "PMID-17989425_T11", "type": "Protein", "text": [ "mdm2" ], "offsets": [ [ 612, 616 ] ], "normalized": [] }, { "id": "PMID-17989425_T12", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 646, 649 ] ], "normalized": [] }, { "id": "PMID-17989425_T13", "type": "Protein", "text": [ "mdm2" ], "offsets": [ [ 693, 697 ] ], "normalized": [] }, { "id": "PMID-17989425_T14", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 773, 776 ] ], "normalized": [] }, { "id": "PMID-17989425_T15", "type": "Protein", "text": [ "mdm2" ], "offsets": [ [ 886, 890 ] ], "normalized": [] }, { "id": "PMID-17989425_T16", "type": "Protein", "text": [ "mdm2" ], "offsets": [ [ 935, 939 ] ], "normalized": [] }, { "id": "PMID-17989425_T17", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1002, 1005 ] ], "normalized": [] }, { "id": "PMID-17989425_T18", "type": "Protein", "text": [ "mdm2" ], "offsets": [ [ 1065, 1069 ] ], "normalized": [] }, { "id": "PMID-17989425_T19", "type": "Protein", "text": [ "mdm2" ], "offsets": [ [ 1124, 1128 ] ], "normalized": [] }, { "id": "PMID-17989425_T20", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1197, 1200 ] ], "normalized": [] }, { "id": "PMID-17989425_T21", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1344, 1347 ] ], "normalized": [] }, { "id": "PMID-17989425_T22", "type": "Protein", "text": [ "mdm2" ], "offsets": [ [ 1351, 1355 ] ], "normalized": [] }, { "id": "PMID-17989425_T23", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1362, 1365 ] ], "normalized": [] }, { "id": "PMID-17989425_T24", "type": "Protein", "text": [ "UbcH5b" ], "offsets": [ [ 1416, 1422 ] ], "normalized": [] }, { "id": "PMID-17989425_T25", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1450, 1459 ] ], "normalized": [] }, { "id": "PMID-17989425_T26", "type": "Protein", "text": [ "mdm2" ], "offsets": [ [ 1637, 1641 ] ], "normalized": [] } ]

[ { "id": "PMID-17989425_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 35, 49 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_T1" } ] }, { "id": "PMID-17989425_E2", "type": "Catalysis", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 35, 49 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_E1" }, { "role": "Cause", "ref_id": "PMID-17989425_T2" } ] }, { "id": "PMID-17989425_E3", "type": "Catalysis", "trigger": { "text": [ "catalyze" ], "offsets": [ [ 505, 513 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_E5" }, { "role": "Cause", "ref_id": "PMID-17989425_T6" } ] }, { "id": "PMID-17989425_E4", "type": "Catalysis", "trigger": { "text": [ "catalyze" ], "offsets": [ [ 505, 513 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_E5" }, { "role": "Cause", "ref_id": "PMID-17989425_T8" } ] }, { "id": "PMID-17989425_E5", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 518, 532 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_T10" } ] }, { "id": "PMID-17989425_E6", "type": "Ubiquitination", "trigger": { "text": [ "autoubiquitination" ], "offsets": [ [ 904, 922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_T16" } ] }, { "id": "PMID-17989425_E7", "type": "Catalysis", "trigger": { "text": [ "autoubiquitination" ], "offsets": [ [ 904, 922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_E6" }, { "role": "Cause", "ref_id": "PMID-17989425_T16" } ] }, { "id": "PMID-17989425_E8", "type": "Ubiquitination", "trigger": { "text": [ "autoubiquitination" ], "offsets": [ [ 1070, 1088 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_T18" } ] }, { "id": "PMID-17989425_E9", "type": "Catalysis", "trigger": { "text": [ "autoubiquitination" ], "offsets": [ [ 1070, 1088 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_E8" }, { "role": "Cause", "ref_id": "PMID-17989425_T18" } ] }, { "id": "PMID-17989425_E10", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1201, 1215 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_T20" } ] }, { "id": "PMID-17989425_E11", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1326, 1340 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_T21" } ] }, { "id": "PMID-17989425_E12", "type": "Catalysis", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1326, 1340 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-17989425_E11" }, { "role": "Cause", "ref_id": "PMID-17989425_T22" } ] } ]

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[]

[ { "id": "PMID-17989773__text", "type": "abstract", "text": [ "Inheritance of an epigenetic mark: the CpG DNA methyltransferase 1 is required for de novo establishment of a complex pattern of non-CpG methylation. \nSite-specific methylation of cytosines is a key epigenetic mark of vertebrate DNA. While a majority of the methylated residues are in the symmetrical (meC)pG:Gp(meC) configuration, a smaller, but significant fraction is found in the CpA, CpT and CpC asymmetric (non-CpG) dinucleotides. CpG methylation is reproducibly maintained by the activity of the DNA methyltransferase 1 (Dnmt1) on the newly replicated hemimethylated substrates (meC)pG:GpC. On the other hand, establishment and hereditary maintenance of non-CpG methylation patterns have not been analyzed in detail. We previously reported the occurrence of site- and allele-specific methylation at both CpG and non-CpG sites. Here we characterize a hereditary complex of non-CpG methylation, with the transgenerational maintenance of three distinct profiles in a constant ratio, associated with extensive CpG methylation. These observations raised the question of the signal leading to the maintenance of the pattern of asymmetric methylation. The complete non-CpG pattern was reinstated at each generation in spite of the fact that the majority of the sperm genomes contained either none or only one methylated non-CpG site. This observation led us to the hypothesis that the stable CpG patterns might act as blueprints for the maintenance of non-CpG DNA methylation. As predicted, non-CpG DNA methylation profiles were abrogated in a mutant lacking Dnmt1, the enzymes responsible for CpG methylation, but not in mutants defective for either Dnmt3a or Dnmt2.\n" ], "offsets": [ [ 0, 1668 ] ] } ]

[ { "id": "PMID-17989773_T1", "type": "Protein", "text": [ "DNA methyltransferase 1" ], "offsets": [ [ 43, 66 ] ], "normalized": [] }, { "id": "PMID-17989773_T2", "type": "Protein", "text": [ "DNA methyltransferase 1" ], "offsets": [ [ 503, 526 ] ], "normalized": [] }, { "id": "PMID-17989773_T3", "type": "Protein", "text": [ "Dnmt1" ], "offsets": [ [ 528, 533 ] ], "normalized": [] }, { "id": "PMID-17989773_T4", "type": "Protein", "text": [ "Dnmt1" ], "offsets": [ [ 1559, 1564 ] ], "normalized": [] }, { "id": "PMID-17989773_T5", "type": "Protein", "text": [ "Dnmt3a" ], "offsets": [ [ 1651, 1657 ] ], "normalized": [] }, { "id": "PMID-17989773_T6", "type": "Protein", "text": [ "Dnmt2" ], "offsets": [ [ 1661, 1666 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-17989773_1", "entity_ids": [ "PMID-17989773_T2", "PMID-17989773_T3" ] } ]

[]

[ { "id": "PMID-18004747__text", "type": "abstract", "text": [ "CpG island hypermethylation in cell-free serum DNA identifies patients with localized prostate cancer. \nBACKGROUND: One of the earliest and most common epigenetic events in prostate carcinogenesis is DNA CpG island (CGI) hypermethylation. Our aim was to analyze the diagnostic and prognostic possibilities of multigene methylation analysis in cell-free serum DNA of prostate cancer (PCA) patients. METHODS: We analyzed serum samples from 226 consecutive patients (168 PCA; 42 benign prostatic hyperplasia (BPH); 5 incidental PCA; 11 healthy individuals). Cell-free DNA was digested with methylation-sensitive restriction endonucleases (HpaII and HinP1I). Subsequently, CGI hypermethylation at GSTP1, PTGS2, Reprimo, and TIG1 was assessed using real-time PCR. RESULTS: CGI hypermethylation at GSTP1, TIG1, PTGS2, and Reprimo was more frequent in PCA (42.3%, 9.5%, 2.4%, and 1.2%, respectively) compared to BPH (7.7%, 0%, 0%, and 0%, respectively) and healthy individuals (all 0%) with a statistical significant difference of GSTP1 (P < 0.0001) and TIG1 (P = 0.038). GSTP1 hypermethylation was also detected in four patients with incidental PCA. Hypermethylation in serum DNA at GSTP1 and hypermethylation at any gene site distinguished between PCA and BPH patients in a highly specific (92%) but less sensitive (42-47%) manner. Neither CGI hypermethylation at a single gene loci nor the combination of multiple gene sites was correlated to the pathological stage, grade or biochemical recurrence following radical prostatectomy. CONCLUSIONS: The detection of aberrant hypermethylation in cell-free serum DNA allows the highly specific diagnosis of PCA. A test based on GSTP1 hypermethylation in serum samples of patients with suspected PCA may help to identify men with increased risk of harboring PCA despite negative prostate biopsy.\n" ], "offsets": [ [ 0, 1835 ] ] } ]

[ { "id": "PMID-18004747_T1", "type": "Protein", "text": [ "HpaII" ], "offsets": [ [ 636, 641 ] ], "normalized": [] }, { "id": "PMID-18004747_T2", "type": "Protein", "text": [ "HinP1I" ], "offsets": [ [ 646, 652 ] ], "normalized": [] }, { "id": "PMID-18004747_T3", "type": "Protein", "text": [ "GSTP1" ], "offsets": [ [ 693, 698 ] ], "normalized": [] }, { "id": "PMID-18004747_T4", "type": "Protein", "text": [ "PTGS2" ], "offsets": [ [ 700, 705 ] ], "normalized": [] }, { "id": "PMID-18004747_T5", "type": "Protein", "text": [ "Reprimo" ], "offsets": [ [ 707, 714 ] ], "normalized": [] }, { "id": "PMID-18004747_T6", "type": "Protein", "text": [ "TIG1" ], "offsets": [ [ 720, 724 ] ], "normalized": [] }, { "id": "PMID-18004747_T7", "type": "Protein", "text": [ "GSTP1" ], "offsets": [ [ 792, 797 ] ], "normalized": [] }, { "id": "PMID-18004747_T8", "type": "Protein", "text": [ "TIG1" ], "offsets": [ [ 799, 803 ] ], "normalized": [] }, { "id": "PMID-18004747_T9", "type": "Protein", "text": [ "PTGS2" ], "offsets": [ [ 805, 810 ] ], "normalized": [] }, { "id": "PMID-18004747_T10", "type": "Protein", "text": [ "Reprimo" ], "offsets": [ [ 816, 823 ] ], "normalized": [] }, { "id": "PMID-18004747_T11", "type": "Protein", "text": [ "GSTP1" ], "offsets": [ [ 1024, 1029 ] ], "normalized": [] }, { "id": "PMID-18004747_T12", "type": "Protein", "text": [ "TIG1" ], "offsets": [ [ 1047, 1051 ] ], "normalized": [] }, { "id": "PMID-18004747_T13", "type": "Protein", "text": [ "GSTP1" ], "offsets": [ [ 1065, 1070 ] ], "normalized": [] }, { "id": "PMID-18004747_T14", "type": "Protein", "text": [ "GSTP1" ], "offsets": [ [ 1177, 1182 ] ], "normalized": [] }, { "id": "PMID-18004747_T15", "type": "Protein", "text": [ "GSTP1" ], "offsets": [ [ 1668, 1673 ] ], "normalized": [] }, { "id": "PMID-18004747_T16", "type": "Entity", "text": [ "CGI" ], "offsets": [ [ 669, 672 ] ], "normalized": [] }, { "id": "PMID-18004747_T18", "type": "Entity", "text": [ "CGI" ], "offsets": [ [ 768, 771 ] ], "normalized": [] } ]

[ { "id": "PMID-18004747_E1", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 673, 689 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18004747_T3" }, { "role": "Site", "ref_id": "PMID-18004747_T16" } ] }, { "id": "PMID-18004747_E2", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 673, 689 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18004747_T4" }, { "role": "Site", "ref_id": "PMID-18004747_T16" } ] }, { "id": "PMID-18004747_E3", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 673, 689 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18004747_T5" }, { "role": "Site", "ref_id": "PMID-18004747_T16" } ] }, { "id": "PMID-18004747_E4", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 673, 689 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18004747_T6" }, { "role": "Site", "ref_id": "PMID-18004747_T16" } ] }, { "id": "PMID-18004747_E5", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 772, 788 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18004747_T7" }, { "role": "Site", "ref_id": "PMID-18004747_T18" } ] }, { "id": "PMID-18004747_E6", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 772, 788 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18004747_T8" }, { "role": "Site", "ref_id": "PMID-18004747_T18" } ] }, { "id": "PMID-18004747_E7", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 772, 788 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18004747_T9" }, { "role": "Site", "ref_id": "PMID-18004747_T18" } ] }, { "id": "PMID-18004747_E8", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 772, 788 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18004747_T10" }, { "role": "Site", "ref_id": "PMID-18004747_T18" } ] }, { "id": "PMID-18004747_E9", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 1071, 1087 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18004747_T13" } ] }, { "id": "PMID-18004747_E10", "type": "DNA_methylation", "trigger": { "text": [ "Hypermethylation" ], "offsets": [ [ 1144, 1160 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18004747_T14" } ] }, { "id": "PMID-18004747_E11", "type": "DNA_methylation", "trigger": { "text": [ "hypermethylation" ], "offsets": [ [ 1674, 1690 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18004747_T15" } ] } ]

[]

[]

[ { "id": "PMID-1803862__text", "type": "abstract", "text": [ "Role of glycosilation in the susceptibility of \"acid labile\" interferon alpha to acid treatment. \nMononuclear cells from blood of healthy donors produce acid-labile interferon (IFN) alpha when stimulated with HIV-infected cells. A large proportion of this IFN appears to be glycosilated, as treatment with neuraminidase causes a shift of the isoelectric point (IP) from pH = 5.2-5.4 to pH = 5.8-6.2. To assess the role of glycosilation in determining the instability of antiviral activity after exposure to acid (pH lower than 4) peripheral blood mononuclear cells (PBMC) were induced to produce IFN with HIV-infected cells in the presence of tunicamycin, an inhibitor of glycosilation. The IFN produced under such experimental conditions (tu-IFN) was acid-stable. Tu-IFN was compared to a standard acid-labile IFN by affinity chromatography on Con A-sepharose. The elution pattern showed that tu-IFN does not bind to the gel, whereas the acid-labile IFN is eluted in two fractions, one unbound, which is stable at pH2, and one bound, which retains the initial acid-lability. These results suggest that acid-labile IFN alpha is largely glycosilated, and that the presence of glycosilated molecules contribute to render the IFN molecule unstable at acidic pH. It is to be determined whether some glycosilated molecule present in the IFN preparation, or glycosilation of the IFN molecule per se, is responsible for acid-lability of the antiviral activity.\n" ], "offsets": [ [ 0, 1454 ] ] } ]

[ { "id": "PMID-1803862_T1", "type": "Protein", "text": [ "Con A" ], "offsets": [ [ 845, 850 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18054500__text", "type": "abstract", "text": [ "Overexpression of post-translationally modified peptides in Escherichia coli by co-expression with modifying enzymes. \nPost-translational modification plays crucial roles in signal transduction in eukaryotic cells. To elucidate the biological function of a protein with a specific post-translational modification, it is necessary to isolate the modified protein. However, it is difficult to incorporate a modified amino acid into a specific position of a protein, in particular, in a large-scale preparation. In order to prepare post-translationally modified proteins in Escherichia coli (E. coli), we have constructed co-expression vectors that contain protein and corresponding enzyme genes. The protein and enzyme are co-expressed in the same E. coli cells and the protein is post-translationally modified in vivo. By using this system, the transcriptional activator cyclic-AMP-response-element-binding protein (CREB) was phosphorylated at Ser-133 and the hypoxia-inducible factor-1alpha (HIF-1alpha) was hydroxylated at Asn-803 in E. coli. Although the constructs of the proteins we used are very flexible and susceptible to degradation by proteases in E. coli when they are expressed alone, the B1 domain of streptococcal protein G (GB1) fused to the N-terminus of the proteins increased the yields dramatically. Site-specific phosphorylation of CREB and hydroxylation of HIF-1alpha were confirmed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and NMR. Our GB1-fusion co-expression system can be used in the same way as conventional protein expression in E. coli, making it a flexible and economical method to produce a large amount of a post-translationally modified protein.\n" ], "offsets": [ [ 0, 1710 ] ] } ]

[ { "id": "PMID-18054500_T1", "type": "Protein", "text": [ "hypoxia-inducible factor-1alpha" ], "offsets": [ [ 959, 990 ] ], "normalized": [] }, { "id": "PMID-18054500_T2", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 992, 1002 ] ], "normalized": [] }, { "id": "PMID-18054500_T3", "type": "Protein", "text": [ "protein G" ], "offsets": [ [ 1227, 1236 ] ], "normalized": [] }, { "id": "PMID-18054500_T4", "type": "Protein", "text": [ "G" ], "offsets": [ [ 1238, 1239 ] ], "normalized": [] }, { "id": "PMID-18054500_T5", "type": "Protein", "text": [ "HIF-1alpha" ], "offsets": [ [ 1377, 1387 ] ], "normalized": [] }, { "id": "PMID-18054500_T7", "type": "Entity", "text": [ "Asn-803" ], "offsets": [ [ 1024, 1031 ] ], "normalized": [] } ]

[ { "id": "PMID-18054500_E1", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylated" ], "offsets": [ [ 1008, 1020 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18054500_T1" }, { "role": "Site", "ref_id": "PMID-18054500_T7" } ] }, { "id": "PMID-18054500_E2", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 1360, 1373 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18054500_T5" } ] } ]

[ { "id": "PMID-18054500_1", "entity_ids": [ "PMID-18054500_T1", "PMID-18054500_T2" ] }, { "id": "PMID-18054500_2", "entity_ids": [ "PMID-18054500_T3", "PMID-18054500_T4" ] } ]

[]

[ { "id": "PMID-18056411__text", "type": "abstract", "text": [ "Site-specific ubiquitination exposes a linear motif to promote interferon-alpha receptor endocytosis. \nLigand-induced endocytosis and lysosomal degradation of cognate receptors regulate the extent of cell signaling. Along with linear endocytic motifs that recruit the adaptin protein complex 2 (AP2)-clathrin molecules, monoubiquitination of receptors has emerged as a major endocytic signal. By investigating ubiquitin-dependent lysosomal degradation of the interferon (IFN)-alpha/beta receptor 1 (IFNAR1) subunit of the type I IFN receptor, we reveal that IFNAR1 is polyubiquitinated via both Lys48- and Lys63-linked chains. The SCF(betaTrcp) (Skp1-Cullin1-F-box complex) E3 ubiquitin ligase that mediates IFNAR1 ubiquitination and degradation in cells can conjugate both types of chains in vitro. Although either polyubiquitin linkage suffices for postinternalization sorting, both types of chains are necessary but not sufficient for robust IFNAR1 turnover and internalization. These processes also depend on the proximity of ubiquitin-acceptor lysines to a linear endocytic motif and on its integrity. Furthermore, ubiquitination of IFNAR1 promotes its interaction with the AP2 adaptin complex that is required for the robust internalization of IFNAR1, implicating cooperation between site-specific ubiquitination and the linear endocytic motif in regulating this process.\n" ], "offsets": [ [ 0, 1378 ] ] } ]

[ { "id": "PMID-18056411_T1", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 410, 419 ] ], "normalized": [] }, { "id": "PMID-18056411_T2", "type": "Protein", "text": [ "interferon (IFN)-alpha/beta receptor 1" ], "offsets": [ [ 459, 497 ] ], "normalized": [] }, { "id": "PMID-18056411_T3", "type": "Protein", "text": [ "IFNAR1" ], "offsets": [ [ 499, 505 ] ], "normalized": [] }, { "id": "PMID-18056411_T4", "type": "Protein", "text": [ "IFNAR1" ], "offsets": [ [ 558, 564 ] ], "normalized": [] }, { "id": "PMID-18056411_T5", "type": "Protein", "text": [ "betaTrcp" ], "offsets": [ [ 635, 643 ] ], "normalized": [] }, { "id": "PMID-18056411_T6", "type": "Protein", "text": [ "Skp1" ], "offsets": [ [ 646, 650 ] ], "normalized": [] }, { "id": "PMID-18056411_T7", "type": "Protein", "text": [ "Cullin1" ], "offsets": [ [ 651, 658 ] ], "normalized": [] }, { "id": "PMID-18056411_T8", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 677, 686 ] ], "normalized": [] }, { "id": "PMID-18056411_T9", "type": "Protein", "text": [ "IFNAR1" ], "offsets": [ [ 708, 714 ] ], "normalized": [] }, { "id": "PMID-18056411_T10", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 820, 829 ] ], "normalized": [] }, { "id": "PMID-18056411_T11", "type": "Protein", "text": [ "IFNAR1" ], "offsets": [ [ 945, 951 ] ], "normalized": [] }, { "id": "PMID-18056411_T12", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1030, 1039 ] ], "normalized": [] }, { "id": "PMID-18056411_T13", "type": "Protein", "text": [ "IFNAR1" ], "offsets": [ [ 1138, 1144 ] ], "normalized": [] }, { "id": "PMID-18056411_T14", "type": "Protein", "text": [ "IFNAR1" ], "offsets": [ [ 1250, 1256 ] ], "normalized": [] } ]

[ { "id": "PMID-18056411_E1", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitinated" ], "offsets": [ [ 568, 585 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18056411_T4" } ] }, { "id": "PMID-18056411_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 715, 729 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18056411_T9" } ] }, { "id": "PMID-18056411_E3", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1120, 1134 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18056411_T13" } ] } ]

[ { "id": "PMID-18056411_1", "entity_ids": [ "PMID-18056411_T2", "PMID-18056411_T3" ] } ]

[]

[ { "id": "PMID-18056437__text", "type": "abstract", "text": [ "Direct transcriptional activation of promyelocytic leukemia protein by IFN regulatory factor 3 induces the p53-dependent growth inhibition of cancer cells. \nIFN regulatory factor 3 (IRF3) is a transcriptional factor that plays a crucial role in activation of innate immunity and inflammation in response to viral infection, and is also involved in p53-dependent inhibition of cell growth. Although functional activation of IRF3 by viral infection is relatively well documented, the biological role and regulatory mechanism underlying cell growth inhibition by IRF3 are poorly understood. Here, we show a novel regulatory pathway connecting IRF3-promyelocytic leukemia protein (PML)-p53 in primary and cancer cell lines. Overexpression of IRF3 induces p53-dependent cell growth inhibition in cancer cell lines with normal p53 activity. In addition, doxycycline-induced expression of IRF3 in U87MG cells inhibits tumor growth in nude mice in vivo. IRF3 is found to increase expression of PML by a direct transcriptional activation as determined by PML-promoter-luciferase and chromatin immunoprecipitation assays. When PML is depleted by RNA interference-mediated knockdown, IRF3 fails to increase p53 acetylation and its transcriptional activity. Taken together, the results of the present study indicate that direct transcriptional activation of PML by IRF3 results in the p53-dependent growth inhibition of normal and cancer cells in vitro and in vivo, which is suggestive of a novel regulatory network between the innate immune response and tumor suppression.\n" ], "offsets": [ [ 0, 1562 ] ] } ]

[ { "id": "PMID-18056437_T1", "type": "Protein", "text": [ "promyelocytic leukemia" ], "offsets": [ [ 37, 59 ] ], "normalized": [] }, { "id": "PMID-18056437_T2", "type": "Protein", "text": [ "IFN regulatory factor 3" ], "offsets": [ [ 71, 94 ] ], "normalized": [] }, { "id": "PMID-18056437_T3", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 107, 110 ] ], "normalized": [] }, { "id": "PMID-18056437_T4", "type": "Protein", "text": [ "IFN regulatory factor 3" ], "offsets": [ [ 157, 180 ] ], "normalized": [] }, { "id": "PMID-18056437_T5", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 182, 186 ] ], "normalized": [] }, { "id": "PMID-18056437_T6", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 348, 351 ] ], "normalized": [] }, { "id": "PMID-18056437_T7", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 423, 427 ] ], "normalized": [] }, { "id": "PMID-18056437_T8", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 560, 564 ] ], "normalized": [] }, { "id": "PMID-18056437_T9", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 640, 644 ] ], "normalized": [] }, { "id": "PMID-18056437_T10", "type": "Protein", "text": [ "promyelocytic leukemia" ], "offsets": [ [ 645, 667 ] ], "normalized": [] }, { "id": "PMID-18056437_T11", "type": "Protein", "text": [ "PML" ], "offsets": [ [ 677, 680 ] ], "normalized": [] }, { "id": "PMID-18056437_T12", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 682, 685 ] ], "normalized": [] }, { "id": "PMID-18056437_T13", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 738, 742 ] ], "normalized": [] }, { "id": "PMID-18056437_T14", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 751, 754 ] ], "normalized": [] }, { "id": "PMID-18056437_T15", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 821, 824 ] ], "normalized": [] }, { "id": "PMID-18056437_T16", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 882, 886 ] ], "normalized": [] }, { "id": "PMID-18056437_T17", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 946, 950 ] ], "normalized": [] }, { "id": "PMID-18056437_T18", "type": "Protein", "text": [ "PML" ], "offsets": [ [ 986, 989 ] ], "normalized": [] }, { "id": "PMID-18056437_T19", "type": "Protein", "text": [ "PML" ], "offsets": [ [ 1046, 1049 ] ], "normalized": [] }, { "id": "PMID-18056437_T20", "type": "Protein", "text": [ "luciferase" ], "offsets": [ [ 1059, 1069 ] ], "normalized": [] }, { "id": "PMID-18056437_T21", "type": "Protein", "text": [ "PML" ], "offsets": [ [ 1117, 1120 ] ], "normalized": [] }, { "id": "PMID-18056437_T22", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 1173, 1177 ] ], "normalized": [] }, { "id": "PMID-18056437_T23", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1196, 1199 ] ], "normalized": [] }, { "id": "PMID-18056437_T24", "type": "Protein", "text": [ "PML" ], "offsets": [ [ 1346, 1349 ] ], "normalized": [] }, { "id": "PMID-18056437_T25", "type": "Protein", "text": [ "IRF3" ], "offsets": [ [ 1353, 1357 ] ], "normalized": [] }, { "id": "PMID-18056437_T26", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1373, 1376 ] ], "normalized": [] } ]

[ { "id": "PMID-18056437_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1200, 1211 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18056437_T23" } ] } ]

[ { "id": "PMID-18056437_1", "entity_ids": [ "PMID-18056437_T4", "PMID-18056437_T5" ] }, { "id": "PMID-18056437_2", "entity_ids": [ "PMID-18056437_T10", "PMID-18056437_T11" ] } ]

[]

[ { "id": "PMID-18056459__text", "type": "abstract", "text": [ "Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET. \nHistone deacetylase inhibitors (HDIs) and HAMLET (human alpha-lactalbumin made lethal to tumor cells) interact with histones, modify the structure of chromatin, and trigger tumor cell death. This study investigated how the combination of HDIs and HAMLET influences cell viability, histone acetylation, and DNA integrity. The pretreatment of tumor cells with HDIs was shown to enhance the lethal effect of HAMLET and the histone hyperacetylation response to HDIs increased even further after HAMLET treatment. HDIs and HAMLET were shown to target different histone domains as HAMLET bound tailless core histones, whereas HDIs modify the acetylation of the histone tail. DNA damage in response to HAMLET was increased by HDIs. The DNA repair response (p21WAFI expression) was induced by both agonists but abolished when the two agonists were combined. The results suggest that the synergy of HDIs and HAMLET is based on different but converging death pathways, both involving chromatin alterations. We speculate that HAMLET and HDIs might be combined to promote tumor cell death in vivo.\n" ], "offsets": [ [ 0, 1160 ] ] } ]

[ { "id": "PMID-18056459_T1", "type": "Protein", "text": [ "Histone" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "PMID-18056459_T2", "type": "Protein", "text": [ "Histone" ], "offsets": [ [ 74, 81 ] ], "normalized": [] }, { "id": "PMID-18056459_T3", "type": "Protein", "text": [ "alpha-lactalbumin" ], "offsets": [ [ 130, 147 ] ], "normalized": [] }, { "id": "PMID-18056459_T4", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 190, 198 ] ], "normalized": [] }, { "id": "PMID-18056459_T5", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 355, 362 ] ], "normalized": [] }, { "id": "PMID-18056459_T6", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 494, 501 ] ], "normalized": [] }, { "id": "PMID-18056459_T7", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 630, 637 ] ], "normalized": [] }, { "id": "PMID-18056459_T8", "type": "Protein", "text": [ "histones" ], "offsets": [ [ 676, 684 ] ], "normalized": [] }, { "id": "PMID-18056459_T9", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 729, 736 ] ], "normalized": [] }, { "id": "PMID-18056459_T10", "type": "Protein", "text": [ "p21" ], "offsets": [ [ 824, 827 ] ], "normalized": [] }, { "id": "PMID-18056459_T11", "type": "Protein", "text": [ "WAFI" ], "offsets": [ [ 827, 831 ] ], "normalized": [] }, { "id": "PMID-18056459_T15", "type": "Entity", "text": [ "tail" ], "offsets": [ [ 737, 741 ] ], "normalized": [] } ]

[ { "id": "PMID-18056459_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 363, 374 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18056459_T5" } ] }, { "id": "PMID-18056459_E2", "type": "Acetylation", "trigger": { "text": [ "hyperacetylation" ], "offsets": [ [ 502, 518 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18056459_T6" } ] }, { "id": "PMID-18056459_E3", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 710, 721 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18056459_T9" }, { "role": "Site", "ref_id": "PMID-18056459_T15" } ] } ]

[ { "id": "PMID-18056459_1", "entity_ids": [ "PMID-18056459_T10", "PMID-18056459_T11" ] } ]

[]

[ { "id": "PMID-18059167__text", "type": "abstract", "text": [ "Inhibition of Stat3 activity by YC-1 enhances chemo-sensitivity in hepatocellular carcinoma. \nThe present study investigated the effect of YC-1, a novel anti-cancer agent, on the chemo-sensitivity of hepatocellular carcinoma (HCC). YC-1 was administered with chemo-cytotoxic drug, cisplatin, both in vitro and in vivo. YC-1 alone downregulated the expression of phosphorylated form of signal transducers and activators of transcription 3 (P-Stat3[705]), a key mediator in chemo-resistance. When combined with cisplatin, YC-1 further promoted tumor cell apoptosis, decreased the expression of P-Stat3(705), Bcl-xL, CyclinD1 and survivin, and induced the cleavage of caspase 9 and PARP. Overexpression of Stat3 reversed YC-1 induced cell death. YC-1 inhibited Stat3 activity by enhancing the polyubiquitination of P-Stat3(705) induced by cisplatin. In the in vivo setting, YC-1 combined with cisplatin remarkably suppressed tumor growth in a HCC xenograft model, and this effect was also accompanied by YC-1 mediated downregulation of P-Stat3(705), Bcl-xL, Cyclin D1 and survivin, and induction of cleaved caspase 9 and PARP in the tumor tissues. In conclusion, the present study demonstrated a novel anti-cancer effect of YC-1 in enhancing chemo-sensitivity of HCC cells to cisplatin through a Stat3 dependent manner. This finding provides insight into design of a new therapeutic strategy to improve efficacy of chemotherapy in HCC patients.\n" ], "offsets": [ [ 0, 1442 ] ] } ]

[ { "id": "PMID-18059167_T1", "type": "Protein", "text": [ "Stat3" ], "offsets": [ [ 14, 19 ] ], "normalized": [] }, { "id": "PMID-18059167_T2", "type": "Protein", "text": [ "signal transducers and activators of transcription 3" ], "offsets": [ [ 385, 437 ] ], "normalized": [] }, { "id": "PMID-18059167_T3", "type": "Protein", "text": [ "Stat3" ], "offsets": [ [ 441, 446 ] ], "normalized": [] }, { "id": "PMID-18059167_T4", "type": "Protein", "text": [ "Stat3" ], "offsets": [ [ 594, 599 ] ], "normalized": [] }, { "id": "PMID-18059167_T5", "type": "Protein", "text": [ "Bcl-xL" ], "offsets": [ [ 606, 612 ] ], "normalized": [] }, { "id": "PMID-18059167_T6", "type": "Protein", "text": [ "CyclinD1" ], "offsets": [ [ 614, 622 ] ], "normalized": [] }, { "id": "PMID-18059167_T7", "type": "Protein", "text": [ "survivin" ], "offsets": [ [ 627, 635 ] ], "normalized": [] }, { "id": "PMID-18059167_T8", "type": "Protein", "text": [ "caspase 9" ], "offsets": [ [ 665, 674 ] ], "normalized": [] }, { "id": "PMID-18059167_T9", "type": "Protein", "text": [ "Stat3" ], "offsets": [ [ 703, 708 ] ], "normalized": [] }, { "id": "PMID-18059167_T10", "type": "Protein", "text": [ "Stat3" ], "offsets": [ [ 758, 763 ] ], "normalized": [] }, { "id": "PMID-18059167_T11", "type": "Protein", "text": [ "Stat3" ], "offsets": [ [ 814, 819 ] ], "normalized": [] }, { "id": "PMID-18059167_T12", "type": "Protein", "text": [ "Stat3" ], "offsets": [ [ 1035, 1040 ] ], "normalized": [] }, { "id": "PMID-18059167_T13", "type": "Protein", "text": [ "Bcl-xL" ], "offsets": [ [ 1047, 1053 ] ], "normalized": [] }, { "id": "PMID-18059167_T14", "type": "Protein", "text": [ "Cyclin D1" ], "offsets": [ [ 1055, 1064 ] ], "normalized": [] }, { "id": "PMID-18059167_T15", "type": "Protein", "text": [ "survivin" ], "offsets": [ [ 1069, 1077 ] ], "normalized": [] }, { "id": "PMID-18059167_T16", "type": "Protein", "text": [ "caspase 9" ], "offsets": [ [ 1104, 1113 ] ], "normalized": [] }, { "id": "PMID-18059167_T17", "type": "Protein", "text": [ "Stat3" ], "offsets": [ [ 1293, 1298 ] ], "normalized": [] }, { "id": "PMID-18059167_T19", "type": "Entity", "text": [ "705" ], "offsets": [ [ 447, 450 ] ], "normalized": [] } ]

[ { "id": "PMID-18059167_E1", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 362, 376 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18059167_T2" }, { "role": "Site", "ref_id": "PMID-18059167_T19" } ] }, { "id": "PMID-18059167_E2", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 790, 808 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18059167_T11" } ] } ]

[ { "id": "PMID-18059167_1", "entity_ids": [ "PMID-18059167_T2", "PMID-18059167_T3" ] } ]

[]

[ { "id": "PMID-18063574__text", "type": "abstract", "text": [ "Kinetic rationale for selectivity toward N- and C-terminal oxygen-dependent degradation domain substrates mediated by a loop region of hypoxia-inducible factor prolyl hydroxylases. \nHydroxylation of two conserved prolyl residues in the N- and C-terminal oxygen-dependent degradation domains (NODD and CODD) of the alpha-subunit of hypoxia-inducible factor (HIF) signals for its degradation via the ubiquitin-proteasome pathway. In human cells, three prolyl hydroxylases (PHDs 1-3) belonging to the Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase family catalyze prolyl hydroxylation with differing selectivity for CODD and NODD. Sequence analysis of the catalytic domains of the PHDs in the light of crystal structures for PHD2, and results for other 2OG oxygenases, suggested that either the C-terminal region or a loop linking two beta-strands (beta2 and beta3 in human PHD2) are important in determining substrate selectivity. Mutation analyses on PHD2 revealed that the beta2beta3 loop is a major determinant in conferring selectivity for CODD over NODD peptides. A chimeric PHD in which the beta2beta3 loop of PHD2 was replaced with that of PHD3 displayed an almost complete selectivity for CODD (in competition experiments), as observed for wild-type PHD3. CODD was observed to bind much more tightly to this chimeric protein than the wild type PHD2 catalytic domain.\n" ], "offsets": [ [ 0, 1378 ] ] } ]

[ { "id": "PMID-18063574_T1", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 398, 407 ] ], "normalized": [] }, { "id": "PMID-18063574_T2", "type": "Protein", "text": [ "PHDs 1" ], "offsets": [ [ 471, 477 ] ], "normalized": [] }, { "id": "PMID-18063574_T3", "type": "Protein", "text": [ "3" ], "offsets": [ [ 478, 479 ] ], "normalized": [] }, { "id": "PMID-18063574_T4", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 727, 731 ] ], "normalized": [] }, { "id": "PMID-18063574_T5", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 876, 880 ] ], "normalized": [] }, { "id": "PMID-18063574_T6", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 955, 959 ] ], "normalized": [] }, { "id": "PMID-18063574_T7", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 1119, 1123 ] ], "normalized": [] }, { "id": "PMID-18063574_T8", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 1150, 1154 ] ], "normalized": [] }, { "id": "PMID-18063574_T9", "type": "Protein", "text": [ "PHD3" ], "offsets": [ [ 1261, 1265 ] ], "normalized": [] }, { "id": "PMID-18063574_T10", "type": "Protein", "text": [ "PHD2" ], "offsets": [ [ 1355, 1359 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18065756__text", "type": "abstract", "text": [ "The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. \nVery little is known about SET- and MYND-containing protein 2 (SMYD2), a member of the SMYD protein family. However, the interest in better understanding the roles of SMYD2 has grown because of recent reports indicating that SMYD2 methylates p53 and histone H3. In this study, we present a combined proteomics and genomics study of SMYD2 designed to elucidate its molecular roles. We report the cytosolic and nuclear interactome of SMYD2 using a combination of immunoprecipitation coupled with high throughput MS, chromatin immunoprecipitation coupled with high throughput MS, and co-immunoprecipitation methods. In particular, we report that SMYD2 interacted with HSP90alpha independently of the SET and MYND domains, with EBP41L3 through the MYND domain, and with p53 through the SET domain. We demonstrated that the interaction of SMYD2 with HSP90alpha enhances SMYD2 histone methyltransferase activity and specificity for histone H3 at lysine 4 (H3K4) in vitro. Interestingly histone H3K36 methyltransferase activity was independent of its interaction with HSP90alpha similar to LSD1 dependence on the androgen receptor. We also showed that the SET domain is required for the methylation at H3K4. We demonstrated using a modified chromatin immunoprecipitation protocol that the SMYD2 gain of function leads to an increase in H3K4 methylation in vivo, whereas no observable levels of H3K36 were detected. We also report that the SMYD2 gain of function was correlated with the up-regulation of 37 and down-regulation of four genes, the majority of which are involved in the cell cycle, chromatin remodeling, and transcriptional regulation. TACC2 is one of the genes up-regulated as a result of SMYD2 gain of function. Up-regulation of TACC2 by SMYD2 occurred as a result of SMYD2 binding to the TACC2 promoter where it methylates H3K4. Furthermore the combination of the SMYD2 interactome with the gene expression data suggests that some of the genes regulated by SMYD2 are closely associated with SMYD2-interacting proteins.\n" ], "offsets": [ [ 0, 2130 ] ] } ]

[ { "id": "PMID-18065756_T1", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 61, 66 ] ], "normalized": [] }, { "id": "PMID-18065756_T2", "type": "Protein", "text": [ "SET- and MYND-containing protein 2" ], "offsets": [ [ 129, 163 ] ], "normalized": [] }, { "id": "PMID-18065756_T3", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 165, 170 ] ], "normalized": [] }, { "id": "PMID-18065756_T4", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 269, 274 ] ], "normalized": [] }, { "id": "PMID-18065756_T5", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 327, 332 ] ], "normalized": [] }, { "id": "PMID-18065756_T6", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 344, 347 ] ], "normalized": [] }, { "id": "PMID-18065756_T7", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 352, 362 ] ], "normalized": [] }, { "id": "PMID-18065756_T8", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 434, 439 ] ], "normalized": [] }, { "id": "PMID-18065756_T9", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 534, 539 ] ], "normalized": [] }, { "id": "PMID-18065756_T10", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 745, 750 ] ], "normalized": [] }, { "id": "PMID-18065756_T11", "type": "Protein", "text": [ "HSP90alpha" ], "offsets": [ [ 767, 777 ] ], "normalized": [] }, { "id": "PMID-18065756_T12", "type": "Protein", "text": [ "EBP41L3" ], "offsets": [ [ 826, 833 ] ], "normalized": [] }, { "id": "PMID-18065756_T13", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 868, 871 ] ], "normalized": [] }, { "id": "PMID-18065756_T14", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 936, 941 ] ], "normalized": [] }, { "id": "PMID-18065756_T15", "type": "Protein", "text": [ "HSP90alpha" ], "offsets": [ [ 947, 957 ] ], "normalized": [] }, { "id": "PMID-18065756_T16", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 967, 972 ] ], "normalized": [] }, { "id": "PMID-18065756_T17", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 1028, 1038 ] ], "normalized": [] }, { "id": "PMID-18065756_T18", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1052, 1054 ] ], "normalized": [] }, { "id": "PMID-18065756_T19", "type": "Protein", "text": [ "histone H3" ], "offsets": [ [ 1082, 1092 ] ], "normalized": [] }, { "id": "PMID-18065756_T20", "type": "Protein", "text": [ "HSP90alpha" ], "offsets": [ [ 1163, 1173 ] ], "normalized": [] }, { "id": "PMID-18065756_T21", "type": "Protein", "text": [ "LSD1" ], "offsets": [ [ 1185, 1189 ] ], "normalized": [] }, { "id": "PMID-18065756_T22", "type": "Protein", "text": [ "androgen receptor" ], "offsets": [ [ 1208, 1225 ] ], "normalized": [] }, { "id": "PMID-18065756_T23", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1297, 1299 ] ], "normalized": [] }, { "id": "PMID-18065756_T24", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 1384, 1389 ] ], "normalized": [] }, { "id": "PMID-18065756_T25", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1431, 1433 ] ], "normalized": [] }, { "id": "PMID-18065756_T26", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1489, 1491 ] ], "normalized": [] }, { "id": "PMID-18065756_T27", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 1534, 1539 ] ], "normalized": [] }, { "id": "PMID-18065756_T28", "type": "Protein", "text": [ "TACC2" ], "offsets": [ [ 1744, 1749 ] ], "normalized": [] }, { "id": "PMID-18065756_T29", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 1798, 1803 ] ], "normalized": [] }, { "id": "PMID-18065756_T30", "type": "Protein", "text": [ "TACC2" ], "offsets": [ [ 1839, 1844 ] ], "normalized": [] }, { "id": "PMID-18065756_T31", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 1848, 1853 ] ], "normalized": [] }, { "id": "PMID-18065756_T32", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 1878, 1883 ] ], "normalized": [] }, { "id": "PMID-18065756_T33", "type": "Protein", "text": [ "TACC2" ], "offsets": [ [ 1899, 1904 ] ], "normalized": [] }, { "id": "PMID-18065756_T34", "type": "Protein", "text": [ "H3" ], "offsets": [ [ 1934, 1936 ] ], "normalized": [] }, { "id": "PMID-18065756_T35", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 1975, 1980 ] ], "normalized": [] }, { "id": "PMID-18065756_T36", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 2068, 2073 ] ], "normalized": [] }, { "id": "PMID-18065756_T37", "type": "Protein", "text": [ "SMYD2" ], "offsets": [ [ 2102, 2107 ] ], "normalized": [] }, { "id": "PMID-18065756_T41", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 1299, 1301 ] ], "normalized": [] }, { "id": "PMID-18065756_T42", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 1433, 1435 ] ], "normalized": [] }, { "id": "PMID-18065756_T45", "type": "Entity", "text": [ "K36" ], "offsets": [ [ 1491, 1494 ] ], "normalized": [] }, { "id": "PMID-18065756_T48", "type": "Entity", "text": [ "K4" ], "offsets": [ [ 1936, 1938 ] ], "normalized": [] } ]

[ { "id": "PMID-18065756_E1", "type": "Methylation", "trigger": { "text": [ "methylates" ], "offsets": [ [ 333, 343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18065756_T6" } ] }, { "id": "PMID-18065756_E2", "type": "Catalysis", "trigger": { "text": [ "methylates" ], "offsets": [ [ 333, 343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18065756_E1" }, { "role": "Cause", "ref_id": "PMID-18065756_T5" } ] }, { "id": "PMID-18065756_E3", "type": "Methylation", "trigger": { "text": [ "methylates" ], "offsets": [ [ 333, 343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18065756_T7" } ] }, { "id": "PMID-18065756_E4", "type": "Catalysis", "trigger": { "text": [ "methylates" ], "offsets": [ [ 333, 343 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18065756_E3" }, { "role": "Cause", "ref_id": "PMID-18065756_T5" } ] }, { "id": "PMID-18065756_E5", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1282, 1293 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18065756_T23" }, { "role": "Site", "ref_id": "PMID-18065756_T41" } ] }, { "id": "PMID-18065756_E6", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1436, 1447 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18065756_T25" }, { "role": "Site", "ref_id": "PMID-18065756_T42" } ] }, { "id": "PMID-18065756_E7", "type": "Catalysis", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1436, 1447 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18065756_E6" }, { "role": "Cause", "ref_id": "PMID-18065756_T24" } ] }, { "id": "PMID-18065756_E8", "type": "Methylation", "trigger": { "text": [ "methylation" ], "offsets": [ [ 1436, 1447 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18065756_T26" }, { "role": "Site", "ref_id": "PMID-18065756_T45" } ] }, { "id": "PMID-18065756_E9", "type": "Catalysis", "trigger": { "text": [ "methylates" ], "offsets": [ [ 1923, 1933 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18065756_E10" }, { "role": "Cause", "ref_id": "PMID-18065756_T32" } ] }, { "id": "PMID-18065756_E10", "type": "Methylation", "trigger": { "text": [ "methylates" ], "offsets": [ [ 1923, 1933 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18065756_T34" }, { "role": "Site", "ref_id": "PMID-18065756_T48" }, { "role": "Contextgene", "ref_id": "PMID-18065756_T33" } ] } ]

[ { "id": "PMID-18065756_1", "entity_ids": [ "PMID-18065756_T2", "PMID-18065756_T3" ] } ]

[]

[ { "id": "PMID-18070108__text", "type": "abstract", "text": [ "Type I receptor binding of bone morphogenetic protein 6 is dependent on N-glycosylation of the ligand. \nBone morphogenetic proteins (BMPs), together with transforming growth factor (TGF)-beta and activins/inhibins, constitute the TGF-beta superfamily of ligands. This superfamily is formed by more than 30 structurally related secreted proteins. The crystal structure of human BMP-6 was determined to a resolution of 2.1 A; the overall structure is similar to that of other TGF-beta superfamily ligands, e.g. BMP-7. The asymmetric unit contains the full dimeric BMP-6, indicating possible asymmetry between the two monomeric subunits. Indeed, the conformation of several loops differs between both monomers. In particular, the prehelix loop, which plays a crucial role in the type I receptor interactions of BMP-2, adopts two rather different conformations in BMP-6, indicating possible dynamic flexibility of the prehelix loop in its unbound conformation. Flexibility of this loop segment has been discussed as an important feature required for promiscuous binding of different type I receptors to BMPs. Further studies investigating the interaction of BMP-6 with different ectodomains of type I receptors revealed that N-glycosylation at Asn73 of BMP-6 in the wrist epitope is crucial for recognition by the activin receptor type I. In the absence of the carbohydrate moiety, activin receptor type I-mediated signaling of BMP-6 is totally diminished. Thus, flexibility within the binding epitope of BMP-6 and an unusual recognition motif, i.e. an N-glycosylation motif, possibly play an important role in type I receptor specificity of BMP-6.\n" ], "offsets": [ [ 0, 1645 ] ] } ]

[ { "id": "PMID-18070108_T1", "type": "Protein", "text": [ "bone morphogenetic protein 6" ], "offsets": [ [ 27, 55 ] ], "normalized": [] }, { "id": "PMID-18070108_T2", "type": "Protein", "text": [ "BMP-6" ], "offsets": [ [ 377, 382 ] ], "normalized": [] }, { "id": "PMID-18070108_T3", "type": "Protein", "text": [ "BMP-7" ], "offsets": [ [ 509, 514 ] ], "normalized": [] }, { "id": "PMID-18070108_T4", "type": "Protein", "text": [ "BMP-6" ], "offsets": [ [ 562, 567 ] ], "normalized": [] }, { "id": "PMID-18070108_T5", "type": "Protein", "text": [ "BMP-2" ], "offsets": [ [ 808, 813 ] ], "normalized": [] }, { "id": "PMID-18070108_T6", "type": "Protein", "text": [ "BMP-6" ], "offsets": [ [ 860, 865 ] ], "normalized": [] }, { "id": "PMID-18070108_T7", "type": "Protein", "text": [ "BMP-6" ], "offsets": [ [ 1154, 1159 ] ], "normalized": [] }, { "id": "PMID-18070108_T8", "type": "Protein", "text": [ "BMP-6" ], "offsets": [ [ 1249, 1254 ] ], "normalized": [] }, { "id": "PMID-18070108_T9", "type": "Protein", "text": [ "activin receptor type I" ], "offsets": [ [ 1310, 1333 ] ], "normalized": [] }, { "id": "PMID-18070108_T10", "type": "Protein", "text": [ "activin receptor type I" ], "offsets": [ [ 1378, 1401 ] ], "normalized": [] }, { "id": "PMID-18070108_T11", "type": "Protein", "text": [ "BMP-6" ], "offsets": [ [ 1424, 1429 ] ], "normalized": [] }, { "id": "PMID-18070108_T12", "type": "Protein", "text": [ "BMP-6" ], "offsets": [ [ 1501, 1506 ] ], "normalized": [] }, { "id": "PMID-18070108_T13", "type": "Protein", "text": [ "BMP-6" ], "offsets": [ [ 1638, 1643 ] ], "normalized": [] }, { "id": "PMID-18070108_T16", "type": "Entity", "text": [ "Asn73" ], "offsets": [ [ 1240, 1245 ] ], "normalized": [] }, { "id": "PMID-18070108_T18", "type": "Entity", "text": [ "carbohydrate moiety" ], "offsets": [ [ 1357, 1376 ] ], "normalized": [] } ]

[ { "id": "PMID-18070108_E1", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 72, 87 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18070108_T1" } ] }, { "id": "PMID-18070108_E2", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 1221, 1236 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18070108_T8" }, { "role": "Site", "ref_id": "PMID-18070108_T16" } ] }, { "id": "PMID-18070108_E3", "type": "Glycosylation", "trigger": { "text": [ "absence" ], "offsets": [ [ 1342, 1349 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18070108_T11" }, { "role": "Sidechain", "ref_id": "PMID-18070108_T18" } ] } ]

[]

[]

[ { "id": "PMID-18075312__text", "type": "abstract", "text": [ "A Cul3-based E3 ligase regulates mitosis and is required to maintain the spindle assembly checkpoint in human cells. \nThe spindle assembly checkpoint (SAC) is a mechanism that prevents premature chromosome segregation in anaphase before all chromosomes are correctly attached to the mitotic spindle. Errors in chromosome segregation lead to aneuploidy, which may be causally involved in tumorgenesis. Kinetochore complexes are the structural components of the SAC, which are tightly regulated by various mechanisms including phosphorylation and ubiquitin-dependent proteolysis. Recent studies shed new light on the regulatory pathways of the ubiquitin proteasome system involved in SAC signaling. Here we present evidence that a Cul3-based E3 ubiquitin-ligase is required to maintain SAC signaling in human cells. Inactivation of the Cul3/KLHL9/KLHL13 ligase leads to premature degradation of Cyclin B and exit from the mitotic state in the presence of microtubule poisons. We discuss possible mechanisms how Cul3 may be required to maintain SAC activity by ubiquitination of the chromosomal passenger protein Aurora B.\n" ], "offsets": [ [ 0, 1120 ] ] } ]

[ { "id": "PMID-18075312_T1", "type": "Protein", "text": [ "Cul3" ], "offsets": [ [ 2, 6 ] ], "normalized": [] }, { "id": "PMID-18075312_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 545, 554 ] ], "normalized": [] }, { "id": "PMID-18075312_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 642, 651 ] ], "normalized": [] }, { "id": "PMID-18075312_T4", "type": "Protein", "text": [ "Cul3" ], "offsets": [ [ 729, 733 ] ], "normalized": [] }, { "id": "PMID-18075312_T5", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 743, 752 ] ], "normalized": [] }, { "id": "PMID-18075312_T6", "type": "Protein", "text": [ "Cul3" ], "offsets": [ [ 834, 838 ] ], "normalized": [] }, { "id": "PMID-18075312_T7", "type": "Protein", "text": [ "KLHL9" ], "offsets": [ [ 839, 844 ] ], "normalized": [] }, { "id": "PMID-18075312_T8", "type": "Protein", "text": [ "KLHL13" ], "offsets": [ [ 845, 851 ] ], "normalized": [] }, { "id": "PMID-18075312_T9", "type": "Protein", "text": [ "Cul3" ], "offsets": [ [ 1009, 1013 ] ], "normalized": [] }, { "id": "PMID-18075312_T10", "type": "Protein", "text": [ "Aurora B" ], "offsets": [ [ 1110, 1118 ] ], "normalized": [] } ]

[ { "id": "PMID-18075312_E1", "type": "Catalysis", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1058, 1072 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18075312_E2" }, { "role": "Cause", "ref_id": "PMID-18075312_T9" } ] }, { "id": "PMID-18075312_E2", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 1058, 1072 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18075312_T10" } ] } ]

[]

[]

[ { "id": "PMID-18082605__text", "type": "abstract", "text": [ "Deubiquitination of FANCD2 is required for DNA crosslink repair. \nMonoubiquitination of FANCD2 and PCNA promotes DNA repair. It causes chromatin accumulation of FANCD2 and facilitates PCNA's recruitment of translesion polymerases to stalled replication. USP1, a protease that removes monoubiquitin from FANCD2 and PCNA, was thought to reverse the DNA damage response of these substrates. We disrupted USP1 in chicken cells to dissect its role in a stable genetic system. USP1 ablation increases FANCD2 and PCNA monoubiquitination but unexpectedly results in DNA crosslinker sensitivity. This defective DNA repair is associated with constitutively chromatin-bound, monoubiquitinated FANCD2. In contrast, persistent PCNA monoubiquitination has negligible impact on DNA repair or mutagenesis. USP1 was previously shown to autocleave after DNA damage. In DT40, USP1 autocleavage is not stimulated by DNA damage, and expressing a noncleavable mutant in the USP1 knockout strain partially rescues crosslinker sensitivity. We conclude that efficient DNA crosslink repair requires FANCD2 deubiquitination, whereas FANCD2 monoubiquitination is not dependent on USP1 autocleavage.\n" ], "offsets": [ [ 0, 1171 ] ] } ]

[ { "id": "PMID-18082605_T1", "type": "Protein", "text": [ "FANCD2" ], "offsets": [ [ 20, 26 ] ], "normalized": [] }, { "id": "PMID-18082605_T2", "type": "Protein", "text": [ "FANCD2" ], "offsets": [ [ 88, 94 ] ], "normalized": [] }, { "id": "PMID-18082605_T3", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 99, 103 ] ], "normalized": [] }, { "id": "PMID-18082605_T4", "type": "Protein", "text": [ "FANCD2" ], "offsets": [ [ 161, 167 ] ], "normalized": [] }, { "id": "PMID-18082605_T5", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 184, 188 ] ], "normalized": [] }, { "id": "PMID-18082605_T6", "type": "Protein", "text": [ "USP1" ], "offsets": [ [ 254, 258 ] ], "normalized": [] }, { "id": "PMID-18082605_T7", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 288, 297 ] ], "normalized": [] }, { "id": "PMID-18082605_T8", "type": "Protein", "text": [ "FANCD2" ], "offsets": [ [ 303, 309 ] ], "normalized": [] }, { "id": "PMID-18082605_T9", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 314, 318 ] ], "normalized": [] }, { "id": "PMID-18082605_T10", "type": "Protein", "text": [ "USP1" ], "offsets": [ [ 401, 405 ] ], "normalized": [] }, { "id": "PMID-18082605_T11", "type": "Protein", "text": [ "USP1" ], "offsets": [ [ 471, 475 ] ], "normalized": [] }, { "id": "PMID-18082605_T12", "type": "Protein", "text": [ "FANCD2" ], "offsets": [ [ 495, 501 ] ], "normalized": [] }, { "id": "PMID-18082605_T13", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 506, 510 ] ], "normalized": [] }, { "id": "PMID-18082605_T14", "type": "Protein", "text": [ "FANCD2" ], "offsets": [ [ 682, 688 ] ], "normalized": [] }, { "id": "PMID-18082605_T15", "type": "Protein", "text": [ "PCNA" ], "offsets": [ [ 714, 718 ] ], "normalized": [] }, { "id": "PMID-18082605_T16", "type": "Protein", "text": [ "USP1" ], "offsets": [ [ 790, 794 ] ], "normalized": [] }, { "id": "PMID-18082605_T17", "type": "Protein", "text": [ "USP1" ], "offsets": [ [ 857, 861 ] ], "normalized": [] }, { "id": "PMID-18082605_T18", "type": "Protein", "text": [ "USP1" ], "offsets": [ [ 952, 956 ] ], "normalized": [] }, { "id": "PMID-18082605_T19", "type": "Protein", "text": [ "FANCD2" ], "offsets": [ [ 1073, 1079 ] ], "normalized": [] }, { "id": "PMID-18082605_T20", "type": "Protein", "text": [ "FANCD2" ], "offsets": [ [ 1106, 1112 ] ], "normalized": [] }, { "id": "PMID-18082605_T21", "type": "Protein", "text": [ "USP1" ], "offsets": [ [ 1152, 1156 ] ], "normalized": [] } ]

[ { "id": "PMID-18082605_E1", "type": "Deubiquitination", "trigger": { "text": [ "Deubiquitination" ], "offsets": [ [ 0, 16 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_T1" } ] }, { "id": "PMID-18082605_E2", "type": "Ubiquitination", "trigger": { "text": [ "Monoubiquitination" ], "offsets": [ [ 66, 84 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_T2" } ] }, { "id": "PMID-18082605_E3", "type": "Ubiquitination", "trigger": { "text": [ "Monoubiquitination" ], "offsets": [ [ 66, 84 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_T3" } ] }, { "id": "PMID-18082605_E4", "type": "Deubiquitination", "trigger": { "text": [ "removes" ], "offsets": [ [ 276, 283 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_T8" } ] }, { "id": "PMID-18082605_E5", "type": "Deubiquitination", "trigger": { "text": [ "removes" ], "offsets": [ [ 276, 283 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_T9" } ] }, { "id": "PMID-18082605_E6", "type": "Catalysis", "trigger": { "text": [ "removes" ], "offsets": [ [ 276, 283 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_E4" }, { "role": "Cause", "ref_id": "PMID-18082605_T6" } ] }, { "id": "PMID-18082605_E7", "type": "Catalysis", "trigger": { "text": [ "removes" ], "offsets": [ [ 276, 283 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_E5" }, { "role": "Cause", "ref_id": "PMID-18082605_T6" } ] }, { "id": "PMID-18082605_E8", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitination" ], "offsets": [ [ 511, 529 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_T12" } ] }, { "id": "PMID-18082605_E9", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitination" ], "offsets": [ [ 511, 529 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_T13" } ] }, { "id": "PMID-18082605_E10", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitinated" ], "offsets": [ [ 664, 681 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_T14" } ] }, { "id": "PMID-18082605_E11", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitination" ], "offsets": [ [ 719, 737 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_T15" } ] }, { "id": "PMID-18082605_E12", "type": "Deubiquitination", "trigger": { "text": [ "deubiquitination" ], "offsets": [ [ 1080, 1096 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_T19" } ] }, { "id": "PMID-18082605_E13", "type": "Ubiquitination", "trigger": { "text": [ "monoubiquitination" ], "offsets": [ [ 1113, 1131 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18082605_T20" } ] } ]

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[ { "id": "PMID-18082611__text", "type": "abstract", "text": [ "Structural organization of the anaphase-promoting complex bound to the mitotic activator Slp1. \nThe anaphase-promoting complex/cyclosome (APC/C) is a conserved multisubunit E3 ubiquitin (Ub) ligase required to signal the degradation of key cell-cycle regulators. Using single particle cryo-electron microscopy (cryo-EM), we have determined a three-dimensional (3D) structure of the core APC/C from Schizosaccharomyces pombe bound to the APC/C activator Slp1/Cdc20. At the 27 A resolution of our density map, the APC/C is a triangular-shaped structure, approximately 19x17x15 nm in size, with a deep internal cavity and a prominent horn-like protrusion emanating from a lip of the cavity. Using antibody labeling and mutant analysis, we have localized 12 of 13 core APC/C components, as well as the position of the activator Slp1, enabling us to propose a structural model of APC/C organization. Comparison of the APC/C with another multiprotein E3 ligase, the SCF complex, uncovers remarkable structural similarities.\n" ], "offsets": [ [ 0, 1018 ] ] } ]

[ { "id": "PMID-18082611_T1", "type": "Protein", "text": [ "Slp1" ], "offsets": [ [ 89, 93 ] ], "normalized": [] }, { "id": "PMID-18082611_T2", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 176, 185 ] ], "normalized": [] }, { "id": "PMID-18082611_T3", "type": "Protein", "text": [ "Ub" ], "offsets": [ [ 187, 189 ] ], "normalized": [] }, { "id": "PMID-18082611_T4", "type": "Protein", "text": [ "Slp1" ], "offsets": [ [ 453, 457 ] ], "normalized": [] }, { "id": "PMID-18082611_T5", "type": "Protein", "text": [ "Cdc20" ], "offsets": [ [ 458, 463 ] ], "normalized": [] }, { "id": "PMID-18082611_T6", "type": "Protein", "text": [ "Slp1" ], "offsets": [ [ 824, 828 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-18082611_1", "entity_ids": [ "PMID-18082611_T2", "PMID-18082611_T3" ] }, { "id": "PMID-18082611_2", "entity_ids": [ "PMID-18082611_T4", "PMID-18082611_T5" ] } ]

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[ { "id": "PMID-1814131__text", "type": "abstract", "text": [ "Effect of glucagon and phorbol myristate acetate on oxidative demethylation and lipid peroxidation in isolated hepatocytes. \nOxidative demethylation of aminopyrine and peroxidation of endogenous lipids induced by cumene hydroperoxide were studied in hepatocytes isolated from fed male rats. Glucagon and phorbol-12-myristate-13-acetate (PMA) inhibited both processes in the concentration-dependent manner. Pretreatment of hepatocytes with 1 microM glucagon decreased oxidative demethylation by 75% and had a much smaller effect on lipid peroxidation. Preincubation with 1 microM PMA inhibited both processes by 25-30%. Phosphorylation of three isoforms of cytochrome P-450 was observed in microsomes isolated from hepatocytes incubated in the presence of [32P]orthophosphate. After incubation with PMA the phosphorylation of all these proteins was increased by 60-100%, whereas glucagon increased the phosphorylation of only one isoform. Consequences of the phosphorylation of various isoforms of cytochrome P-450 for metabolic functions of the monooxygenase system are discussed.\n" ], "offsets": [ [ 0, 1081 ] ] } ]

[ { "id": "PMID-1814131_T1", "type": "Protein", "text": [ "glucagon" ], "offsets": [ [ 10, 18 ] ], "normalized": [] }, { "id": "PMID-1814131_T2", "type": "Protein", "text": [ "Glucagon" ], "offsets": [ [ 291, 299 ] ], "normalized": [] }, { "id": "PMID-1814131_T3", "type": "Protein", "text": [ "glucagon" ], "offsets": [ [ 448, 456 ] ], "normalized": [] }, { "id": "PMID-1814131_T4", "type": "Protein", "text": [ "glucagon" ], "offsets": [ [ 878, 886 ] ], "normalized": [] } ]

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[ { "id": "PMID-181681__text", "type": "abstract", "text": [ "Catecholamine receptor agonists: effects on motor activity and rate of tyrosine hydroxylation in mouse brain. \nMotor activity during the first 5 min in a motility meter was measured in mice given 0.025-3.2 mg/kg of the dopamine and noradrenaline receptor agonists apomorphine and clonidine, respectively. The accumulation of Dopa, as induced by the inhibitor of aromatic amino acid decarboxylase, NSD 1015, was measured in parallel in two dopamine-rich regions, i.e. the limbic system and the corpus striatum, and in two noradrenaline-rich regions, i.e. the neocortex and the lower brain stem. Low doses (0.025-0.2 mg/kg) of apomorphine reduced locomotion in a dose-dependent manner, while the reduction after higher doses was less pronounced, indicating a biphasic dose-response relationship. Clonidine caused a dose-dependent locomotor depression. When low doses of the two drugs were combined, the inhibitory effect observed was at least additive. When clonidine was combined with a high dose of apomorphine (0.8 mg/kg), it caused a significant inhibition of locomotion in a dose of 0.1-0.2 mg/kg, but not after 0.8 mg/kg, indicating a biphasic dose-response relationship. Either drug given alone reduced Dopa accumulation after inhibition of its decarboxylation, in all regions, but smaller doses of apomorphine had a clearcut effect only in the dopamine-rich regions, whereas the lowest dose of clonidine investigated (0.05 mg/kg) had an inhibitory effect on Dopa formation only in the neocortex. The relationship between the dose of apomorphine and Dopa formation in the neocortex appeared biphasic, the highest dose (3.2 mg/kg) having no significant effect. Further, apomorphine in this dose accelerated the disappearance of noradrenaline after inhibition of synthesis by alpha-methyltyrosine. Reversal of reserpine-induced suppression of motor activity was taken to indicate postsynaptic receptor activation. The threshold dose of apomorphine causing reversal was 0.2 mg/kg. The inhibitory effect of e.g. 0.05 mg/kg on locomotion and on Dopa formation suggests a preferential activation of inhibitory autoregulatory dopamine receptors by low doses of this drug. A similar trend was observed for clonidine. The basal importance of dopamine neurones for the locomotor function studied in the present paper is illustrated by the marked inhibition by low doses of apomorphine. On the other hand, the observations with clonidine suggest a somewhat less striking and perhaps less direct influence of noradrenaline neurones on motor activity. Mice with a low motor activity, as induced e.g. by reserpine or, in another experiment, mice adapted to the motility meter, displayed an increased motor activity after higher doses of apomorphine (from 0.2 and 2 mg/kg, respectively), whereas all doses depressed the initial high motor activity. Probably, high motor activity requires active dopamine neurones, making this behaviour more susceptible to interference with autoregulatory mechanisms, whereas a low basal activity may be more affected by activation of postsynaptic dopamine receptors.\n" ], "offsets": [ [ 0, 3091 ] ] } ]

[ { "id": "PMID-181681_T1", "type": "Protein", "text": [ "aromatic amino acid decarboxylase" ], "offsets": [ [ 362, 395 ] ], "normalized": [] } ]

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[ { "id": "PMID-18172270__text", "type": "abstract", "text": [ "Clinical and molecular responses in lung cancer patients receiving Romidepsin. \nPURPOSE: Our preclinical experiments indicated that Romidepsin (Depsipeptide FK228; DP) mediates growth arrest and apoptosis in cultured lung cancer cells. A phase II trial was done to examine clinical and molecular responses mediated by this histone deacetylase inhibitor in lung cancer patients. EXPERIMENTAL DESIGN: Nineteen patients with neoplasms refractory to standard therapy received 4-h DP infusions (17.8 mg/m(2)) on days 1 and 7 of a 21-day cycle. Each full course of therapy consisted of two identical 21-day cycles. Plasma DP levels were evaluated by liquid chromatography-mass spectrometry techniques. A variety of molecular end points were assessed in tumor biopsies via immunohistochemistry techniques. Long oligo arrays were used to examine gene expression profiles in laser-captured tumor cells before and after DP exposure, relative to lung cancer cells and adjacent normal bronchial epithelia from patients undergoing pulmonary resections. RESULTS: Nineteen patients were evaluable for toxicity assessment; 18 were evaluable for treatment response. Myelosuppression was dose limiting in one individual. No significant cardiac toxicities were observed. Maximum steady-state plasma DP concentrations ranged from 384 to 1,114 ng/mL. No objective responses were observed. Transient stabilization of disease was noted in nine patients. DP enhanced acetylation of histone H4, increased p21 expression in lung cancer cells, and seemed to shift global gene expression profiles in these cells toward those detected in normal bronchial epithelia. CONCLUSION: Although exhibiting minimal clinical efficacy at this dose and schedule, DP mediates biological effects that may warrant further evaluation of this histone deacetylase inhibitor in combination with novel-targeted agents in lung cancer patients.\n" ], "offsets": [ [ 0, 1894 ] ] } ]

[ { "id": "PMID-18172270_T1", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 323, 330 ] ], "normalized": [] }, { "id": "PMID-18172270_T2", "type": "Protein", "text": [ "histone H4" ], "offsets": [ [ 1458, 1468 ] ], "normalized": [] }, { "id": "PMID-18172270_T3", "type": "Protein", "text": [ "p21" ], "offsets": [ [ 1480, 1483 ] ], "normalized": [] }, { "id": "PMID-18172270_T4", "type": "Protein", "text": [ "histone" ], "offsets": [ [ 1797, 1804 ] ], "normalized": [] } ]

[ { "id": "PMID-18172270_E1", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 1443, 1454 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18172270_T2" }, { "role": "Contextgene", "ref_id": "PMID-18172270_T3" } ] } ]

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[ { "id": "PMID-18174169__text", "type": "abstract", "text": [ "Glucose deprivation stimulates O-GlcNAc modification of proteins through up-regulation of O-linked N-acetylglucosaminyltransferase. \nO-Linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification of proteins that functions as a nutrient sensing mechanism. Here we report on regulation of O-GlcNAcylation over a broad range of glucose concentrations. We have discovered a significant induction of O-GlcNAc modification of a limited number of proteins under conditions of glucose deprivation. Beginning 12 h after treatment, glucose-deprived human hepatocellular carcinoma (HepG2) cells demonstrate a 7.8-fold increase in total O-GlcNAc modification compared with cells cultured in normal glucose (5 mm; p = 0.008). Some of the targets of glucose deprivation-induced O-GlcNAcylation are distinct from those modified in response to high glucose (20 mm) or glucosamine (10 mm) treatment, suggesting differential targeting with glucose deprivation and glucose excess. O-GlcNAcylation of glycogen synthase is significantly increased with glucose deprivation, and this O-GlcNAc increase contributes to a 60% decrease (p = 0.004) in glycogen synthase activity. Increased O-GlcNAc modification is not mediated by increased UDP-GlcNAc, the rate-limiting substrate for O-GlcNAcylation. Rather, the mRNA for nucleocytoplasmic O-linked N-acetylglucosaminyltransferase (OGT) increases 3.4-fold within 6 h of glucose deprivation (p = 0.006). Within 12 h, OGT protein increases 1.7-fold (p = 0.01) compared with normal glucose-treated cells. In addition, 12-h glucose deprivation leads to a 49% decrease in O-GlcNAcase protein levels (p = 0.03). We conclude that increased O-GlcNAc modification stimulated by glucose deprivation results from increased OGT and decreased O-GlcNAcase levels and that these changes affect cell metabolism, thus inactivating glycogen synthase.\n" ], "offsets": [ [ 0, 1871 ] ] } ]

[ { "id": "PMID-18174169_T1", "type": "Protein", "text": [ "O-linked N-acetylglucosaminyltransferase" ], "offsets": [ [ 90, 130 ] ], "normalized": [] }, { "id": "PMID-18174169_T2", "type": "Protein", "text": [ "O-linked N-acetylglucosaminyltransferase" ], "offsets": [ [ 1328, 1368 ] ], "normalized": [] }, { "id": "PMID-18174169_T3", "type": "Protein", "text": [ "OGT" ], "offsets": [ [ 1370, 1373 ] ], "normalized": [] }, { "id": "PMID-18174169_T4", "type": "Protein", "text": [ "OGT" ], "offsets": [ [ 1454, 1457 ] ], "normalized": [] }, { "id": "PMID-18174169_T5", "type": "Protein", "text": [ "O-GlcNAcase" ], "offsets": [ [ 1605, 1616 ] ], "normalized": [] }, { "id": "PMID-18174169_T6", "type": "Protein", "text": [ "O-GlcNAcase" ], "offsets": [ [ 1768, 1779 ] ], "normalized": [] } ]

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[ { "id": "PMID-18180283__text", "type": "abstract", "text": [ "Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase. \nInterleukin 1 (IL-1) has been reported to stimulate the polyubiquitination and disappearance of IL-1 receptor-associated kinase 1 (IRAK1) within minutes. It has been thought that the polyubiquitin chains attached to IRAK1 are linked via Lys48 of ubiquitin, leading to its destruction by the proteasome and explaining the rapid IL-1-induced disappearance of IRAK1. In this paper, we demonstrate that IL-1 stimulates the formation of K63-pUb-IRAK1 and not K48-pUb-IRAK1 and that the IL-1-induced disappearance of IRAK1 is not blocked by inhibition of the proteasome. We also show that IL-1 triggers the interaction of K63-pUb-IRAK1 with NEMO, a regulatory subunit of the IkappaBalpha kinase (IKK) complex, but not with the NEMO[D311N] mutant that cannot bind K63-pUb chains. Moreover, unlike wild-type NEMO, the NEMO[D311N] mutant was unable to restore IL-1-stimulated NF-kappaB-dependent gene transcription to NEMO-deficient cells. Our data suggest a model in which the recruitment of the NEMO-IKK complex to K63-pUb-IRAK1 and the recruitment of the TAK1 complex to TRAF6 facilitate the TAK1-catalyzed activation of IKK by the TRAF6-IRAK1 complex.\n" ], "offsets": [ [ 0, 1320 ] ] } ]

[ { "id": "PMID-18180283_T1", "type": "Protein", "text": [ "IL-1 receptor-associated kinase 1" ], "offsets": [ [ 68, 101 ] ], "normalized": [] }, { "id": "PMID-18180283_T2", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 116, 120 ] ], "normalized": [] }, { "id": "PMID-18180283_T3", "type": "Protein", "text": [ "IL-1 receptor-associated kinase 1" ], "offsets": [ [ 269, 302 ] ], "normalized": [] }, { "id": "PMID-18180283_T4", "type": "Protein", "text": [ "IRAK1" ], "offsets": [ [ 304, 309 ] ], "normalized": [] }, { "id": "PMID-18180283_T5", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 360, 369 ] ], "normalized": [] }, { "id": "PMID-18180283_T6", "type": "Protein", "text": [ "IRAK1" ], "offsets": [ [ 389, 394 ] ], "normalized": [] }, { "id": "PMID-18180283_T7", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 419, 428 ] ], "normalized": [] }, { "id": "PMID-18180283_T8", "type": "Protein", "text": [ "IRAK1" ], "offsets": [ [ 530, 535 ] ], "normalized": [] }, { "id": "PMID-18180283_T9", "type": "Protein", "text": [ "IRAK1" ], "offsets": [ [ 613, 618 ] ], "normalized": [] }, { "id": "PMID-18180283_T10", "type": "Protein", "text": [ "IRAK1" ], "offsets": [ [ 635, 640 ] ], "normalized": [] }, { "id": "PMID-18180283_T11", "type": "Protein", "text": [ "IRAK1" ], "offsets": [ [ 684, 689 ] ], "normalized": [] }, { "id": "PMID-18180283_T12", "type": "Protein", "text": [ "IRAK1" ], "offsets": [ [ 797, 802 ] ], "normalized": [] }, { "id": "PMID-18180283_T13", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 808, 812 ] ], "normalized": [] }, { "id": "PMID-18180283_T14", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 894, 898 ] ], "normalized": [] }, { "id": "PMID-18180283_T15", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 973, 977 ] ], "normalized": [] }, { "id": "PMID-18180283_T16", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 983, 987 ] ], "normalized": [] }, { "id": "PMID-18180283_T17", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 1082, 1086 ] ], "normalized": [] }, { "id": "PMID-18180283_T18", "type": "Protein", "text": [ "NEMO" ], "offsets": [ [ 1161, 1165 ] ], "normalized": [] }, { "id": "PMID-18180283_T19", "type": "Protein", "text": [ "IRAK1" ], "offsets": [ [ 1189, 1194 ] ], "normalized": [] }, { "id": "PMID-18180283_T20", "type": "Protein", "text": [ "TAK1" ], "offsets": [ [ 1222, 1226 ] ], "normalized": [] }, { "id": "PMID-18180283_T21", "type": "Protein", "text": [ "TRAF6" ], "offsets": [ [ 1238, 1243 ] ], "normalized": [] }, { "id": "PMID-18180283_T22", "type": "Protein", "text": [ "TAK1" ], "offsets": [ [ 1259, 1263 ] ], "normalized": [] }, { "id": "PMID-18180283_T23", "type": "Protein", "text": [ "TRAF6" ], "offsets": [ [ 1299, 1304 ] ], "normalized": [] }, { "id": "PMID-18180283_T24", "type": "Protein", "text": [ "IRAK1" ], "offsets": [ [ 1305, 1310 ] ], "normalized": [] } ]

[ { "id": "PMID-18180283_E1", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 46, 64 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18180283_T1" } ] }, { "id": "PMID-18180283_E2", "type": "Ubiquitination", "trigger": { "text": [ "polyubiquitination" ], "offsets": [ [ 229, 247 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18180283_T3" } ] }, { "id": "PMID-18180283_E3", "type": "Ubiquitination", "trigger": { "text": [ "attached" ], "offsets": [ [ 377, 385 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18180283_T6" } ] } ]

[ { "id": "PMID-18180283_1", "entity_ids": [ "PMID-18180283_T3", "PMID-18180283_T4" ] } ]

[]

[ { "id": "PMID-18199748__text", "type": "abstract", "text": [ "Inhibition of p97-dependent protein degradation by Eeyarestatin I. \nElimination of misfolded proteins from the endoplasmic reticulum (ER) by ER-associated degradation involves substrate retrotranslocation from the ER lumen into the cytosol for degradation by the proteasome. For many substrates, retrotranslocation requires the action of ubiquitinating enzymes, which polyubiquitinate substrates emerging from the ER lumen, and of the p97-Ufd1-Npl4 ATPase complex, which hydrolyzes ATP to dislocate polyubiquitinated substrates into the cytosol. Polypeptides extracted by p97 are eventually transferred to the proteasome for destruction. In mammalian cells, ERAD can be blocked by a chemical inhibitor termed Eeyarestatin I, but the mechanism of EerI action is unclear. Here we report that EerI can associate with a p97 complex to inhibit ERAD. The interaction of EerI with the p97 complex appears to negatively influence a deubiquitinating process that is mediated by p97-associated deubiquitinating enzymes. We further show that ataxin-3, a p97-associated deubiquitinating enzyme previously implicated in ER-associated degradation, is among those affected. Interestingly, p97-associated deubiquitination is also involved in degradation of a soluble substrate. Our analyses establish a role for a novel deubiquitinating process in proteasome-dependent protein turnover.\n" ], "offsets": [ [ 0, 1371 ] ] } ]

[ { "id": "PMID-18199748_T1", "type": "Protein", "text": [ "p97" ], "offsets": [ [ 14, 17 ] ], "normalized": [] }, { "id": "PMID-18199748_T2", "type": "Protein", "text": [ "p97" ], "offsets": [ [ 435, 438 ] ], "normalized": [] }, { "id": "PMID-18199748_T3", "type": "Protein", "text": [ "Ufd1" ], "offsets": [ [ 439, 443 ] ], "normalized": [] }, { "id": "PMID-18199748_T4", "type": "Protein", "text": [ "Npl4" ], "offsets": [ [ 444, 448 ] ], "normalized": [] }, { "id": "PMID-18199748_T5", "type": "Protein", "text": [ "p97" ], "offsets": [ [ 572, 575 ] ], "normalized": [] }, { "id": "PMID-18199748_T6", "type": "Protein", "text": [ "p97" ], "offsets": [ [ 816, 819 ] ], "normalized": [] }, { "id": "PMID-18199748_T7", "type": "Protein", "text": [ "p97" ], "offsets": [ [ 878, 881 ] ], "normalized": [] }, { "id": "PMID-18199748_T8", "type": "Protein", "text": [ "p97" ], "offsets": [ [ 969, 972 ] ], "normalized": [] }, { "id": "PMID-18199748_T9", "type": "Protein", "text": [ "ataxin-3" ], "offsets": [ [ 1031, 1039 ] ], "normalized": [] }, { "id": "PMID-18199748_T10", "type": "Protein", "text": [ "p97" ], "offsets": [ [ 1043, 1046 ] ], "normalized": [] }, { "id": "PMID-18199748_T11", "type": "Protein", "text": [ "p97" ], "offsets": [ [ 1174, 1177 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "PMID-18202189__text", "type": "abstract", "text": [ "Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations. \nMutations in the PLA2G6 gene, which encodes group VIA calcium-independent phospholipase A2 (iPLA(2)beta), were recently identified in patients with infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation. A pathological hallmark of these childhood neurodegenerative diseases is the presence of distinctive spheroids in distal axons that contain accumulated membranes. We used iPLA(2)beta-KO mice generated by homologous recombination to investigate neurodegenerative consequences of PLA2G6 mutations. iPLA(2)beta-KO mice developed age-dependent neurological impairment that was evident in rotarod, balance, and climbing tests by 13 months of age. The primary abnormality underlying this neurological impairment was the formation of spheroids containing tubulovesicular membranes remarkably similar to human INAD. Spheroids were strongly labeled with anti-ubiquitin antibodies. Accumulation of ubiquitinated protein in spheroids was evident in some brain regions as early as 4 months of age, and the onset of motor impairment correlated with a dramatic increase in ubiquitin-positive spheroids throughout the neuropil in nearly all brain regions. Furthermore accumulating ubiquitinated proteins were observed primarily in insoluble fractions of brain tissue, implicating protein aggregation in this pathogenic process. These results indicate that loss of iPLA(2)beta causes age-dependent impairment of axonal membrane homeostasis and protein degradation pathways, leading to age-dependent neurological impairment. iPLA(2)beta-KO mice will be useful for further studies of pathogenesis and experimental interventions in INAD and neurodegeneration with brain iron accumulation.\n" ], "offsets": [ [ 0, 1864 ] ] } ]

[ { "id": "PMID-18202189_T1", "type": "Protein", "text": [ "PLA2G6" ], "offsets": [ [ 136, 142 ] ], "normalized": [] }, { "id": "PMID-18202189_T2", "type": "Protein", "text": [ "PLA2G6" ], "offsets": [ [ 172, 178 ] ], "normalized": [] }, { "id": "PMID-18202189_T3", "type": "Protein", "text": [ "calcium-independent phospholipase A2" ], "offsets": [ [ 209, 245 ] ], "normalized": [] }, { "id": "PMID-18202189_T4", "type": "Protein", "text": [ "iPLA(2)beta" ], "offsets": [ [ 247, 258 ] ], "normalized": [] }, { "id": "PMID-18202189_T5", "type": "Protein", "text": [ "iPLA(2)beta" ], "offsets": [ [ 565, 576 ] ], "normalized": [] }, { "id": "PMID-18202189_T6", "type": "Protein", "text": [ "PLA2G6" ], "offsets": [ [ 672, 678 ] ], "normalized": [] }, { "id": "PMID-18202189_T7", "type": "Protein", "text": [ "iPLA(2)beta" ], "offsets": [ [ 690, 701 ] ], "normalized": [] }, { "id": "PMID-18202189_T8", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1044, 1053 ] ], "normalized": [] }, { "id": "PMID-18202189_T9", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1253, 1262 ] ], "normalized": [] }, { "id": "PMID-18202189_T10", "type": "Protein", "text": [ "iPLA(2)beta" ], "offsets": [ [ 1543, 1554 ] ], "normalized": [] }, { "id": "PMID-18202189_T11", "type": "Protein", "text": [ "iPLA(2)beta" ], "offsets": [ [ 1702, 1713 ] ], "normalized": [] } ]

[]

[ { "id": "PMID-18202189_1", "entity_ids": [ "PMID-18202189_T2", "PMID-18202189_T3", "PMID-18202189_T4" ] } ]

[]

[ { "id": "PMID-18223694__text", "type": "abstract", "text": [ "Chaperone-dependent stabilization and degradation of p53 mutants. \np53 missense mutant proteins commonly show increased stability compared to wild-type p53, which is thought to depend largely on the inability of mutant p53 to induce the ubiquitin ligase MDM2. However, recent work using mouse models has shown that the accumulation of mutant p53 occurs only in tumour cells, indicating that stabilization requires additional factors. To clarify the stabilization of p53 mutants in tumours, we analysed factors that affect their folding and degradation. Although all missense mutants that we studied are more stable than wild-type p53, the levels correlate with individual structural characteristics, which may be reflected in different gain-of-function properties. In the absence of Hsp90 activity, the less stable unfolded p53 mutants preferentially associate in a complex with Hsp70 and CHIP (carboxy terminus of Hsp70-interacting protein), and we show that CHIP is responsible for ubiquitination and degradation of these mutants. The demonstration of a complex interplay between Hsp90, Hsp70 and CHIP that regulate the stability of different p53 mutant proteins improves our understanding of the pro-tumorigenic effects of increased Hsp90 activity during multi-stage carcinogenesis. Understanding the roles of Hsp90, Hsp70 and CHIP in cancers may also provide an important avenue through which to target p53 to enhance treatment of human cancers.\n" ], "offsets": [ [ 0, 1450 ] ] } ]

[ { "id": "PMID-18223694_T1", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 53, 56 ] ], "normalized": [] }, { "id": "PMID-18223694_T2", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 67, 70 ] ], "normalized": [] }, { "id": "PMID-18223694_T3", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 152, 155 ] ], "normalized": [] }, { "id": "PMID-18223694_T4", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 219, 222 ] ], "normalized": [] }, { "id": "PMID-18223694_T5", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 237, 246 ] ], "normalized": [] }, { "id": "PMID-18223694_T6", "type": "Protein", "text": [ "MDM2" ], "offsets": [ [ 254, 258 ] ], "normalized": [] }, { "id": "PMID-18223694_T7", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 342, 345 ] ], "normalized": [] }, { "id": "PMID-18223694_T8", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 466, 469 ] ], "normalized": [] }, { "id": "PMID-18223694_T9", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 630, 633 ] ], "normalized": [] }, { "id": "PMID-18223694_T10", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 824, 827 ] ], "normalized": [] }, { "id": "PMID-18223694_T11", "type": "Protein", "text": [ "CHIP" ], "offsets": [ [ 889, 893 ] ], "normalized": [] }, { "id": "PMID-18223694_T12", "type": "Protein", "text": [ "carboxy terminus of Hsp70-interacting protein" ], "offsets": [ [ 895, 940 ] ], "normalized": [] }, { "id": "PMID-18223694_T13", "type": "Protein", "text": [ "CHIP" ], "offsets": [ [ 960, 964 ] ], "normalized": [] }, { "id": "PMID-18223694_T14", "type": "Protein", "text": [ "CHIP" ], "offsets": [ [ 1099, 1103 ] ], "normalized": [] }, { "id": "PMID-18223694_T15", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1145, 1148 ] ], "normalized": [] }, { "id": "PMID-18223694_T16", "type": "Protein", "text": [ "CHIP" ], "offsets": [ [ 1330, 1334 ] ], "normalized": [] }, { "id": "PMID-18223694_T17", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1407, 1410 ] ], "normalized": [] } ]

[ { "id": "PMID-18223694_E1", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 984, 998 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18223694_T10" } ] }, { "id": "PMID-18223694_E2", "type": "Catalysis", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 984, 998 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18223694_E1" }, { "role": "Cause", "ref_id": "PMID-18223694_T11" } ] } ]

[ { "id": "PMID-18223694_1", "entity_ids": [ "PMID-18223694_T11", "PMID-18223694_T12" ] } ]

[]

[ { "id": "PMID-18235976__text", "type": "abstract", "text": [ "N-glycosylation at Asn residues 554 and 566 of E-cadherin affects cell cycle progression through extracellular signal-regulated protein kinase signaling pathway. \nE-cadherin, which has a widely acknowledged role in mediating calcium-dependent cell-cell adhesion between epithelial cells, also functions as a tumor suppressor. The ectodomain of human E-cadherin contains four potential N-glycosylation sites at Asn residues 554, 566, 618, and 633. We investigated the role of E-cadherin N-glycosylation in cell cycle progression by site-directed mutagenesis. We showed previously that all four potential N-glycosylation sites of E-cadherin were N-glycosylated in human breast carcinoma MDA-MB-435 cells. Removal of N-glycan at Asn633 dramatically affected E-cadherin stability. In this study we showed that E-cadherin mutant missing N-glycans at Asn554, Asn566 and Asn618 failed to induce cell cycle arrest in G1 phase and to suppress cell proliferation in comparison with wild-type E-cadherin. Moreover, N-glycans at Asn554 and Asn566, but not at Asn618, seemed to be indispensable for E-cadherin-mediated suppression of cell cycle progression. Removal of N-glycans at either Asn554 or Asn566 of E-cadherin was accompanied with the activation of the extracellular signal-regulated protein kinase signaling pathway. After treatment with PD98059, an inhibitor of the extracellular signal-regulated protein kinase signaling pathway, wild-type E-cadherin transfected MDA-MB-435 and E-cadherin N-glycosylation-deficient mutant transfected MDA-MB-435 cells had equivalent numbers of cells in G1 phase. These findings implied that N-glycosylation might be crucial for E-cadherin-mediated suppression of cell cycle progression.\n" ], "offsets": [ [ 0, 1720 ] ] } ]

[ { "id": "PMID-18235976_T1", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 47, 57 ] ], "normalized": [] }, { "id": "PMID-18235976_T2", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 163, 173 ] ], "normalized": [] }, { "id": "PMID-18235976_T3", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 350, 360 ] ], "normalized": [] }, { "id": "PMID-18235976_T4", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 475, 485 ] ], "normalized": [] }, { "id": "PMID-18235976_T5", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 628, 638 ] ], "normalized": [] }, { "id": "PMID-18235976_T6", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 755, 765 ] ], "normalized": [] }, { "id": "PMID-18235976_T7", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 806, 816 ] ], "normalized": [] }, { "id": "PMID-18235976_T8", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 982, 992 ] ], "normalized": [] }, { "id": "PMID-18235976_T9", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 1196, 1206 ] ], "normalized": [] }, { "id": "PMID-18235976_T10", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 1440, 1450 ] ], "normalized": [] }, { "id": "PMID-18235976_T11", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 1478, 1488 ] ], "normalized": [] }, { "id": "PMID-18235976_T12", "type": "Protein", "text": [ "E-cadherin" ], "offsets": [ [ 1661, 1671 ] ], "normalized": [] }, { "id": "PMID-18235976_T14", "type": "Entity", "text": [ "Asn residues 554" ], "offsets": [ [ 19, 35 ] ], "normalized": [] }, { "id": "PMID-18235976_T15", "type": "Entity", "text": [ "566" ], "offsets": [ [ 40, 43 ] ], "normalized": [] }, { "id": "PMID-18235976_T17", "type": "Entity", "text": [ "N-glycosylation sites" ], "offsets": [ [ 603, 624 ] ], "normalized": [] }, { "id": "PMID-18235976_T20", "type": "Entity", "text": [ "N-glycan" ], "offsets": [ [ 714, 722 ] ], "normalized": [] }, { "id": "PMID-18235976_T21", "type": "Entity", "text": [ "Asn633" ], "offsets": [ [ 726, 732 ] ], "normalized": [] }, { "id": "PMID-18235976_T23", "type": "Entity", "text": [ "N-glycans" ], "offsets": [ [ 1156, 1165 ] ], "normalized": [] }, { "id": "PMID-18235976_T24", "type": "Entity", "text": [ "Asn554" ], "offsets": [ [ 1176, 1182 ] ], "normalized": [] }, { "id": "PMID-18235976_T25", "type": "Entity", "text": [ "Asn566" ], "offsets": [ [ 1186, 1192 ] ], "normalized": [] } ]

[ { "id": "PMID-18235976_E1", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 0, 15 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18235976_T1" }, { "role": "Site", "ref_id": "PMID-18235976_T14" } ] }, { "id": "PMID-18235976_E2", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 0, 15 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18235976_T1" }, { "role": "Site", "ref_id": "PMID-18235976_T15" } ] }, { "id": "PMID-18235976_E3", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 486, 501 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18235976_T4" } ] }, { "id": "PMID-18235976_E4", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylated" ], "offsets": [ [ 644, 658 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18235976_T5" }, { "role": "Site", "ref_id": "PMID-18235976_T17" } ] }, { "id": "PMID-18235976_E5", "type": "Deglycosylation", "trigger": { "text": [ "Removal" ], "offsets": [ [ 703, 710 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18235976_T6" }, { "role": "Site", "ref_id": "PMID-18235976_T21" }, { "role": "Sidechain", "ref_id": "PMID-18235976_T20" } ] }, { "id": "PMID-18235976_E6", "type": "Deglycosylation", "trigger": { "text": [ "Removal" ], "offsets": [ [ 1145, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18235976_T9" }, { "role": "Site", "ref_id": "PMID-18235976_T24" }, { "role": "Sidechain", "ref_id": "PMID-18235976_T23" } ] }, { "id": "PMID-18235976_E7", "type": "Deglycosylation", "trigger": { "text": [ "Removal" ], "offsets": [ [ 1145, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18235976_T9" }, { "role": "Site", "ref_id": "PMID-18235976_T25" }, { "role": "Sidechain", "ref_id": "PMID-18235976_T23" } ] }, { "id": "PMID-18235976_E8", "type": "Glycosylation", "trigger": { "text": [ "N-glycosylation" ], "offsets": [ [ 1624, 1639 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-18235976_T12" } ] } ]

[]

[]

[ { "id": "PMID-18240569__text", "type": "abstract", "text": [ "[Prothyomosin alpha interaction with KEAP1 doesn't lead to prothymosin alpha ubiquination and degradation] \nProthymosin alpha (ProTalpha) is a highly conserved protein in vertebrates that possesses a number of biological functions. One of these functions of ProTalpha is the ability to enhance antioxidant defence system of a cell via its interaction with Keap1 protein. Keap1 is a repressor of Nrf2, a transcription factor responsible for activation of genes that code for defensive proteins. While bound to Nrf2, Keap1 exports Nrf2 from the nucleus to the cytoplasm and, being adaptor protein for ubiquitin ligase, promotes ubiquitination of Nrf2 and its subsequent degradation by 26S proteasome. ProTalpha and Nrf2 compete for interaction with Keap1, therefore ProTalpha is able to liberate Nrf2 from complex with Keap1 and hence contribute to Nrf2-dependent transcription. Here we were interested in elucidating possible consequences for ProTalpha of its interaction with Keap1. We have shown that, despite ProTalpha interaction with Keap1, ProTalpha is a stable protein. In contrast to Nrf2 ProTalpha was not subjected to Keap-dependent ubiquitination, degradation and export from the nucleus. Furthermore, ubiquitination of ProTalpha was undetectable even when Keap1 and ubiquitin were overexpressed. It appears that ProTalpha contribution to Nrf2-dependent transcription is accomplished via the increase of free Nrf2 rather then the increase of total intracellular amount of Nrf2.\n" ], "offsets": [ [ 0, 1488 ] ] } ]

[ { "id": "PMID-18240569_T1", "type": "Protein", "text": [ "Prothyomosin alpha" ], "offsets": [ [ 1, 19 ] ], "normalized": [] }, { "id": "PMID-18240569_T2", "type": "Protein", "text": [ "KEAP1" ], "offsets": [ [ 37, 42 ] ], "normalized": [] }, { "id": "PMID-18240569_T3", "type": "Protein", "text": [ "prothymosin alpha" ], "offsets": [ [ 59, 76 ] ], "normalized": [] }, { "id": "PMID-18240569_T4", "type": "Protein", "text": [ "Prothymosin alpha" ], "offsets": [ [ 108, 125 ] ], "normalized": [] }, { "id": "PMID-18240569_T5", "type": "Protein", "text": [ "ProTalpha" ], "offsets": [ [ 127, 136 ] ], "normalized": [] }, { "id": "PMID-18240569_T6", "type": "Protein", "text": [ "ProTalpha" ], "offsets": [ [ 258, 267 ] ], "normalized": [] }, { "id": "PMID-18240569_T7", "type": "Protein", "text": [ "Keap1" ], "offsets": [ [ 356, 361 ] ], "normalized": [] }, { "id": "PMID-18240569_T8", "type": "Protein", "text": [ "Keap1" ], "offsets": [ [ 371, 376 ] ], "normalized": [] }, { "id": "PMID-18240569_T9", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 395, 399 ] ], "normalized": [] }, { "id": "PMID-18240569_T10", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 509, 513 ] ], "normalized": [] }, { "id": "PMID-18240569_T11", "type": "Protein", "text": [ "Keap1" ], "offsets": [ [ 515, 520 ] ], "normalized": [] }, { "id": "PMID-18240569_T12", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 529, 533 ] ], "normalized": [] }, { "id": "PMID-18240569_T13", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 599, 608 ] ], "normalized": [] }, { "id": "PMID-18240569_T14", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 644, 648 ] ], "normalized": [] }, { "id": "PMID-18240569_T15", "type": "Protein", "text": [ "ProTalpha" ], "offsets": [ [ 699, 708 ] ], "normalized": [] }, { "id": "PMID-18240569_T16", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 713, 717 ] ], "normalized": [] }, { "id": "PMID-18240569_T17", "type": "Protein", "text": [ "Keap1" ], "offsets": [ [ 747, 752 ] ], "normalized": [] }, { "id": "PMID-18240569_T18", "type": "Protein", "text": [ "ProTalpha" ], "offsets": [ [ 764, 773 ] ], "normalized": [] }, { "id": "PMID-18240569_T19", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 794, 798 ] ], "normalized": [] }, { "id": "PMID-18240569_T20", "type": "Protein", "text": [ "Keap1" ], "offsets": [ [ 817, 822 ] ], "normalized": [] }, { "id": "PMID-18240569_T21", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 847, 851 ] ], "normalized": [] }, { "id": "PMID-18240569_T22", "type": "Protein", "text": [ "ProTalpha" ], "offsets": [ [ 942, 951 ] ], "normalized": [] }, { "id": "PMID-18240569_T23", "type": "Protein", "text": [ "Keap1" ], "offsets": [ [ 976, 981 ] ], "normalized": [] }, { "id": "PMID-18240569_T24", "type": "Protein", "text": [ "ProTalpha" ], "offsets": [ [ 1011, 1020 ] ], "normalized": [] }, { "id": "PMID-18240569_T25", "type": "Protein", "text": [ "Keap1" ], "offsets": [ [ 1038, 1043 ] ], "normalized": [] }, { "id": "PMID-18240569_T26", "type": "Protein", "text": [ "ProTalpha" ], "offsets": [ [ 1045, 1054 ] ], "normalized": [] }, { "id": "PMID-18240569_T27", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 1091, 1095 ] ], "normalized": [] }, { "id": "PMID-18240569_T28", "type": "Protein", "text": [ "ProTalpha" ], "offsets": [ [ 1096, 1105 ] ], "normalized": [] }, { "id": "PMID-18240569_T29", "type": "Protein", "text": [ "ProTalpha" ], "offsets": [ [ 1230, 1239 ] ], "normalized": [] }, { "id": "PMID-18240569_T30", "type": "Protein", "text": [ "Keap1" ], "offsets": [ [ 1267, 1272 ] ], "normalized": [] }, { "id": "PMID-18240569_T31", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1277, 1286 ] ], "normalized": [] }, { "id": "PMID-18240569_T32", "type": "Protein", "text": [ "ProTalpha" ], "offsets": [ [ 1323, 1332 ] ], "normalized": [] }, { "id": "PMID-18240569_T33", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 1349, 1353 ] ], "normalized": [] }, { "id": "PMID-18240569_T34", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 1419, 1423 ] ], "normalized": [] }, { "id": "PMID-18240569_T35", "type": "Protein", "text": [ "Nrf2" ], "offsets": [ [ 1482, 1486 ] ], "normalized": [] } ]

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