Datasets:

bigbio

/

bionlp_st_2013_pc

like 1

[ { "id": "PMID-19374191__text", "type": "abstract", "text": [ "[CCR4, HTLV-1 infection, and ATL oncogenesis]. \nAdult T-cell leukemia (ATL) is a malignancy of mature CD4+ T cells that is etiologically associated with the infection of human T-cell leukemia virus type 1 (HTLV-1), an exogenous human retrovirus. Previously, we have shown that leukemic cells of most ATL patients express CCR4, a chemokine receptor known to be selectively expressed by T cell subsets such as Th2 cells, skin-homing memory/effector T cells, and regulatory T cells. Therefore, the expression of CCR4 suggests that ATL cells are mostly derived from one of these T cell subsets. We have also shown that Tax, the HTLV-1-encoded potent transcriptional activator, strongly induces the expression of CCL22, a CCR4 ligand, which promotes the cell-dependent transmission of HTLV-1 from HTLV-1-infected T cells to CCR4+ target T cells by inducing close cell-to-cell interactions. We have also shown that ATL cells aberrantly express the AP-1 family member Fra-2 which, by forming the heterodimer with JunD, potently induces the expression of not only CCR4 but also the genes such as c-Myb, MDM2 and Bcl-6, the well-known proto-oncogenes. Thus, Fra-2 is a novel oncogene of ATL, and CCR4 may be regarded as a useful tumor marker of ATL.\n" ], "offsets": [ [ 0, 1241 ] ] } ]

[ { "id": "PMID-19374191_T1", "type": "Gene_or_gene_product", "text": [ "CCR4" ], "offsets": [ [ 1, 5 ] ], "normalized": [] }, { "id": "PMID-19374191_T2", "type": "Gene_or_gene_product", "text": [ "CD4" ], "offsets": [ [ 102, 105 ] ], "normalized": [] }, { "id": "PMID-19374191_T3", "type": "Gene_or_gene_product", "text": [ "CCR4" ], "offsets": [ [ 321, 325 ] ], "normalized": [] }, { "id": "PMID-19374191_T4", "type": "Gene_or_gene_product", "text": [ "CCR4" ], "offsets": [ [ 509, 513 ] ], "normalized": [] }, { "id": "PMID-19374191_T5", "type": "Gene_or_gene_product", "text": [ "Tax" ], "offsets": [ [ 615, 618 ] ], "normalized": [] }, { "id": "PMID-19374191_T6", "type": "Gene_or_gene_product", "text": [ "CCL22" ], "offsets": [ [ 708, 713 ] ], "normalized": [] }, { "id": "PMID-19374191_T7", "type": "Gene_or_gene_product", "text": [ "CCR4" ], "offsets": [ [ 717, 721 ] ], "normalized": [] }, { "id": "PMID-19374191_T8", "type": "Gene_or_gene_product", "text": [ "CCR4" ], "offsets": [ [ 819, 823 ] ], "normalized": [] }, { "id": "PMID-19374191_T9", "type": "Gene_or_gene_product", "text": [ "AP-1" ], "offsets": [ [ 942, 946 ] ], "normalized": [] }, { "id": "PMID-19374191_T10", "type": "Gene_or_gene_product", "text": [ "Fra-2" ], "offsets": [ [ 961, 966 ] ], "normalized": [] }, { "id": "PMID-19374191_T11", "type": "Gene_or_gene_product", "text": [ "JunD" ], "offsets": [ [ 1006, 1010 ] ], "normalized": [] }, { "id": "PMID-19374191_T12", "type": "Gene_or_gene_product", "text": [ "CCR4" ], "offsets": [ [ 1056, 1060 ] ], "normalized": [] }, { "id": "PMID-19374191_T13", "type": "Gene_or_gene_product", "text": [ "c-Myb" ], "offsets": [ [ 1088, 1093 ] ], "normalized": [] }, { "id": "PMID-19374191_T14", "type": "Gene_or_gene_product", "text": [ "MDM2" ], "offsets": [ [ 1095, 1099 ] ], "normalized": [] }, { "id": "PMID-19374191_T15", "type": "Gene_or_gene_product", "text": [ "Bcl-6" ], "offsets": [ [ 1104, 1109 ] ], "normalized": [] }, { "id": "PMID-19374191_T16", "type": "Gene_or_gene_product", "text": [ "Fra-2" ], "offsets": [ [ 1149, 1154 ] ], "normalized": [] }, { "id": "PMID-19374191_T17", "type": "Gene_or_gene_product", "text": [ "CCR4" ], "offsets": [ [ 1187, 1191 ] ], "normalized": [] } ]

[ { "id": "PMID-19374191_E1", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 137, 147 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_T2" } ] }, { "id": "PMID-19374191_E2", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 313, 320 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_T3" } ] }, { "id": "PMID-19374191_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 495, 505 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_T4" } ] }, { "id": "PMID-19374191_E4", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 682, 689 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19374191_T5" }, { "role": "Theme", "ref_id": "PMID-19374191_E6" } ] }, { "id": "PMID-19374191_E5", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 682, 689 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19374191_T5" }, { "role": "Theme", "ref_id": "PMID-19374191_E7" } ] }, { "id": "PMID-19374191_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 694, 704 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_T6" } ] }, { "id": "PMID-19374191_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 694, 704 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_T7" } ] }, { "id": "PMID-19374191_E8", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 930, 937 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_T10" } ] }, { "id": "PMID-19374191_E9", "type": "Positive_regulation", "trigger": { "text": [ "express" ], "offsets": [ [ 930, 937 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_E8" }, { "role": "Cause", "ref_id": "PMID-19374191_E10" } ] }, { "id": "PMID-19374191_E10", "type": "Binding", "trigger": { "text": [ "forming" ], "offsets": [ [ 977, 984 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_T11" } ] }, { "id": "PMID-19374191_E11", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 1021, 1028 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19374191_T10" }, { "role": "Theme", "ref_id": "PMID-19374191_E15" } ] }, { "id": "PMID-19374191_E12", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 1021, 1028 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19374191_T10" }, { "role": "Theme", "ref_id": "PMID-19374191_E16" } ] }, { "id": "PMID-19374191_E13", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 1021, 1028 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19374191_T10" }, { "role": "Theme", "ref_id": "PMID-19374191_E17" } ] }, { "id": "PMID-19374191_E14", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 1021, 1028 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19374191_T10" }, { "role": "Theme", "ref_id": "PMID-19374191_E18" } ] }, { "id": "PMID-19374191_E15", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1033, 1043 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_T12" } ] }, { "id": "PMID-19374191_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1033, 1043 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_T13" } ] }, { "id": "PMID-19374191_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1033, 1043 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_T14" } ] }, { "id": "PMID-19374191_E18", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1033, 1043 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19374191_T15" } ] } ]

[]

[]

[ { "id": "PMID-19376776__text", "type": "abstract", "text": [ "Notch1 signaling sensitizes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human hepatocellular carcinoma cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. \nNotch signaling plays a critical role in regulating cell proliferation, differentiation, and apoptosis. Our previous study showed that overexpression of Notch1 could inhibit human hepatocellular carcinoma (HCC) cell growth by arresting the cell cycle and inducing apoptosis. HCC cells are resistant to apoptotic induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), so new therapeutic approaches have been explored to sensitize HCC cells to TRAIL-induced apoptosis. We are wondering whether and how Notch1 signaling can enhance the sensitivity of HCC cells to TRAIL-induced apoptosis. In this study, we found that overexpression of ICN, the constitutive activated form of Notch1, up-regulated p53 protein expression in HCC cells by inhibiting proteasome degradation. p53 up-regulation was further observed in human primary hepatocellular carcinoma cells after activation of Notch signaling. Inhibition of the Akt/Hdm2 pathway by Notch1 signaling was responsible for the suppression of p53 proteasomal degradation, thus contributing to the Notch1 signaling-mediated up-regulation of p53 expression. Accordingly, Notch1 signaling could make HCC cells more sensitive to TRAIL-induced apoptosis, whereas Notch1 signaling lost the synergistic promotion of TRAIL-induced apoptosis in p53-silenced HepG2 HCC cells and p53-defective Hep3B HCC cells. The data suggest that enhancement of TRAIL-induced apoptosis by Notch1 signaling is dependent upon p53 up-regulation. Furthermore, Notch1 signaling could enhance DR5 expression in a p53-dependent manner. Taken together, Notch1 signaling sensitizes TRAIL-induced apoptosis in HCC cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. Thus, our results suggest that activation of Notch1 signaling may be a promising approach to improve the therapeutic efficacy of TRAIL-resistant HCC.\n" ], "offsets": [ [ 0, 2136 ] ] } ]

[ { "id": "PMID-19376776_T1", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "PMID-19376776_T2", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor-related apoptosis-inducing ligand" ], "offsets": [ [ 28, 83 ] ], "normalized": [] }, { "id": "PMID-19376776_T3", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 156, 159 ] ], "normalized": [] }, { "id": "PMID-19376776_T4", "type": "Gene_or_gene_product", "text": [ "Hdm2" ], "offsets": [ [ 160, 164 ] ], "normalized": [] }, { "id": "PMID-19376776_T5", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 174, 177 ] ], "normalized": [] }, { "id": "PMID-19376776_T6", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 208, 211 ] ], "normalized": [] }, { "id": "PMID-19376776_T7", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 222, 225 ] ], "normalized": [] }, { "id": "PMID-19376776_T8", "type": "Gene_or_gene_product", "text": [ "Notch" ], "offsets": [ [ 239, 244 ] ], "normalized": [] }, { "id": "PMID-19376776_T9", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 392, 398 ] ], "normalized": [] }, { "id": "PMID-19376776_T10", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor-related apoptosis-inducing ligand" ], "offsets": [ [ 564, 619 ] ], "normalized": [] }, { "id": "PMID-19376776_T11", "type": "Gene_or_gene_product", "text": [ "TRAIL" ], "offsets": [ [ 621, 626 ] ], "normalized": [] }, { "id": "PMID-19376776_T12", "type": "Gene_or_gene_product", "text": [ "TRAIL" ], "offsets": [ [ 704, 709 ] ], "normalized": [] }, { "id": "PMID-19376776_T13", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 762, 768 ] ], "normalized": [] }, { "id": "PMID-19376776_T14", "type": "Gene_or_gene_product", "text": [ "TRAIL" ], "offsets": [ [ 823, 828 ] ], "normalized": [] }, { "id": "PMID-19376776_T15", "type": "Gene_or_gene_product", "text": [ "ICN" ], "offsets": [ [ 895, 898 ] ], "normalized": [] }, { "id": "PMID-19376776_T16", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 935, 941 ] ], "normalized": [] }, { "id": "PMID-19376776_T17", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 956, 959 ] ], "normalized": [] }, { "id": "PMID-19376776_T18", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1030, 1033 ] ], "normalized": [] }, { "id": "PMID-19376776_T19", "type": "Gene_or_gene_product", "text": [ "Notch" ], "offsets": [ [ 1137, 1142 ] ], "normalized": [] }, { "id": "PMID-19376776_T20", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1172, 1175 ] ], "normalized": [] }, { "id": "PMID-19376776_T21", "type": "Gene_or_gene_product", "text": [ "Hdm2" ], "offsets": [ [ 1176, 1180 ] ], "normalized": [] }, { "id": "PMID-19376776_T22", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 1192, 1198 ] ], "normalized": [] }, { "id": "PMID-19376776_T23", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1248, 1251 ] ], "normalized": [] }, { "id": "PMID-19376776_T24", "type": "Cellular_component", "text": [ "proteasomal" ], "offsets": [ [ 1252, 1263 ] ], "normalized": [] }, { "id": "PMID-19376776_T25", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 1302, 1308 ] ], "normalized": [] }, { "id": "PMID-19376776_T26", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1345, 1348 ] ], "normalized": [] }, { "id": "PMID-19376776_T27", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 1374, 1380 ] ], "normalized": [] }, { "id": "PMID-19376776_T28", "type": "Gene_or_gene_product", "text": [ "TRAIL" ], "offsets": [ [ 1430, 1435 ] ], "normalized": [] }, { "id": "PMID-19376776_T29", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 1463, 1469 ] ], "normalized": [] }, { "id": "PMID-19376776_T30", "type": "Gene_or_gene_product", "text": [ "TRAIL" ], "offsets": [ [ 1514, 1519 ] ], "normalized": [] }, { "id": "PMID-19376776_T31", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1541, 1544 ] ], "normalized": [] }, { "id": "PMID-19376776_T32", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1574, 1577 ] ], "normalized": [] }, { "id": "PMID-19376776_T33", "type": "Gene_or_gene_product", "text": [ "TRAIL" ], "offsets": [ [ 1642, 1647 ] ], "normalized": [] }, { "id": "PMID-19376776_T34", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 1669, 1675 ] ], "normalized": [] }, { "id": "PMID-19376776_T35", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1704, 1707 ] ], "normalized": [] }, { "id": "PMID-19376776_T36", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 1736, 1742 ] ], "normalized": [] }, { "id": "PMID-19376776_T37", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 1767, 1770 ] ], "normalized": [] }, { "id": "PMID-19376776_T38", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1787, 1790 ] ], "normalized": [] }, { "id": "PMID-19376776_T39", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 1825, 1831 ] ], "normalized": [] }, { "id": "PMID-19376776_T40", "type": "Gene_or_gene_product", "text": [ "TRAIL" ], "offsets": [ [ 1853, 1858 ] ], "normalized": [] }, { "id": "PMID-19376776_T41", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1904, 1907 ] ], "normalized": [] }, { "id": "PMID-19376776_T42", "type": "Gene_or_gene_product", "text": [ "Hdm2" ], "offsets": [ [ 1908, 1912 ] ], "normalized": [] }, { "id": "PMID-19376776_T43", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1922, 1925 ] ], "normalized": [] }, { "id": "PMID-19376776_T44", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 1956, 1959 ] ], "normalized": [] }, { "id": "PMID-19376776_T45", "type": "Gene_or_gene_product", "text": [ "DR5" ], "offsets": [ [ 1970, 1973 ] ], "normalized": [] }, { "id": "PMID-19376776_T46", "type": "Gene_or_gene_product", "text": [ "Notch1" ], "offsets": [ [ 2031, 2037 ] ], "normalized": [] }, { "id": "PMID-19376776_T47", "type": "Gene_or_gene_product", "text": [ "TRAIL" ], "offsets": [ [ 2115, 2120 ] ], "normalized": [] } ]

[ { "id": "PMID-19376776_E1", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 7, 16 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T1" } ] }, { "id": "PMID-19376776_E2", "type": "Regulation", "trigger": { "text": [ "sensitizes" ], "offsets": [ [ 17, 27 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E5" }, { "role": "Cause", "ref_id": "PMID-19376776_E6" } ] }, { "id": "PMID-19376776_E3", "type": "Regulation", "trigger": { "text": [ "sensitizes" ], "offsets": [ [ 17, 27 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E5" }, { "role": "Cause", "ref_id": "PMID-19376776_E10" } ] }, { "id": "PMID-19376776_E4", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 84, 91 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_T2" }, { "role": "Theme", "ref_id": "PMID-19376776_E5" } ] }, { "id": "PMID-19376776_E5", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 92, 101 ] ] }, "arguments": [] }, { "id": "PMID-19376776_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 145, 155 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_E1" }, { "role": "Theme", "ref_id": "PMID-19376776_E9" } ] }, { "id": "PMID-19376776_E7", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 165, 173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E9" }, { "role": "Cause", "ref_id": "PMID-19376776_T3" } ] }, { "id": "PMID-19376776_E8", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 165, 173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E9" }, { "role": "Cause", "ref_id": "PMID-19376776_T4" } ] }, { "id": "PMID-19376776_E9", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 178, 189 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T5" } ] }, { "id": "PMID-19376776_E10", "type": "Positive_regulation", "trigger": { "text": [ "up-regulating" ], "offsets": [ [ 194, 207 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E12" }, { "role": "Cause", "ref_id": "PMID-19376776_E1" } ] }, { "id": "PMID-19376776_E11", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 212, 221 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_T6" }, { "role": "Theme", "ref_id": "PMID-19376776_E12" } ] }, { "id": "PMID-19376776_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 226, 236 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T7" } ] }, { "id": "PMID-19376776_E13", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 245, 254 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T8" } ] }, { "id": "PMID-19376776_E14", "type": "Regulation", "trigger": { "text": [ "plays a critical role" ], "offsets": [ [ 255, 276 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E15" }, { "role": "Cause", "ref_id": "PMID-19376776_E13" } ] }, { "id": "PMID-19376776_E15", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 280, 290 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E16" } ] }, { "id": "PMID-19376776_E16", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 332, 341 ] ] }, "arguments": [] }, { "id": "PMID-19376776_E17", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 374, 388 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T9" } ] }, { "id": "PMID-19376776_E18", "type": "Negative_regulation", "trigger": { "text": [ "arresting" ], "offsets": [ [ 465, 474 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E19" }, { "role": "Cause", "ref_id": "PMID-19376776_E17" } ] }, { "id": "PMID-19376776_E19", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 479, 489 ] ] }, "arguments": [] }, { "id": "PMID-19376776_E20", "type": "Positive_regulation", "trigger": { "text": [ "inducing" ], "offsets": [ [ 494, 502 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E21" }, { "role": "Cause", "ref_id": "PMID-19376776_E17" } ] }, { "id": "PMID-19376776_E21", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 503, 512 ] ] }, "arguments": [] }, { "id": "PMID-19376776_E22", "type": "Negative_regulation", "trigger": { "text": [ "resistant" ], "offsets": [ [ 528, 537 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E24" } ] }, { "id": "PMID-19376776_E23", "type": "Pathway", "trigger": { "text": [ "apoptotic" ], "offsets": [ [ 541, 550 ] ] }, "arguments": [] }, { "id": "PMID-19376776_E24", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 551, 560 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E23" }, { "role": "Cause", "ref_id": "PMID-19376776_T10" } ] }, { "id": "PMID-19376776_E25", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 710, 717 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_T12" }, { "role": "Theme", "ref_id": "PMID-19376776_E26" } ] }, { "id": "PMID-19376776_E26", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 718, 727 ] ] }, "arguments": [] }, { "id": "PMID-19376776_E27", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 769, 778 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T13" } ] }, { "id": "PMID-19376776_E28", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 829, 836 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_T14" }, { "role": "Theme", "ref_id": "PMID-19376776_E29" } ] }, { "id": "PMID-19376776_E29", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 837, 846 ] ] }, "arguments": [] }, { "id": "PMID-19376776_E30", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 877, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T15" } ] }, { "id": "PMID-19376776_E31", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 917, 926 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T16" } ] }, { "id": "PMID-19376776_E32", "type": "Positive_regulation", "trigger": { "text": [ "up-regulated" ], "offsets": [ [ 943, 955 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_E30" }, { "role": "Theme", "ref_id": "PMID-19376776_E33" } ] }, { "id": "PMID-19376776_E33", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 968, 978 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T17" } ] }, { "id": "PMID-19376776_E34", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 1034, 1047 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T18" } ] }, { "id": "PMID-19376776_E35", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1123, 1133 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E36" } ] }, { "id": "PMID-19376776_E36", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1143, 1152 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T19" } ] }, { "id": "PMID-19376776_E37", "type": "Negative_regulation", "trigger": { "text": [ "Inhibition" ], "offsets": [ [ 1154, 1164 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E38" }, { "role": "Cause", "ref_id": "PMID-19376776_E39" } ] }, { "id": "PMID-19376776_E38", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1181, 1188 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T20" }, { "role": "Participant", "ref_id": "PMID-19376776_T21" } ] }, { "id": "PMID-19376776_E39", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1199, 1208 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T22" } ] }, { "id": "PMID-19376776_E40", "type": "Positive_regulation", "trigger": { "text": [ "responsible" ], "offsets": [ [ 1213, 1224 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_E37" }, { "role": "Theme", "ref_id": "PMID-19376776_E41" } ] }, { "id": "PMID-19376776_E41", "type": "Negative_regulation", "trigger": { "text": [ "suppression" ], "offsets": [ [ 1233, 1244 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E42" } ] }, { "id": "PMID-19376776_E42", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1264, 1275 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T23" } ] }, { "id": "PMID-19376776_E43", "type": "Positive_regulation", "trigger": { "text": [ "contributing" ], "offsets": [ [ 1282, 1294 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E46" }, { "role": "Cause", "ref_id": "PMID-19376776_E41" } ] }, { "id": "PMID-19376776_E44", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1309, 1318 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T25" } ] }, { "id": "PMID-19376776_E45", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1319, 1327 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E46" }, { "role": "Cause", "ref_id": "PMID-19376776_E44" } ] }, { "id": "PMID-19376776_E46", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 1328, 1341 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E47" } ] }, { "id": "PMID-19376776_E47", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1349, 1359 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T26" } ] }, { "id": "PMID-19376776_E48", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1381, 1390 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T27" } ] }, { "id": "PMID-19376776_E49", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1436, 1443 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_T28" }, { "role": "Theme", "ref_id": "PMID-19376776_E50" } ] }, { "id": "PMID-19376776_E50", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1444, 1453 ] ] }, "arguments": [] }, { "id": "PMID-19376776_E51", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1470, 1479 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T29" } ] }, { "id": "PMID-19376776_E52", "type": "Negative_regulation", "trigger": { "text": [ "lost" ], "offsets": [ [ 1480, 1484 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E53" } ] }, { "id": "PMID-19376776_E53", "type": "Positive_regulation", "trigger": { "text": [ "promotion" ], "offsets": [ [ 1501, 1510 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E55" } ] }, { "id": "PMID-19376776_E54", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1520, 1527 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_T30" }, { "role": "Theme", "ref_id": "PMID-19376776_E55" } ] }, { "id": "PMID-19376776_E55", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1528, 1537 ] ] }, "arguments": [] }, { "id": "PMID-19376776_E56", "type": "Inactivation", "trigger": { "text": [ "silenced" ], "offsets": [ [ 1545, 1553 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T31" } ] }, { "id": "PMID-19376776_E57", "type": "Inactivation", "trigger": { "text": [ "defective" ], "offsets": [ [ 1578, 1587 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T32" } ] }, { "id": "PMID-19376776_E58", "type": "Positive_regulation", "trigger": { "text": [ "enhancement" ], "offsets": [ [ 1627, 1638 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E60" }, { "role": "Cause", "ref_id": "PMID-19376776_E61" } ] }, { "id": "PMID-19376776_E59", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1648, 1655 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_T33" }, { "role": "Theme", "ref_id": "PMID-19376776_E60" } ] }, { "id": "PMID-19376776_E60", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1656, 1665 ] ] }, "arguments": [] }, { "id": "PMID-19376776_E61", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1676, 1685 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T34" } ] }, { "id": "PMID-19376776_E62", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1689, 1698 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E58" }, { "role": "Cause", "ref_id": "PMID-19376776_E63" } ] }, { "id": "PMID-19376776_E63", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 1708, 1721 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T35" } ] }, { "id": "PMID-19376776_E64", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1743, 1752 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T36" } ] }, { "id": "PMID-19376776_E65", "type": "Positive_regulation", "trigger": { "text": [ "enhance" ], "offsets": [ [ 1759, 1766 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_E64" }, { "role": "Theme", "ref_id": "PMID-19376776_E66" } ] }, { "id": "PMID-19376776_E66", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1771, 1781 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T37" } ] }, { "id": "PMID-19376776_E67", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1791, 1800 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_T38" }, { "role": "Theme", "ref_id": "PMID-19376776_E65" } ] }, { "id": "PMID-19376776_E68", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1832, 1841 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T39" } ] }, { "id": "PMID-19376776_E69", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1859, 1866 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_T40" }, { "role": "Theme", "ref_id": "PMID-19376776_E70" } ] }, { "id": "PMID-19376776_E70", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1867, 1876 ] ] }, "arguments": [] }, { "id": "PMID-19376776_E71", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 1893, 1903 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_E68" }, { "role": "Theme", "ref_id": "PMID-19376776_E73" } ] }, { "id": "PMID-19376776_E72", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 1893, 1903 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_E68" }, { "role": "Theme", "ref_id": "PMID-19376776_E74" } ] }, { "id": "PMID-19376776_E73", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1913, 1921 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E75" }, { "role": "Cause", "ref_id": "PMID-19376776_T41" } ] }, { "id": "PMID-19376776_E74", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1913, 1921 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E75" }, { "role": "Cause", "ref_id": "PMID-19376776_T42" } ] }, { "id": "PMID-19376776_E75", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1926, 1937 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T43" } ] }, { "id": "PMID-19376776_E76", "type": "Positive_regulation", "trigger": { "text": [ "up-regulating" ], "offsets": [ [ 1942, 1955 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E78" }, { "role": "Cause", "ref_id": "PMID-19376776_E68" } ] }, { "id": "PMID-19376776_E77", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1960, 1969 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19376776_T44" }, { "role": "Theme", "ref_id": "PMID-19376776_E78" } ] }, { "id": "PMID-19376776_E78", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1974, 1984 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_T45" } ] }, { "id": "PMID-19376776_E79", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 2017, 2027 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19376776_E80" } ] }, { "id": "PMID-19376776_E80", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 2038, 2047 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19376776_T46" } ] } ]

[ { "id": "PMID-19376776_1", "entity_ids": [ "PMID-19376776_T11", "PMID-19376776_T10" ] } ]

[]

[ { "id": "PMID-19379726__text", "type": "abstract", "text": [ "Pyrrolidine dithiocarbamate, a NF-kappaB inhibitor, upregulates MMP-1 and MMP-13 in IL-1beta-stimulated rheumatoid arthritis fibroblast-like synoviocytes. \nActivated NF-kappaB plays an important role in the expression of matrix metalloproteinase (MMP)-1 and MMP-13 in rheumatoid arthritis and osteoarthritis. The objective of this study was to determine the effects of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) on the expression of MMPs in IL-1beta-stimulated fibroblast-like synoviocytes (FLSs) of rheumatoid arthritis patients. FLSs were treated with IL-1beta (10 ng/ml) for 24 h in the presence or absence of PDTC. The level of MMP-1 and MMP-13 increased in response to PDTC in time- and dose-dependent manners in IL-1beta-stimulated FLSs; the expressions of IL-6 and vascular endothelial growth factor (VEGF) decreased in a PDTC concentration-dependent manner. However, PDTC-mediated repression of IL-6 and VEGF expression was not observed in TNF-alpha-stimulated rheumatoid arthritis FLSs. In contrast, other NF-kappaB inhibitors, such as fenofibrate, N-acetylcysteine and MG132, decreased MMP expression in IL-1beta-stimulated FLSs. The stimulatory effect of PDTC on MMP expression was not mimicked by specific inhibitors of the mitogen-activated protein kinase (MAPK) signaling pathway. Treatments with 100 muM PDTC did not inhibit the phosphorylation of p-ERK1/2, p-P38, and p-JNK, or the transnuclear migration of NF-kappaB through degradation of IkappaB-alpha in IL-1beta-stimulated FLSs. These results suggest that the increase of MMP expression may occur in a stimuli-specific manner or by an NF-kappaB independent mechanism. Therefore, therapeutic NF-kappaB inhibitors should be thoroughly studied before their clinical use in treating rheumatoid arthritis, as undesirable genes may be upregulated through unknown mechanisms, possibly resulting in worse symptoms.\n" ], "offsets": [ [ 0, 1894 ] ] } ]

[ { "id": "PMID-19379726_T1", "type": "Simple_chemical", "text": [ "Pyrrolidine dithiocarbamate" ], "offsets": [ [ 0, 27 ] ], "normalized": [] }, { "id": "PMID-19379726_T2", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 31, 40 ] ], "normalized": [] }, { "id": "PMID-19379726_T3", "type": "Gene_or_gene_product", "text": [ "MMP-1" ], "offsets": [ [ 64, 69 ] ], "normalized": [] }, { "id": "PMID-19379726_T4", "type": "Gene_or_gene_product", "text": [ "MMP-13" ], "offsets": [ [ 74, 80 ] ], "normalized": [] }, { "id": "PMID-19379726_T5", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 84, 92 ] ], "normalized": [] }, { "id": "PMID-19379726_T6", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 166, 175 ] ], "normalized": [] }, { "id": "PMID-19379726_T7", "type": "Gene_or_gene_product", "text": [ "matrix metalloproteinase (MMP)-1" ], "offsets": [ [ 221, 253 ] ], "normalized": [] }, { "id": "PMID-19379726_T8", "type": "Gene_or_gene_product", "text": [ "MMP-13" ], "offsets": [ [ 258, 264 ] ], "normalized": [] }, { "id": "PMID-19379726_T9", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 373, 382 ] ], "normalized": [] }, { "id": "PMID-19379726_T10", "type": "Simple_chemical", "text": [ "pyrrolidine dithiocarbamate" ], "offsets": [ [ 393, 420 ] ], "normalized": [] }, { "id": "PMID-19379726_T11", "type": "Simple_chemical", "text": [ "PDTC" ], "offsets": [ [ 422, 426 ] ], "normalized": [] }, { "id": "PMID-19379726_T12", "type": "Gene_or_gene_product", "text": [ "MMPs" ], "offsets": [ [ 449, 453 ] ], "normalized": [] }, { "id": "PMID-19379726_T13", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 457, 465 ] ], "normalized": [] }, { "id": "PMID-19379726_T14", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 570, 578 ] ], "normalized": [] }, { "id": "PMID-19379726_T15", "type": "Simple_chemical", "text": [ "PDTC" ], "offsets": [ [ 629, 633 ] ], "normalized": [] }, { "id": "PMID-19379726_T16", "type": "Gene_or_gene_product", "text": [ "MMP-1" ], "offsets": [ [ 648, 653 ] ], "normalized": [] }, { "id": "PMID-19379726_T17", "type": "Gene_or_gene_product", "text": [ "MMP-13" ], "offsets": [ [ 658, 664 ] ], "normalized": [] }, { "id": "PMID-19379726_T18", "type": "Simple_chemical", "text": [ "PDTC" ], "offsets": [ [ 690, 694 ] ], "normalized": [] }, { "id": "PMID-19379726_T19", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 734, 742 ] ], "normalized": [] }, { "id": "PMID-19379726_T20", "type": "Gene_or_gene_product", "text": [ "IL-6" ], "offsets": [ [ 779, 783 ] ], "normalized": [] }, { "id": "PMID-19379726_T21", "type": "Gene_or_gene_product", "text": [ "vascular endothelial growth factor" ], "offsets": [ [ 788, 822 ] ], "normalized": [] }, { "id": "PMID-19379726_T22", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 824, 828 ] ], "normalized": [] }, { "id": "PMID-19379726_T23", "type": "Simple_chemical", "text": [ "PDTC" ], "offsets": [ [ 845, 849 ] ], "normalized": [] }, { "id": "PMID-19379726_T24", "type": "Simple_chemical", "text": [ "PDTC" ], "offsets": [ [ 891, 895 ] ], "normalized": [] }, { "id": "PMID-19379726_T25", "type": "Gene_or_gene_product", "text": [ "IL-6" ], "offsets": [ [ 919, 923 ] ], "normalized": [] }, { "id": "PMID-19379726_T26", "type": "Gene_or_gene_product", "text": [ "VEGF" ], "offsets": [ [ 928, 932 ] ], "normalized": [] }, { "id": "PMID-19379726_T27", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 964, 973 ] ], "normalized": [] }, { "id": "PMID-19379726_T28", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1031, 1040 ] ], "normalized": [] }, { "id": "PMID-19379726_T29", "type": "Simple_chemical", "text": [ "fenofibrate" ], "offsets": [ [ 1061, 1072 ] ], "normalized": [] }, { "id": "PMID-19379726_T30", "type": "Simple_chemical", "text": [ "N-acetylcysteine" ], "offsets": [ [ 1074, 1090 ] ], "normalized": [] }, { "id": "PMID-19379726_T31", "type": "Simple_chemical", "text": [ "MG132" ], "offsets": [ [ 1095, 1100 ] ], "normalized": [] }, { "id": "PMID-19379726_T32", "type": "Gene_or_gene_product", "text": [ "MMP" ], "offsets": [ [ 1112, 1115 ] ], "normalized": [] }, { "id": "PMID-19379726_T33", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 1130, 1138 ] ], "normalized": [] }, { "id": "PMID-19379726_T34", "type": "Simple_chemical", "text": [ "PDTC" ], "offsets": [ [ 1182, 1186 ] ], "normalized": [] }, { "id": "PMID-19379726_T35", "type": "Gene_or_gene_product", "text": [ "MMP" ], "offsets": [ [ 1190, 1193 ] ], "normalized": [] }, { "id": "PMID-19379726_T36", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein kinase" ], "offsets": [ [ 1252, 1284 ] ], "normalized": [] }, { "id": "PMID-19379726_T37", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 1286, 1290 ] ], "normalized": [] }, { "id": "PMID-19379726_T38", "type": "Simple_chemical", "text": [ "PDTC" ], "offsets": [ [ 1335, 1339 ] ], "normalized": [] }, { "id": "PMID-19379726_T39", "type": "Gene_or_gene_product", "text": [ "ERK1/2" ], "offsets": [ [ 1381, 1387 ] ], "normalized": [] }, { "id": "PMID-19379726_T40", "type": "Gene_or_gene_product", "text": [ "P38" ], "offsets": [ [ 1391, 1394 ] ], "normalized": [] }, { "id": "PMID-19379726_T41", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 1402, 1405 ] ], "normalized": [] }, { "id": "PMID-19379726_T42", "type": "Cellular_component", "text": [ "transnuclear" ], "offsets": [ [ 1414, 1426 ] ], "normalized": [] }, { "id": "PMID-19379726_T43", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1440, 1449 ] ], "normalized": [] }, { "id": "PMID-19379726_T44", "type": "Gene_or_gene_product", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1473, 1486 ] ], "normalized": [] }, { "id": "PMID-19379726_T45", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 1490, 1498 ] ], "normalized": [] }, { "id": "PMID-19379726_T46", "type": "Gene_or_gene_product", "text": [ "MMP" ], "offsets": [ [ 1559, 1562 ] ], "normalized": [] }, { "id": "PMID-19379726_T47", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1622, 1631 ] ], "normalized": [] }, { "id": "PMID-19379726_T48", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1678, 1687 ] ], "normalized": [] } ]

[ { "id": "PMID-19379726_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 41, 50 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T2" }, { "role": "Cause", "ref_id": "PMID-19379726_T1" } ] }, { "id": "PMID-19379726_E2", "type": "Positive_regulation", "trigger": { "text": [ "upregulates" ], "offsets": [ [ 52, 63 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T1" }, { "role": "Theme", "ref_id": "PMID-19379726_T3" } ] }, { "id": "PMID-19379726_E3", "type": "Positive_regulation", "trigger": { "text": [ "upregulates" ], "offsets": [ [ 52, 63 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T1" }, { "role": "Theme", "ref_id": "PMID-19379726_T4" } ] }, { "id": "PMID-19379726_E4", "type": "Activation", "trigger": { "text": [ "Activated" ], "offsets": [ [ 156, 165 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T6" } ] }, { "id": "PMID-19379726_E5", "type": "Positive_regulation", "trigger": { "text": [ "plays an important role" ], "offsets": [ [ 176, 199 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_E4" }, { "role": "Theme", "ref_id": "PMID-19379726_E7" } ] }, { "id": "PMID-19379726_E6", "type": "Positive_regulation", "trigger": { "text": [ "plays an important role" ], "offsets": [ [ 176, 199 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_E4" }, { "role": "Theme", "ref_id": "PMID-19379726_E8" } ] }, { "id": "PMID-19379726_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 207, 217 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T7" } ] }, { "id": "PMID-19379726_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 207, 217 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T8" } ] }, { "id": "PMID-19379726_E9", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 358, 365 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T11" }, { "role": "Theme", "ref_id": "PMID-19379726_E11" } ] }, { "id": "PMID-19379726_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 383, 392 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T9" }, { "role": "Cause", "ref_id": "PMID-19379726_T10" } ] }, { "id": "PMID-19379726_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 435, 445 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T12" } ] }, { "id": "PMID-19379726_E12", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 665, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T17" } ] }, { "id": "PMID-19379726_E13", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 665, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T16" } ] }, { "id": "PMID-19379726_E14", "type": "Positive_regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 678, 686 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T18" }, { "role": "Theme", "ref_id": "PMID-19379726_E12" } ] }, { "id": "PMID-19379726_E15", "type": "Positive_regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 678, 686 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T18" }, { "role": "Theme", "ref_id": "PMID-19379726_E13" } ] }, { "id": "PMID-19379726_E16", "type": "Gene_expression", "trigger": { "text": [ "expressions" ], "offsets": [ [ 764, 775 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T20" } ] }, { "id": "PMID-19379726_E17", "type": "Gene_expression", "trigger": { "text": [ "expressions" ], "offsets": [ [ 764, 775 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T22" } ] }, { "id": "PMID-19379726_E18", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 830, 839 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_E16" } ] }, { "id": "PMID-19379726_E19", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 830, 839 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_E17" } ] }, { "id": "PMID-19379726_E20", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 896, 904 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T24" }, { "role": "Theme", "ref_id": "PMID-19379726_E22" } ] }, { "id": "PMID-19379726_E21", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 896, 904 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T24" }, { "role": "Theme", "ref_id": "PMID-19379726_E23" } ] }, { "id": "PMID-19379726_E22", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 905, 915 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_E24" } ] }, { "id": "PMID-19379726_E23", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 905, 915 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_E25" } ] }, { "id": "PMID-19379726_E24", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 933, 943 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T25" } ] }, { "id": "PMID-19379726_E25", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 933, 943 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T26" } ] }, { "id": "PMID-19379726_E26", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 1041, 1051 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T28" }, { "role": "Cause", "ref_id": "PMID-19379726_T29" } ] }, { "id": "PMID-19379726_E27", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 1041, 1051 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T28" }, { "role": "Cause", "ref_id": "PMID-19379726_T30" } ] }, { "id": "PMID-19379726_E28", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 1041, 1051 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T28" }, { "role": "Cause", "ref_id": "PMID-19379726_T31" } ] }, { "id": "PMID-19379726_E29", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 1102, 1111 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_E32" }, { "role": "Cause", "ref_id": "PMID-19379726_T29" } ] }, { "id": "PMID-19379726_E30", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 1102, 1111 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_E32" }, { "role": "Cause", "ref_id": "PMID-19379726_T30" } ] }, { "id": "PMID-19379726_E31", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 1102, 1111 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_E32" }, { "role": "Cause", "ref_id": "PMID-19379726_T31" } ] }, { "id": "PMID-19379726_E32", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1116, 1126 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T32" } ] }, { "id": "PMID-19379726_E33", "type": "Positive_regulation", "trigger": { "text": [ "stimulatory" ], "offsets": [ [ 1160, 1171 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_E34" } ] }, { "id": "PMID-19379726_E34", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1172, 1178 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T34" }, { "role": "Theme", "ref_id": "PMID-19379726_E35" } ] }, { "id": "PMID-19379726_E35", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1194, 1204 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T35" } ] }, { "id": "PMID-19379726_E36", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 1234, 1244 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_E37" } ] }, { "id": "PMID-19379726_E37", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 1292, 1309 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-19379726_T37" } ] }, { "id": "PMID-19379726_E38", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1348, 1355 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T38" }, { "role": "Theme", "ref_id": "PMID-19379726_E42" } ] }, { "id": "PMID-19379726_E39", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1348, 1355 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T38" }, { "role": "Theme", "ref_id": "PMID-19379726_E43" } ] }, { "id": "PMID-19379726_E40", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1348, 1355 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T38" }, { "role": "Theme", "ref_id": "PMID-19379726_E44" } ] }, { "id": "PMID-19379726_E41", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1348, 1355 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_E45" }, { "role": "Cause", "ref_id": "PMID-19379726_E46" } ] }, { "id": "PMID-19379726_E42", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1360, 1375 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T39" } ] }, { "id": "PMID-19379726_E43", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1360, 1375 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T40" } ] }, { "id": "PMID-19379726_E44", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1360, 1375 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T41" } ] }, { "id": "PMID-19379726_E45", "type": "Transport", "trigger": { "text": [ "migration" ], "offsets": [ [ 1427, 1436 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T43" }, { "role": "ToLoc", "ref_id": "PMID-19379726_T42" } ] }, { "id": "PMID-19379726_E46", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1458, 1469 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T44" } ] }, { "id": "PMID-19379726_E47", "type": "Positive_regulation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1458, 1469 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19379726_T38" }, { "role": "Theme", "ref_id": "PMID-19379726_E46" } ] }, { "id": "PMID-19379726_E48", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 1547, 1555 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_E49" } ] }, { "id": "PMID-19379726_E49", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1563, 1573 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T46" } ] }, { "id": "PMID-19379726_E50", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 1688, 1698 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19379726_T48" } ] } ]

[ { "id": "PMID-19379726_1", "entity_ids": [ "PMID-19379726_T10", "PMID-19379726_T11" ] }, { "id": "PMID-19379726_2", "entity_ids": [ "PMID-19379726_T21", "PMID-19379726_T22" ] }, { "id": "PMID-19379726_3", "entity_ids": [ "PMID-19379726_T36", "PMID-19379726_T37" ] } ]

[]

[ { "id": "PMID-19491259__text", "type": "abstract", "text": [ "PUMA suppresses intestinal tumorigenesis in mice. \nDefective apoptosis contributes to tumorigenesis, although the critical molecular targets remain to be fully characterized. PUMA, a BH3-only protein essential for p53-dependent apoptosis, has been shown to suppress lymphomagenesis. In this study, we investigated the role of PUMA in intestinal tumorigenesis using two animal models. In the azoxymethane (AOM)/dextran sulfate sodium salt model, PUMA deficiency increased the multiplicity and size of colon tumors but reduced the frequency of beta-catenin hotspot mutations. The absence of PUMA led to a significantly elevated incidence of precursor lesions induced by AOM. AOM was found to induce p53-dependent PUMA expression and PUMA-dependent apoptosis in the colonic crypts and stem cell compartment. Furthermore, PUMA deficiency significantly enhanced the formation of spontaneous macroadenomas and microadenomas in the distal small intestine and colon of APC(Min/+) mice. These results show an essential role of PUMA-mediated apoptosis in suppressing intestinal tumorigenesis in mice.\n" ], "offsets": [ [ 0, 1091 ] ] } ]

[ { "id": "PMID-19491259_T1", "type": "Gene_or_gene_product", "text": [ "PUMA" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-19491259_T2", "type": "Gene_or_gene_product", "text": [ "PUMA" ], "offsets": [ [ 175, 179 ] ], "normalized": [] }, { "id": "PMID-19491259_T3", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 214, 217 ] ], "normalized": [] }, { "id": "PMID-19491259_T4", "type": "Gene_or_gene_product", "text": [ "PUMA" ], "offsets": [ [ 326, 330 ] ], "normalized": [] }, { "id": "PMID-19491259_T5", "type": "Simple_chemical", "text": [ "azoxymethane" ], "offsets": [ [ 391, 403 ] ], "normalized": [] }, { "id": "PMID-19491259_T6", "type": "Simple_chemical", "text": [ "AOM" ], "offsets": [ [ 405, 408 ] ], "normalized": [] }, { "id": "PMID-19491259_T7", "type": "Simple_chemical", "text": [ "dextran" ], "offsets": [ [ 410, 417 ] ], "normalized": [] }, { "id": "PMID-19491259_T8", "type": "Simple_chemical", "text": [ "sulfate sodium salt" ], "offsets": [ [ 418, 437 ] ], "normalized": [] }, { "id": "PMID-19491259_T9", "type": "Gene_or_gene_product", "text": [ "PUMA" ], "offsets": [ [ 445, 449 ] ], "normalized": [] }, { "id": "PMID-19491259_T10", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 542, 554 ] ], "normalized": [] }, { "id": "PMID-19491259_T11", "type": "Gene_or_gene_product", "text": [ "PUMA" ], "offsets": [ [ 589, 593 ] ], "normalized": [] }, { "id": "PMID-19491259_T12", "type": "Simple_chemical", "text": [ "AOM" ], "offsets": [ [ 668, 671 ] ], "normalized": [] }, { "id": "PMID-19491259_T13", "type": "Simple_chemical", "text": [ "AOM" ], "offsets": [ [ 673, 676 ] ], "normalized": [] }, { "id": "PMID-19491259_T14", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 697, 700 ] ], "normalized": [] }, { "id": "PMID-19491259_T15", "type": "Gene_or_gene_product", "text": [ "PUMA" ], "offsets": [ [ 711, 715 ] ], "normalized": [] }, { "id": "PMID-19491259_T16", "type": "Gene_or_gene_product", "text": [ "PUMA" ], "offsets": [ [ 731, 735 ] ], "normalized": [] }, { "id": "PMID-19491259_T17", "type": "Gene_or_gene_product", "text": [ "PUMA" ], "offsets": [ [ 818, 822 ] ], "normalized": [] }, { "id": "PMID-19491259_T18", "type": "Gene_or_gene_product", "text": [ "APC" ], "offsets": [ [ 961, 964 ] ], "normalized": [] }, { "id": "PMID-19491259_T19", "type": "Gene_or_gene_product", "text": [ "PUMA" ], "offsets": [ [ 1018, 1022 ] ], "normalized": [] } ]

[ { "id": "PMID-19491259_E1", "type": "Negative_regulation", "trigger": { "text": [ "Defective" ], "offsets": [ [ 51, 60 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19491259_E2" } ] }, { "id": "PMID-19491259_E2", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 61, 70 ] ] }, "arguments": [] }, { "id": "PMID-19491259_E3", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 200, 209 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19491259_T2" }, { "role": "Theme", "ref_id": "PMID-19491259_E5" } ] }, { "id": "PMID-19491259_E4", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 218, 227 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19491259_T3" }, { "role": "Theme", "ref_id": "PMID-19491259_E5" } ] }, { "id": "PMID-19491259_E5", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 228, 237 ] ] }, "arguments": [] }, { "id": "PMID-19491259_E6", "type": "Inactivation", "trigger": { "text": [ "deficiency" ], "offsets": [ [ 450, 460 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19491259_T9" } ] }, { "id": "PMID-19491259_E7", "type": "Inactivation", "trigger": { "text": [ "absence" ], "offsets": [ [ 578, 585 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19491259_T11" } ] }, { "id": "PMID-19491259_E8", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 690, 696 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19491259_T13" }, { "role": "Theme", "ref_id": "PMID-19491259_E11" } ] }, { "id": "PMID-19491259_E9", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 690, 696 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19491259_T13" }, { "role": "Theme", "ref_id": "PMID-19491259_E13" } ] }, { "id": "PMID-19491259_E10", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 701, 710 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19491259_T14" }, { "role": "Theme", "ref_id": "PMID-19491259_E11" } ] }, { "id": "PMID-19491259_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 716, 726 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19491259_T15" } ] }, { "id": "PMID-19491259_E12", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 736, 745 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19491259_T16" }, { "role": "Theme", "ref_id": "PMID-19491259_E13" } ] }, { "id": "PMID-19491259_E13", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 746, 755 ] ] }, "arguments": [] }, { "id": "PMID-19491259_E14", "type": "Inactivation", "trigger": { "text": [ "deficiency" ], "offsets": [ [ 823, 833 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19491259_T17" } ] }, { "id": "PMID-19491259_E15", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1023, 1031 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19491259_T19" }, { "role": "Theme", "ref_id": "PMID-19491259_E16" } ] }, { "id": "PMID-19491259_E16", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1032, 1041 ] ] }, "arguments": [] } ]

[ { "id": "PMID-19491259_1", "entity_ids": [ "PMID-19491259_T5", "PMID-19491259_T6" ] } ]

[]

[ { "id": "PMID-19837266__text", "type": "abstract", "text": [ "TP53 R72P and MDM2 SNP309 polymorphisms in modification of childhood acute lymphoblastic leukemia susceptibility. \nGenomic and immunologic surveillance mechanisms are crucial in protection from cancer. The tumor suppressor protein p53, encoded by TP53, is a major regulator of genome surveillance. Among the natural sequence variants of TP53, rs1042522 (R72P) modifies the risk for solid tumors. To investigate its relevance in childhood acute lymphoblastic leukemia (ALL) susceptibility, we genotyped 114 cases and 414 newborn controls from Wales (UK) for polymorphisms in TP53 (R72P), its negative regulator MDM2 (single-nucleotide polymorphism SNP309, rs2279744), and selected HLA complex genes whose products interact with TP53. TP53 R72P showed a risk association with gene dosage effect (P=0.002) resulting in a strong association of homozygous genotype (OR=2.9, 95% CI=1.5-5.6) and no sex effect. SNP309 did not show any association with primary susceptibility to childhood ALL, even after stratification by sex. However, females with SNP309 minor allele had earlier onset of childhood ALL (median age at diagnosis was 36 months in females, but 60 months in males; P=0.002). The HLA complex genes did not show any statistically significant interaction with R72P. We have therefore identified TP53 R72P as a possible risk modifier for childhood ALL and the association of MDM2 with age at onset with sex effect suggests prenatal hormonal programming of childhood ALL susceptibility.\n" ], "offsets": [ [ 0, 1489 ] ] } ]

[ { "id": "PMID-19837266_T1", "type": "Gene_or_gene_product", "text": [ "TP53" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-19837266_T2", "type": "Gene_or_gene_product", "text": [ "MDM2" ], "offsets": [ [ 14, 18 ] ], "normalized": [] }, { "id": "PMID-19837266_T3", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 231, 234 ] ], "normalized": [] }, { "id": "PMID-19837266_T4", "type": "Gene_or_gene_product", "text": [ "TP53" ], "offsets": [ [ 247, 251 ] ], "normalized": [] }, { "id": "PMID-19837266_T5", "type": "Gene_or_gene_product", "text": [ "TP53" ], "offsets": [ [ 337, 341 ] ], "normalized": [] }, { "id": "PMID-19837266_T6", "type": "Gene_or_gene_product", "text": [ "TP53" ], "offsets": [ [ 574, 578 ] ], "normalized": [] }, { "id": "PMID-19837266_T7", "type": "Gene_or_gene_product", "text": [ "MDM2" ], "offsets": [ [ 610, 614 ] ], "normalized": [] }, { "id": "PMID-19837266_T8", "type": "Complex", "text": [ "HLA" ], "offsets": [ [ 680, 683 ] ], "normalized": [] }, { "id": "PMID-19837266_T9", "type": "Gene_or_gene_product", "text": [ "TP53" ], "offsets": [ [ 727, 731 ] ], "normalized": [] }, { "id": "PMID-19837266_T10", "type": "Gene_or_gene_product", "text": [ "TP53" ], "offsets": [ [ 733, 737 ] ], "normalized": [] }, { "id": "PMID-19837266_T11", "type": "Complex", "text": [ "HLA" ], "offsets": [ [ 1186, 1189 ] ], "normalized": [] }, { "id": "PMID-19837266_T12", "type": "Gene_or_gene_product", "text": [ "TP53" ], "offsets": [ [ 1299, 1303 ] ], "normalized": [] }, { "id": "PMID-19837266_T13", "type": "Gene_or_gene_product", "text": [ "MDM2" ], "offsets": [ [ 1378, 1382 ] ], "normalized": [] } ]

[ { "id": "PMID-19837266_E1", "type": "Negative_regulation", "trigger": { "text": [ "regulator" ], "offsets": [ [ 600, 609 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-19837266_T7" }, { "role": "Theme", "ref_id": "PMID-19837266_T6" } ] }, { "id": "PMID-19837266_E2", "type": "Binding", "trigger": { "text": [ "interact" ], "offsets": [ [ 713, 721 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19837266_T9" }, { "role": "Theme", "ref_id": "PMID-19837266_T8" } ] }, { "id": "PMID-19837266_E3", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1247, 1258 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19837266_T11" } ] }, { "id": "PMID-19837266_E4", "type": "Regulation", "trigger": { "text": [ "association" ], "offsets": [ [ 1363, 1374 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-19837266_T13" }, { "role": "Cause", "ref_id": "PMID-19837266_T12" } ] } ]

[]

[]

[ { "id": "PMID-20832726__text", "type": "abstract", "text": [ "A feed-forward circuit controlling inducible NF-kappaB target gene activation by promoter histone demethylation. \nActivation of transcription from a silenced state is crucial to achieve specific gene expression in many biological contexts. Methylation of lysine 9 on histone H3 (H3K9) is widely associated with transcriptional silencing, and its disappearance is linked to the activation of several inflammatory genes by NF-kappaB. Here we describe that this event is controlled by a feed-forward circuit catalyzed by the activity of the histone demethylase Aof1 (also known as Lsd2/Kdm1b). We find that Aof1 is required for removal of dimethyl H3K9 at specific promoters, and thereby it controls stimulus-induced recruitment of NF-kappaB and gene expression. However, Aof1 is itself recruited by interaction with the c-Rel subunit of NF-kappaB, which is found at low levels associated with promoters in unstimulated cells. Thus, at these tightly regulated genes, NF-kappaB functions both as a transcriptional activator and as an upstream targeting signal that marks promoters to be derepressed by histone demethylation.\n" ], "offsets": [ [ 0, 1121 ] ] } ]

[ { "id": "PMID-20832726_T1", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 45, 54 ] ], "normalized": [] }, { "id": "PMID-20832726_T2", "type": "Gene_or_gene_product", "text": [ "histone" ], "offsets": [ [ 90, 97 ] ], "normalized": [] }, { "id": "PMID-20832726_T3", "type": "Simple_chemical", "text": [ "lysine 9" ], "offsets": [ [ 255, 263 ] ], "normalized": [] }, { "id": "PMID-20832726_T4", "type": "Gene_or_gene_product", "text": [ "histone H3" ], "offsets": [ [ 267, 277 ] ], "normalized": [] }, { "id": "PMID-20832726_T5", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 279, 281 ] ], "normalized": [] }, { "id": "PMID-20832726_T6", "type": "Simple_chemical", "text": [ "K9" ], "offsets": [ [ 281, 283 ] ], "normalized": [] }, { "id": "PMID-20832726_T7", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 421, 430 ] ], "normalized": [] }, { "id": "PMID-20832726_T8", "type": "Gene_or_gene_product", "text": [ "histone" ], "offsets": [ [ 538, 545 ] ], "normalized": [] }, { "id": "PMID-20832726_T9", "type": "Gene_or_gene_product", "text": [ "Aof1" ], "offsets": [ [ 558, 562 ] ], "normalized": [] }, { "id": "PMID-20832726_T10", "type": "Gene_or_gene_product", "text": [ "Lsd2" ], "offsets": [ [ 578, 582 ] ], "normalized": [] }, { "id": "PMID-20832726_T11", "type": "Gene_or_gene_product", "text": [ "Kdm1b" ], "offsets": [ [ 583, 588 ] ], "normalized": [] }, { "id": "PMID-20832726_T12", "type": "Gene_or_gene_product", "text": [ "Aof1" ], "offsets": [ [ 604, 608 ] ], "normalized": [] }, { "id": "PMID-20832726_T13", "type": "Gene_or_gene_product", "text": [ "H3" ], "offsets": [ [ 645, 647 ] ], "normalized": [] }, { "id": "PMID-20832726_T14", "type": "Simple_chemical", "text": [ "K9" ], "offsets": [ [ 647, 649 ] ], "normalized": [] }, { "id": "PMID-20832726_T15", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 729, 738 ] ], "normalized": [] }, { "id": "PMID-20832726_T16", "type": "Gene_or_gene_product", "text": [ "Aof1" ], "offsets": [ [ 769, 773 ] ], "normalized": [] }, { "id": "PMID-20832726_T17", "type": "Gene_or_gene_product", "text": [ "c-Rel" ], "offsets": [ [ 818, 823 ] ], "normalized": [] }, { "id": "PMID-20832726_T18", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 835, 844 ] ], "normalized": [] }, { "id": "PMID-20832726_T19", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 964, 973 ] ], "normalized": [] }, { "id": "PMID-20832726_T20", "type": "Gene_or_gene_product", "text": [ "histone" ], "offsets": [ [ 1098, 1105 ] ], "normalized": [] } ]

[ { "id": "PMID-20832726_E1", "type": "Demethylation", "trigger": { "text": [ "demethylation" ], "offsets": [ [ 98, 111 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20832726_T2" } ] }, { "id": "PMID-20832726_E2", "type": "Methylation", "trigger": { "text": [ "Methylation" ], "offsets": [ [ 240, 251 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-20832726_T3" }, { "role": "Theme", "ref_id": "PMID-20832726_T4" } ] }, { "id": "PMID-20832726_E3", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 295, 305 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20832726_E2" } ] }, { "id": "PMID-20832726_E4", "type": "Demethylation", "trigger": { "text": [ "disappearance" ], "offsets": [ [ 346, 359 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-20832726_T3" }, { "role": "Theme", "ref_id": "PMID-20832726_T4" } ] }, { "id": "PMID-20832726_E5", "type": "Demethylation", "trigger": { "text": [ "demethylase" ], "offsets": [ [ 546, 557 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20832726_T8" }, { "role": "Cause", "ref_id": "PMID-20832726_T9" } ] }, { "id": "PMID-20832726_E6", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 612, 620 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-20832726_T12" }, { "role": "Theme", "ref_id": "PMID-20832726_E7" } ] }, { "id": "PMID-20832726_E7", "type": "Degradation", "trigger": { "text": [ "removal" ], "offsets": [ [ 625, 632 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20832726_T13" } ] }, { "id": "PMID-20832726_E8", "type": "Methylation", "trigger": { "text": [ "dimethyl" ], "offsets": [ [ 636, 644 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-20832726_T14" }, { "role": "Theme", "ref_id": "PMID-20832726_T13" } ] }, { "id": "PMID-20832726_E9", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 688, 696 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20832726_E10" }, { "role": "Cause", "ref_id": "PMID-20832726_T12" } ] }, { "id": "PMID-20832726_E10", "type": "Transport", "trigger": { "text": [ "recruitment" ], "offsets": [ [ 714, 725 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20832726_T15" } ] }, { "id": "PMID-20832726_E11", "type": "Transport", "trigger": { "text": [ "recruited" ], "offsets": [ [ 784, 793 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20832726_T16" } ] }, { "id": "PMID-20832726_E12", "type": "Positive_regulation", "trigger": { "text": [ "recruited" ], "offsets": [ [ 784, 793 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20832726_E11" }, { "role": "Cause", "ref_id": "PMID-20832726_E13" } ] }, { "id": "PMID-20832726_E13", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 797, 808 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20832726_T17" }, { "role": "Theme", "ref_id": "PMID-20832726_T16" } ] }, { "id": "PMID-20832726_E14", "type": "Demethylation", "trigger": { "text": [ "demethylation" ], "offsets": [ [ 1106, 1119 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20832726_T20" } ] } ]

[ { "id": "PMID-20832726_1", "entity_ids": [ "PMID-20832726_T3", "PMID-20832726_T6" ] }, { "id": "PMID-20832726_2", "entity_ids": [ "PMID-20832726_T5", "PMID-20832726_T4" ] }, { "id": "PMID-20832726_3", "entity_ids": [ "PMID-20832726_T9", "PMID-20832726_T10", "PMID-20832726_T11" ] } ]

[]

[ { "id": "PMID-20970423__text", "type": "abstract", "text": [ "NEMO stabilizes c-Myc through direct interaction in the nucleus. \nThe transcription factor c-Myc is a cellular oncoprotein generally upregulated in most of human cancers. NF-kappaB essential modulator (NEMO) caused phosphorylation and stabilization of c-Myc protein in the nucleus through direct interaction. The interaction caused reduced ubiquitination of c-Myc by inhibiting ubiquitinating activity of Fbw7 without blocking the interaction between c-Myc and Fbw7. As a consequence, NEMO enhanced the expression of several selected c-Myc targets. Compared to the classical role as an essential subunit for the activity of IKK complex, stabilization of c-Myc by direct interaction is a unique function of NEMO, representing a new mechanism to regulate c-Myc activity.\n" ], "offsets": [ [ 0, 769 ] ] } ]

[ { "id": "PMID-20970423_T1", "type": "Gene_or_gene_product", "text": [ "NEMO" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-20970423_T2", "type": "Gene_or_gene_product", "text": [ "c-Myc" ], "offsets": [ [ 16, 21 ] ], "normalized": [] }, { "id": "PMID-20970423_T3", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 56, 63 ] ], "normalized": [] }, { "id": "PMID-20970423_T4", "type": "Gene_or_gene_product", "text": [ "c-Myc" ], "offsets": [ [ 91, 96 ] ], "normalized": [] }, { "id": "PMID-20970423_T5", "type": "Gene_or_gene_product", "text": [ "NF-kappaB essential modulator" ], "offsets": [ [ 171, 200 ] ], "normalized": [] }, { "id": "PMID-20970423_T6", "type": "Gene_or_gene_product", "text": [ "NEMO" ], "offsets": [ [ 202, 206 ] ], "normalized": [] }, { "id": "PMID-20970423_T7", "type": "Gene_or_gene_product", "text": [ "c-Myc" ], "offsets": [ [ 252, 257 ] ], "normalized": [] }, { "id": "PMID-20970423_T8", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 273, 280 ] ], "normalized": [] }, { "id": "PMID-20970423_T9", "type": "Gene_or_gene_product", "text": [ "c-Myc" ], "offsets": [ [ 358, 363 ] ], "normalized": [] }, { "id": "PMID-20970423_T10", "type": "Gene_or_gene_product", "text": [ "Fbw7" ], "offsets": [ [ 405, 409 ] ], "normalized": [] }, { "id": "PMID-20970423_T11", "type": "Gene_or_gene_product", "text": [ "c-Myc" ], "offsets": [ [ 451, 456 ] ], "normalized": [] }, { "id": "PMID-20970423_T12", "type": "Gene_or_gene_product", "text": [ "Fbw7" ], "offsets": [ [ 461, 465 ] ], "normalized": [] }, { "id": "PMID-20970423_T13", "type": "Gene_or_gene_product", "text": [ "NEMO" ], "offsets": [ [ 485, 489 ] ], "normalized": [] }, { "id": "PMID-20970423_T14", "type": "Gene_or_gene_product", "text": [ "c-Myc" ], "offsets": [ [ 534, 539 ] ], "normalized": [] }, { "id": "PMID-20970423_T15", "type": "Complex", "text": [ "IKK" ], "offsets": [ [ 624, 627 ] ], "normalized": [] }, { "id": "PMID-20970423_T16", "type": "Gene_or_gene_product", "text": [ "c-Myc" ], "offsets": [ [ 654, 659 ] ], "normalized": [] }, { "id": "PMID-20970423_T17", "type": "Gene_or_gene_product", "text": [ "NEMO" ], "offsets": [ [ 706, 710 ] ], "normalized": [] }, { "id": "PMID-20970423_T18", "type": "Gene_or_gene_product", "text": [ "c-Myc" ], "offsets": [ [ 753, 758 ] ], "normalized": [] } ]

[ { "id": "PMID-20970423_E1", "type": "Regulation", "trigger": { "text": [ "stabilizes" ], "offsets": [ [ 5, 15 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-20970423_E2" }, { "role": "Theme", "ref_id": "PMID-20970423_T2" } ] }, { "id": "PMID-20970423_E2", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 37, 48 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_T2" }, { "role": "Theme", "ref_id": "PMID-20970423_T1" } ] }, { "id": "PMID-20970423_E3", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 133, 144 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_T4" } ] }, { "id": "PMID-20970423_E4", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 208, 214 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-20970423_E8" }, { "role": "Theme", "ref_id": "PMID-20970423_E6" } ] }, { "id": "PMID-20970423_E5", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 208, 214 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-20970423_E8" }, { "role": "Theme", "ref_id": "PMID-20970423_E7" } ] }, { "id": "PMID-20970423_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 215, 230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_T7" } ] }, { "id": "PMID-20970423_E7", "type": "Regulation", "trigger": { "text": [ "stabilization" ], "offsets": [ [ 235, 248 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_T7" } ] }, { "id": "PMID-20970423_E8", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 296, 307 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_T7" }, { "role": "Theme", "ref_id": "PMID-20970423_T6" } ] }, { "id": "PMID-20970423_E9", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 325, 331 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-20970423_E12" }, { "role": "Theme", "ref_id": "PMID-20970423_E10" } ] }, { "id": "PMID-20970423_E10", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 332, 339 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_E11" } ] }, { "id": "PMID-20970423_E11", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 340, 354 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_T9" } ] }, { "id": "PMID-20970423_E12", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 367, 377 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_E13" } ] }, { "id": "PMID-20970423_E13", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinating" ], "offsets": [ [ 378, 392 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_T10" } ] }, { "id": "PMID-20970423_E14", "type": "Negative_regulation", "trigger": { "text": [ "blocking" ], "offsets": [ [ 418, 426 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_E15" } ] }, { "id": "PMID-20970423_E15", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 431, 442 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_T11" }, { "role": "Theme", "ref_id": "PMID-20970423_T12" } ] }, { "id": "PMID-20970423_E16", "type": "Regulation", "trigger": { "text": [ "stabilization" ], "offsets": [ [ 637, 650 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_T16" } ] }, { "id": "PMID-20970423_E17", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 670, 681 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_T17" }, { "role": "Theme", "ref_id": "PMID-20970423_T16" } ] }, { "id": "PMID-20970423_E18", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 744, 752 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-20970423_T18" } ] } ]

[ { "id": "PMID-20970423_1", "entity_ids": [ "PMID-20970423_T5", "PMID-20970423_T6" ] } ]

[]

[ { "id": "PMID-21042750__text", "type": "abstract", "text": [ "Interaction between nuclear insulin receptor substrate-2 and NF-kappaB in IGF-1 induces response in breast cancer cells. \nDespite significant homology between IRS-1 and IRS-2, recent studies have revealed distinct functions for these adaptor proteins in regulating breast cancer progression. Thus far, most of the studies on breast cancer have focused upon IRS-1, the biological pattern of IRS-2 is limited. We demonstrated that depletion of endogenous IRS-2 by antisense strategies impaired cell proliferation after serum withdrawal, blunted PI3K/Akt and NF-kappaB activation in IGF-1 induced response in MCF-7 and BT-20 breast cancer cells. In addition, IGF-1 promote nuclear translocation of IRS-2 and NF-kappaB in MCF-7 and BT-20 cells. Nuclear IRS-2 interaction with NF-kappaB-p65 and PI3K binding tyrosine residues of IRS-2 are crucial for the NF-kappaB activities. Moreover, nuclear IRS-2 is recruited to the cyclin D1 promoter both in MCF-7 and BT-20 cells. The selective inhibition of NF-kappaB-65 abolished the occupancy of IRS-2 to the cyclin D1 promoters. Our studies suggest that IRS-2 plays a significant role by activating, at least in part, NF-kappaB via PI3K/Akt pathway in IGF-1-induced responses in breast cancer cells and the crosstalk between nuclear IRS-2 and NF-kappaB might be responsible for transcriptional progression of the breast cancer cells.\n" ], "offsets": [ [ 0, 1373 ] ] } ]

[ { "id": "PMID-21042750_T1", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 20, 27 ] ], "normalized": [] }, { "id": "PMID-21042750_T2", "type": "Gene_or_gene_product", "text": [ "insulin receptor substrate-2" ], "offsets": [ [ 28, 56 ] ], "normalized": [] }, { "id": "PMID-21042750_T3", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 61, 70 ] ], "normalized": [] }, { "id": "PMID-21042750_T4", "type": "Gene_or_gene_product", "text": [ "IGF-1" ], "offsets": [ [ 74, 79 ] ], "normalized": [] }, { "id": "PMID-21042750_T5", "type": "Gene_or_gene_product", "text": [ "IRS-1" ], "offsets": [ [ 159, 164 ] ], "normalized": [] }, { "id": "PMID-21042750_T6", "type": "Gene_or_gene_product", "text": [ "IRS-2" ], "offsets": [ [ 169, 174 ] ], "normalized": [] }, { "id": "PMID-21042750_T7", "type": "Gene_or_gene_product", "text": [ "IRS-1" ], "offsets": [ [ 357, 362 ] ], "normalized": [] }, { "id": "PMID-21042750_T8", "type": "Gene_or_gene_product", "text": [ "IRS-2" ], "offsets": [ [ 390, 395 ] ], "normalized": [] }, { "id": "PMID-21042750_T9", "type": "Gene_or_gene_product", "text": [ "IRS-2" ], "offsets": [ [ 453, 458 ] ], "normalized": [] }, { "id": "PMID-21042750_T10", "type": "Gene_or_gene_product", "text": [ "PI3K" ], "offsets": [ [ 543, 547 ] ], "normalized": [] }, { "id": "PMID-21042750_T11", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 548, 551 ] ], "normalized": [] }, { "id": "PMID-21042750_T12", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 556, 565 ] ], "normalized": [] }, { "id": "PMID-21042750_T13", "type": "Gene_or_gene_product", "text": [ "IGF-1" ], "offsets": [ [ 580, 585 ] ], "normalized": [] }, { "id": "PMID-21042750_T14", "type": "Gene_or_gene_product", "text": [ "IGF-1" ], "offsets": [ [ 656, 661 ] ], "normalized": [] }, { "id": "PMID-21042750_T15", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 670, 677 ] ], "normalized": [] }, { "id": "PMID-21042750_T16", "type": "Gene_or_gene_product", "text": [ "IRS-2" ], "offsets": [ [ 695, 700 ] ], "normalized": [] }, { "id": "PMID-21042750_T17", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 705, 714 ] ], "normalized": [] }, { "id": "PMID-21042750_T18", "type": "Cellular_component", "text": [ "Nuclear" ], "offsets": [ [ 741, 748 ] ], "normalized": [] }, { "id": "PMID-21042750_T19", "type": "Gene_or_gene_product", "text": [ "IRS-2" ], "offsets": [ [ 749, 754 ] ], "normalized": [] }, { "id": "PMID-21042750_T20", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 772, 781 ] ], "normalized": [] }, { "id": "PMID-21042750_T21", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 782, 785 ] ], "normalized": [] }, { "id": "PMID-21042750_T22", "type": "Gene_or_gene_product", "text": [ "PI3K" ], "offsets": [ [ 790, 794 ] ], "normalized": [] }, { "id": "PMID-21042750_T23", "type": "Simple_chemical", "text": [ "tyrosine" ], "offsets": [ [ 803, 811 ] ], "normalized": [] }, { "id": "PMID-21042750_T24", "type": "Gene_or_gene_product", "text": [ "IRS-2" ], "offsets": [ [ 824, 829 ] ], "normalized": [] }, { "id": "PMID-21042750_T25", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 850, 859 ] ], "normalized": [] }, { "id": "PMID-21042750_T26", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 882, 889 ] ], "normalized": [] }, { "id": "PMID-21042750_T27", "type": "Gene_or_gene_product", "text": [ "IRS-2" ], "offsets": [ [ 890, 895 ] ], "normalized": [] }, { "id": "PMID-21042750_T28", "type": "Gene_or_gene_product", "text": [ "cyclin D1" ], "offsets": [ [ 916, 925 ] ], "normalized": [] }, { "id": "PMID-21042750_T29", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 994, 1003 ] ], "normalized": [] }, { "id": "PMID-21042750_T30", "type": "Gene_or_gene_product", "text": [ "65" ], "offsets": [ [ 1004, 1006 ] ], "normalized": [] }, { "id": "PMID-21042750_T31", "type": "Gene_or_gene_product", "text": [ "IRS-2" ], "offsets": [ [ 1034, 1039 ] ], "normalized": [] }, { "id": "PMID-21042750_T32", "type": "Gene_or_gene_product", "text": [ "cyclin D1" ], "offsets": [ [ 1047, 1056 ] ], "normalized": [] }, { "id": "PMID-21042750_T33", "type": "Gene_or_gene_product", "text": [ "IRS-2" ], "offsets": [ [ 1093, 1098 ] ], "normalized": [] }, { "id": "PMID-21042750_T34", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1157, 1166 ] ], "normalized": [] }, { "id": "PMID-21042750_T35", "type": "Gene_or_gene_product", "text": [ "PI3K" ], "offsets": [ [ 1171, 1175 ] ], "normalized": [] }, { "id": "PMID-21042750_T36", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1176, 1179 ] ], "normalized": [] }, { "id": "PMID-21042750_T37", "type": "Gene_or_gene_product", "text": [ "IGF-1" ], "offsets": [ [ 1191, 1196 ] ], "normalized": [] }, { "id": "PMID-21042750_T38", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1264, 1271 ] ], "normalized": [] }, { "id": "PMID-21042750_T39", "type": "Gene_or_gene_product", "text": [ "IRS-2" ], "offsets": [ [ 1272, 1277 ] ], "normalized": [] }, { "id": "PMID-21042750_T40", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1282, 1291 ] ], "normalized": [] } ]

[ { "id": "PMID-21042750_E1", "type": "Binding", "trigger": { "text": [ "Interaction" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T2" }, { "role": "Theme", "ref_id": "PMID-21042750_T3" } ] }, { "id": "PMID-21042750_E2", "type": "Negative_regulation", "trigger": { "text": [ "depletion" ], "offsets": [ [ 429, 438 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T9" } ] }, { "id": "PMID-21042750_E3", "type": "Negative_regulation", "trigger": { "text": [ "blunted" ], "offsets": [ [ 535, 542 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21042750_E2" }, { "role": "Theme", "ref_id": "PMID-21042750_E6" } ] }, { "id": "PMID-21042750_E4", "type": "Negative_regulation", "trigger": { "text": [ "blunted" ], "offsets": [ [ 535, 542 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21042750_E2" }, { "role": "Theme", "ref_id": "PMID-21042750_E7" } ] }, { "id": "PMID-21042750_E5", "type": "Negative_regulation", "trigger": { "text": [ "blunted" ], "offsets": [ [ 535, 542 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21042750_E2" }, { "role": "Theme", "ref_id": "PMID-21042750_E8" } ] }, { "id": "PMID-21042750_E6", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 566, 576 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T10" } ] }, { "id": "PMID-21042750_E7", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 566, 576 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T11" } ] }, { "id": "PMID-21042750_E8", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 566, 576 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T12" } ] }, { "id": "PMID-21042750_E9", "type": "Positive_regulation", "trigger": { "text": [ "promote" ], "offsets": [ [ 662, 669 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21042750_T14" }, { "role": "Theme", "ref_id": "PMID-21042750_E11" } ] }, { "id": "PMID-21042750_E10", "type": "Positive_regulation", "trigger": { "text": [ "promote" ], "offsets": [ [ 662, 669 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21042750_T14" }, { "role": "Theme", "ref_id": "PMID-21042750_E12" } ] }, { "id": "PMID-21042750_E11", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 678, 691 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-21042750_T15" }, { "role": "ToLoc", "ref_id": "PMID-21042750_T15" }, { "role": "Theme", "ref_id": "PMID-21042750_T16" } ] }, { "id": "PMID-21042750_E12", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 678, 691 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-21042750_T15" }, { "role": "ToLoc", "ref_id": "PMID-21042750_T15" }, { "role": "Theme", "ref_id": "PMID-21042750_T17" } ] }, { "id": "PMID-21042750_E13", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 755, 766 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T19" }, { "role": "Theme", "ref_id": "PMID-21042750_T20" }, { "role": "Theme", "ref_id": "PMID-21042750_T21" } ] }, { "id": "PMID-21042750_E14", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 795, 802 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T22" }, { "role": "Theme", "ref_id": "PMID-21042750_T23" } ] }, { "id": "PMID-21042750_E15", "type": "Positive_regulation", "trigger": { "text": [ "crucial" ], "offsets": [ [ 834, 841 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T25" }, { "role": "Cause", "ref_id": "PMID-21042750_E13" } ] }, { "id": "PMID-21042750_E16", "type": "Positive_regulation", "trigger": { "text": [ "crucial" ], "offsets": [ [ 834, 841 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T25" }, { "role": "Cause", "ref_id": "PMID-21042750_E14" } ] }, { "id": "PMID-21042750_E17", "type": "Binding", "trigger": { "text": [ "recruited" ], "offsets": [ [ 899, 908 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T27" }, { "role": "Theme", "ref_id": "PMID-21042750_T28" } ] }, { "id": "PMID-21042750_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 980, 990 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T29" } ] }, { "id": "PMID-21042750_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 980, 990 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T30" } ] }, { "id": "PMID-21042750_E20", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 1007, 1016 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_E22" }, { "role": "Cause", "ref_id": "PMID-21042750_E18" } ] }, { "id": "PMID-21042750_E21", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 1007, 1016 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_E22" }, { "role": "Cause", "ref_id": "PMID-21042750_E19" } ] }, { "id": "PMID-21042750_E22", "type": "Binding", "trigger": { "text": [ "occupancy" ], "offsets": [ [ 1021, 1030 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T31" }, { "role": "Theme", "ref_id": "PMID-21042750_T32" } ] }, { "id": "PMID-21042750_E23", "type": "Regulation", "trigger": { "text": [ "plays a significant role" ], "offsets": [ [ 1099, 1123 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21042750_T33" }, { "role": "Theme", "ref_id": "PMID-21042750_E24" } ] }, { "id": "PMID-21042750_E24", "type": "Activation", "trigger": { "text": [ "activating" ], "offsets": [ [ 1127, 1137 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T34" }, { "role": "Cause", "ref_id": "PMID-21042750_E25" } ] }, { "id": "PMID-21042750_E25", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1180, 1187 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21042750_T35" }, { "role": "Participant", "ref_id": "PMID-21042750_T36" } ] }, { "id": "PMID-21042750_E26", "type": "Binding", "trigger": { "text": [ "crosstalk" ], "offsets": [ [ 1246, 1255 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21042750_T39" }, { "role": "Theme", "ref_id": "PMID-21042750_T40" } ] } ]

[]

[]

[ { "id": "PMID-21078404__text", "type": "abstract", "text": [ "Regulation of Angiotensin II receptor signaling by cysteine modification of NF-kappaB. \nAngiotensin II (Ang II) is a major vasoactive peptide of the renin-angiotensin system. Ang II is originally found as one of potent vasoconstrictors, but is now attracted attention as an essential mediator of many cardiovascular problems, including endothelial dysfunction, arrhythmia and structural remodeling of cardiovascular systems. Most of the known pathophysiological effects of Ang II are mediated through Ang type1 receptors (AT(1)Rs), and the up-regulation of AT(1)Rs is one of important causes by which Ang II can contribute to cardiovascular diseases. A growing body of evidence has suggested that reactive oxygen species (ROS) and reactive nitrogen species (RNS) play important roles in the regulation of AT(1)R signaling. In cardiac fibroblasts, stimulation with cytokines or bacterial toxins induces AT(1)R up-regulation through NADPH oxidase-dependent ROS production. In contrast, nitric oxide (NO) decreases AT(1)R density through cysteine modification (S-nitrosylation) of a transcriptional factor, nuclear factor kappaB (NF-kappaB). The difference between the effects of ROS and NO on AT(1)R expression may be caused by the difference between intracellular location of ROS signaling and that of NO signaling, as the agonist-induced S-nitrosylation of NF-kappaB requires a local interaction between NO synthase (NOS) and NF-kappaB in the perinuclear region. Thus, the spatial and temporal regulation of cysteine modification by ROS or RNS may underlie the resultant changes of AT(1)R signaling induced by agonist stimulation.\n" ], "offsets": [ [ 0, 1631 ] ] } ]

[ { "id": "PMID-21078404_T1", "type": "Gene_or_gene_product", "text": [ "Angiotensin II receptor" ], "offsets": [ [ 14, 37 ] ], "normalized": [] }, { "id": "PMID-21078404_T2", "type": "Simple_chemical", "text": [ "cysteine" ], "offsets": [ [ 51, 59 ] ], "normalized": [] }, { "id": "PMID-21078404_T3", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 76, 85 ] ], "normalized": [] }, { "id": "PMID-21078404_T4", "type": "Gene_or_gene_product", "text": [ "Angiotensin II" ], "offsets": [ [ 88, 102 ] ], "normalized": [] }, { "id": "PMID-21078404_T5", "type": "Gene_or_gene_product", "text": [ "Ang II" ], "offsets": [ [ 104, 110 ] ], "normalized": [] }, { "id": "PMID-21078404_T6", "type": "Gene_or_gene_product", "text": [ "renin" ], "offsets": [ [ 149, 154 ] ], "normalized": [] }, { "id": "PMID-21078404_T7", "type": "Gene_or_gene_product", "text": [ "angiotensin" ], "offsets": [ [ 155, 166 ] ], "normalized": [] }, { "id": "PMID-21078404_T8", "type": "Gene_or_gene_product", "text": [ "Ang II" ], "offsets": [ [ 175, 181 ] ], "normalized": [] }, { "id": "PMID-21078404_T9", "type": "Gene_or_gene_product", "text": [ "Ang II" ], "offsets": [ [ 473, 479 ] ], "normalized": [] }, { "id": "PMID-21078404_T10", "type": "Gene_or_gene_product", "text": [ "Ang type1 receptors" ], "offsets": [ [ 501, 520 ] ], "normalized": [] }, { "id": "PMID-21078404_T11", "type": "Gene_or_gene_product", "text": [ "AT(1)Rs" ], "offsets": [ [ 522, 529 ] ], "normalized": [] }, { "id": "PMID-21078404_T12", "type": "Gene_or_gene_product", "text": [ "AT(1)Rs" ], "offsets": [ [ 557, 564 ] ], "normalized": [] }, { "id": "PMID-21078404_T13", "type": "Gene_or_gene_product", "text": [ "Ang II" ], "offsets": [ [ 601, 607 ] ], "normalized": [] }, { "id": "PMID-21078404_T14", "type": "Simple_chemical", "text": [ "reactive oxygen species" ], "offsets": [ [ 697, 720 ] ], "normalized": [] }, { "id": "PMID-21078404_T15", "type": "Simple_chemical", "text": [ "ROS" ], "offsets": [ [ 722, 725 ] ], "normalized": [] }, { "id": "PMID-21078404_T16", "type": "Simple_chemical", "text": [ "reactive nitrogen species" ], "offsets": [ [ 731, 756 ] ], "normalized": [] }, { "id": "PMID-21078404_T17", "type": "Simple_chemical", "text": [ "RNS" ], "offsets": [ [ 758, 761 ] ], "normalized": [] }, { "id": "PMID-21078404_T18", "type": "Gene_or_gene_product", "text": [ "AT(1)R" ], "offsets": [ [ 805, 811 ] ], "normalized": [] }, { "id": "PMID-21078404_T19", "type": "Gene_or_gene_product", "text": [ "AT(1)R" ], "offsets": [ [ 902, 908 ] ], "normalized": [] }, { "id": "PMID-21078404_T20", "type": "Gene_or_gene_product", "text": [ "NADPH oxidase" ], "offsets": [ [ 931, 944 ] ], "normalized": [] }, { "id": "PMID-21078404_T21", "type": "Simple_chemical", "text": [ "ROS" ], "offsets": [ [ 955, 958 ] ], "normalized": [] }, { "id": "PMID-21078404_T22", "type": "Simple_chemical", "text": [ "nitric oxide" ], "offsets": [ [ 984, 996 ] ], "normalized": [] }, { "id": "PMID-21078404_T23", "type": "Simple_chemical", "text": [ "NO" ], "offsets": [ [ 998, 1000 ] ], "normalized": [] }, { "id": "PMID-21078404_T24", "type": "Gene_or_gene_product", "text": [ "AT(1)R" ], "offsets": [ [ 1012, 1018 ] ], "normalized": [] }, { "id": "PMID-21078404_T25", "type": "Simple_chemical", "text": [ "cysteine" ], "offsets": [ [ 1035, 1043 ] ], "normalized": [] }, { "id": "PMID-21078404_T26", "type": "Complex", "text": [ "nuclear factor kappaB" ], "offsets": [ [ 1104, 1125 ] ], "normalized": [] }, { "id": "PMID-21078404_T27", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1127, 1136 ] ], "normalized": [] }, { "id": "PMID-21078404_T28", "type": "Simple_chemical", "text": [ "ROS" ], "offsets": [ [ 1177, 1180 ] ], "normalized": [] }, { "id": "PMID-21078404_T29", "type": "Simple_chemical", "text": [ "NO" ], "offsets": [ [ 1185, 1187 ] ], "normalized": [] }, { "id": "PMID-21078404_T30", "type": "Gene_or_gene_product", "text": [ "AT(1)R" ], "offsets": [ [ 1191, 1197 ] ], "normalized": [] }, { "id": "PMID-21078404_T31", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 1249, 1262 ] ], "normalized": [] }, { "id": "PMID-21078404_T32", "type": "Simple_chemical", "text": [ "ROS" ], "offsets": [ [ 1275, 1278 ] ], "normalized": [] }, { "id": "PMID-21078404_T33", "type": "Simple_chemical", "text": [ "NO" ], "offsets": [ [ 1301, 1303 ] ], "normalized": [] }, { "id": "PMID-21078404_T34", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1357, 1366 ] ], "normalized": [] }, { "id": "PMID-21078404_T35", "type": "Gene_or_gene_product", "text": [ "NO synthase" ], "offsets": [ [ 1404, 1415 ] ], "normalized": [] }, { "id": "PMID-21078404_T36", "type": "Gene_or_gene_product", "text": [ "NOS" ], "offsets": [ [ 1417, 1420 ] ], "normalized": [] }, { "id": "PMID-21078404_T37", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1426, 1435 ] ], "normalized": [] }, { "id": "PMID-21078404_T38", "type": "Simple_chemical", "text": [ "cysteine" ], "offsets": [ [ 1508, 1516 ] ], "normalized": [] }, { "id": "PMID-21078404_T39", "type": "Simple_chemical", "text": [ "ROS" ], "offsets": [ [ 1533, 1536 ] ], "normalized": [] }, { "id": "PMID-21078404_T40", "type": "Simple_chemical", "text": [ "RNS" ], "offsets": [ [ 1540, 1543 ] ], "normalized": [] }, { "id": "PMID-21078404_T41", "type": "Gene_or_gene_product", "text": [ "AT(1)R" ], "offsets": [ [ 1582, 1588 ] ], "normalized": [] } ]

[ { "id": "PMID-21078404_E1", "type": "Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E2" }, { "role": "Cause", "ref_id": "PMID-21078404_E3" } ] }, { "id": "PMID-21078404_E2", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 38, 47 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21078404_T1" } ] }, { "id": "PMID-21078404_E3", "type": "Conversion", "trigger": { "text": [ "modification" ], "offsets": [ [ 60, 72 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_T3" } ] }, { "id": "PMID-21078404_E4", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 462, 469 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_T9" } ] }, { "id": "PMID-21078404_E5", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 484, 492 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E4" }, { "role": "Cause", "ref_id": "PMID-21078404_T11" } ] }, { "id": "PMID-21078404_E6", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 540, 553 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_T12" } ] }, { "id": "PMID-21078404_E7", "type": "Regulation", "trigger": { "text": [ "play important roles" ], "offsets": [ [ 763, 783 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E9" }, { "role": "Cause", "ref_id": "PMID-21078404_T15" } ] }, { "id": "PMID-21078404_E8", "type": "Regulation", "trigger": { "text": [ "play important roles" ], "offsets": [ [ 763, 783 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E9" }, { "role": "Cause", "ref_id": "PMID-21078404_T17" } ] }, { "id": "PMID-21078404_E9", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 791, 801 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E10" } ] }, { "id": "PMID-21078404_E10", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 812, 821 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21078404_T18" } ] }, { "id": "PMID-21078404_E11", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 894, 901 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E12" }, { "role": "Cause", "ref_id": "PMID-21078404_E14" } ] }, { "id": "PMID-21078404_E12", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 909, 922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_T19" } ] }, { "id": "PMID-21078404_E13", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 945, 954 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21078404_T20" }, { "role": "Theme", "ref_id": "PMID-21078404_E14" } ] }, { "id": "PMID-21078404_E14", "type": "Conversion", "trigger": { "text": [ "production" ], "offsets": [ [ 959, 969 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-21078404_T21" } ] }, { "id": "PMID-21078404_E15", "type": "Negative_regulation", "trigger": { "text": [ "decreases" ], "offsets": [ [ 1002, 1011 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_T24" }, { "role": "Cause", "ref_id": "PMID-21078404_T22" } ] }, { "id": "PMID-21078404_E16", "type": "Negative_regulation", "trigger": { "text": [ "decreases" ], "offsets": [ [ 1002, 1011 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_T24" }, { "role": "Cause", "ref_id": "PMID-21078404_E17" } ] }, { "id": "PMID-21078404_E17", "type": "Conversion", "trigger": { "text": [ "modification" ], "offsets": [ [ 1044, 1056 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_T26" } ] }, { "id": "PMID-21078404_E18", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1166, 1173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E20" }, { "role": "Cause", "ref_id": "PMID-21078404_T28" } ] }, { "id": "PMID-21078404_E19", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1166, 1173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E20" }, { "role": "Cause", "ref_id": "PMID-21078404_T29" } ] }, { "id": "PMID-21078404_E20", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1198, 1208 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_T30" } ] }, { "id": "PMID-21078404_E21", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 1216, 1222 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21078404_E26" }, { "role": "Theme", "ref_id": "PMID-21078404_E18" } ] }, { "id": "PMID-21078404_E22", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 1216, 1222 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21078404_E25" }, { "role": "Theme", "ref_id": "PMID-21078404_E18" } ] }, { "id": "PMID-21078404_E23", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 1216, 1222 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21078404_E26" }, { "role": "Theme", "ref_id": "PMID-21078404_E19" } ] }, { "id": "PMID-21078404_E24", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 1216, 1222 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21078404_E25" }, { "role": "Theme", "ref_id": "PMID-21078404_E19" } ] }, { "id": "PMID-21078404_E25", "type": "Localization", "trigger": { "text": [ "location" ], "offsets": [ [ 1263, 1271 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-21078404_T31" }, { "role": "Theme", "ref_id": "PMID-21078404_T32" } ] }, { "id": "PMID-21078404_E26", "type": "Localization", "trigger": { "text": [ "location" ], "offsets": [ [ 1263, 1271 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-21078404_T31" }, { "role": "Theme", "ref_id": "PMID-21078404_T33" } ] }, { "id": "PMID-21078404_E27", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1279, 1288 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21078404_T32" } ] }, { "id": "PMID-21078404_E28", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1304, 1313 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21078404_T33" } ] }, { "id": "PMID-21078404_E29", "type": "Conversion", "trigger": { "text": [ "S-nitrosylation" ], "offsets": [ [ 1338, 1353 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_T34" } ] }, { "id": "PMID-21078404_E30", "type": "Positive_regulation", "trigger": { "text": [ "requires" ], "offsets": [ [ 1367, 1375 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E29" }, { "role": "Cause", "ref_id": "PMID-21078404_E31" } ] }, { "id": "PMID-21078404_E31", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1384, 1395 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_T37" }, { "role": "Theme", "ref_id": "PMID-21078404_T35" } ] }, { "id": "PMID-21078404_E32", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1494, 1504 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E34" }, { "role": "Cause", "ref_id": "PMID-21078404_T39" } ] }, { "id": "PMID-21078404_E33", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1494, 1504 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E34" }, { "role": "Cause", "ref_id": "PMID-21078404_T40" } ] }, { "id": "PMID-21078404_E34", "type": "Conversion", "trigger": { "text": [ "modification" ], "offsets": [ [ 1517, 1529 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_T38" } ] }, { "id": "PMID-21078404_E35", "type": "Positive_regulation", "trigger": { "text": [ "underlie" ], "offsets": [ [ 1548, 1556 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E37" }, { "role": "Cause", "ref_id": "PMID-21078404_E32" } ] }, { "id": "PMID-21078404_E36", "type": "Positive_regulation", "trigger": { "text": [ "underlie" ], "offsets": [ [ 1548, 1556 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E37" }, { "role": "Cause", "ref_id": "PMID-21078404_E33" } ] }, { "id": "PMID-21078404_E37", "type": "Positive_regulation", "trigger": { "text": [ "resultant" ], "offsets": [ [ 1561, 1570 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E38" } ] }, { "id": "PMID-21078404_E38", "type": "Regulation", "trigger": { "text": [ "changes" ], "offsets": [ [ 1571, 1578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E39" } ] }, { "id": "PMID-21078404_E39", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1589, 1598 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21078404_T41" } ] }, { "id": "PMID-21078404_E40", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1599, 1606 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21078404_E38" } ] } ]

[ { "id": "PMID-21078404_1", "entity_ids": [ "PMID-21078404_T4", "PMID-21078404_T5" ] }, { "id": "PMID-21078404_2", "entity_ids": [ "PMID-21078404_T10", "PMID-21078404_T11" ] }, { "id": "PMID-21078404_3", "entity_ids": [ "PMID-21078404_T14", "PMID-21078404_T15" ] }, { "id": "PMID-21078404_4", "entity_ids": [ "PMID-21078404_T16", "PMID-21078404_T17" ] }, { "id": "PMID-21078404_5", "entity_ids": [ "PMID-21078404_T22", "PMID-21078404_T23" ] }, { "id": "PMID-21078404_6", "entity_ids": [ "PMID-21078404_T26", "PMID-21078404_T27" ] }, { "id": "PMID-21078404_7", "entity_ids": [ "PMID-21078404_T35", "PMID-21078404_T36" ] } ]

[]

[ { "id": "PMID-21098220__text", "type": "abstract", "text": [ "Negative feedback regulation of NF-kappaB action by CITED2 in the nucleus. \nNF-kappaB is a family of important transcription factors that modulate immunity, development, inflammation, and cancer. The biological activity of NF-kappaB is subjected to various spatial and temporal regulations. Bioinformatics analysis predicts that CITED2 is topologically close to NF-kappaB in the protein interaction networks. In this study, we show that ectopic expression or knockdown of CITED2 attenuates or potentiates, respectively, the expression of NF-kappaB-responsive genes. Mechanistically, CITED2 constitutively localizes inside the nucleus and interacts specifically with the coactivator p300. This prevents p65 from binding to p300, impairs p65 acetylation, and attenuates p65 binding to its cognate promoters. Furthermore, LPS induces CITED2 expression via NF-kappaB in macrophages. CITED2 sensitizes cells to TNF-alpha-induced apoptosis. Collectively, this study identifies CITED2 as a novel regulator of NF-kappaB in the nucleus, which reveals a negative feedback mechanism for NF-kappaB signaling.\n" ], "offsets": [ [ 0, 1097 ] ] } ]

[ { "id": "PMID-21098220_T1", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 32, 41 ] ], "normalized": [] }, { "id": "PMID-21098220_T2", "type": "Gene_or_gene_product", "text": [ "CITED2" ], "offsets": [ [ 52, 58 ] ], "normalized": [] }, { "id": "PMID-21098220_T3", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 66, 73 ] ], "normalized": [] }, { "id": "PMID-21098220_T4", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 76, 85 ] ], "normalized": [] }, { "id": "PMID-21098220_T5", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 223, 232 ] ], "normalized": [] }, { "id": "PMID-21098220_T6", "type": "Gene_or_gene_product", "text": [ "CITED2" ], "offsets": [ [ 329, 335 ] ], "normalized": [] }, { "id": "PMID-21098220_T7", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 362, 371 ] ], "normalized": [] }, { "id": "PMID-21098220_T8", "type": "Gene_or_gene_product", "text": [ "CITED2" ], "offsets": [ [ 472, 478 ] ], "normalized": [] }, { "id": "PMID-21098220_T9", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 538, 547 ] ], "normalized": [] }, { "id": "PMID-21098220_T10", "type": "Gene_or_gene_product", "text": [ "CITED2" ], "offsets": [ [ 583, 589 ] ], "normalized": [] }, { "id": "PMID-21098220_T11", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 626, 633 ] ], "normalized": [] }, { "id": "PMID-21098220_T12", "type": "Gene_or_gene_product", "text": [ "p300" ], "offsets": [ [ 682, 686 ] ], "normalized": [] }, { "id": "PMID-21098220_T13", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 702, 705 ] ], "normalized": [] }, { "id": "PMID-21098220_T14", "type": "Gene_or_gene_product", "text": [ "p300" ], "offsets": [ [ 722, 726 ] ], "normalized": [] }, { "id": "PMID-21098220_T15", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 736, 739 ] ], "normalized": [] }, { "id": "PMID-21098220_T16", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 768, 771 ] ], "normalized": [] }, { "id": "PMID-21098220_T17", "type": "Simple_chemical", "text": [ "LPS" ], "offsets": [ [ 819, 822 ] ], "normalized": [] }, { "id": "PMID-21098220_T18", "type": "Gene_or_gene_product", "text": [ "CITED2" ], "offsets": [ [ 831, 837 ] ], "normalized": [] }, { "id": "PMID-21098220_T19", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 853, 862 ] ], "normalized": [] }, { "id": "PMID-21098220_T20", "type": "Gene_or_gene_product", "text": [ "CITED2" ], "offsets": [ [ 879, 885 ] ], "normalized": [] }, { "id": "PMID-21098220_T21", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 906, 915 ] ], "normalized": [] }, { "id": "PMID-21098220_T22", "type": "Gene_or_gene_product", "text": [ "CITED2" ], "offsets": [ [ 971, 977 ] ], "normalized": [] }, { "id": "PMID-21098220_T23", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1002, 1011 ] ], "normalized": [] }, { "id": "PMID-21098220_T24", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 1019, 1026 ] ], "normalized": [] }, { "id": "PMID-21098220_T25", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1076, 1085 ] ], "normalized": [] } ]

[ { "id": "PMID-21098220_E1", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 18, 28 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_T1" }, { "role": "Cause", "ref_id": "PMID-21098220_T2" } ] }, { "id": "PMID-21098220_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 445, 455 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_T8" } ] }, { "id": "PMID-21098220_E3", "type": "Inactivation", "trigger": { "text": [ "knockdown" ], "offsets": [ [ 459, 468 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_T8" } ] }, { "id": "PMID-21098220_E4", "type": "Localization", "trigger": { "text": [ "localizes" ], "offsets": [ [ 605, 614 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_T10" }, { "role": "AtLoc", "ref_id": "PMID-21098220_T11" } ] }, { "id": "PMID-21098220_E5", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 638, 647 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_T10" }, { "role": "Theme", "ref_id": "PMID-21098220_T12" } ] }, { "id": "PMID-21098220_E6", "type": "Activation", "trigger": { "text": [ "coactivator" ], "offsets": [ [ 670, 681 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_T12" } ] }, { "id": "PMID-21098220_E7", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 693, 701 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21098220_E5" }, { "role": "Theme", "ref_id": "PMID-21098220_E8" } ] }, { "id": "PMID-21098220_E8", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 711, 718 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_T14" }, { "role": "Theme", "ref_id": "PMID-21098220_T13" } ] }, { "id": "PMID-21098220_E9", "type": "Negative_regulation", "trigger": { "text": [ "impairs" ], "offsets": [ [ 728, 735 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21098220_E5" }, { "role": "Theme", "ref_id": "PMID-21098220_E10" } ] }, { "id": "PMID-21098220_E10", "type": "Acetylation", "trigger": { "text": [ "acetylation" ], "offsets": [ [ 740, 751 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_T15" } ] }, { "id": "PMID-21098220_E11", "type": "Negative_regulation", "trigger": { "text": [ "attenuates" ], "offsets": [ [ 757, 767 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_E12" }, { "role": "Cause", "ref_id": "PMID-21098220_E5" } ] }, { "id": "PMID-21098220_E12", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 772, 779 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_T16" } ] }, { "id": "PMID-21098220_E13", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 823, 830 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21098220_T17" }, { "role": "Theme", "ref_id": "PMID-21098220_E15" } ] }, { "id": "PMID-21098220_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 838, 848 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_T18" } ] }, { "id": "PMID-21098220_E15", "type": "Positive_regulation", "trigger": { "text": [ "expression" ], "offsets": [ [ 838, 848 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21098220_T19" }, { "role": "Theme", "ref_id": "PMID-21098220_E14" } ] }, { "id": "PMID-21098220_E16", "type": "Regulation", "trigger": { "text": [ "sensitizes" ], "offsets": [ [ 886, 896 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21098220_T20" }, { "role": "Theme", "ref_id": "PMID-21098220_E18" } ] }, { "id": "PMID-21098220_E17", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 916, 923 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_E18" }, { "role": "Cause", "ref_id": "PMID-21098220_T21" } ] }, { "id": "PMID-21098220_E18", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 924, 933 ] ] }, "arguments": [] }, { "id": "PMID-21098220_E19", "type": "Regulation", "trigger": { "text": [ "regulator" ], "offsets": [ [ 989, 998 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21098220_T23" }, { "role": "Cause", "ref_id": "PMID-21098220_T22" } ] }, { "id": "PMID-21098220_E20", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1086, 1095 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21098220_T25" } ] } ]

[]

[]

[ { "id": "PMID-21106746__text", "type": "abstract", "text": [ "The activator protein 1 binding motifs within the human cytomegalovirus major immediate-early enhancer are functionally redundant and act in a cooperative manner with the NF-{kappa}B sites during acute infection. \nHuman cytomegalovirus (HCMV) infection causes a rapid induction of c-Fos and c-Jun, the major subunits of activator protein 1 (AP-1), which in turn have been postulated to activate the viral immediate-early (IE) genes. Accordingly, the major IE promoter (MIEP) enhancer, a critical control region for initiating lytic HCMV infection and reactivation from the latent state, contains one well-characterized AP-1 site and a second candidate interaction site. In this study we explored the role of these AP-1 elements in the context of the infection. We first show that the distal candidate AP-1 motif binds c-Fos/c-Jun heterodimers (AP-1 complex) and confers c-Fos/c-Jun-mediated activity to a core promoter. Site-directed mutagenesis studies indicate that both AP-1 response elements are critical for 12-O-tetradecanoylphorbol-13-acetate (TPA)-enhanced MIEP activity in transient-transfection assays. In marked contrast to the results obtained with the isolated promoter, disruption of the AP-1 recognition sites of the MIEP in the context of the infectious HCMV genome has no significant influence on the expression of the MIE protein IE1 or viral replication in different cell types. Moreover, a chimeric murine CMV driven by the HCMV MIEP (hMCMV-ES) with the two AP-1 binding sites mutated is not compromised in virulence, is able to grow and disseminate to different organs of the newborn mice as efficiently as the parental virus, and is competent in reactivation. We show, however, that combined inactivation of the enhancer AP-1 and NF-kappaB recognition sites leads to an attenuation of the hMCMV-ES in the neonatal murine infection model, not observed when each single element is abolished. Altogether, these results underline the functional redundancy of the MIEP elements, highlighting the plasticity of this region, which probably evolved to ensure maximal transcriptional performance across many diverse environments.\n" ], "offsets": [ [ 0, 2143 ] ] } ]

[ { "id": "PMID-21106746_T1", "type": "Complex", "text": [ "activator protein 1" ], "offsets": [ [ 4, 23 ] ], "normalized": [] }, { "id": "PMID-21106746_T2", "type": "Complex", "text": [ "NF-{kappa}B" ], "offsets": [ [ 171, 182 ] ], "normalized": [] }, { "id": "PMID-21106746_T3", "type": "Gene_or_gene_product", "text": [ "c-Fos" ], "offsets": [ [ 281, 286 ] ], "normalized": [] }, { "id": "PMID-21106746_T4", "type": "Gene_or_gene_product", "text": [ "c-Jun" ], "offsets": [ [ 291, 296 ] ], "normalized": [] }, { "id": "PMID-21106746_T5", "type": "Complex", "text": [ "activator protein 1" ], "offsets": [ [ 320, 339 ] ], "normalized": [] }, { "id": "PMID-21106746_T6", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 341, 345 ] ], "normalized": [] }, { "id": "PMID-21106746_T7", "type": "Gene_or_gene_product", "text": [ "major IE promoter" ], "offsets": [ [ 450, 467 ] ], "normalized": [] }, { "id": "PMID-21106746_T8", "type": "Gene_or_gene_product", "text": [ "MIEP" ], "offsets": [ [ 469, 473 ] ], "normalized": [] }, { "id": "PMID-21106746_T9", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 619, 623 ] ], "normalized": [] }, { "id": "PMID-21106746_T10", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 714, 718 ] ], "normalized": [] }, { "id": "PMID-21106746_T11", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 801, 805 ] ], "normalized": [] }, { "id": "PMID-21106746_T12", "type": "Complex", "text": [ "c-Fos/c-Jun" ], "offsets": [ [ 818, 829 ] ], "normalized": [] }, { "id": "PMID-21106746_T13", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 844, 848 ] ], "normalized": [] }, { "id": "PMID-21106746_T14", "type": "Complex", "text": [ "c-Fos/c-Jun" ], "offsets": [ [ 870, 881 ] ], "normalized": [] }, { "id": "PMID-21106746_T15", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 973, 977 ] ], "normalized": [] }, { "id": "PMID-21106746_T16", "type": "Simple_chemical", "text": [ "12-O-tetradecanoylphorbol-13-acetate" ], "offsets": [ [ 1013, 1049 ] ], "normalized": [] }, { "id": "PMID-21106746_T17", "type": "Simple_chemical", "text": [ "TPA" ], "offsets": [ [ 1051, 1054 ] ], "normalized": [] }, { "id": "PMID-21106746_T18", "type": "Gene_or_gene_product", "text": [ "MIEP" ], "offsets": [ [ 1065, 1069 ] ], "normalized": [] }, { "id": "PMID-21106746_T19", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 1202, 1206 ] ], "normalized": [] }, { "id": "PMID-21106746_T20", "type": "Gene_or_gene_product", "text": [ "MIEP" ], "offsets": [ [ 1232, 1236 ] ], "normalized": [] }, { "id": "PMID-21106746_T21", "type": "Gene_or_gene_product", "text": [ "IE1" ], "offsets": [ [ 1348, 1351 ] ], "normalized": [] }, { "id": "PMID-21106746_T22", "type": "Gene_or_gene_product", "text": [ "MIEP" ], "offsets": [ [ 1449, 1453 ] ], "normalized": [] }, { "id": "PMID-21106746_T23", "type": "Gene_or_gene_product", "text": [ "hMCMV-ES" ], "offsets": [ [ 1455, 1463 ] ], "normalized": [] }, { "id": "PMID-21106746_T24", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 1478, 1482 ] ], "normalized": [] }, { "id": "PMID-21106746_T25", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 1743, 1747 ] ], "normalized": [] }, { "id": "PMID-21106746_T26", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1752, 1761 ] ], "normalized": [] }, { "id": "PMID-21106746_T27", "type": "Gene_or_gene_product", "text": [ "hMCMV-ES" ], "offsets": [ [ 1811, 1819 ] ], "normalized": [] }, { "id": "PMID-21106746_T28", "type": "Gene_or_gene_product", "text": [ "MIEP" ], "offsets": [ [ 1981, 1985 ] ], "normalized": [] } ]

[ { "id": "PMID-21106746_E1", "type": "Binding", "trigger": { "text": [ "cooperative" ], "offsets": [ [ 143, 154 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21106746_T2" }, { "role": "Theme", "ref_id": "PMID-21106746_T1" } ] }, { "id": "PMID-21106746_E2", "type": "Positive_regulation", "trigger": { "text": [ "causes" ], "offsets": [ [ 253, 259 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21106746_E4" } ] }, { "id": "PMID-21106746_E3", "type": "Positive_regulation", "trigger": { "text": [ "causes" ], "offsets": [ [ 253, 259 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21106746_E5" } ] }, { "id": "PMID-21106746_E4", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 268, 277 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21106746_T3" } ] }, { "id": "PMID-21106746_E5", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 268, 277 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21106746_T4" } ] }, { "id": "PMID-21106746_E6", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 812, 817 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21106746_T11" }, { "role": "Theme", "ref_id": "PMID-21106746_T12" } ] }, { "id": "PMID-21106746_E7", "type": "Positive_regulation", "trigger": { "text": [ "critical" ], "offsets": [ [ 1000, 1008 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21106746_T18" } ] }, { "id": "PMID-21106746_E8", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 1056, 1064 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21106746_T17" }, { "role": "Theme", "ref_id": "PMID-21106746_T18" } ] }, { "id": "PMID-21106746_E9", "type": "Regulation", "trigger": { "text": [ "influence" ], "offsets": [ [ 1301, 1310 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21106746_E10" } ] }, { "id": "PMID-21106746_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1318, 1328 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21106746_T21" } ] } ]

[ { "id": "PMID-21106746_1", "entity_ids": [ "PMID-21106746_T5", "PMID-21106746_T6" ] }, { "id": "PMID-21106746_2", "entity_ids": [ "PMID-21106746_T7", "PMID-21106746_T8" ] }, { "id": "PMID-21106746_3", "entity_ids": [ "PMID-21106746_T16", "PMID-21106746_T17" ] } ]

[]

[ { "id": "PMID-21145111__text", "type": "abstract", "text": [ "IL-17R activation of human periodontal ligament fibroblasts induces IL-23 p19 production: Differential involvement of NF-kappaB versus JNK/AP-1 pathways. \nInterleukin (IL)-23 is an essential cytokine involved in the expansion of a novel CD4(+) T helper subset known as Th17, which has been implicated in the pathogenesis of periodontitis recently. This study hypothesised that Th17 signature cytokine IL-17 may target specialised human periodontal ligament fibroblasts (hPDLFs) for production of IL-23 p19, a key subunit of IL-23. Primary hPDLFs had steady expression of IL-17 receptor (IL-17R) mRNA and surface-bound protein. IL-17 was capable of stimulating the expression of IL-23 p19 mRNA and protein in cultured hPDLFs, which was attenuated by IL-17 or IL-17R neutralising antibodies. In accordance with the enhanced expression of IL-23 p19, IL-17 stimulation resulted in rapid activation of Akt, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) 1/2, c-Jun-N-terminal kinase (JNK), nuclear factor-kappaB (NF-kappaB), and activator protein-1 (AP-1) in hPDLFs. Inhibitors of Akt, p38 MAPK, ERK 1/2, or NF-kappaB significantly suppressed, whereas blocking JNK and AP-1 substantially augmented IL-23 p19 production from IL-17-stimulated hPDLFs. Moreover, IL-17-initiated NF-kappaB activation was blocked by Akt, p38 MAPK, or ERK 1/2 inhibition, while AP-1 activity was specifically abrogated by JNK inhibition. Thus, these results provide evidence that hPDLFs are a target of Th17, and that IL-17 appears to up-regulate the expression of IL-23 p19 via a homeostatic mechanism involving Akt-, p38 MAPK-, and ERK 1/2-dependent NF-kappaB signalling versus the JNK/AP-1 pathway. Taken together, our findings suggest that disruption of the interaction between IL-17 and IL-23 may be a potential therapeutic approach in the treatment of periodontitis.\n" ], "offsets": [ [ 0, 1887 ] ] } ]

[ { "id": "PMID-21145111_T1", "type": "Complex", "text": [ "IL-17R" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "PMID-21145111_T2", "type": "Complex", "text": [ "IL-23" ], "offsets": [ [ 68, 73 ] ], "normalized": [] }, { "id": "PMID-21145111_T3", "type": "Gene_or_gene_product", "text": [ "p19" ], "offsets": [ [ 74, 77 ] ], "normalized": [] }, { "id": "PMID-21145111_T4", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 118, 127 ] ], "normalized": [] }, { "id": "PMID-21145111_T5", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 135, 138 ] ], "normalized": [] }, { "id": "PMID-21145111_T6", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 139, 143 ] ], "normalized": [] }, { "id": "PMID-21145111_T7", "type": "Complex", "text": [ "Interleukin (IL)-23" ], "offsets": [ [ 155, 174 ] ], "normalized": [] }, { "id": "PMID-21145111_T8", "type": "Gene_or_gene_product", "text": [ "CD4" ], "offsets": [ [ 237, 240 ] ], "normalized": [] }, { "id": "PMID-21145111_T9", "type": "Complex", "text": [ "IL-17" ], "offsets": [ [ 401, 406 ] ], "normalized": [] }, { "id": "PMID-21145111_T10", "type": "Complex", "text": [ "IL-23" ], "offsets": [ [ 496, 501 ] ], "normalized": [] }, { "id": "PMID-21145111_T11", "type": "Gene_or_gene_product", "text": [ "p19" ], "offsets": [ [ 502, 505 ] ], "normalized": [] }, { "id": "PMID-21145111_T12", "type": "Complex", "text": [ "IL-23" ], "offsets": [ [ 524, 529 ] ], "normalized": [] }, { "id": "PMID-21145111_T13", "type": "Complex", "text": [ "IL-17 receptor" ], "offsets": [ [ 571, 585 ] ], "normalized": [] }, { "id": "PMID-21145111_T14", "type": "Complex", "text": [ "IL-17R" ], "offsets": [ [ 587, 593 ] ], "normalized": [] }, { "id": "PMID-21145111_T15", "type": "Complex", "text": [ "IL-17" ], "offsets": [ [ 627, 632 ] ], "normalized": [] }, { "id": "PMID-21145111_T16", "type": "Complex", "text": [ "IL-23" ], "offsets": [ [ 678, 683 ] ], "normalized": [] }, { "id": "PMID-21145111_T17", "type": "Gene_or_gene_product", "text": [ "p19" ], "offsets": [ [ 684, 687 ] ], "normalized": [] }, { "id": "PMID-21145111_T18", "type": "Complex", "text": [ "IL-17" ], "offsets": [ [ 749, 754 ] ], "normalized": [] }, { "id": "PMID-21145111_T19", "type": "Complex", "text": [ "IL-17R" ], "offsets": [ [ 758, 764 ] ], "normalized": [] }, { "id": "PMID-21145111_T20", "type": "Complex", "text": [ "IL-23" ], "offsets": [ [ 836, 841 ] ], "normalized": [] }, { "id": "PMID-21145111_T21", "type": "Gene_or_gene_product", "text": [ "p19" ], "offsets": [ [ 842, 845 ] ], "normalized": [] }, { "id": "PMID-21145111_T22", "type": "Complex", "text": [ "IL-17" ], "offsets": [ [ 847, 852 ] ], "normalized": [] }, { "id": "PMID-21145111_T23", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 897, 900 ] ], "normalized": [] }, { "id": "PMID-21145111_T24", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 902, 905 ] ], "normalized": [] }, { "id": "PMID-21145111_T25", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein kinase" ], "offsets": [ [ 906, 938 ] ], "normalized": [] }, { "id": "PMID-21145111_T26", "type": "Gene_or_gene_product", "text": [ "MAPK" ], "offsets": [ [ 940, 944 ] ], "normalized": [] }, { "id": "PMID-21145111_T27", "type": "Gene_or_gene_product", "text": [ "extracellular signal-regulated kinase (ERK) 1/2" ], "offsets": [ [ 947, 994 ] ], "normalized": [] }, { "id": "PMID-21145111_T28", "type": "Gene_or_gene_product", "text": [ "c-Jun-N-terminal kinase" ], "offsets": [ [ 996, 1019 ] ], "normalized": [] }, { "id": "PMID-21145111_T29", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 1021, 1024 ] ], "normalized": [] }, { "id": "PMID-21145111_T30", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 1027, 1048 ] ], "normalized": [] }, { "id": "PMID-21145111_T31", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1050, 1059 ] ], "normalized": [] }, { "id": "PMID-21145111_T32", "type": "Complex", "text": [ "activator protein-1" ], "offsets": [ [ 1066, 1085 ] ], "normalized": [] }, { "id": "PMID-21145111_T33", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 1087, 1091 ] ], "normalized": [] }, { "id": "PMID-21145111_T34", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1118, 1121 ] ], "normalized": [] }, { "id": "PMID-21145111_T35", "type": "Gene_or_gene_product", "text": [ "p38 MAPK" ], "offsets": [ [ 1123, 1131 ] ], "normalized": [] }, { "id": "PMID-21145111_T36", "type": "Gene_or_gene_product", "text": [ "ERK 1/2" ], "offsets": [ [ 1133, 1140 ] ], "normalized": [] }, { "id": "PMID-21145111_T37", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1145, 1154 ] ], "normalized": [] }, { "id": "PMID-21145111_T38", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 1198, 1201 ] ], "normalized": [] }, { "id": "PMID-21145111_T39", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 1206, 1210 ] ], "normalized": [] }, { "id": "PMID-21145111_T40", "type": "Complex", "text": [ "IL-23" ], "offsets": [ [ 1235, 1240 ] ], "normalized": [] }, { "id": "PMID-21145111_T41", "type": "Gene_or_gene_product", "text": [ "p19" ], "offsets": [ [ 1241, 1244 ] ], "normalized": [] }, { "id": "PMID-21145111_T42", "type": "Complex", "text": [ "IL-17" ], "offsets": [ [ 1261, 1266 ] ], "normalized": [] }, { "id": "PMID-21145111_T43", "type": "Complex", "text": [ "IL-17" ], "offsets": [ [ 1296, 1301 ] ], "normalized": [] }, { "id": "PMID-21145111_T44", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1312, 1321 ] ], "normalized": [] }, { "id": "PMID-21145111_T45", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1348, 1351 ] ], "normalized": [] }, { "id": "PMID-21145111_T46", "type": "Gene_or_gene_product", "text": [ "p38 MAPK" ], "offsets": [ [ 1353, 1361 ] ], "normalized": [] }, { "id": "PMID-21145111_T47", "type": "Gene_or_gene_product", "text": [ "ERK 1/2" ], "offsets": [ [ 1366, 1373 ] ], "normalized": [] }, { "id": "PMID-21145111_T48", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 1392, 1396 ] ], "normalized": [] }, { "id": "PMID-21145111_T49", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 1436, 1439 ] ], "normalized": [] }, { "id": "PMID-21145111_T50", "type": "Complex", "text": [ "IL-17" ], "offsets": [ [ 1532, 1537 ] ], "normalized": [] }, { "id": "PMID-21145111_T51", "type": "Complex", "text": [ "IL-23" ], "offsets": [ [ 1579, 1584 ] ], "normalized": [] }, { "id": "PMID-21145111_T52", "type": "Gene_or_gene_product", "text": [ "p19" ], "offsets": [ [ 1585, 1588 ] ], "normalized": [] }, { "id": "PMID-21145111_T53", "type": "Gene_or_gene_product", "text": [ "Akt" ], "offsets": [ [ 1627, 1630 ] ], "normalized": [] }, { "id": "PMID-21145111_T54", "type": "Gene_or_gene_product", "text": [ "p38 MAPK" ], "offsets": [ [ 1633, 1641 ] ], "normalized": [] }, { "id": "PMID-21145111_T55", "type": "Gene_or_gene_product", "text": [ "ERK 1/2" ], "offsets": [ [ 1648, 1655 ] ], "normalized": [] }, { "id": "PMID-21145111_T56", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1666, 1675 ] ], "normalized": [] }, { "id": "PMID-21145111_T57", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 1698, 1701 ] ], "normalized": [] }, { "id": "PMID-21145111_T58", "type": "Complex", "text": [ "AP-1" ], "offsets": [ [ 1702, 1706 ] ], "normalized": [] }, { "id": "PMID-21145111_T59", "type": "Complex", "text": [ "IL-17" ], "offsets": [ [ 1796, 1801 ] ], "normalized": [] }, { "id": "PMID-21145111_T60", "type": "Complex", "text": [ "IL-23" ], "offsets": [ [ 1806, 1811 ] ], "normalized": [] } ]

[ { "id": "PMID-21145111_E1", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 7, 17 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T1" } ] }, { "id": "PMID-21145111_E2", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 60, 67 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_E1" }, { "role": "Theme", "ref_id": "PMID-21145111_E3" } ] }, { "id": "PMID-21145111_E3", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 78, 88 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T3" } ] }, { "id": "PMID-21145111_E4", "type": "Regulation", "trigger": { "text": [ "involvement" ], "offsets": [ [ 103, 114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T4" } ] }, { "id": "PMID-21145111_E5", "type": "Regulation", "trigger": { "text": [ "involvement" ], "offsets": [ [ 103, 114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E6" } ] }, { "id": "PMID-21145111_E6", "type": "Pathway", "trigger": { "text": [ "pathways" ], "offsets": [ [ 144, 152 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21145111_T5" }, { "role": "Participant", "ref_id": "PMID-21145111_T6" } ] }, { "id": "PMID-21145111_E7", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 181, 190 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T7" } ] }, { "id": "PMID-21145111_E8", "type": "Positive_regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 200, 208 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E9" }, { "role": "Cause", "ref_id": "PMID-21145111_T7" } ] }, { "id": "PMID-21145111_E9", "type": "Gene_expression", "trigger": { "text": [ "expansion" ], "offsets": [ [ 216, 225 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T8" } ] }, { "id": "PMID-21145111_E10", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 482, 492 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T11" } ] }, { "id": "PMID-21145111_E11", "type": "Positive_regulation", "trigger": { "text": [ "stimulating" ], "offsets": [ [ 648, 659 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_T15" }, { "role": "Theme", "ref_id": "PMID-21145111_E12" } ] }, { "id": "PMID-21145111_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 664, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T17" } ] }, { "id": "PMID-21145111_E13", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 813, 821 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E14" } ] }, { "id": "PMID-21145111_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 822, 832 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T21" } ] }, { "id": "PMID-21145111_E15", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 853, 864 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T22" } ] }, { "id": "PMID-21145111_E16", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 865, 873 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_E15" }, { "role": "Theme", "ref_id": "PMID-21145111_E23" } ] }, { "id": "PMID-21145111_E17", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 865, 873 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_E15" }, { "role": "Theme", "ref_id": "PMID-21145111_E24" } ] }, { "id": "PMID-21145111_E18", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 865, 873 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_E15" }, { "role": "Theme", "ref_id": "PMID-21145111_E25" } ] }, { "id": "PMID-21145111_E19", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 865, 873 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_E15" }, { "role": "Theme", "ref_id": "PMID-21145111_E26" } ] }, { "id": "PMID-21145111_E20", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 865, 873 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_E15" }, { "role": "Theme", "ref_id": "PMID-21145111_E27" } ] }, { "id": "PMID-21145111_E21", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 865, 873 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_E15" }, { "role": "Theme", "ref_id": "PMID-21145111_E28" } ] }, { "id": "PMID-21145111_E22", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 865, 873 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_E15" }, { "role": "Theme", "ref_id": "PMID-21145111_E29" } ] }, { "id": "PMID-21145111_E23", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 883, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T23" } ] }, { "id": "PMID-21145111_E24", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 883, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T24" } ] }, { "id": "PMID-21145111_E25", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 883, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T25" } ] }, { "id": "PMID-21145111_E26", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 883, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T27" } ] }, { "id": "PMID-21145111_E27", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 883, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T28" } ] }, { "id": "PMID-21145111_E28", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 883, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T30" } ] }, { "id": "PMID-21145111_E29", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 883, 893 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T32" } ] }, { "id": "PMID-21145111_E30", "type": "Negative_regulation", "trigger": { "text": [ "Inhibitors" ], "offsets": [ [ 1104, 1114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T34" } ] }, { "id": "PMID-21145111_E31", "type": "Negative_regulation", "trigger": { "text": [ "Inhibitors" ], "offsets": [ [ 1104, 1114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T35" } ] }, { "id": "PMID-21145111_E32", "type": "Negative_regulation", "trigger": { "text": [ "Inhibitors" ], "offsets": [ [ 1104, 1114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T36" } ] }, { "id": "PMID-21145111_E33", "type": "Negative_regulation", "trigger": { "text": [ "Inhibitors" ], "offsets": [ [ 1104, 1114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T37" } ] }, { "id": "PMID-21145111_E34", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1169, 1179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E30" } ] }, { "id": "PMID-21145111_E35", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1169, 1179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E31" } ] }, { "id": "PMID-21145111_E36", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1169, 1179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E32" } ] }, { "id": "PMID-21145111_E37", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1169, 1179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E33" } ] }, { "id": "PMID-21145111_E38", "type": "Negative_regulation", "trigger": { "text": [ "blocking" ], "offsets": [ [ 1189, 1197 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T38" } ] }, { "id": "PMID-21145111_E39", "type": "Negative_regulation", "trigger": { "text": [ "blocking" ], "offsets": [ [ 1189, 1197 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T39" } ] }, { "id": "PMID-21145111_E40", "type": "Positive_regulation", "trigger": { "text": [ "augmented" ], "offsets": [ [ 1225, 1234 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E42" }, { "role": "Cause", "ref_id": "PMID-21145111_E38" } ] }, { "id": "PMID-21145111_E41", "type": "Positive_regulation", "trigger": { "text": [ "augmented" ], "offsets": [ [ 1225, 1234 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E42" }, { "role": "Cause", "ref_id": "PMID-21145111_E39" } ] }, { "id": "PMID-21145111_E42", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 1245, 1255 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T41" } ] }, { "id": "PMID-21145111_E43", "type": "Positive_regulation", "trigger": { "text": [ "initiated" ], "offsets": [ [ 1302, 1311 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_T43" }, { "role": "Theme", "ref_id": "PMID-21145111_E44" } ] }, { "id": "PMID-21145111_E44", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1322, 1332 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T44" } ] }, { "id": "PMID-21145111_E45", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1337, 1344 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E44" }, { "role": "Cause", "ref_id": "PMID-21145111_E48" } ] }, { "id": "PMID-21145111_E46", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1337, 1344 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E44" }, { "role": "Cause", "ref_id": "PMID-21145111_E49" } ] }, { "id": "PMID-21145111_E47", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1337, 1344 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E44" }, { "role": "Cause", "ref_id": "PMID-21145111_E50" } ] }, { "id": "PMID-21145111_E48", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1374, 1384 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T45" } ] }, { "id": "PMID-21145111_E49", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1374, 1384 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T46" } ] }, { "id": "PMID-21145111_E50", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1374, 1384 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T47" } ] }, { "id": "PMID-21145111_E51", "type": "Negative_regulation", "trigger": { "text": [ "abrogated" ], "offsets": [ [ 1423, 1432 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_E52" }, { "role": "Theme", "ref_id": "PMID-21145111_T48" } ] }, { "id": "PMID-21145111_E52", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1440, 1450 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T49" } ] }, { "id": "PMID-21145111_E53", "type": "Positive_regulation", "trigger": { "text": [ "up-regulate" ], "offsets": [ [ 1549, 1560 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_E54" }, { "role": "Cause", "ref_id": "PMID-21145111_E55" } ] }, { "id": "PMID-21145111_E54", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1565, 1575 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T52" } ] }, { "id": "PMID-21145111_E55", "type": "Positive_regulation", "trigger": { "text": [ "involving" ], "offsets": [ [ 1617, 1626 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21145111_T50" }, { "role": "Theme", "ref_id": "PMID-21145111_E59" } ] }, { "id": "PMID-21145111_E56", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1656, 1665 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T56" }, { "role": "Cause", "ref_id": "PMID-21145111_T53" } ] }, { "id": "PMID-21145111_E57", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1656, 1665 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T56" }, { "role": "Cause", "ref_id": "PMID-21145111_T54" } ] }, { "id": "PMID-21145111_E58", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1656, 1665 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T56" }, { "role": "Cause", "ref_id": "PMID-21145111_T55" } ] }, { "id": "PMID-21145111_E59", "type": "Pathway", "trigger": { "text": [ "signalling" ], "offsets": [ [ 1676, 1686 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21145111_T56" } ] }, { "id": "PMID-21145111_E60", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1707, 1714 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21145111_T57" }, { "role": "Participant", "ref_id": "PMID-21145111_T58" } ] }, { "id": "PMID-21145111_E61", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1776, 1787 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21145111_T59" }, { "role": "Theme", "ref_id": "PMID-21145111_T60" } ] } ]

[ { "id": "PMID-21145111_1", "entity_ids": [ "PMID-21145111_T13", "PMID-21145111_T14" ] }, { "id": "PMID-21145111_2", "entity_ids": [ "PMID-21145111_T25", "PMID-21145111_T26" ] }, { "id": "PMID-21145111_3", "entity_ids": [ "PMID-21145111_T28", "PMID-21145111_T29" ] }, { "id": "PMID-21145111_4", "entity_ids": [ "PMID-21145111_T30", "PMID-21145111_T31" ] }, { "id": "PMID-21145111_5", "entity_ids": [ "PMID-21145111_T33", "PMID-21145111_T32" ] } ]

[]

[ { "id": "PMID-21189258__text", "type": "abstract", "text": [ "Inhibition of proinflammatory RANTES expression by TGF-beta1 is mediated by glycogen synthase kinase-3beta-dependent beta-catenin signaling. \nTGF-beta1 is a pleiotropic cytokine with potent anti-inflammation property. However, the mechanisms underlying TGF-beta1 suppression of inflammation remain largely unexplored. In this study, we demonstrated that TGF-beta1 inhibited TNF-alpha- or IL-1-induced RANTES expression in human kidney tubular epithelial cells (HKC-8). To delineate the mechanism by which TGF-beta1 inhibits RANTES expression, we examined the potential signal pathway activated by TGF-beta1 in suppressing NF-kappaB signaling. TGF-beta1 affected neither TNF-alpha-induced IkappaBalpha phosphorylation and subsequent degradation, nor p65 NF-kappaB phosphorylation and its nuclear translocation. However, TGF-beta1 could inhibit p65 and p50 binding to the kappaB site in human RANTES promoter as revealed by chromatin immunoprecipitation assay and protein-DNA binding assay. We found that TGF-beta1 induced glycogen synthase kinase-3beta (GSK-3beta) phosphorylation on Ser-9 in HKC-8 cells, leading to its inactivation. Knockdown of GSK-3beta mimicked TGF-beta1 and inhibited RANTES induction, whereas overexpression of GSK-3beta abolished the inhibitory effect of TGF-beta1 and completely restored RANTES expression. Furthermore, TGF-beta1 induced the dephosphorylation and activation of beta-catenin, a major downstream target of GSK-3beta. Ectopic expression of constitutively active beta-catenin mimicked the TGF-beta1 effect and completely suppressed RANTES expression induced by TNF-alpha. Interestingly, TGF-beta1 induced a physical interaction between beta-catenin and p65 NF-kappaB, which prevented p65 binding to the kappaB site, sequestered its trans-activating activity, and repressed p65-mediated gene transcription. We conclude that TGF-beta1 inhibition of proinflammatory RANTES expression is mediated by beta-catenin-triggered blockade of NF-kappaB signaling.\n" ], "offsets": [ [ 0, 1990 ] ] } ]

[ { "id": "PMID-21189258_T1", "type": "Gene_or_gene_product", "text": [ "RANTES" ], "offsets": [ [ 30, 36 ] ], "normalized": [] }, { "id": "PMID-21189258_T2", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 51, 60 ] ], "normalized": [] }, { "id": "PMID-21189258_T3", "type": "Gene_or_gene_product", "text": [ "glycogen synthase kinase-3beta" ], "offsets": [ [ 76, 106 ] ], "normalized": [] }, { "id": "PMID-21189258_T4", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 117, 129 ] ], "normalized": [] }, { "id": "PMID-21189258_T5", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 142, 151 ] ], "normalized": [] }, { "id": "PMID-21189258_T6", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 253, 262 ] ], "normalized": [] }, { "id": "PMID-21189258_T7", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 354, 363 ] ], "normalized": [] }, { "id": "PMID-21189258_T8", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 374, 383 ] ], "normalized": [] }, { "id": "PMID-21189258_T9", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 388, 392 ] ], "normalized": [] }, { "id": "PMID-21189258_T10", "type": "Gene_or_gene_product", "text": [ "RANTES" ], "offsets": [ [ 401, 407 ] ], "normalized": [] }, { "id": "PMID-21189258_T11", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 505, 514 ] ], "normalized": [] }, { "id": "PMID-21189258_T12", "type": "Gene_or_gene_product", "text": [ "RANTES" ], "offsets": [ [ 524, 530 ] ], "normalized": [] }, { "id": "PMID-21189258_T13", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 597, 606 ] ], "normalized": [] }, { "id": "PMID-21189258_T14", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 622, 631 ] ], "normalized": [] }, { "id": "PMID-21189258_T15", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 643, 652 ] ], "normalized": [] }, { "id": "PMID-21189258_T16", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 670, 679 ] ], "normalized": [] }, { "id": "PMID-21189258_T17", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 688, 700 ] ], "normalized": [] }, { "id": "PMID-21189258_T18", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 749, 752 ] ], "normalized": [] }, { "id": "PMID-21189258_T19", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 753, 762 ] ], "normalized": [] }, { "id": "PMID-21189258_T20", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 787, 794 ] ], "normalized": [] }, { "id": "PMID-21189258_T21", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 819, 828 ] ], "normalized": [] }, { "id": "PMID-21189258_T22", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 843, 846 ] ], "normalized": [] }, { "id": "PMID-21189258_T23", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 851, 854 ] ], "normalized": [] }, { "id": "PMID-21189258_T24", "type": "Complex", "text": [ "kappaB" ], "offsets": [ [ 870, 876 ] ], "normalized": [] }, { "id": "PMID-21189258_T25", "type": "Gene_or_gene_product", "text": [ "RANTES" ], "offsets": [ [ 891, 897 ] ], "normalized": [] }, { "id": "PMID-21189258_T26", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 922, 931 ] ], "normalized": [] }, { "id": "PMID-21189258_T27", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 1003, 1012 ] ], "normalized": [] }, { "id": "PMID-21189258_T28", "type": "Gene_or_gene_product", "text": [ "glycogen synthase kinase-3beta" ], "offsets": [ [ 1021, 1051 ] ], "normalized": [] }, { "id": "PMID-21189258_T29", "type": "Gene_or_gene_product", "text": [ "GSK-3beta" ], "offsets": [ [ 1053, 1062 ] ], "normalized": [] }, { "id": "PMID-21189258_T30", "type": "Simple_chemical", "text": [ "Ser-9" ], "offsets": [ [ 1083, 1088 ] ], "normalized": [] }, { "id": "PMID-21189258_T31", "type": "Gene_or_gene_product", "text": [ "GSK-3beta" ], "offsets": [ [ 1147, 1156 ] ], "normalized": [] }, { "id": "PMID-21189258_T32", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 1166, 1175 ] ], "normalized": [] }, { "id": "PMID-21189258_T33", "type": "Gene_or_gene_product", "text": [ "RANTES" ], "offsets": [ [ 1190, 1196 ] ], "normalized": [] }, { "id": "PMID-21189258_T34", "type": "Gene_or_gene_product", "text": [ "GSK-3beta" ], "offsets": [ [ 1234, 1243 ] ], "normalized": [] }, { "id": "PMID-21189258_T35", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 1279, 1288 ] ], "normalized": [] }, { "id": "PMID-21189258_T36", "type": "Gene_or_gene_product", "text": [ "RANTES" ], "offsets": [ [ 1313, 1319 ] ], "normalized": [] }, { "id": "PMID-21189258_T37", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 1345, 1354 ] ], "normalized": [] }, { "id": "PMID-21189258_T38", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1403, 1415 ] ], "normalized": [] }, { "id": "PMID-21189258_T39", "type": "Gene_or_gene_product", "text": [ "GSK-3beta" ], "offsets": [ [ 1446, 1455 ] ], "normalized": [] }, { "id": "PMID-21189258_T40", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1501, 1513 ] ], "normalized": [] }, { "id": "PMID-21189258_T41", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 1527, 1536 ] ], "normalized": [] }, { "id": "PMID-21189258_T42", "type": "Gene_or_gene_product", "text": [ "RANTES" ], "offsets": [ [ 1570, 1576 ] ], "normalized": [] }, { "id": "PMID-21189258_T43", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 1599, 1608 ] ], "normalized": [] }, { "id": "PMID-21189258_T44", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 1625, 1634 ] ], "normalized": [] }, { "id": "PMID-21189258_T45", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1674, 1686 ] ], "normalized": [] }, { "id": "PMID-21189258_T46", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1691, 1694 ] ], "normalized": [] }, { "id": "PMID-21189258_T47", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1695, 1704 ] ], "normalized": [] }, { "id": "PMID-21189258_T48", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1722, 1725 ] ], "normalized": [] }, { "id": "PMID-21189258_T49", "type": "Complex", "text": [ "kappaB" ], "offsets": [ [ 1741, 1747 ] ], "normalized": [] }, { "id": "PMID-21189258_T50", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1811, 1814 ] ], "normalized": [] }, { "id": "PMID-21189258_T51", "type": "Gene_or_gene_product", "text": [ "TGF-beta1" ], "offsets": [ [ 1861, 1870 ] ], "normalized": [] }, { "id": "PMID-21189258_T52", "type": "Gene_or_gene_product", "text": [ "RANTES" ], "offsets": [ [ 1901, 1907 ] ], "normalized": [] }, { "id": "PMID-21189258_T53", "type": "Gene_or_gene_product", "text": [ "beta-catenin" ], "offsets": [ [ 1934, 1946 ] ], "normalized": [] }, { "id": "PMID-21189258_T54", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1969, 1978 ] ], "normalized": [] } ]

[ { "id": "PMID-21189258_E1", "type": "Negative_regulation", "trigger": { "text": [ "Inhibition" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E2" }, { "role": "Cause", "ref_id": "PMID-21189258_T2" } ] }, { "id": "PMID-21189258_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 37, 47 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T1" } ] }, { "id": "PMID-21189258_E3", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 64, 72 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E1" }, { "role": "Cause", "ref_id": "PMID-21189258_E5" } ] }, { "id": "PMID-21189258_E4", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 107, 116 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T3" }, { "role": "Theme", "ref_id": "PMID-21189258_E5" } ] }, { "id": "PMID-21189258_E5", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 130, 139 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21189258_T4" } ] }, { "id": "PMID-21189258_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 364, 373 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T7" }, { "role": "Theme", "ref_id": "PMID-21189258_E9" } ] }, { "id": "PMID-21189258_E7", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 393, 400 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E9" }, { "role": "Cause", "ref_id": "PMID-21189258_T8" } ] }, { "id": "PMID-21189258_E8", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 393, 400 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E9" }, { "role": "Cause", "ref_id": "PMID-21189258_T9" } ] }, { "id": "PMID-21189258_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 408, 418 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T10" } ] }, { "id": "PMID-21189258_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 515, 523 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T11" }, { "role": "Theme", "ref_id": "PMID-21189258_E11" } ] }, { "id": "PMID-21189258_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 531, 541 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T12" } ] }, { "id": "PMID-21189258_E12", "type": "Negative_regulation", "trigger": { "text": [ "suppressing" ], "offsets": [ [ 610, 621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E13" } ] }, { "id": "PMID-21189258_E13", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 632, 641 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21189258_T14" } ] }, { "id": "PMID-21189258_E14", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 653, 661 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T15" }, { "role": "Theme", "ref_id": "PMID-21189258_E21" } ] }, { "id": "PMID-21189258_E15", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 653, 661 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T15" }, { "role": "Theme", "ref_id": "PMID-21189258_E22" } ] }, { "id": "PMID-21189258_E16", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 653, 661 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T15" }, { "role": "Theme", "ref_id": "PMID-21189258_E23" } ] }, { "id": "PMID-21189258_E17", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 653, 661 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T15" }, { "role": "Theme", "ref_id": "PMID-21189258_E25" } ] }, { "id": "PMID-21189258_E18", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 653, 661 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T15" }, { "role": "Theme", "ref_id": "PMID-21189258_E24" } ] }, { "id": "PMID-21189258_E19", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 653, 661 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T15" }, { "role": "Theme", "ref_id": "PMID-21189258_E26" } ] }, { "id": "PMID-21189258_E20", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 680, 687 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T16" }, { "role": "Theme", "ref_id": "PMID-21189258_E21" } ] }, { "id": "PMID-21189258_E21", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 701, 716 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T17" } ] }, { "id": "PMID-21189258_E22", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 732, 743 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T17" } ] }, { "id": "PMID-21189258_E23", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 763, 778 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T18" } ] }, { "id": "PMID-21189258_E24", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 763, 778 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T19" } ] }, { "id": "PMID-21189258_E25", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 795, 808 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-21189258_T20" }, { "role": "ToLoc", "ref_id": "PMID-21189258_T20" }, { "role": "Theme", "ref_id": "PMID-21189258_T18" } ] }, { "id": "PMID-21189258_E26", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 795, 808 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-21189258_T20" }, { "role": "ToLoc", "ref_id": "PMID-21189258_T20" }, { "role": "Theme", "ref_id": "PMID-21189258_T19" } ] }, { "id": "PMID-21189258_E27", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 835, 842 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T21" }, { "role": "Theme", "ref_id": "PMID-21189258_E29" } ] }, { "id": "PMID-21189258_E28", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 835, 842 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T21" }, { "role": "Theme", "ref_id": "PMID-21189258_E30" } ] }, { "id": "PMID-21189258_E29", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 855, 862 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T22" }, { "role": "Theme", "ref_id": "PMID-21189258_T24" } ] }, { "id": "PMID-21189258_E30", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 855, 862 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T23" }, { "role": "Theme", "ref_id": "PMID-21189258_T24" } ] }, { "id": "PMID-21189258_E31", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1013, 1020 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T27" }, { "role": "Theme", "ref_id": "PMID-21189258_E32" } ] }, { "id": "PMID-21189258_E32", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1064, 1079 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T29" }, { "role": "Site", "ref_id": "PMID-21189258_T30" } ] }, { "id": "PMID-21189258_E33", "type": "Positive_regulation", "trigger": { "text": [ "leading" ], "offsets": [ [ 1105, 1112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E34" }, { "role": "Cause", "ref_id": "PMID-21189258_E32" } ] }, { "id": "PMID-21189258_E34", "type": "Inactivation", "trigger": { "text": [ "inactivation" ], "offsets": [ [ 1120, 1132 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T29" } ] }, { "id": "PMID-21189258_E35", "type": "Inactivation", "trigger": { "text": [ "Knockdown" ], "offsets": [ [ 1134, 1143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T31" } ] }, { "id": "PMID-21189258_E36", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1180, 1189 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E37" }, { "role": "Cause", "ref_id": "PMID-21189258_E35" } ] }, { "id": "PMID-21189258_E37", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1197, 1206 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T33" } ] }, { "id": "PMID-21189258_E38", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1216, 1230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T34" } ] }, { "id": "PMID-21189258_E39", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 1244, 1253 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_E38" }, { "role": "Theme", "ref_id": "PMID-21189258_E41" } ] }, { "id": "PMID-21189258_E40", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 1258, 1268 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E41" } ] }, { "id": "PMID-21189258_E41", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1269, 1275 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T35" }, { "role": "Theme", "ref_id": "PMID-21189258_E43" } ] }, { "id": "PMID-21189258_E42", "type": "Positive_regulation", "trigger": { "text": [ "restored" ], "offsets": [ [ 1304, 1312 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E43" }, { "role": "Cause", "ref_id": "PMID-21189258_E38" } ] }, { "id": "PMID-21189258_E43", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1320, 1330 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T36" } ] }, { "id": "PMID-21189258_E44", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1355, 1362 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T37" }, { "role": "Theme", "ref_id": "PMID-21189258_E46" } ] }, { "id": "PMID-21189258_E45", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1355, 1362 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T37" }, { "role": "Theme", "ref_id": "PMID-21189258_E47" } ] }, { "id": "PMID-21189258_E46", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylation" ], "offsets": [ [ 1367, 1384 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T38" } ] }, { "id": "PMID-21189258_E47", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1389, 1399 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T38" } ] }, { "id": "PMID-21189258_E48", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 1436, 1442 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T38" }, { "role": "Cause", "ref_id": "PMID-21189258_T39" } ] }, { "id": "PMID-21189258_E49", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1465, 1475 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T40" } ] }, { "id": "PMID-21189258_E50", "type": "Activation", "trigger": { "text": [ "active" ], "offsets": [ [ 1494, 1500 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T40" } ] }, { "id": "PMID-21189258_E51", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1559, 1569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E52" }, { "role": "Cause", "ref_id": "PMID-21189258_E49" } ] }, { "id": "PMID-21189258_E52", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1577, 1587 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T42" } ] }, { "id": "PMID-21189258_E53", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1588, 1595 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E52" }, { "role": "Cause", "ref_id": "PMID-21189258_T43" } ] }, { "id": "PMID-21189258_E54", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1635, 1642 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T44" }, { "role": "Theme", "ref_id": "PMID-21189258_E55" } ] }, { "id": "PMID-21189258_E55", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1654, 1665 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T45" }, { "role": "Theme", "ref_id": "PMID-21189258_T46" }, { "role": "Theme", "ref_id": "PMID-21189258_T47" } ] }, { "id": "PMID-21189258_E56", "type": "Negative_regulation", "trigger": { "text": [ "prevented" ], "offsets": [ [ 1712, 1721 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E57" }, { "role": "Cause", "ref_id": "PMID-21189258_E54" } ] }, { "id": "PMID-21189258_E57", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1726, 1733 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T48" }, { "role": "Theme", "ref_id": "PMID-21189258_T49" } ] }, { "id": "PMID-21189258_E58", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1871, 1881 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T51" }, { "role": "Theme", "ref_id": "PMID-21189258_E59" } ] }, { "id": "PMID-21189258_E59", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1908, 1918 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_T52" } ] }, { "id": "PMID-21189258_E60", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1922, 1930 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E58" }, { "role": "Cause", "ref_id": "PMID-21189258_E62" } ] }, { "id": "PMID-21189258_E61", "type": "Positive_regulation", "trigger": { "text": [ "triggered" ], "offsets": [ [ 1947, 1956 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21189258_T53" }, { "role": "Theme", "ref_id": "PMID-21189258_E62" } ] }, { "id": "PMID-21189258_E62", "type": "Negative_regulation", "trigger": { "text": [ "blockade" ], "offsets": [ [ 1957, 1965 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21189258_E63" } ] }, { "id": "PMID-21189258_E63", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1979, 1988 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21189258_T54" } ] } ]

[ { "id": "PMID-21189258_1", "entity_ids": [ "PMID-21189258_T28", "PMID-21189258_T29" ] } ]

[]

[ { "id": "PMID-21262351__text", "type": "abstract", "text": [ "Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway. \nKeap1 is an inhibitor of Nrf2 involved in Nrf2-dependent antioxidant response. However, the mechanisms on how Keap1 regulates Nrf2-ARE signaling pathway remains to be determined. Here, by using a yeast two-hybrid technology, p65 subunit of NF-kappaB transcription factor was identified as a partner of Keap1. We show that Keap1 physically associated with p65 in vivo and in vitro. Overexpression of p65 inhibited Nrf2-dependent transcription induced by diethylmaleate (DEM) or tert-butyl hydroxyquinone (tBHQ). Knock down of Keap1 by RNA interference partially blocked the repression of Nrf2-mediated activation by p65. It was demonstrated that p65 decreased Nrf2 binding to its cognate DNA sequences and enhanced Nrf2 ubiquitination. The N-terminal region of p65 is necessary for both the interaction with Keap1 and its transcriptional suppression activity. Moreover, nuclear translocation of Keap1 was augmented by p65. Taken together, our findings suggest that NF-kappaB signaling inhibits Nrf2-ARE pathway through the interaction of p65 and Keap1.\n" ], "offsets": [ [ 0, 1126 ] ] } ]

[ { "id": "PMID-21262351_T1", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 15, 18 ] ], "normalized": [] }, { "id": "PMID-21262351_T2", "type": "Gene_or_gene_product", "text": [ "Keap1" ], "offsets": [ [ 34, 39 ] ], "normalized": [] }, { "id": "PMID-21262351_T3", "type": "Gene_or_gene_product", "text": [ "Nrf2" ], "offsets": [ [ 55, 59 ] ], "normalized": [] }, { "id": "PMID-21262351_T4", "type": "Gene_or_gene_product", "text": [ "ARE" ], "offsets": [ [ 60, 63 ] ], "normalized": [] }, { "id": "PMID-21262351_T5", "type": "Gene_or_gene_product", "text": [ "Keap1" ], "offsets": [ [ 74, 79 ] ], "normalized": [] }, { "id": "PMID-21262351_T6", "type": "Gene_or_gene_product", "text": [ "Nrf2" ], "offsets": [ [ 99, 103 ] ], "normalized": [] }, { "id": "PMID-21262351_T7", "type": "Gene_or_gene_product", "text": [ "Nrf2" ], "offsets": [ [ 116, 120 ] ], "normalized": [] }, { "id": "PMID-21262351_T8", "type": "Gene_or_gene_product", "text": [ "Keap1" ], "offsets": [ [ 184, 189 ] ], "normalized": [] }, { "id": "PMID-21262351_T9", "type": "Gene_or_gene_product", "text": [ "Nrf2" ], "offsets": [ [ 200, 204 ] ], "normalized": [] }, { "id": "PMID-21262351_T10", "type": "Gene_or_gene_product", "text": [ "ARE" ], "offsets": [ [ 205, 208 ] ], "normalized": [] }, { "id": "PMID-21262351_T11", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 299, 302 ] ], "normalized": [] }, { "id": "PMID-21262351_T12", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 314, 323 ] ], "normalized": [] }, { "id": "PMID-21262351_T13", "type": "Gene_or_gene_product", "text": [ "Keap1" ], "offsets": [ [ 376, 381 ] ], "normalized": [] }, { "id": "PMID-21262351_T14", "type": "Gene_or_gene_product", "text": [ "Keap1" ], "offsets": [ [ 396, 401 ] ], "normalized": [] }, { "id": "PMID-21262351_T15", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 429, 432 ] ], "normalized": [] }, { "id": "PMID-21262351_T16", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 473, 476 ] ], "normalized": [] }, { "id": "PMID-21262351_T17", "type": "Gene_or_gene_product", "text": [ "Nrf2" ], "offsets": [ [ 487, 491 ] ], "normalized": [] }, { "id": "PMID-21262351_T18", "type": "Simple_chemical", "text": [ "diethylmaleate" ], "offsets": [ [ 527, 541 ] ], "normalized": [] }, { "id": "PMID-21262351_T19", "type": "Simple_chemical", "text": [ "DEM" ], "offsets": [ [ 543, 546 ] ], "normalized": [] }, { "id": "PMID-21262351_T20", "type": "Simple_chemical", "text": [ "tert-butyl hydroxyquinone" ], "offsets": [ [ 551, 576 ] ], "normalized": [] }, { "id": "PMID-21262351_T21", "type": "Simple_chemical", "text": [ "tBHQ" ], "offsets": [ [ 578, 582 ] ], "normalized": [] }, { "id": "PMID-21262351_T22", "type": "Gene_or_gene_product", "text": [ "Keap1" ], "offsets": [ [ 599, 604 ] ], "normalized": [] }, { "id": "PMID-21262351_T23", "type": "Gene_or_gene_product", "text": [ "Nrf2" ], "offsets": [ [ 661, 665 ] ], "normalized": [] }, { "id": "PMID-21262351_T24", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 689, 692 ] ], "normalized": [] }, { "id": "PMID-21262351_T25", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 719, 722 ] ], "normalized": [] }, { "id": "PMID-21262351_T26", "type": "Gene_or_gene_product", "text": [ "Nrf2" ], "offsets": [ [ 733, 737 ] ], "normalized": [] }, { "id": "PMID-21262351_T27", "type": "Gene_or_gene_product", "text": [ "Nrf2" ], "offsets": [ [ 788, 792 ] ], "normalized": [] }, { "id": "PMID-21262351_T28", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 834, 837 ] ], "normalized": [] }, { "id": "PMID-21262351_T29", "type": "Gene_or_gene_product", "text": [ "Keap1" ], "offsets": [ [ 881, 886 ] ], "normalized": [] }, { "id": "PMID-21262351_T30", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 943, 950 ] ], "normalized": [] }, { "id": "PMID-21262351_T31", "type": "Gene_or_gene_product", "text": [ "Keap1" ], "offsets": [ [ 968, 973 ] ], "normalized": [] }, { "id": "PMID-21262351_T32", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 991, 994 ] ], "normalized": [] }, { "id": "PMID-21262351_T33", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1038, 1047 ] ], "normalized": [] }, { "id": "PMID-21262351_T34", "type": "Gene_or_gene_product", "text": [ "Nrf2" ], "offsets": [ [ 1067, 1071 ] ], "normalized": [] }, { "id": "PMID-21262351_T35", "type": "Gene_or_gene_product", "text": [ "ARE" ], "offsets": [ [ 1072, 1075 ] ], "normalized": [] }, { "id": "PMID-21262351_T36", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1111, 1114 ] ], "normalized": [] }, { "id": "PMID-21262351_T37", "type": "Gene_or_gene_product", "text": [ "Keap1" ], "offsets": [ [ 1119, 1124 ] ], "normalized": [] } ]

[ { "id": "PMID-21262351_E1", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 19, 28 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_T1" }, { "role": "Theme", "ref_id": "PMID-21262351_T2" } ] }, { "id": "PMID-21262351_E2", "type": "Negative_regulation", "trigger": { "text": [ "repress" ], "offsets": [ [ 43, 50 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21262351_E1" }, { "role": "Theme", "ref_id": "PMID-21262351_E3" } ] }, { "id": "PMID-21262351_E3", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 64, 71 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21262351_T3" }, { "role": "Participant", "ref_id": "PMID-21262351_T4" } ] }, { "id": "PMID-21262351_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 86, 95 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21262351_T5" }, { "role": "Theme", "ref_id": "PMID-21262351_T6" } ] }, { "id": "PMID-21262351_E5", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 190, 199 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21262351_T8" }, { "role": "Theme", "ref_id": "PMID-21262351_E6" } ] }, { "id": "PMID-21262351_E6", "type": "Pathway", "trigger": { "text": [ "signaling pathway" ], "offsets": [ [ 209, 226 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21262351_T9" }, { "role": "Participant", "ref_id": "PMID-21262351_T10" } ] }, { "id": "PMID-21262351_E7", "type": "Binding", "trigger": { "text": [ "associated" ], "offsets": [ [ 413, 423 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_T14" }, { "role": "Theme", "ref_id": "PMID-21262351_T15" } ] }, { "id": "PMID-21262351_E8", "type": "Gene_expression", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 455, 469 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_T16" } ] }, { "id": "PMID-21262351_E9", "type": "Inactivation", "trigger": { "text": [ "Knock down" ], "offsets": [ [ 585, 595 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_T22" } ] }, { "id": "PMID-21262351_E10", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 723, 732 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21262351_T25" }, { "role": "Theme", "ref_id": "PMID-21262351_E11" } ] }, { "id": "PMID-21262351_E11", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 738, 745 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_T26" } ] }, { "id": "PMID-21262351_E12", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 779, 787 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_E13" }, { "role": "Cause", "ref_id": "PMID-21262351_T25" } ] }, { "id": "PMID-21262351_E13", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitination" ], "offsets": [ [ 793, 807 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_T27" } ] }, { "id": "PMID-21262351_E14", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 864, 875 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_T28" }, { "role": "Theme", "ref_id": "PMID-21262351_T29" } ] }, { "id": "PMID-21262351_E15", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 951, 964 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_T31" }, { "role": "FromLoc", "ref_id": "PMID-21262351_T30" }, { "role": "ToLoc", "ref_id": "PMID-21262351_T30" } ] }, { "id": "PMID-21262351_E16", "type": "Positive_regulation", "trigger": { "text": [ "augmented" ], "offsets": [ [ 978, 987 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_E15" }, { "role": "Cause", "ref_id": "PMID-21262351_T32" } ] }, { "id": "PMID-21262351_E17", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1048, 1057 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21262351_T33" } ] }, { "id": "PMID-21262351_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 1058, 1066 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_E20" }, { "role": "Cause", "ref_id": "PMID-21262351_E17" } ] }, { "id": "PMID-21262351_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 1058, 1066 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_E20" }, { "role": "Cause", "ref_id": "PMID-21262351_E21" } ] }, { "id": "PMID-21262351_E20", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1076, 1083 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21262351_T34" }, { "role": "Participant", "ref_id": "PMID-21262351_T35" } ] }, { "id": "PMID-21262351_E21", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1096, 1107 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21262351_T36" }, { "role": "Theme", "ref_id": "PMID-21262351_T37" } ] } ]

[ { "id": "PMID-21262351_1", "entity_ids": [ "PMID-21262351_T18", "PMID-21262351_T19" ] }, { "id": "PMID-21262351_2", "entity_ids": [ "PMID-21262351_T21", "PMID-21262351_T20" ] } ]

[]

[ { "id": "PMID-21334713__text", "type": "abstract", "text": [ "Overexpression of Forkhead Box M1 transcription factor and nuclear factor-kappaB in laryngeal squamous cell carcinoma: a potential indicator for poor prognosis. \nThe Forkhead Box M1 transcription factor and nuclear factor-kappaB have been shown to play important roles in the development and progression of human cancers. However, the functional significance of Forkhead Box M1 transcription factor in laryngeal squamous cell carcinoma and the correlation between Forkhead Box M1 transcription factor and nuclear factor-kappaB remain unclear. In the current study, we have shown that Forkhead Box M1 transcription factor and nuclear factor-kappaB were significantly overexpressed in laryngeal squamous cell carcinoma tissues and precancerous lesions, compared with adjacent normal tissues (both P < .001). The overexpression of Forkhead Box M1 transcription factor was significantly associated with histologic differentiation (rs = 0.321, P = .002), T stage (rs = 0.276, P = .009), lymph node metastasis (rs = 0.266, P = .012), and clinical stage (rs = 0.272, P = .010); overexpression of nuclear factor-kappaB was significantly associated with T stage (rs = 0.404, P < .001), lymph node metastasis (rs = 0.293, P = .005), and clinical stage (rs = 0.425, P < .001). Overexpressions of both Forkhead Box M1 transcription factor and nuclear factor-kappaB were associated with worse overall survival (P = .041 and P < .001, respectively). Multivariate Cox regression analysis showed that T stage, lymph node metastasis, and nuclear factor-kappaB were independent prognostic factors for laryngeal squamous cell carcinoma (P = .038, P = .014, and P = .005, respectively). Furthermore, a significant correlation was observed between Forkhead Box M1 transcription factor and nuclear factor-kappaB (rs = 0.683, P < .001), indicating the potential direct or indirect interaction between them. In conclusion, our results suggest that overexpressions of Forkhead Box M1 transcription factor and nuclear factor-kappaB and the possible interaction between them may play important roles in the development and progression of laryngeal squamous cell carcinoma, and Forkhead Box M1 transcription factor and nuclear factor-kappaB may serve as useful prognostic markers for laryngeal squamous cell carcinoma.\n" ], "offsets": [ [ 0, 2291 ] ] } ]

[ { "id": "PMID-21334713_T1", "type": "Gene_or_gene_product", "text": [ "Forkhead Box M1" ], "offsets": [ [ 18, 33 ] ], "normalized": [] }, { "id": "PMID-21334713_T2", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 59, 80 ] ], "normalized": [] }, { "id": "PMID-21334713_T3", "type": "Gene_or_gene_product", "text": [ "Forkhead Box M1" ], "offsets": [ [ 166, 181 ] ], "normalized": [] }, { "id": "PMID-21334713_T4", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 207, 228 ] ], "normalized": [] }, { "id": "PMID-21334713_T5", "type": "Gene_or_gene_product", "text": [ "Forkhead Box M1" ], "offsets": [ [ 362, 377 ] ], "normalized": [] }, { "id": "PMID-21334713_T6", "type": "Gene_or_gene_product", "text": [ "Forkhead Box M1" ], "offsets": [ [ 464, 479 ] ], "normalized": [] }, { "id": "PMID-21334713_T7", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 505, 526 ] ], "normalized": [] }, { "id": "PMID-21334713_T8", "type": "Gene_or_gene_product", "text": [ "Forkhead Box M1" ], "offsets": [ [ 584, 599 ] ], "normalized": [] }, { "id": "PMID-21334713_T9", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 625, 646 ] ], "normalized": [] }, { "id": "PMID-21334713_T10", "type": "Gene_or_gene_product", "text": [ "Forkhead Box M1" ], "offsets": [ [ 828, 843 ] ], "normalized": [] }, { "id": "PMID-21334713_T11", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 1089, 1110 ] ], "normalized": [] }, { "id": "PMID-21334713_T12", "type": "Gene_or_gene_product", "text": [ "Forkhead Box M1" ], "offsets": [ [ 1290, 1305 ] ], "normalized": [] }, { "id": "PMID-21334713_T13", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 1331, 1352 ] ], "normalized": [] }, { "id": "PMID-21334713_T14", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 1521, 1542 ] ], "normalized": [] }, { "id": "PMID-21334713_T15", "type": "Gene_or_gene_product", "text": [ "Forkhead Box M1" ], "offsets": [ [ 1727, 1742 ] ], "normalized": [] }, { "id": "PMID-21334713_T16", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 1768, 1789 ] ], "normalized": [] }, { "id": "PMID-21334713_T17", "type": "Gene_or_gene_product", "text": [ "Forkhead Box M1" ], "offsets": [ [ 1943, 1958 ] ], "normalized": [] }, { "id": "PMID-21334713_T18", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 1984, 2005 ] ], "normalized": [] }, { "id": "PMID-21334713_T19", "type": "Gene_or_gene_product", "text": [ "Forkhead Box M1" ], "offsets": [ [ 2150, 2165 ] ], "normalized": [] }, { "id": "PMID-21334713_T20", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 2191, 2212 ] ], "normalized": [] } ]

[ { "id": "PMID-21334713_E1", "type": "Gene_expression", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 0, 14 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21334713_T1" } ] }, { "id": "PMID-21334713_E2", "type": "Gene_expression", "trigger": { "text": [ "overexpressed" ], "offsets": [ [ 666, 679 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21334713_T8" } ] }, { "id": "PMID-21334713_E3", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 810, 824 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21334713_T10" } ] }, { "id": "PMID-21334713_E4", "type": "Gene_expression", "trigger": { "text": [ "Overexpressions" ], "offsets": [ [ 1266, 1281 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21334713_T12" } ] }, { "id": "PMID-21334713_E5", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1858, 1869 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21334713_T16" }, { "role": "Theme", "ref_id": "PMID-21334713_T15" } ] }, { "id": "PMID-21334713_E6", "type": "Gene_expression", "trigger": { "text": [ "overexpressions" ], "offsets": [ [ 1924, 1939 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21334713_T17" } ] }, { "id": "PMID-21334713_E7", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 2023, 2034 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21334713_T18" }, { "role": "Theme", "ref_id": "PMID-21334713_T17" } ] } ]

[]

[]

[ { "id": "PMID-21346255__text", "type": "abstract", "text": [ "C/EBPalpha and C/EBPalpha oncoproteins regulate nfkb1 and displace histone deacetylases from NF-kappaB p50 homodimers to induce NF-kappaB target genes. \nMutated CEBPA defines a subgroup of acute myeloid leukemia (AML). We have previously shown that C/EBPalpha or its AML mutants synergize with NF-kappaB p50 to activate antiapoptotic genes, including BCL2 and FLIP. Furthermore, p50 binds and activates the CEBPA gene in myeloid cells. We now report that C/EBPalpha or C/EBPalpha leucine zipper AML mutants bind in vivo to the nfkb1 (p50) promoter and induce its expression even in the presence of cycloheximide. Induction of p50 by C/EBPalpha depends on 2 conserved kappaB sites in the nfkb1 promoter. C/EBPalpha did not induce p65 expression. Thus, C/EBPalpha and p50 reciprocally regulate each other's expression, establishing a positive feedback relationship. Although p50 homodimers inhibit transcription, C/EBPalpha and p50 synergistically activate antiapoptotic genes. ChIP analysis showed that C/EBPalpha diminishes the occupation of histone deacetylase 1 (HDAC1) or HDAC3 on the endogenous FLIP promoter but not in mice lacking p50. Coimmunoprecipitation confirmed that C/EBPalpha, its AML variants, or C/EBPbeta disrupt interaction between p50 and HDACs dependent on the C/EBP basic region. These findings suggest that C/EBPs displace HDACs from p50 homodimers bound to antiapoptotic genes, contributing to NF-kappaB dysregulation in leukemia, and that the C/EBPalpha:p50 complex is a potential therapeutic target.\n" ], "offsets": [ [ 0, 1525 ] ] } ]

[ { "id": "PMID-21346255_T1", "type": "Gene_or_gene_product", "text": [ "C/EBPalpha" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "PMID-21346255_T2", "type": "Gene_or_gene_product", "text": [ "C/EBPalpha" ], "offsets": [ [ 15, 25 ] ], "normalized": [] }, { "id": "PMID-21346255_T3", "type": "Gene_or_gene_product", "text": [ "nfkb1" ], "offsets": [ [ 48, 53 ] ], "normalized": [] }, { "id": "PMID-21346255_T4", "type": "Gene_or_gene_product", "text": [ "histone deacetylases" ], "offsets": [ [ 67, 87 ] ], "normalized": [] }, { "id": "PMID-21346255_T5", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 93, 102 ] ], "normalized": [] }, { "id": "PMID-21346255_T6", "type": "Complex", "text": [ "p50 homodimers" ], "offsets": [ [ 103, 117 ] ], "normalized": [] }, { "id": "PMID-21346255_T7", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 128, 137 ] ], "normalized": [] }, { "id": "PMID-21346255_T8", "type": "Gene_or_gene_product", "text": [ "CEBPA" ], "offsets": [ [ 161, 166 ] ], "normalized": [] }, { "id": "PMID-21346255_T9", "type": "Gene_or_gene_product", "text": [ "C/EBPalpha" ], "offsets": [ [ 249, 259 ] ], "normalized": [] }, { "id": "PMID-21346255_T10", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 294, 303 ] ], "normalized": [] }, { "id": "PMID-21346255_T11", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 304, 307 ] ], "normalized": [] }, { "id": "PMID-21346255_T12", "type": "Gene_or_gene_product", "text": [ "BCL2" ], "offsets": [ [ 351, 355 ] ], "normalized": [] }, { "id": "PMID-21346255_T13", "type": "Gene_or_gene_product", "text": [ "FLIP" ], "offsets": [ [ 360, 364 ] ], "normalized": [] }, { "id": "PMID-21346255_T14", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 379, 382 ] ], "normalized": [] }, { "id": "PMID-21346255_T15", "type": "Gene_or_gene_product", "text": [ "CEBPA" ], "offsets": [ [ 407, 412 ] ], "normalized": [] }, { "id": "PMID-21346255_T16", "type": "Gene_or_gene_product", "text": [ "C/EBPalpha" ], "offsets": [ [ 455, 465 ] ], "normalized": [] }, { "id": "PMID-21346255_T17", "type": "Gene_or_gene_product", "text": [ "C/EBPalpha" ], "offsets": [ [ 469, 479 ] ], "normalized": [] }, { "id": "PMID-21346255_T18", "type": "Simple_chemical", "text": [ "leucine" ], "offsets": [ [ 480, 487 ] ], "normalized": [] }, { "id": "PMID-21346255_T19", "type": "Gene_or_gene_product", "text": [ "nfkb1" ], "offsets": [ [ 527, 532 ] ], "normalized": [] }, { "id": "PMID-21346255_T20", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 534, 537 ] ], "normalized": [] }, { "id": "PMID-21346255_T21", "type": "Simple_chemical", "text": [ "cycloheximide" ], "offsets": [ [ 598, 611 ] ], "normalized": [] }, { "id": "PMID-21346255_T22", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 626, 629 ] ], "normalized": [] }, { "id": "PMID-21346255_T23", "type": "Gene_or_gene_product", "text": [ "C/EBPalpha" ], "offsets": [ [ 633, 643 ] ], "normalized": [] }, { "id": "PMID-21346255_T24", "type": "Complex", "text": [ "kappaB" ], "offsets": [ [ 667, 673 ] ], "normalized": [] }, { "id": "PMID-21346255_T25", "type": "Gene_or_gene_product", "text": [ "nfkb1" ], "offsets": [ [ 687, 692 ] ], "normalized": [] }, { "id": "PMID-21346255_T26", "type": "Gene_or_gene_product", "text": [ "C/EBPalpha" ], "offsets": [ [ 703, 713 ] ], "normalized": [] }, { "id": "PMID-21346255_T27", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 729, 732 ] ], "normalized": [] }, { "id": "PMID-21346255_T28", "type": "Gene_or_gene_product", "text": [ "C/EBPalpha" ], "offsets": [ [ 751, 761 ] ], "normalized": [] }, { "id": "PMID-21346255_T29", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 766, 769 ] ], "normalized": [] }, { "id": "PMID-21346255_T30", "type": "Complex", "text": [ "p50 homodimers" ], "offsets": [ [ 873, 887 ] ], "normalized": [] }, { "id": "PMID-21346255_T31", "type": "Gene_or_gene_product", "text": [ "C/EBPalpha" ], "offsets": [ [ 911, 921 ] ], "normalized": [] }, { "id": "PMID-21346255_T32", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 926, 929 ] ], "normalized": [] }, { "id": "PMID-21346255_T33", "type": "Gene_or_gene_product", "text": [ "C/EBPalpha" ], "offsets": [ [ 1002, 1012 ] ], "normalized": [] }, { "id": "PMID-21346255_T34", "type": "Gene_or_gene_product", "text": [ "histone deacetylase 1" ], "offsets": [ [ 1042, 1063 ] ], "normalized": [] }, { "id": "PMID-21346255_T35", "type": "Gene_or_gene_product", "text": [ "HDAC1" ], "offsets": [ [ 1065, 1070 ] ], "normalized": [] }, { "id": "PMID-21346255_T36", "type": "Gene_or_gene_product", "text": [ "HDAC3" ], "offsets": [ [ 1075, 1080 ] ], "normalized": [] }, { "id": "PMID-21346255_T37", "type": "Gene_or_gene_product", "text": [ "FLIP" ], "offsets": [ [ 1099, 1103 ] ], "normalized": [] }, { "id": "PMID-21346255_T38", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 1137, 1140 ] ], "normalized": [] }, { "id": "PMID-21346255_T39", "type": "Gene_or_gene_product", "text": [ "C/EBPalpha" ], "offsets": [ [ 1179, 1189 ] ], "normalized": [] }, { "id": "PMID-21346255_T40", "type": "Gene_or_gene_product", "text": [ "C/EBPbeta" ], "offsets": [ [ 1212, 1221 ] ], "normalized": [] }, { "id": "PMID-21346255_T41", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 1250, 1253 ] ], "normalized": [] }, { "id": "PMID-21346255_T42", "type": "Gene_or_gene_product", "text": [ "HDACs" ], "offsets": [ [ 1258, 1263 ] ], "normalized": [] }, { "id": "PMID-21346255_T43", "type": "Gene_or_gene_product", "text": [ "C/EBP" ], "offsets": [ [ 1281, 1286 ] ], "normalized": [] }, { "id": "PMID-21346255_T44", "type": "Gene_or_gene_product", "text": [ "C/EBPs" ], "offsets": [ [ 1329, 1335 ] ], "normalized": [] }, { "id": "PMID-21346255_T45", "type": "Gene_or_gene_product", "text": [ "HDACs" ], "offsets": [ [ 1345, 1350 ] ], "normalized": [] }, { "id": "PMID-21346255_T46", "type": "Complex", "text": [ "p50 homodimers" ], "offsets": [ [ 1356, 1370 ] ], "normalized": [] }, { "id": "PMID-21346255_T47", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1417, 1426 ] ], "normalized": [] }, { "id": "PMID-21346255_T48", "type": "Complex", "text": [ "C/EBPalpha:p50" ], "offsets": [ [ 1467, 1481 ] ], "normalized": [] } ]

[ { "id": "PMID-21346255_E1", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 39, 47 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21346255_T1" }, { "role": "Theme", "ref_id": "PMID-21346255_T3" } ] }, { "id": "PMID-21346255_E2", "type": "Dissociation", "trigger": { "text": [ "displace" ], "offsets": [ [ 58, 66 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-21346255_T4" }, { "role": "Theme", "ref_id": "PMID-21346255_T5" } ] }, { "id": "PMID-21346255_E3", "type": "Positive_regulation", "trigger": { "text": [ "displace" ], "offsets": [ [ 58, 66 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21346255_T1" }, { "role": "Theme", "ref_id": "PMID-21346255_E2" } ] }, { "id": "PMID-21346255_E4", "type": "Dissociation", "trigger": { "text": [ "displace" ], "offsets": [ [ 58, 66 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-21346255_T4" }, { "role": "Theme", "ref_id": "PMID-21346255_T6" } ] }, { "id": "PMID-21346255_E5", "type": "Positive_regulation", "trigger": { "text": [ "displace" ], "offsets": [ [ 58, 66 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21346255_T1" }, { "role": "Theme", "ref_id": "PMID-21346255_E4" } ] }, { "id": "PMID-21346255_E6", "type": "Positive_regulation", "trigger": { "text": [ "synergize" ], "offsets": [ [ 279, 288 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21346255_T9" }, { "role": "Theme", "ref_id": "PMID-21346255_T10" } ] }, { "id": "PMID-21346255_E7", "type": "Positive_regulation", "trigger": { "text": [ "synergize" ], "offsets": [ [ 279, 288 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21346255_T9" }, { "role": "Theme", "ref_id": "PMID-21346255_T11" } ] }, { "id": "PMID-21346255_E8", "type": "Activation", "trigger": { "text": [ "activate" ], "offsets": [ [ 311, 319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T12" }, { "role": "Cause", "ref_id": "PMID-21346255_E6" } ] }, { "id": "PMID-21346255_E9", "type": "Activation", "trigger": { "text": [ "activate" ], "offsets": [ [ 311, 319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T13" }, { "role": "Cause", "ref_id": "PMID-21346255_E6" } ] }, { "id": "PMID-21346255_E10", "type": "Activation", "trigger": { "text": [ "activate" ], "offsets": [ [ 311, 319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T13" }, { "role": "Cause", "ref_id": "PMID-21346255_E7" } ] }, { "id": "PMID-21346255_E11", "type": "Activation", "trigger": { "text": [ "activate" ], "offsets": [ [ 311, 319 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T12" }, { "role": "Cause", "ref_id": "PMID-21346255_E7" } ] }, { "id": "PMID-21346255_E12", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 383, 387 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T14" }, { "role": "Theme", "ref_id": "PMID-21346255_T15" } ] }, { "id": "PMID-21346255_E13", "type": "Activation", "trigger": { "text": [ "activates" ], "offsets": [ [ 393, 402 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T15" }, { "role": "Cause", "ref_id": "PMID-21346255_E12" } ] }, { "id": "PMID-21346255_E14", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 507, 511 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T20" }, { "role": "Theme", "ref_id": "PMID-21346255_T16" } ] }, { "id": "PMID-21346255_E15", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 552, 558 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_E16" }, { "role": "Cause", "ref_id": "PMID-21346255_E14" } ] }, { "id": "PMID-21346255_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 563, 573 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T20" } ] }, { "id": "PMID-21346255_E17", "type": "Positive_regulation", "trigger": { "text": [ "Induction" ], "offsets": [ [ 613, 622 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T22" }, { "role": "Cause", "ref_id": "PMID-21346255_T23" } ] }, { "id": "PMID-21346255_E18", "type": "Positive_regulation", "trigger": { "text": [ "depends" ], "offsets": [ [ 644, 651 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_E17" } ] }, { "id": "PMID-21346255_E19", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 722, 728 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21346255_T26" }, { "role": "Theme", "ref_id": "PMID-21346255_E20" } ] }, { "id": "PMID-21346255_E20", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 733, 743 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T27" } ] }, { "id": "PMID-21346255_E21", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 783, 791 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21346255_T29" }, { "role": "Theme", "ref_id": "PMID-21346255_E23" } ] }, { "id": "PMID-21346255_E22", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 783, 791 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21346255_T28" }, { "role": "Theme", "ref_id": "PMID-21346255_E24" } ] }, { "id": "PMID-21346255_E23", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 805, 815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T28" } ] }, { "id": "PMID-21346255_E24", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 805, 815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T29" } ] }, { "id": "PMID-21346255_E25", "type": "Negative_regulation", "trigger": { "text": [ "diminishes" ], "offsets": [ [ 1013, 1023 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21346255_T33" }, { "role": "Theme", "ref_id": "PMID-21346255_E28" } ] }, { "id": "PMID-21346255_E26", "type": "Negative_regulation", "trigger": { "text": [ "diminishes" ], "offsets": [ [ 1013, 1023 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21346255_T33" }, { "role": "Theme", "ref_id": "PMID-21346255_E27" } ] }, { "id": "PMID-21346255_E27", "type": "Binding", "trigger": { "text": [ "occupation" ], "offsets": [ [ 1028, 1038 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T34" }, { "role": "Theme", "ref_id": "PMID-21346255_T37" } ] }, { "id": "PMID-21346255_E28", "type": "Binding", "trigger": { "text": [ "occupation" ], "offsets": [ [ 1028, 1038 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T36" }, { "role": "Theme", "ref_id": "PMID-21346255_T37" } ] }, { "id": "PMID-21346255_E29", "type": "Negative_regulation", "trigger": { "text": [ "disrupt" ], "offsets": [ [ 1222, 1229 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_E31" }, { "role": "Cause", "ref_id": "PMID-21346255_T39" } ] }, { "id": "PMID-21346255_E30", "type": "Negative_regulation", "trigger": { "text": [ "disrupt" ], "offsets": [ [ 1222, 1229 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_E31" }, { "role": "Cause", "ref_id": "PMID-21346255_T40" } ] }, { "id": "PMID-21346255_E31", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1230, 1241 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T41" }, { "role": "Theme", "ref_id": "PMID-21346255_T42" } ] }, { "id": "PMID-21346255_E32", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1264, 1273 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_E31" } ] }, { "id": "PMID-21346255_E33", "type": "Dissociation", "trigger": { "text": [ "displace" ], "offsets": [ [ 1336, 1344 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-21346255_T45" }, { "role": "Theme", "ref_id": "PMID-21346255_T46" } ] }, { "id": "PMID-21346255_E34", "type": "Positive_regulation", "trigger": { "text": [ "displace" ], "offsets": [ [ 1336, 1344 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21346255_T44" }, { "role": "Theme", "ref_id": "PMID-21346255_E33" } ] }, { "id": "PMID-21346255_E35", "type": "Positive_regulation", "trigger": { "text": [ "contributing" ], "offsets": [ [ 1401, 1413 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_E36" }, { "role": "Cause", "ref_id": "PMID-21346255_E33" } ] }, { "id": "PMID-21346255_E36", "type": "Negative_regulation", "trigger": { "text": [ "dysregulation" ], "offsets": [ [ 1427, 1440 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21346255_T47" } ] } ]

[ { "id": "PMID-21346255_1", "entity_ids": [ "PMID-21346255_T19", "PMID-21346255_T20" ] }, { "id": "PMID-21346255_2", "entity_ids": [ "PMID-21346255_T34", "PMID-21346255_T35" ] } ]

[]

[ { "id": "PMID-21408173__text", "type": "abstract", "text": [ "Optineurin is required for CYLD-dependent inhibition of TNFalpha-induced NF-kappaB activation. \nThe nuclear factor kappa B (NF-kappaB) regulates genes that function in diverse cellular processes like inflammation, immunity and cell survival. The activation of NF-kappaB is tightly controlled and the deubiquitinase CYLD has emerged as a key negative regulator of NF-kappaB signalling. Optineurin, mutated in certain glaucomas and amyotrophic lateral sclerosis, is also a negative regulator of NF-kappaB activation. It competes with NEMO (NF-kappaB essential modulator) for binding to ubiquitinated RIP (receptor interacting protein) to prevent NF-kappaB activation. Recently we identified CYLD as optineurin-interacting protein. Here we have analysed the functional significance of interaction of optineurin with CYLD. Our results show that a glaucoma-associated mutant of optineurin, H486R, is altered in its interaction with CYLD. Unlike wild-type optineurin, the H486R mutant did not inhibit tumour necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. CYLD mediated inhibition of TNFalpha-induced NF-kappaB activation was abrogated by expression of the H486R mutant. Upon knockdown of optineurin, CYLD was unable to inhibit TNFalpha-induced NF-kappaB activation and showed drastically reduced interaction with ubiquitinated RIP. The level of ubiquitinated RIP was increased in optineurin knockdown cells. Deubiquitination of RIP by over-expressed CYLD was abrogated in optineurin knockdown cells. These results suggest that optineurin regulates NF-kappaB activation by mediating interaction of CYLD with ubiquitinated RIP thus facilitating deubiquitination of RIP.\n" ], "offsets": [ [ 0, 1678 ] ] } ]

[ { "id": "PMID-21408173_T1", "type": "Gene_or_gene_product", "text": [ "Optineurin" ], "offsets": [ [ 0, 10 ] ], "normalized": [] }, { "id": "PMID-21408173_T2", "type": "Gene_or_gene_product", "text": [ "CYLD" ], "offsets": [ [ 27, 31 ] ], "normalized": [] }, { "id": "PMID-21408173_T3", "type": "Gene_or_gene_product", "text": [ "TNFalpha" ], "offsets": [ [ 56, 64 ] ], "normalized": [] }, { "id": "PMID-21408173_T4", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 73, 82 ] ], "normalized": [] }, { "id": "PMID-21408173_T5", "type": "Complex", "text": [ "nuclear factor kappa B" ], "offsets": [ [ 100, 122 ] ], "normalized": [] }, { "id": "PMID-21408173_T6", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 124, 133 ] ], "normalized": [] }, { "id": "PMID-21408173_T7", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 260, 269 ] ], "normalized": [] }, { "id": "PMID-21408173_T8", "type": "Gene_or_gene_product", "text": [ "CYLD" ], "offsets": [ [ 315, 319 ] ], "normalized": [] }, { "id": "PMID-21408173_T9", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 363, 372 ] ], "normalized": [] }, { "id": "PMID-21408173_T10", "type": "Gene_or_gene_product", "text": [ "Optineurin" ], "offsets": [ [ 385, 395 ] ], "normalized": [] }, { "id": "PMID-21408173_T11", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 493, 502 ] ], "normalized": [] }, { "id": "PMID-21408173_T12", "type": "Gene_or_gene_product", "text": [ "NEMO" ], "offsets": [ [ 532, 536 ] ], "normalized": [] }, { "id": "PMID-21408173_T13", "type": "Gene_or_gene_product", "text": [ "NF-kappaB essential modulator" ], "offsets": [ [ 538, 567 ] ], "normalized": [] }, { "id": "PMID-21408173_T14", "type": "Gene_or_gene_product", "text": [ "RIP" ], "offsets": [ [ 598, 601 ] ], "normalized": [] }, { "id": "PMID-21408173_T15", "type": "Gene_or_gene_product", "text": [ "receptor interacting protein" ], "offsets": [ [ 603, 631 ] ], "normalized": [] }, { "id": "PMID-21408173_T16", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 644, 653 ] ], "normalized": [] }, { "id": "PMID-21408173_T17", "type": "Gene_or_gene_product", "text": [ "CYLD" ], "offsets": [ [ 689, 693 ] ], "normalized": [] }, { "id": "PMID-21408173_T18", "type": "Gene_or_gene_product", "text": [ "optineurin" ], "offsets": [ [ 697, 707 ] ], "normalized": [] }, { "id": "PMID-21408173_T19", "type": "Gene_or_gene_product", "text": [ "optineurin" ], "offsets": [ [ 797, 807 ] ], "normalized": [] }, { "id": "PMID-21408173_T20", "type": "Gene_or_gene_product", "text": [ "CYLD" ], "offsets": [ [ 813, 817 ] ], "normalized": [] }, { "id": "PMID-21408173_T21", "type": "Gene_or_gene_product", "text": [ "optineurin" ], "offsets": [ [ 873, 883 ] ], "normalized": [] }, { "id": "PMID-21408173_T22", "type": "Gene_or_gene_product", "text": [ "H486R" ], "offsets": [ [ 885, 890 ] ], "normalized": [] }, { "id": "PMID-21408173_T23", "type": "Gene_or_gene_product", "text": [ "CYLD" ], "offsets": [ [ 927, 931 ] ], "normalized": [] }, { "id": "PMID-21408173_T24", "type": "Gene_or_gene_product", "text": [ "optineurin" ], "offsets": [ [ 950, 960 ] ], "normalized": [] }, { "id": "PMID-21408173_T25", "type": "Gene_or_gene_product", "text": [ "H486R" ], "offsets": [ [ 966, 971 ] ], "normalized": [] }, { "id": "PMID-21408173_T26", "type": "Gene_or_gene_product", "text": [ "tumour necrosis factor alpha" ], "offsets": [ [ 995, 1023 ] ], "normalized": [] }, { "id": "PMID-21408173_T27", "type": "Gene_or_gene_product", "text": [ "TNFalpha" ], "offsets": [ [ 1025, 1033 ] ], "normalized": [] }, { "id": "PMID-21408173_T28", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1043, 1052 ] ], "normalized": [] }, { "id": "PMID-21408173_T29", "type": "Gene_or_gene_product", "text": [ "CYLD" ], "offsets": [ [ 1065, 1069 ] ], "normalized": [] }, { "id": "PMID-21408173_T30", "type": "Gene_or_gene_product", "text": [ "TNFalpha" ], "offsets": [ [ 1093, 1101 ] ], "normalized": [] }, { "id": "PMID-21408173_T31", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1110, 1119 ] ], "normalized": [] }, { "id": "PMID-21408173_T32", "type": "Gene_or_gene_product", "text": [ "H486R" ], "offsets": [ [ 1166, 1171 ] ], "normalized": [] }, { "id": "PMID-21408173_T33", "type": "Gene_or_gene_product", "text": [ "optineurin" ], "offsets": [ [ 1198, 1208 ] ], "normalized": [] }, { "id": "PMID-21408173_T34", "type": "Gene_or_gene_product", "text": [ "CYLD" ], "offsets": [ [ 1210, 1214 ] ], "normalized": [] }, { "id": "PMID-21408173_T35", "type": "Gene_or_gene_product", "text": [ "TNFalpha" ], "offsets": [ [ 1237, 1245 ] ], "normalized": [] }, { "id": "PMID-21408173_T36", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1254, 1263 ] ], "normalized": [] }, { "id": "PMID-21408173_T37", "type": "Gene_or_gene_product", "text": [ "RIP" ], "offsets": [ [ 1337, 1340 ] ], "normalized": [] }, { "id": "PMID-21408173_T38", "type": "Gene_or_gene_product", "text": [ "RIP" ], "offsets": [ [ 1369, 1372 ] ], "normalized": [] }, { "id": "PMID-21408173_T39", "type": "Gene_or_gene_product", "text": [ "optineurin" ], "offsets": [ [ 1390, 1400 ] ], "normalized": [] }, { "id": "PMID-21408173_T40", "type": "Gene_or_gene_product", "text": [ "RIP" ], "offsets": [ [ 1438, 1441 ] ], "normalized": [] }, { "id": "PMID-21408173_T41", "type": "Gene_or_gene_product", "text": [ "CYLD" ], "offsets": [ [ 1460, 1464 ] ], "normalized": [] }, { "id": "PMID-21408173_T42", "type": "Gene_or_gene_product", "text": [ "optineurin" ], "offsets": [ [ 1482, 1492 ] ], "normalized": [] }, { "id": "PMID-21408173_T43", "type": "Gene_or_gene_product", "text": [ "optineurin" ], "offsets": [ [ 1537, 1547 ] ], "normalized": [] }, { "id": "PMID-21408173_T44", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1558, 1567 ] ], "normalized": [] }, { "id": "PMID-21408173_T45", "type": "Gene_or_gene_product", "text": [ "CYLD" ], "offsets": [ [ 1607, 1611 ] ], "normalized": [] }, { "id": "PMID-21408173_T46", "type": "Gene_or_gene_product", "text": [ "RIP" ], "offsets": [ [ 1631, 1634 ] ], "normalized": [] }, { "id": "PMID-21408173_T47", "type": "Gene_or_gene_product", "text": [ "RIP" ], "offsets": [ [ 1673, 1676 ] ], "normalized": [] } ]

[ { "id": "PMID-21408173_E1", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 14, 22 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21408173_T1" }, { "role": "Theme", "ref_id": "PMID-21408173_E3" } ] }, { "id": "PMID-21408173_E2", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 32, 41 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21408173_T2" }, { "role": "Theme", "ref_id": "PMID-21408173_E3" } ] }, { "id": "PMID-21408173_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 42, 52 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E5" } ] }, { "id": "PMID-21408173_E4", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 65, 72 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21408173_T3" }, { "role": "Theme", "ref_id": "PMID-21408173_E5" } ] }, { "id": "PMID-21408173_E5", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 83, 93 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T4" } ] }, { "id": "PMID-21408173_E6", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 246, 256 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T7" } ] }, { "id": "PMID-21408173_E7", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 281, 291 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E6" } ] }, { "id": "PMID-21408173_E8", "type": "Deubiquitination", "trigger": { "text": [ "deubiquitinase" ], "offsets": [ [ 300, 314 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T8" } ] }, { "id": "PMID-21408173_E9", "type": "Negative_regulation", "trigger": { "text": [ "negative regulator" ], "offsets": [ [ 341, 359 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E10" }, { "role": "Cause", "ref_id": "PMID-21408173_T8" } ] }, { "id": "PMID-21408173_E10", "type": "Pathway", "trigger": { "text": [ "signalling" ], "offsets": [ [ 373, 383 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21408173_T9" } ] }, { "id": "PMID-21408173_E11", "type": "Negative_regulation", "trigger": { "text": [ "negative regulator" ], "offsets": [ [ 471, 489 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E12" } ] }, { "id": "PMID-21408173_E12", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 503, 513 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T11" } ] }, { "id": "PMID-21408173_E13", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 573, 580 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T12" }, { "role": "Theme", "ref_id": "PMID-21408173_T14" } ] }, { "id": "PMID-21408173_E14", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 584, 597 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T14" } ] }, { "id": "PMID-21408173_E15", "type": "Negative_regulation", "trigger": { "text": [ "prevent" ], "offsets": [ [ 636, 643 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E16" }, { "role": "Cause", "ref_id": "PMID-21408173_E13" } ] }, { "id": "PMID-21408173_E16", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 654, 664 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T16" } ] }, { "id": "PMID-21408173_E17", "type": "Binding", "trigger": { "text": [ "interacting" ], "offsets": [ [ 708, 719 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T18" }, { "role": "Theme", "ref_id": "PMID-21408173_T17" } ] }, { "id": "PMID-21408173_E18", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 782, 793 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T19" }, { "role": "Theme", "ref_id": "PMID-21408173_T20" } ] }, { "id": "PMID-21408173_E19", "type": "Regulation", "trigger": { "text": [ "altered" ], "offsets": [ [ 895, 902 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E20" } ] }, { "id": "PMID-21408173_E20", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 910, 921 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T23" }, { "role": "Theme", "ref_id": "PMID-21408173_T22" } ] }, { "id": "PMID-21408173_E21", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 987, 994 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E24" }, { "role": "Cause", "ref_id": "PMID-21408173_T25" } ] }, { "id": "PMID-21408173_E22", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 987, 994 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E24" }, { "role": "Cause", "ref_id": "PMID-21408173_T24" } ] }, { "id": "PMID-21408173_E23", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1035, 1042 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21408173_T26" }, { "role": "Theme", "ref_id": "PMID-21408173_E24" } ] }, { "id": "PMID-21408173_E24", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1053, 1063 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T28" } ] }, { "id": "PMID-21408173_E25", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1070, 1078 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21408173_T29" }, { "role": "Theme", "ref_id": "PMID-21408173_E26" } ] }, { "id": "PMID-21408173_E26", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1079, 1089 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E28" } ] }, { "id": "PMID-21408173_E27", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1102, 1109 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21408173_T30" }, { "role": "Theme", "ref_id": "PMID-21408173_E28" } ] }, { "id": "PMID-21408173_E28", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1120, 1130 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T31" } ] }, { "id": "PMID-21408173_E29", "type": "Negative_regulation", "trigger": { "text": [ "abrogated" ], "offsets": [ [ 1135, 1144 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E26" }, { "role": "Cause", "ref_id": "PMID-21408173_E30" } ] }, { "id": "PMID-21408173_E30", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1148, 1158 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T32" } ] }, { "id": "PMID-21408173_E31", "type": "Inactivation", "trigger": { "text": [ "knockdown" ], "offsets": [ [ 1185, 1194 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T33" } ] }, { "id": "PMID-21408173_E32", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1229, 1236 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E34" }, { "role": "Cause", "ref_id": "PMID-21408173_T34" } ] }, { "id": "PMID-21408173_E33", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1246, 1253 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21408173_T35" }, { "role": "Theme", "ref_id": "PMID-21408173_E34" } ] }, { "id": "PMID-21408173_E34", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1264, 1274 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T36" } ] }, { "id": "PMID-21408173_E35", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1298, 1305 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E36" }, { "role": "Cause", "ref_id": "PMID-21408173_T34" } ] }, { "id": "PMID-21408173_E36", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1306, 1317 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T37" } ] }, { "id": "PMID-21408173_E37", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 1323, 1336 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T37" } ] }, { "id": "PMID-21408173_E38", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 1355, 1368 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T38" } ] }, { "id": "PMID-21408173_E39", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1377, 1386 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E38" } ] }, { "id": "PMID-21408173_E40", "type": "Deubiquitination", "trigger": { "text": [ "Deubiquitination" ], "offsets": [ [ 1418, 1434 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T40" } ] }, { "id": "PMID-21408173_E41", "type": "Gene_expression", "trigger": { "text": [ "over-expressed" ], "offsets": [ [ 1445, 1459 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T41" } ] }, { "id": "PMID-21408173_E42", "type": "Negative_regulation", "trigger": { "text": [ "abrogated" ], "offsets": [ [ 1469, 1478 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E40" } ] }, { "id": "PMID-21408173_E43", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 1548, 1557 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E44" }, { "role": "Cause", "ref_id": "PMID-21408173_E45" } ] }, { "id": "PMID-21408173_E44", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1568, 1578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T44" } ] }, { "id": "PMID-21408173_E45", "type": "Positive_regulation", "trigger": { "text": [ "mediating" ], "offsets": [ [ 1582, 1591 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E46" }, { "role": "Cause", "ref_id": "PMID-21408173_T43" } ] }, { "id": "PMID-21408173_E46", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1592, 1603 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T45" }, { "role": "Theme", "ref_id": "PMID-21408173_T46" } ] }, { "id": "PMID-21408173_E47", "type": "Ubiquitination", "trigger": { "text": [ "ubiquitinated" ], "offsets": [ [ 1617, 1630 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T46" } ] }, { "id": "PMID-21408173_E48", "type": "Positive_regulation", "trigger": { "text": [ "facilitating" ], "offsets": [ [ 1640, 1652 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_E49" }, { "role": "Cause", "ref_id": "PMID-21408173_E43" } ] }, { "id": "PMID-21408173_E49", "type": "Deubiquitination", "trigger": { "text": [ "deubiquitination" ], "offsets": [ [ 1653, 1669 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21408173_T47" } ] } ]

[ { "id": "PMID-21408173_1", "entity_ids": [ "PMID-21408173_T5", "PMID-21408173_T6" ] }, { "id": "PMID-21408173_2", "entity_ids": [ "PMID-21408173_T13", "PMID-21408173_T12" ] }, { "id": "PMID-21408173_3", "entity_ids": [ "PMID-21408173_T14", "PMID-21408173_T15" ] }, { "id": "PMID-21408173_4", "entity_ids": [ "PMID-21408173_T26", "PMID-21408173_T27" ] } ]

[]

[ { "id": "PMID-21411116__text", "type": "abstract", "text": [ "Identification of CD44 as a downstream target of noncanonical NF-kappaB pathway activated by human T-cell leukemia virus type 1-encoded Tax protein. \nOur previous study showed Human T-cell leukemia virus type 1 Tax induces osteopontin (OPN) expression by transactivating its promoter. As an extension, we investigated here the possible influence of Tax on CD44, an important receptor for OPN. Co-expression of Tax, but not its NF-kappaB-defective mutant, significantly increased the reporter gene expression directed by CD44 promoter. Tax-mediated CD44 activation was largely diminished by disrupting an element similar to the noncanonical kappabeta site found in other IKKalpha target genes, and further, co-transfection of RelB siRNA abolished CD44 induction by Tax, suggesting an involvement of noncanonical NF-kappaB pathway in Tax-mediated transactivation. Consistently, chromatin immunoprecipitation revealed a specific interaction of CD44 promoter with RelB-containing complex. Together, these results indicate that D44 gene is one of the downstream target genes of aberrantly activated noncanonical NF-kappaB signaling by Tax, providing an additional line of evidence explaining how Tax-induced NF-kappaB signaling is integrated into a fate-determining cellular program.\n" ], "offsets": [ [ 0, 1279 ] ] } ]

[ { "id": "PMID-21411116_T1", "type": "Gene_or_gene_product", "text": [ "CD44" ], "offsets": [ [ 18, 22 ] ], "normalized": [] }, { "id": "PMID-21411116_T2", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 62, 71 ] ], "normalized": [] }, { "id": "PMID-21411116_T3", "type": "Gene_or_gene_product", "text": [ "Tax" ], "offsets": [ [ 136, 139 ] ], "normalized": [] }, { "id": "PMID-21411116_T4", "type": "Gene_or_gene_product", "text": [ "Tax" ], "offsets": [ [ 211, 214 ] ], "normalized": [] }, { "id": "PMID-21411116_T5", "type": "Gene_or_gene_product", "text": [ "osteopontin" ], "offsets": [ [ 223, 234 ] ], "normalized": [] }, { "id": "PMID-21411116_T6", "type": "Gene_or_gene_product", "text": [ "OPN" ], "offsets": [ [ 236, 239 ] ], "normalized": [] }, { "id": "PMID-21411116_T7", "type": "Gene_or_gene_product", "text": [ "Tax" ], "offsets": [ [ 349, 352 ] ], "normalized": [] }, { "id": "PMID-21411116_T8", "type": "Gene_or_gene_product", "text": [ "CD44" ], "offsets": [ [ 356, 360 ] ], "normalized": [] }, { "id": "PMID-21411116_T9", "type": "Gene_or_gene_product", "text": [ "OPN" ], "offsets": [ [ 388, 391 ] ], "normalized": [] }, { "id": "PMID-21411116_T10", "type": "Gene_or_gene_product", "text": [ "Tax" ], "offsets": [ [ 410, 413 ] ], "normalized": [] }, { "id": "PMID-21411116_T11", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 427, 436 ] ], "normalized": [] }, { "id": "PMID-21411116_T12", "type": "Gene_or_gene_product", "text": [ "CD44" ], "offsets": [ [ 520, 524 ] ], "normalized": [] }, { "id": "PMID-21411116_T13", "type": "Gene_or_gene_product", "text": [ "Tax" ], "offsets": [ [ 535, 538 ] ], "normalized": [] }, { "id": "PMID-21411116_T14", "type": "Gene_or_gene_product", "text": [ "CD44" ], "offsets": [ [ 548, 552 ] ], "normalized": [] }, { "id": "PMID-21411116_T15", "type": "Gene_or_gene_product", "text": [ "IKKalpha" ], "offsets": [ [ 670, 678 ] ], "normalized": [] }, { "id": "PMID-21411116_T16", "type": "Gene_or_gene_product", "text": [ "RelB" ], "offsets": [ [ 725, 729 ] ], "normalized": [] }, { "id": "PMID-21411116_T17", "type": "Gene_or_gene_product", "text": [ "CD44" ], "offsets": [ [ 746, 750 ] ], "normalized": [] }, { "id": "PMID-21411116_T18", "type": "Gene_or_gene_product", "text": [ "Tax" ], "offsets": [ [ 764, 767 ] ], "normalized": [] }, { "id": "PMID-21411116_T19", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 811, 820 ] ], "normalized": [] }, { "id": "PMID-21411116_T20", "type": "Gene_or_gene_product", "text": [ "Tax" ], "offsets": [ [ 832, 835 ] ], "normalized": [] }, { "id": "PMID-21411116_T21", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 876, 885 ] ], "normalized": [] }, { "id": "PMID-21411116_T22", "type": "Gene_or_gene_product", "text": [ "CD44" ], "offsets": [ [ 941, 945 ] ], "normalized": [] }, { "id": "PMID-21411116_T23", "type": "Gene_or_gene_product", "text": [ "RelB" ], "offsets": [ [ 960, 964 ] ], "normalized": [] }, { "id": "PMID-21411116_T24", "type": "Gene_or_gene_product", "text": [ "D44" ], "offsets": [ [ 1023, 1026 ] ], "normalized": [] }, { "id": "PMID-21411116_T25", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1107, 1116 ] ], "normalized": [] }, { "id": "PMID-21411116_T26", "type": "Gene_or_gene_product", "text": [ "Tax" ], "offsets": [ [ 1130, 1133 ] ], "normalized": [] }, { "id": "PMID-21411116_T27", "type": "Gene_or_gene_product", "text": [ "Tax" ], "offsets": [ [ 1191, 1194 ] ], "normalized": [] }, { "id": "PMID-21411116_T28", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1203, 1212 ] ], "normalized": [] } ]

[ { "id": "PMID-21411116_E1", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 39, 45 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_T1" }, { "role": "Cause", "ref_id": "PMID-21411116_E2" } ] }, { "id": "PMID-21411116_E2", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 72, 79 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21411116_T2" } ] }, { "id": "PMID-21411116_E3", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 80, 89 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_E2" }, { "role": "Cause", "ref_id": "PMID-21411116_T3" } ] }, { "id": "PMID-21411116_E4", "type": "Negative_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 215, 222 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21411116_T4" }, { "role": "Theme", "ref_id": "PMID-21411116_E5" } ] }, { "id": "PMID-21411116_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 241, 251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_T6" } ] }, { "id": "PMID-21411116_E6", "type": "Regulation", "trigger": { "text": [ "influence" ], "offsets": [ [ 336, 345 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21411116_T7" }, { "role": "Theme", "ref_id": "PMID-21411116_T8" } ] }, { "id": "PMID-21411116_E7", "type": "Gene_expression", "trigger": { "text": [ "Co-expression" ], "offsets": [ [ 393, 406 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_T10" } ] }, { "id": "PMID-21411116_E8", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 539, 547 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21411116_T13" }, { "role": "Theme", "ref_id": "PMID-21411116_E9" } ] }, { "id": "PMID-21411116_E9", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 553, 563 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_T14" } ] }, { "id": "PMID-21411116_E10", "type": "Negative_regulation", "trigger": { "text": [ "diminished" ], "offsets": [ [ 576, 586 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_E9" } ] }, { "id": "PMID-21411116_E11", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 736, 745 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_E12" } ] }, { "id": "PMID-21411116_E12", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 751, 760 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_T17" }, { "role": "Cause", "ref_id": "PMID-21411116_T18" } ] }, { "id": "PMID-21411116_E13", "type": "Positive_regulation", "trigger": { "text": [ "involvement" ], "offsets": [ [ 783, 794 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21411116_E14" }, { "role": "Theme", "ref_id": "PMID-21411116_E16" } ] }, { "id": "PMID-21411116_E14", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 821, 828 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21411116_T19" } ] }, { "id": "PMID-21411116_E15", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 836, 844 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21411116_T20" }, { "role": "Theme", "ref_id": "PMID-21411116_E16" } ] }, { "id": "PMID-21411116_E16", "type": "Positive_regulation", "trigger": { "text": [ "transactivation" ], "offsets": [ [ 845, 860 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_T17" } ] }, { "id": "PMID-21411116_E17", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 926, 937 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_T22" } ] }, { "id": "PMID-21411116_E18", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 1057, 1063 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_T24" }, { "role": "Cause", "ref_id": "PMID-21411116_E20" } ] }, { "id": "PMID-21411116_E19", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1084, 1093 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21411116_E20" }, { "role": "Cause", "ref_id": "PMID-21411116_T26" } ] }, { "id": "PMID-21411116_E20", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1117, 1126 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21411116_T25" } ] }, { "id": "PMID-21411116_E21", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1195, 1202 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21411116_T27" }, { "role": "Theme", "ref_id": "PMID-21411116_E22" } ] }, { "id": "PMID-21411116_E22", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1213, 1222 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21411116_T28" } ] } ]

[ { "id": "PMID-21411116_1", "entity_ids": [ "PMID-21411116_T5", "PMID-21411116_T6" ] } ]

[]

[ { "id": "PMID-21708266__text", "type": "abstract", "text": [ "Purification of SUMO-1 modified IkappaBalpha and complex formation with NF-kappaB. \nCovalent modification of proteins with SUMO (Small Ubiquitin-like MOdifier) affects many cellular processes, including transcriptional regulation, DNA repair and signal transduction. Although hundreds of SUMO targets have been identified, many biological outcomes of protein sumoylation remain poorly understood. In particular, biochemical and structural analysis can only be easily conducted if highly pure sumoylated substrates are available. Purification of sumoylated substrates in vitro or in bacteria have been previously reported but separating the sumoylated protein from the undesired unmodified fraction is often technically challenging, inefficient and time consuming. Here we develop a new vector system for in vivo sumoylation in Escherichia coli which improves purification of sumoylated proteins. We describe the purification of IkappaBalpha, its sumoylation, the subsequent separation and purification of the modified and the unmodified forms and the purification of the complex IkappaBalpha-SUMO-1/NF-kappaB. After a first GST affinity chromatography and GST-tag removal, a unique metal-ion affinity chromatography using a 6xHis-SUMO-1 tag results in mgs of highly pure SUMO-1 modified IkappaBalpha. Our pure SUMO-1 modified IkappaB/NF-kappaB complex could be a useful tool to identify new interaction partner specific of the SUMO-1 modified IkappaBalpha form. This approach may be extended to other SUMO substrates not isolable by classical chromatography techniques.\n" ], "offsets": [ [ 0, 1570 ] ] } ]

[ { "id": "PMID-21708266_T1", "type": "Gene_or_gene_product", "text": [ "SUMO-1" ], "offsets": [ [ 16, 22 ] ], "normalized": [] }, { "id": "PMID-21708266_T2", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 32, 44 ] ], "normalized": [] }, { "id": "PMID-21708266_T3", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 72, 81 ] ], "normalized": [] }, { "id": "PMID-21708266_T4", "type": "Gene_or_gene_product", "text": [ "SUMO" ], "offsets": [ [ 123, 127 ] ], "normalized": [] }, { "id": "PMID-21708266_T5", "type": "Gene_or_gene_product", "text": [ "Small Ubiquitin-like MOdifier" ], "offsets": [ [ 129, 158 ] ], "normalized": [] }, { "id": "PMID-21708266_T6", "type": "Gene_or_gene_product", "text": [ "SUMO" ], "offsets": [ [ 288, 292 ] ], "normalized": [] }, { "id": "PMID-21708266_T7", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 928, 940 ] ], "normalized": [] }, { "id": "PMID-21708266_T8", "type": "Complex", "text": [ "IkappaBalpha-SUMO-1/NF-kappaB" ], "offsets": [ [ 1079, 1108 ] ], "normalized": [] }, { "id": "PMID-21708266_T9", "type": "Gene_or_gene_product", "text": [ "GST" ], "offsets": [ [ 1124, 1127 ] ], "normalized": [] }, { "id": "PMID-21708266_T10", "type": "Gene_or_gene_product", "text": [ "GST" ], "offsets": [ [ 1156, 1159 ] ], "normalized": [] }, { "id": "PMID-21708266_T11", "type": "Gene_or_gene_product", "text": [ "His-SUMO-1" ], "offsets": [ [ 1226, 1236 ] ], "normalized": [] }, { "id": "PMID-21708266_T12", "type": "Gene_or_gene_product", "text": [ "SUMO-1" ], "offsets": [ [ 1271, 1277 ] ], "normalized": [] }, { "id": "PMID-21708266_T13", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 1287, 1299 ] ], "normalized": [] }, { "id": "PMID-21708266_T14", "type": "Gene_or_gene_product", "text": [ "SUMO-1" ], "offsets": [ [ 1310, 1316 ] ], "normalized": [] }, { "id": "PMID-21708266_T15", "type": "Complex", "text": [ "IkappaB/NF-kappaB" ], "offsets": [ [ 1326, 1343 ] ], "normalized": [] }, { "id": "PMID-21708266_T16", "type": "Gene_or_gene_product", "text": [ "SUMO-1" ], "offsets": [ [ 1427, 1433 ] ], "normalized": [] }, { "id": "PMID-21708266_T17", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 1443, 1455 ] ], "normalized": [] }, { "id": "PMID-21708266_T18", "type": "Gene_or_gene_product", "text": [ "SUMO" ], "offsets": [ [ 1501, 1505 ] ], "normalized": [] } ]

[ { "id": "PMID-21708266_E1", "type": "Conversion", "trigger": { "text": [ "modified" ], "offsets": [ [ 23, 31 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21708266_T2" }, { "role": "Theme", "ref_id": "PMID-21708266_T1" } ] }, { "id": "PMID-21708266_E2", "type": "Binding", "trigger": { "text": [ "complex formation" ], "offsets": [ [ 49, 66 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21708266_T3" }, { "role": "Theme", "ref_id": "PMID-21708266_T1" } ] }, { "id": "PMID-21708266_E3", "type": "Conversion", "trigger": { "text": [ "sumoylation" ], "offsets": [ [ 946, 957 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21708266_T7" } ] }, { "id": "PMID-21708266_E4", "type": "Conversion", "trigger": { "text": [ "modified" ], "offsets": [ [ 1278, 1286 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21708266_T12" }, { "role": "Theme", "ref_id": "PMID-21708266_T13" } ] }, { "id": "PMID-21708266_E5", "type": "Conversion", "trigger": { "text": [ "modified" ], "offsets": [ [ 1317, 1325 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21708266_T14" }, { "role": "Theme", "ref_id": "PMID-21708266_T15" } ] }, { "id": "PMID-21708266_E6", "type": "Conversion", "trigger": { "text": [ "modified" ], "offsets": [ [ 1434, 1442 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21708266_T16" }, { "role": "Theme", "ref_id": "PMID-21708266_T17" } ] } ]

[ { "id": "PMID-21708266_1", "entity_ids": [ "PMID-21708266_T4", "PMID-21708266_T5" ] } ]

[]

[ { "id": "PMID-21734074__text", "type": "abstract", "text": [ "The dual function cytokine IL-33 interacts with the transcription factor NF-kappaB to dampen NF-kappaB-stimulated gene transcription. \nFull-length IL-33 is a member of the IL-1 family of cytokines, which can act in an autocrine or paracrine manner by binding to the IL-33R on several different target cell types. In addition, IL-33 can act in an intracrine fashion by translocating to the nucleus, where it binds to the chromatin and modulates gene expression. In this article, we report that full-length IL-33, but not mature IL-33, interacts with the transcription factor NF-kappaB. This interaction occurs between the N-terminal part of IL-33 from aa 66-109 and the N-terminal Rel homology domain of NF-kappaB p65. Coimmunoprecipitation experiments in cells overexpressing IL-33 or endogenously expressing IL-33 revealed rhIL-1beta-stimulated association between IL-33 and p65, whereas binding to the p50 subunit was constitutive. The biological consequence of IL-33/NF-kappaB complex formation was reduction in NF-kappaB p65 binding to its cognate DNA and impairment of p65-triggered transactivation. Overexpression of IL-33 resulted in a reduction and delay in the rhIL-1beta-stimulated expression of endogenous NF-kappaB target genes such as IkappaBalpha, TNF-alpha, and C-REL. We suggest that nuclear IL-33 sequesters nuclear NF-kappaB and reduces NF-kappaB-triggered gene expression to dampen proinflammatory signaling.\n" ], "offsets": [ [ 0, 1428 ] ] } ]

[ { "id": "PMID-21734074_T1", "type": "Gene_or_gene_product", "text": [ "IL-33" ], "offsets": [ [ 27, 32 ] ], "normalized": [] }, { "id": "PMID-21734074_T2", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 73, 82 ] ], "normalized": [] }, { "id": "PMID-21734074_T3", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 93, 102 ] ], "normalized": [] }, { "id": "PMID-21734074_T4", "type": "Gene_or_gene_product", "text": [ "IL-33" ], "offsets": [ [ 147, 152 ] ], "normalized": [] }, { "id": "PMID-21734074_T5", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 172, 176 ] ], "normalized": [] }, { "id": "PMID-21734074_T6", "type": "Gene_or_gene_product", "text": [ "IL-33R" ], "offsets": [ [ 266, 272 ] ], "normalized": [] }, { "id": "PMID-21734074_T7", "type": "Gene_or_gene_product", "text": [ "IL-33" ], "offsets": [ [ 326, 331 ] ], "normalized": [] }, { "id": "PMID-21734074_T8", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 389, 396 ] ], "normalized": [] }, { "id": "PMID-21734074_T9", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 420, 429 ] ], "normalized": [] }, { "id": "PMID-21734074_T10", "type": "Gene_or_gene_product", "text": [ "IL-33" ], "offsets": [ [ 505, 510 ] ], "normalized": [] }, { "id": "PMID-21734074_T11", "type": "Gene_or_gene_product", "text": [ "IL-33" ], "offsets": [ [ 527, 532 ] ], "normalized": [] }, { "id": "PMID-21734074_T12", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 574, 583 ] ], "normalized": [] }, { "id": "PMID-21734074_T13", "type": "Gene_or_gene_product", "text": [ "IL-33" ], "offsets": [ [ 640, 645 ] ], "normalized": [] }, { "id": "PMID-21734074_T14", "type": "Simple_chemical", "text": [ "aa 66" ], "offsets": [ [ 651, 656 ] ], "normalized": [] }, { "id": "PMID-21734074_T15", "type": "Simple_chemical", "text": [ "109" ], "offsets": [ [ 657, 660 ] ], "normalized": [] }, { "id": "PMID-21734074_T16", "type": "Gene_or_gene_product", "text": [ "Rel" ], "offsets": [ [ 680, 683 ] ], "normalized": [] }, { "id": "PMID-21734074_T17", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 703, 712 ] ], "normalized": [] }, { "id": "PMID-21734074_T18", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 713, 716 ] ], "normalized": [] }, { "id": "PMID-21734074_T19", "type": "Gene_or_gene_product", "text": [ "IL-33" ], "offsets": [ [ 776, 781 ] ], "normalized": [] }, { "id": "PMID-21734074_T20", "type": "Gene_or_gene_product", "text": [ "IL-33" ], "offsets": [ [ 809, 814 ] ], "normalized": [] }, { "id": "PMID-21734074_T21", "type": "Gene_or_gene_product", "text": [ "rhIL-1beta" ], "offsets": [ [ 824, 834 ] ], "normalized": [] }, { "id": "PMID-21734074_T22", "type": "Gene_or_gene_product", "text": [ "IL-33" ], "offsets": [ [ 866, 871 ] ], "normalized": [] }, { "id": "PMID-21734074_T23", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 876, 879 ] ], "normalized": [] }, { "id": "PMID-21734074_T24", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 904, 907 ] ], "normalized": [] }, { "id": "PMID-21734074_T25", "type": "Complex", "text": [ "IL-33/NF-kappaB" ], "offsets": [ [ 964, 979 ] ], "normalized": [] }, { "id": "PMID-21734074_T26", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1015, 1024 ] ], "normalized": [] }, { "id": "PMID-21734074_T27", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1025, 1028 ] ], "normalized": [] }, { "id": "PMID-21734074_T28", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1074, 1077 ] ], "normalized": [] }, { "id": "PMID-21734074_T29", "type": "Gene_or_gene_product", "text": [ "IL-33" ], "offsets": [ [ 1123, 1128 ] ], "normalized": [] }, { "id": "PMID-21734074_T30", "type": "Gene_or_gene_product", "text": [ "rhIL-1beta" ], "offsets": [ [ 1170, 1180 ] ], "normalized": [] }, { "id": "PMID-21734074_T31", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1217, 1226 ] ], "normalized": [] }, { "id": "PMID-21734074_T32", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 1248, 1260 ] ], "normalized": [] }, { "id": "PMID-21734074_T33", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 1262, 1271 ] ], "normalized": [] }, { "id": "PMID-21734074_T34", "type": "Gene_or_gene_product", "text": [ "C-REL" ], "offsets": [ [ 1277, 1282 ] ], "normalized": [] }, { "id": "PMID-21734074_T35", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1300, 1307 ] ], "normalized": [] }, { "id": "PMID-21734074_T36", "type": "Gene_or_gene_product", "text": [ "IL-33" ], "offsets": [ [ 1308, 1313 ] ], "normalized": [] }, { "id": "PMID-21734074_T37", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1325, 1332 ] ], "normalized": [] }, { "id": "PMID-21734074_T38", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1333, 1342 ] ], "normalized": [] }, { "id": "PMID-21734074_T39", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1355, 1364 ] ], "normalized": [] } ]

[ { "id": "PMID-21734074_E1", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 33, 42 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T1" }, { "role": "Theme", "ref_id": "PMID-21734074_T2" } ] }, { "id": "PMID-21734074_E2", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 251, 258 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T6" } ] }, { "id": "PMID-21734074_E3", "type": "Transport", "trigger": { "text": [ "translocating" ], "offsets": [ [ 368, 381 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-21734074_T8" }, { "role": "Theme", "ref_id": "PMID-21734074_T7" } ] }, { "id": "PMID-21734074_E4", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 407, 412 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T7" } ] }, { "id": "PMID-21734074_E5", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 534, 543 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T10" }, { "role": "Theme", "ref_id": "PMID-21734074_T12" } ] }, { "id": "PMID-21734074_E6", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 590, 601 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T10" }, { "role": "Theme", "ref_id": "PMID-21734074_T12" } ] }, { "id": "PMID-21734074_E7", "type": "Gene_expression", "trigger": { "text": [ "overexpressing" ], "offsets": [ [ 761, 775 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T19" } ] }, { "id": "PMID-21734074_E8", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 798, 808 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T20" } ] }, { "id": "PMID-21734074_E9", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 835, 845 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_T21" }, { "role": "Theme", "ref_id": "PMID-21734074_E10" } ] }, { "id": "PMID-21734074_E10", "type": "Binding", "trigger": { "text": [ "association" ], "offsets": [ [ 846, 857 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T22" }, { "role": "Theme", "ref_id": "PMID-21734074_T23" } ] }, { "id": "PMID-21734074_E11", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 889, 896 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T24" } ] }, { "id": "PMID-21734074_E12", "type": "Positive_regulation", "trigger": { "text": [ "consequence" ], "offsets": [ [ 949, 960 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_E13" } ] }, { "id": "PMID-21734074_E13", "type": "Binding", "trigger": { "text": [ "formation" ], "offsets": [ [ 988, 997 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T25" } ] }, { "id": "PMID-21734074_E14", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 1002, 1011 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_E12" }, { "role": "Theme", "ref_id": "PMID-21734074_E15" } ] }, { "id": "PMID-21734074_E15", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1029, 1036 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T26" }, { "role": "Theme", "ref_id": "PMID-21734074_T27" } ] }, { "id": "PMID-21734074_E16", "type": "Gene_expression", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 1105, 1119 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T29" } ] }, { "id": "PMID-21734074_E17", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1129, 1137 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_E16" }, { "role": "Theme", "ref_id": "PMID-21734074_E23" } ] }, { "id": "PMID-21734074_E18", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1129, 1137 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_E16" }, { "role": "Theme", "ref_id": "PMID-21734074_E26" } ] }, { "id": "PMID-21734074_E19", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1129, 1137 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_E16" }, { "role": "Theme", "ref_id": "PMID-21734074_E27" } ] }, { "id": "PMID-21734074_E20", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1129, 1137 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_E16" }, { "role": "Theme", "ref_id": "PMID-21734074_E28" } ] }, { "id": "PMID-21734074_E21", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1129, 1137 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_E16" }, { "role": "Theme", "ref_id": "PMID-21734074_E24" } ] }, { "id": "PMID-21734074_E22", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1129, 1137 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_E16" }, { "role": "Theme", "ref_id": "PMID-21734074_E25" } ] }, { "id": "PMID-21734074_E23", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 1143, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_E32" } ] }, { "id": "PMID-21734074_E24", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 1143, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_E33" } ] }, { "id": "PMID-21734074_E25", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 1143, 1152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_E34" } ] }, { "id": "PMID-21734074_E26", "type": "Negative_regulation", "trigger": { "text": [ "delay" ], "offsets": [ [ 1157, 1162 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_E32" } ] }, { "id": "PMID-21734074_E27", "type": "Negative_regulation", "trigger": { "text": [ "delay" ], "offsets": [ [ 1157, 1162 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_E33" } ] }, { "id": "PMID-21734074_E28", "type": "Negative_regulation", "trigger": { "text": [ "delay" ], "offsets": [ [ 1157, 1162 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_E34" } ] }, { "id": "PMID-21734074_E29", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1181, 1191 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_T30" }, { "role": "Theme", "ref_id": "PMID-21734074_E32" } ] }, { "id": "PMID-21734074_E30", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1181, 1191 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_T30" }, { "role": "Theme", "ref_id": "PMID-21734074_E33" } ] }, { "id": "PMID-21734074_E31", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1181, 1191 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_T30" }, { "role": "Theme", "ref_id": "PMID-21734074_E34" } ] }, { "id": "PMID-21734074_E32", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1192, 1202 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T32" } ] }, { "id": "PMID-21734074_E33", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1192, 1202 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T33" } ] }, { "id": "PMID-21734074_E34", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1192, 1202 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T34" } ] }, { "id": "PMID-21734074_E35", "type": "Transport", "trigger": { "text": [ "sequesters" ], "offsets": [ [ 1314, 1324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T38" } ] }, { "id": "PMID-21734074_E36", "type": "Positive_regulation", "trigger": { "text": [ "sequesters" ], "offsets": [ [ 1314, 1324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_E35" }, { "role": "Cause", "ref_id": "PMID-21734074_T36" } ] }, { "id": "PMID-21734074_E37", "type": "Negative_regulation", "trigger": { "text": [ "reduces" ], "offsets": [ [ 1347, 1354 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_T36" }, { "role": "Theme", "ref_id": "PMID-21734074_E43" } ] }, { "id": "PMID-21734074_E38", "type": "Negative_regulation", "trigger": { "text": [ "reduces" ], "offsets": [ [ 1347, 1354 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_T36" }, { "role": "Theme", "ref_id": "PMID-21734074_E44" } ] }, { "id": "PMID-21734074_E39", "type": "Negative_regulation", "trigger": { "text": [ "reduces" ], "offsets": [ [ 1347, 1354 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_T36" }, { "role": "Theme", "ref_id": "PMID-21734074_E45" } ] }, { "id": "PMID-21734074_E40", "type": "Positive_regulation", "trigger": { "text": [ "triggered" ], "offsets": [ [ 1365, 1374 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_T39" }, { "role": "Theme", "ref_id": "PMID-21734074_E43" } ] }, { "id": "PMID-21734074_E41", "type": "Positive_regulation", "trigger": { "text": [ "triggered" ], "offsets": [ [ 1365, 1374 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_T39" }, { "role": "Theme", "ref_id": "PMID-21734074_E44" } ] }, { "id": "PMID-21734074_E42", "type": "Positive_regulation", "trigger": { "text": [ "triggered" ], "offsets": [ [ 1365, 1374 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21734074_T39" }, { "role": "Theme", "ref_id": "PMID-21734074_E45" } ] }, { "id": "PMID-21734074_E43", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1380, 1390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T32" } ] }, { "id": "PMID-21734074_E44", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1380, 1390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T33" } ] }, { "id": "PMID-21734074_E45", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1380, 1390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21734074_T34" } ] } ]

[]

[]

[ { "id": "PMID-21821668__text", "type": "abstract", "text": [ "Mapping of NRF binding motifs of NF-kappaB p65 subunit. \nNF-kappaB repressing factor (NRF) is a nuclear transcription factor that binds to a specific DNA sequence in NF-kappaB target promoters. Previous reports suggested that NRF interferes with the transcriptional activity of NF-kappaB binding sites through a direct interaction with NF-kappaB subunits. The aim of this study was to map specific NRF binding domains in the NF-kappaB proteins, p65 and p50. Our data demonstrate that NRF is able to interact with the p65 subunit and inhibit its transcription enhancing activity in reporter gene experiments. Using tandem affinity purifications (TAP), we show that NRF protein significantly binds to the endogenous p65, subunit but not to the p50 subunit. The selective binding activity of the NRF protein is consistently mediated by the N-terminal domain of NRF (Amino acids 1-380). Moreover, the Rel homology domain (RHD) of p65 is sufficient for binding to the N-terminal domain of NRF. Using detailed peptide mapping studies, we finally identify three peptide motifs in p65 RHD showing distinctive binding specificities for the NRF protein. According to the predicted structure of p65, all three peptide motifs align within an exposed region of p65 and might hint at promising targets for inhibitors.\n" ], "offsets": [ [ 0, 1304 ] ] } ]

[ { "id": "PMID-21821668_T1", "type": "Gene_or_gene_product", "text": [ "NRF" ], "offsets": [ [ 11, 14 ] ], "normalized": [] }, { "id": "PMID-21821668_T2", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 33, 42 ] ], "normalized": [] }, { "id": "PMID-21821668_T3", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 43, 46 ] ], "normalized": [] }, { "id": "PMID-21821668_T4", "type": "Gene_or_gene_product", "text": [ "NF-kappaB repressing factor" ], "offsets": [ [ 57, 84 ] ], "normalized": [] }, { "id": "PMID-21821668_T5", "type": "Gene_or_gene_product", "text": [ "NRF" ], "offsets": [ [ 86, 89 ] ], "normalized": [] }, { "id": "PMID-21821668_T6", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 96, 103 ] ], "normalized": [] }, { "id": "PMID-21821668_T7", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 166, 175 ] ], "normalized": [] }, { "id": "PMID-21821668_T8", "type": "Gene_or_gene_product", "text": [ "NRF" ], "offsets": [ [ 226, 229 ] ], "normalized": [] }, { "id": "PMID-21821668_T9", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 278, 287 ] ], "normalized": [] }, { "id": "PMID-21821668_T10", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 336, 345 ] ], "normalized": [] }, { "id": "PMID-21821668_T11", "type": "Gene_or_gene_product", "text": [ "NRF" ], "offsets": [ [ 398, 401 ] ], "normalized": [] }, { "id": "PMID-21821668_T12", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 425, 434 ] ], "normalized": [] }, { "id": "PMID-21821668_T13", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 445, 448 ] ], "normalized": [] }, { "id": "PMID-21821668_T14", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 453, 456 ] ], "normalized": [] }, { "id": "PMID-21821668_T15", "type": "Gene_or_gene_product", "text": [ "NRF" ], "offsets": [ [ 484, 487 ] ], "normalized": [] }, { "id": "PMID-21821668_T16", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 517, 520 ] ], "normalized": [] }, { "id": "PMID-21821668_T17", "type": "Gene_or_gene_product", "text": [ "NRF" ], "offsets": [ [ 664, 667 ] ], "normalized": [] }, { "id": "PMID-21821668_T18", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 714, 717 ] ], "normalized": [] }, { "id": "PMID-21821668_T19", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 742, 745 ] ], "normalized": [] }, { "id": "PMID-21821668_T20", "type": "Gene_or_gene_product", "text": [ "NRF" ], "offsets": [ [ 793, 796 ] ], "normalized": [] }, { "id": "PMID-21821668_T21", "type": "Gene_or_gene_product", "text": [ "NRF" ], "offsets": [ [ 858, 861 ] ], "normalized": [] }, { "id": "PMID-21821668_T22", "type": "Simple_chemical", "text": [ "Amino acids 1" ], "offsets": [ [ 863, 876 ] ], "normalized": [] }, { "id": "PMID-21821668_T23", "type": "Simple_chemical", "text": [ "380" ], "offsets": [ [ 877, 880 ] ], "normalized": [] }, { "id": "PMID-21821668_T24", "type": "Gene_or_gene_product", "text": [ "Rel" ], "offsets": [ [ 897, 900 ] ], "normalized": [] }, { "id": "PMID-21821668_T25", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 926, 929 ] ], "normalized": [] }, { "id": "PMID-21821668_T26", "type": "Gene_or_gene_product", "text": [ "NRF" ], "offsets": [ [ 984, 987 ] ], "normalized": [] }, { "id": "PMID-21821668_T27", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1073, 1076 ] ], "normalized": [] }, { "id": "PMID-21821668_T28", "type": "Gene_or_gene_product", "text": [ "NRF" ], "offsets": [ [ 1131, 1134 ] ], "normalized": [] }, { "id": "PMID-21821668_T29", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1184, 1187 ] ], "normalized": [] }, { "id": "PMID-21821668_T30", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1248, 1251 ] ], "normalized": [] } ]

[ { "id": "PMID-21821668_E1", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 15, 22 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T1" }, { "role": "Theme", "ref_id": "PMID-21821668_T3" }, { "role": "Theme", "ref_id": "PMID-21821668_T2" } ] }, { "id": "PMID-21821668_E2", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 130, 135 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T4" } ] }, { "id": "PMID-21821668_E3", "type": "Negative_regulation", "trigger": { "text": [ "interferes" ], "offsets": [ [ 230, 240 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21821668_E4" }, { "role": "Theme", "ref_id": "PMID-21821668_E6" } ] }, { "id": "PMID-21821668_E4", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 288, 295 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T9" } ] }, { "id": "PMID-21821668_E5", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 319, 330 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T10" } ] }, { "id": "PMID-21821668_E6", "type": "Positive_regulation", "trigger": { "text": [ "interaction" ], "offsets": [ [ 319, 330 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_E5" }, { "role": "Cause", "ref_id": "PMID-21821668_T8" } ] }, { "id": "PMID-21821668_E7", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 402, 409 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T11" }, { "role": "Theme", "ref_id": "PMID-21821668_T13" } ] }, { "id": "PMID-21821668_E8", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 402, 409 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T11" }, { "role": "Theme", "ref_id": "PMID-21821668_T14" } ] }, { "id": "PMID-21821668_E9", "type": "Binding", "trigger": { "text": [ "interact" ], "offsets": [ [ 499, 507 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T15" }, { "role": "Theme", "ref_id": "PMID-21821668_T16" } ] }, { "id": "PMID-21821668_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 533, 540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_E11" }, { "role": "Cause", "ref_id": "PMID-21821668_T15" } ] }, { "id": "PMID-21821668_E11", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 545, 558 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T16" } ] }, { "id": "PMID-21821668_E12", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 690, 695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T17" }, { "role": "Theme", "ref_id": "PMID-21821668_T18" } ] }, { "id": "PMID-21821668_E13", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 690, 695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T17" }, { "role": "Theme", "ref_id": "PMID-21821668_T19" } ] }, { "id": "PMID-21821668_E14", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 769, 776 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T20" } ] }, { "id": "PMID-21821668_E15", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 821, 829 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_E14" } ] }, { "id": "PMID-21821668_E16", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 948, 955 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T26" }, { "role": "Theme", "ref_id": "PMID-21821668_T25" } ] }, { "id": "PMID-21821668_E17", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1101, 1108 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21821668_T27" }, { "role": "Theme", "ref_id": "PMID-21821668_T28" } ] } ]

[ { "id": "PMID-21821668_1", "entity_ids": [ "PMID-21821668_T4", "PMID-21821668_T5" ] } ]

[]

[ { "id": "PMID-21859840__text", "type": "abstract", "text": [ "A novel kinase inhibitor of FADD phosphorylation chemosensitizes through the inhibition of NF-kappaB. \nFas-associated protein with death domain (FADD) is a cytosolic adapter protein essential for mediating death receptor-induced apoptosis. It has also been implicated in a number of nonapoptotic activities including embryogenesis, cell-cycle progression, cell proliferation, and tumorigenesis. Our recent studies have shown that high levels of phosphorylated FADD (p-FADD) in tumor cells correlate with increased activation of the antiapoptotic transcription factor NF-kappaB and is a biomarker for aggressive disease and poor clinical outcome. These findings suggest that inhibition of FADD phosphorylation is a viable target for cancer therapy. A high-throughput screen using a cell-based assay for monitoring FADD-kinase activity identified NSC 47147 as a small molecule inhibitor of FADD phosphorylation. The compound was evaluated in live cells and mouse tumors for its efficacy as an inhibitor of FADD-kinase activity through the inhibition of casein kinase 1alpha. NSC 47147 was shown to decrease levels of p-FADD and NF-kappaB activity such that combination therapy leads to greater induction of apoptosis and enhanced tumor control than either agent alone. The studies described here show the utility of bioluminescent cell-based assays for the identification of active compounds and the validation of drug-target interaction in a living subject. In addition, the presented results provide proof-of-principle studies as to the validity of targeting FADD-kinase activity as a novel cancer therapy strategy.\n" ], "offsets": [ [ 0, 1616 ] ] } ]

[ { "id": "PMID-21859840_T1", "type": "Gene_or_gene_product", "text": [ "FADD" ], "offsets": [ [ 28, 32 ] ], "normalized": [] }, { "id": "PMID-21859840_T2", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 91, 100 ] ], "normalized": [] }, { "id": "PMID-21859840_T3", "type": "Gene_or_gene_product", "text": [ "Fas-associated protein with death domain" ], "offsets": [ [ 103, 143 ] ], "normalized": [] }, { "id": "PMID-21859840_T4", "type": "Gene_or_gene_product", "text": [ "FADD" ], "offsets": [ [ 145, 149 ] ], "normalized": [] }, { "id": "PMID-21859840_T5", "type": "Cellular_component", "text": [ "cytosolic" ], "offsets": [ [ 156, 165 ] ], "normalized": [] }, { "id": "PMID-21859840_T6", "type": "Gene_or_gene_product", "text": [ "FADD" ], "offsets": [ [ 460, 464 ] ], "normalized": [] }, { "id": "PMID-21859840_T7", "type": "Gene_or_gene_product", "text": [ "FADD" ], "offsets": [ [ 468, 472 ] ], "normalized": [] }, { "id": "PMID-21859840_T8", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 567, 576 ] ], "normalized": [] }, { "id": "PMID-21859840_T9", "type": "Gene_or_gene_product", "text": [ "FADD" ], "offsets": [ [ 688, 692 ] ], "normalized": [] }, { "id": "PMID-21859840_T10", "type": "Gene_or_gene_product", "text": [ "FADD" ], "offsets": [ [ 813, 817 ] ], "normalized": [] }, { "id": "PMID-21859840_T11", "type": "Simple_chemical", "text": [ "NSC 47147" ], "offsets": [ [ 845, 854 ] ], "normalized": [] }, { "id": "PMID-21859840_T12", "type": "Gene_or_gene_product", "text": [ "FADD" ], "offsets": [ [ 888, 892 ] ], "normalized": [] }, { "id": "PMID-21859840_T13", "type": "Gene_or_gene_product", "text": [ "FADD" ], "offsets": [ [ 1004, 1008 ] ], "normalized": [] }, { "id": "PMID-21859840_T14", "type": "Gene_or_gene_product", "text": [ "casein kinase 1alpha" ], "offsets": [ [ 1051, 1071 ] ], "normalized": [] }, { "id": "PMID-21859840_T15", "type": "Simple_chemical", "text": [ "NSC 47147" ], "offsets": [ [ 1073, 1082 ] ], "normalized": [] }, { "id": "PMID-21859840_T16", "type": "Gene_or_gene_product", "text": [ "FADD" ], "offsets": [ [ 1117, 1121 ] ], "normalized": [] }, { "id": "PMID-21859840_T17", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1126, 1135 ] ], "normalized": [] }, { "id": "PMID-21859840_T18", "type": "Gene_or_gene_product", "text": [ "FADD" ], "offsets": [ [ 1559, 1563 ] ], "normalized": [] } ]

[ { "id": "PMID-21859840_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 15, 24 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_E2" } ] }, { "id": "PMID-21859840_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 33, 48 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_T1" } ] }, { "id": "PMID-21859840_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 77, 87 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_T2" } ] }, { "id": "PMID-21859840_E4", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 182, 191 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_E5" }, { "role": "Cause", "ref_id": "PMID-21859840_T4" } ] }, { "id": "PMID-21859840_E5", "type": "Positive_regulation", "trigger": { "text": [ "mediating" ], "offsets": [ [ 196, 205 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_E6" } ] }, { "id": "PMID-21859840_E6", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 229, 238 ] ] }, "arguments": [] }, { "id": "PMID-21859840_E7", "type": "Regulation", "trigger": { "text": [ "implicated" ], "offsets": [ [ 257, 267 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21859840_T4" }, { "role": "Theme", "ref_id": "PMID-21859840_E8" } ] }, { "id": "PMID-21859840_E8", "type": "Pathway", "trigger": { "text": [ "cell-cycle" ], "offsets": [ [ 332, 342 ] ] }, "arguments": [] }, { "id": "PMID-21859840_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 445, 459 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_T6" } ] }, { "id": "PMID-21859840_E10", "type": "Regulation", "trigger": { "text": [ "correlate" ], "offsets": [ [ 489, 498 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21859840_T7" }, { "role": "Theme", "ref_id": "PMID-21859840_E11" } ] }, { "id": "PMID-21859840_E11", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 504, 513 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_E12" } ] }, { "id": "PMID-21859840_E12", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 514, 524 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_T8" } ] }, { "id": "PMID-21859840_E13", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 674, 684 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_E14" } ] }, { "id": "PMID-21859840_E14", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 693, 708 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_T9" } ] }, { "id": "PMID-21859840_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 875, 884 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21859840_T11" }, { "role": "Theme", "ref_id": "PMID-21859840_E16" } ] }, { "id": "PMID-21859840_E16", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 893, 908 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_T12" } ] }, { "id": "PMID-21859840_E17", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1037, 1047 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_T14" } ] }, { "id": "PMID-21859840_E18", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1096, 1104 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21859840_T15" }, { "role": "Theme", "ref_id": "PMID-21859840_T16" } ] }, { "id": "PMID-21859840_E19", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 1096, 1104 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21859840_T15" }, { "role": "Theme", "ref_id": "PMID-21859840_T17" } ] }, { "id": "PMID-21859840_E20", "type": "Positive_regulation", "trigger": { "text": [ "leads" ], "offsets": [ [ 1175, 1180 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_E21" } ] }, { "id": "PMID-21859840_E21", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1192, 1201 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21859840_E22" } ] }, { "id": "PMID-21859840_E22", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1205, 1214 ] ] }, "arguments": [] } ]

[ { "id": "PMID-21859840_1", "entity_ids": [ "PMID-21859840_T3", "PMID-21859840_T4" ] }, { "id": "PMID-21859840_2", "entity_ids": [ "PMID-21859840_T6", "PMID-21859840_T7" ] } ]

[]

[ { "id": "PMID-21976665__text", "type": "abstract", "text": [ "Uncoupling of Pyrin-only protein 2 (POP2)-mediated dual regulation of NF-kappaB and the inflammasome. \nActivation of transcription factor NF-kappaB and inflammasome-directed caspase-1 cleavage of IL-1beta are key processes in the inflammatory response to pathogen or host-derived signals. Pyrin-only proteins (POPs) are restricted to Old World monkeys, apes, and humans and have previously been shown to impair inflammasome assembly and/or NF-kappaB p65 transcriptional activity in transfected epithelial cells. However, the biological role of POP2 and the molecular basis for its observed functions are not well understood. In this report we demonstrate that POP2 regulates TNFalpha and IL-1beta responses in human monocytic THP-1 cells and in stable transfectants of mouse J774A.1 macrophages. Deletion analysis of POP2 revealed that the first alpha-helix (residues 1-19) is necessary and sufficient for both inflammasome and NF-kappaB inhibitory functions. Further, key acidic residues Glu(6), Asp(8), and Glu(16), believed critical for Pyrin/Pyrin domain interaction, are important for inflammasome inhibition. Moreover, these mutations did not reduce the effect of POP2 upon NF-kappaB, indicating that the inflammasome and NF-kappaB inhibitory properties of POP2 can be uncoupled mechanistically. Collectively, these data demonstrate that POP2 acts as a regulator of inflammatory signals and exerts its two known functions through distinct modalities employed by its first alpha-helix.\n" ], "offsets": [ [ 0, 1491 ] ] } ]

[ { "id": "PMID-21976665_T1", "type": "Gene_or_gene_product", "text": [ "Pyrin-only protein 2" ], "offsets": [ [ 14, 34 ] ], "normalized": [] }, { "id": "PMID-21976665_T2", "type": "Gene_or_gene_product", "text": [ "POP2" ], "offsets": [ [ 36, 40 ] ], "normalized": [] }, { "id": "PMID-21976665_T3", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 70, 79 ] ], "normalized": [] }, { "id": "PMID-21976665_T4", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 138, 147 ] ], "normalized": [] }, { "id": "PMID-21976665_T5", "type": "Gene_or_gene_product", "text": [ "caspase-1" ], "offsets": [ [ 174, 183 ] ], "normalized": [] }, { "id": "PMID-21976665_T6", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 196, 204 ] ], "normalized": [] }, { "id": "PMID-21976665_T7", "type": "Gene_or_gene_product", "text": [ "Pyrin-only proteins" ], "offsets": [ [ 289, 308 ] ], "normalized": [] }, { "id": "PMID-21976665_T8", "type": "Gene_or_gene_product", "text": [ "POPs" ], "offsets": [ [ 310, 314 ] ], "normalized": [] }, { "id": "PMID-21976665_T9", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 440, 449 ] ], "normalized": [] }, { "id": "PMID-21976665_T10", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 450, 453 ] ], "normalized": [] }, { "id": "PMID-21976665_T11", "type": "Gene_or_gene_product", "text": [ "POP2" ], "offsets": [ [ 544, 548 ] ], "normalized": [] }, { "id": "PMID-21976665_T12", "type": "Gene_or_gene_product", "text": [ "POP2" ], "offsets": [ [ 660, 664 ] ], "normalized": [] }, { "id": "PMID-21976665_T13", "type": "Gene_or_gene_product", "text": [ "TNFalpha" ], "offsets": [ [ 675, 683 ] ], "normalized": [] }, { "id": "PMID-21976665_T14", "type": "Gene_or_gene_product", "text": [ "IL-1beta" ], "offsets": [ [ 688, 696 ] ], "normalized": [] }, { "id": "PMID-21976665_T15", "type": "Gene_or_gene_product", "text": [ "POP2" ], "offsets": [ [ 817, 821 ] ], "normalized": [] }, { "id": "PMID-21976665_T16", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 928, 937 ] ], "normalized": [] }, { "id": "PMID-21976665_T17", "type": "Simple_chemical", "text": [ "Glu(6)" ], "offsets": [ [ 989, 995 ] ], "normalized": [] }, { "id": "PMID-21976665_T18", "type": "Simple_chemical", "text": [ "Asp(8)" ], "offsets": [ [ 997, 1003 ] ], "normalized": [] }, { "id": "PMID-21976665_T19", "type": "Simple_chemical", "text": [ "Glu(16)" ], "offsets": [ [ 1009, 1016 ] ], "normalized": [] }, { "id": "PMID-21976665_T20", "type": "Gene_or_gene_product", "text": [ "Pyrin" ], "offsets": [ [ 1040, 1045 ] ], "normalized": [] }, { "id": "PMID-21976665_T21", "type": "Gene_or_gene_product", "text": [ "Pyrin" ], "offsets": [ [ 1046, 1051 ] ], "normalized": [] }, { "id": "PMID-21976665_T22", "type": "Gene_or_gene_product", "text": [ "POP2" ], "offsets": [ [ 1170, 1174 ] ], "normalized": [] }, { "id": "PMID-21976665_T23", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1180, 1189 ] ], "normalized": [] }, { "id": "PMID-21976665_T24", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1228, 1237 ] ], "normalized": [] }, { "id": "PMID-21976665_T25", "type": "Gene_or_gene_product", "text": [ "POP2" ], "offsets": [ [ 1263, 1267 ] ], "normalized": [] }, { "id": "PMID-21976665_T26", "type": "Gene_or_gene_product", "text": [ "POP2" ], "offsets": [ [ 1344, 1348 ] ], "normalized": [] } ]

[ { "id": "PMID-21976665_E1", "type": "Regulation", "trigger": { "text": [ "Uncoupling" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21976665_E3" } ] }, { "id": "PMID-21976665_E2", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 42, 50 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21976665_T1" }, { "role": "Theme", "ref_id": "PMID-21976665_E3" } ] }, { "id": "PMID-21976665_E3", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 56, 66 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21976665_T3" } ] }, { "id": "PMID-21976665_E4", "type": "Activation", "trigger": { "text": [ "Activation" ], "offsets": [ [ 103, 113 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21976665_T4" } ] }, { "id": "PMID-21976665_E5", "type": "Dissociation", "trigger": { "text": [ "cleavage" ], "offsets": [ [ 184, 192 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-21976665_T5" } ] }, { "id": "PMID-21976665_E6", "type": "Negative_regulation", "trigger": { "text": [ "impair" ], "offsets": [ [ 404, 410 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21976665_T10" }, { "role": "Cause", "ref_id": "PMID-21976665_T7" } ] }, { "id": "PMID-21976665_E7", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 665, 674 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21976665_T12" }, { "role": "Theme", "ref_id": "PMID-21976665_E9" } ] }, { "id": "PMID-21976665_E8", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 665, 674 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21976665_T12" }, { "role": "Theme", "ref_id": "PMID-21976665_E10" } ] }, { "id": "PMID-21976665_E9", "type": "Positive_regulation", "trigger": { "text": [ "responses" ], "offsets": [ [ 697, 706 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21976665_T13" } ] }, { "id": "PMID-21976665_E10", "type": "Positive_regulation", "trigger": { "text": [ "responses" ], "offsets": [ [ 697, 706 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21976665_T14" } ] }, { "id": "PMID-21976665_E11", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 877, 886 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21976665_T15" }, { "role": "Theme", "ref_id": "PMID-21976665_E12" } ] }, { "id": "PMID-21976665_E12", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 938, 948 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21976665_T16" } ] }, { "id": "PMID-21976665_E13", "type": "Positive_regulation", "trigger": { "text": [ "critical" ], "offsets": [ [ 1027, 1035 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21976665_T15" }, { "role": "Theme", "ref_id": "PMID-21976665_E14" } ] }, { "id": "PMID-21976665_E14", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1059, 1070 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21976665_T20" }, { "role": "Theme", "ref_id": "PMID-21976665_T21" } ] }, { "id": "PMID-21976665_E15", "type": "Negative_regulation", "trigger": { "text": [ "reduce" ], "offsets": [ [ 1149, 1155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21976665_E16" } ] }, { "id": "PMID-21976665_E16", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1160, 1166 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21976665_T22" } ] }, { "id": "PMID-21976665_E17", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 1238, 1248 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21976665_T24" }, { "role": "Theme", "ref_id": "PMID-21976665_T25" } ] }, { "id": "PMID-21976665_E18", "type": "Regulation", "trigger": { "text": [ "uncoupled" ], "offsets": [ [ 1275, 1284 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21976665_E17" } ] } ]

[ { "id": "PMID-21976665_1", "entity_ids": [ "PMID-21976665_T1", "PMID-21976665_T2" ] }, { "id": "PMID-21976665_2", "entity_ids": [ "PMID-21976665_T8", "PMID-21976665_T7" ] } ]

[]

[ { "id": "PMID-21983831__text", "type": "abstract", "text": [ "The kinase GLK controls autoimmunity and NF-kappaB signaling by activating the kinase PKC-theta in T cells. \nProtein kinase C-theta (PKC-theta) is required for activation of the transcription factor NF-kappaB induced by signaling via the T cell antigen receptor (TCR); however, the direct activator of PKC-theta is unknown. We report that the kinase GLK (MAP4K3) directly activated PKC-theta during TCR signaling. TCR signaling activated GLK by inducing its direct interaction with the upstream adaptor SLP-76. GLK-deficient mice had impaired immune responses and were resistant to experimental autoimmune encephalomyelitis. Consistent with that, people with systemic lupus erythematosus had considerable enhanced GLK expression and activation of PKC-theta and the kinase IKK in T cells, and the frequency of GLK-overexpressing T cells was directly correlated with disease severity. Thus, GLK is a direct activator of PKC-theta, and activation of GLK-PKC-theta-IKK could be used as new diagnostic biomarkers and therapeutic targets for systemic lupus erythematosus.\n" ], "offsets": [ [ 0, 1066 ] ] } ]

[ { "id": "PMID-21983831_T1", "type": "Gene_or_gene_product", "text": [ "GLK" ], "offsets": [ [ 11, 14 ] ], "normalized": [] }, { "id": "PMID-21983831_T2", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 41, 50 ] ], "normalized": [] }, { "id": "PMID-21983831_T3", "type": "Gene_or_gene_product", "text": [ "PKC-theta" ], "offsets": [ [ 86, 95 ] ], "normalized": [] }, { "id": "PMID-21983831_T4", "type": "Gene_or_gene_product", "text": [ "Protein kinase C-theta" ], "offsets": [ [ 109, 131 ] ], "normalized": [] }, { "id": "PMID-21983831_T5", "type": "Gene_or_gene_product", "text": [ "PKC-theta" ], "offsets": [ [ 133, 142 ] ], "normalized": [] }, { "id": "PMID-21983831_T6", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 199, 208 ] ], "normalized": [] }, { "id": "PMID-21983831_T7", "type": "Complex", "text": [ "T cell antigen receptor" ], "offsets": [ [ 238, 261 ] ], "normalized": [] }, { "id": "PMID-21983831_T8", "type": "Complex", "text": [ "TCR" ], "offsets": [ [ 263, 266 ] ], "normalized": [] }, { "id": "PMID-21983831_T9", "type": "Gene_or_gene_product", "text": [ "PKC-theta" ], "offsets": [ [ 302, 311 ] ], "normalized": [] }, { "id": "PMID-21983831_T10", "type": "Gene_or_gene_product", "text": [ "GLK" ], "offsets": [ [ 350, 353 ] ], "normalized": [] }, { "id": "PMID-21983831_T11", "type": "Gene_or_gene_product", "text": [ "MAP4K3" ], "offsets": [ [ 355, 361 ] ], "normalized": [] }, { "id": "PMID-21983831_T12", "type": "Gene_or_gene_product", "text": [ "PKC-theta" ], "offsets": [ [ 382, 391 ] ], "normalized": [] }, { "id": "PMID-21983831_T13", "type": "Complex", "text": [ "TCR" ], "offsets": [ [ 399, 402 ] ], "normalized": [] }, { "id": "PMID-21983831_T14", "type": "Complex", "text": [ "TCR" ], "offsets": [ [ 414, 417 ] ], "normalized": [] }, { "id": "PMID-21983831_T15", "type": "Gene_or_gene_product", "text": [ "GLK" ], "offsets": [ [ 438, 441 ] ], "normalized": [] }, { "id": "PMID-21983831_T16", "type": "Gene_or_gene_product", "text": [ "SLP-76" ], "offsets": [ [ 503, 509 ] ], "normalized": [] }, { "id": "PMID-21983831_T17", "type": "Gene_or_gene_product", "text": [ "GLK" ], "offsets": [ [ 511, 514 ] ], "normalized": [] }, { "id": "PMID-21983831_T18", "type": "Gene_or_gene_product", "text": [ "GLK" ], "offsets": [ [ 714, 717 ] ], "normalized": [] }, { "id": "PMID-21983831_T19", "type": "Gene_or_gene_product", "text": [ "PKC-theta" ], "offsets": [ [ 747, 756 ] ], "normalized": [] }, { "id": "PMID-21983831_T20", "type": "Complex", "text": [ "IKK" ], "offsets": [ [ 772, 775 ] ], "normalized": [] }, { "id": "PMID-21983831_T21", "type": "Gene_or_gene_product", "text": [ "GLK" ], "offsets": [ [ 809, 812 ] ], "normalized": [] }, { "id": "PMID-21983831_T22", "type": "Gene_or_gene_product", "text": [ "GLK" ], "offsets": [ [ 889, 892 ] ], "normalized": [] }, { "id": "PMID-21983831_T23", "type": "Gene_or_gene_product", "text": [ "PKC-theta" ], "offsets": [ [ 918, 927 ] ], "normalized": [] }, { "id": "PMID-21983831_T24", "type": "Gene_or_gene_product", "text": [ "GLK" ], "offsets": [ [ 947, 950 ] ], "normalized": [] }, { "id": "PMID-21983831_T25", "type": "Gene_or_gene_product", "text": [ "PKC-theta" ], "offsets": [ [ 951, 960 ] ], "normalized": [] }, { "id": "PMID-21983831_T26", "type": "Complex", "text": [ "IKK" ], "offsets": [ [ 961, 964 ] ], "normalized": [] } ]

[ { "id": "PMID-21983831_E1", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 15, 23 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_E2" }, { "role": "Cause", "ref_id": "PMID-21983831_E3" } ] }, { "id": "PMID-21983831_E2", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 51, 60 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21983831_T2" } ] }, { "id": "PMID-21983831_E3", "type": "Activation", "trigger": { "text": [ "activating" ], "offsets": [ [ 64, 74 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_T3" }, { "role": "Cause", "ref_id": "PMID-21983831_T1" } ] }, { "id": "PMID-21983831_E4", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 147, 155 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21983831_T4" }, { "role": "Theme", "ref_id": "PMID-21983831_E5" } ] }, { "id": "PMID-21983831_E5", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 160, 170 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_T6" } ] }, { "id": "PMID-21983831_E6", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 209, 216 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_T6" }, { "role": "Cause", "ref_id": "PMID-21983831_T7" } ] }, { "id": "PMID-21983831_E7", "type": "Activation", "trigger": { "text": [ "activator" ], "offsets": [ [ 289, 298 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_T9" } ] }, { "id": "PMID-21983831_E8", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 372, 381 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_T12" }, { "role": "Cause", "ref_id": "PMID-21983831_T10" } ] }, { "id": "PMID-21983831_E9", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 403, 412 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21983831_T13" } ] }, { "id": "PMID-21983831_E10", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 418, 427 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-21983831_T14" } ] }, { "id": "PMID-21983831_E11", "type": "Activation", "trigger": { "text": [ "v" ], "offsets": [ [ 432, 433 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21983831_E12" }, { "role": "Theme", "ref_id": "PMID-21983831_T15" } ] }, { "id": "PMID-21983831_E12", "type": "Positive_regulation", "trigger": { "text": [ "inducing" ], "offsets": [ [ 445, 453 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21983831_E10" }, { "role": "Theme", "ref_id": "PMID-21983831_E13" } ] }, { "id": "PMID-21983831_E13", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 465, 476 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_T16" }, { "role": "Theme", "ref_id": "PMID-21983831_T15" } ] }, { "id": "PMID-21983831_E14", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 705, 713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_E17" } ] }, { "id": "PMID-21983831_E15", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 705, 713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_E18" } ] }, { "id": "PMID-21983831_E16", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 705, 713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_E19" } ] }, { "id": "PMID-21983831_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 718, 728 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_T18" } ] }, { "id": "PMID-21983831_E18", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 733, 743 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_T19" } ] }, { "id": "PMID-21983831_E19", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 733, 743 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_T20" } ] }, { "id": "PMID-21983831_E20", "type": "Gene_expression", "trigger": { "text": [ "overexpressing" ], "offsets": [ [ 813, 827 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_T21" } ] }, { "id": "PMID-21983831_E21", "type": "Activation", "trigger": { "text": [ "activator" ], "offsets": [ [ 905, 914 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-21983831_T23" }, { "role": "Cause", "ref_id": "PMID-21983831_T22" } ] }, { "id": "PMID-21983831_E22", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 933, 943 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21983831_T22" }, { "role": "Theme", "ref_id": "PMID-21983831_T24" } ] }, { "id": "PMID-21983831_E23", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 933, 943 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21983831_T22" }, { "role": "Theme", "ref_id": "PMID-21983831_T25" } ] }, { "id": "PMID-21983831_E24", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 933, 943 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-21983831_T22" }, { "role": "Theme", "ref_id": "PMID-21983831_T26" } ] } ]

[ { "id": "PMID-21983831_1", "entity_ids": [ "PMID-21983831_T4", "PMID-21983831_T5" ] }, { "id": "PMID-21983831_2", "entity_ids": [ "PMID-21983831_T7", "PMID-21983831_T8" ] }, { "id": "PMID-21983831_3", "entity_ids": [ "PMID-21983831_T10", "PMID-21983831_T11" ] } ]

[]

[ { "id": "PMID-22001530__text", "type": "abstract", "text": [ "PPARgamma and NF-kappaB regulate the gene promoter activity of their shared repressor, TNIP1. \nHuman TNFAIP3 interacting protein 1 (TNIP1) has diverse functions including support of HIV replication through its interaction with viral Nef and matrix proteins, reduction of TNFalpha-induced signaling through its interaction with NF-kappaB pathway proteins, and corepression of agonist-bound retinoic acid receptors and peroxisome proliferator-activated receptors (PPAR). The wide tissue distribution of TNIP1 provides the opportunity to influence numerous cellular responses in these roles and defining control of TNIP1 expression would be central to improved understanding of its impact on cell function. We cloned 6kb of the human TNIP1 promoter and performed predictive and functional analyses to identify regulatory elements. The promoter region proximal to the transcription start site is GC-rich without a recognizable TATA box. In contrast to this proximal ~500bp region, 6kb of the promoter increased reporter construct constitutive activity over five-fold. Throughout the 6kb length, in silico analysis identified several potential binding sites for both constitutive and inducible transcription factors; among the latter were candidate NF-kappaB binding sequences and peroxisome proliferator response elements (PPREs). We tested NF-kappaB and PPAR regulation of the endogenous TNIP1 gene and cloned promoter by expression studies, electrophoretic mobility shift assays, and chromatin immunoprecipitations. We validated NF-kappaB sites in the TNIP1 promoter proximal and distal regions as well as one PPRE in the distal region. The ultimate control of the TNIP1 promoter is likely to be a combination of constitutive transcription factors and those subject to activation such as NF-kappaB and PPAR.\n" ], "offsets": [ [ 0, 1806 ] ] } ]

[ { "id": "PMID-22001530_T1", "type": "Gene_or_gene_product", "text": [ "PPARgamma" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "PMID-22001530_T2", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 14, 23 ] ], "normalized": [] }, { "id": "PMID-22001530_T3", "type": "Gene_or_gene_product", "text": [ "TNIP1" ], "offsets": [ [ 87, 92 ] ], "normalized": [] }, { "id": "PMID-22001530_T4", "type": "Gene_or_gene_product", "text": [ "TNFAIP3 interacting protein 1" ], "offsets": [ [ 101, 130 ] ], "normalized": [] }, { "id": "PMID-22001530_T5", "type": "Gene_or_gene_product", "text": [ "TNIP1" ], "offsets": [ [ 132, 137 ] ], "normalized": [] }, { "id": "PMID-22001530_T6", "type": "Gene_or_gene_product", "text": [ "Nef" ], "offsets": [ [ 233, 236 ] ], "normalized": [] }, { "id": "PMID-22001530_T7", "type": "Cellular_component", "text": [ "matrix" ], "offsets": [ [ 241, 247 ] ], "normalized": [] }, { "id": "PMID-22001530_T8", "type": "Gene_or_gene_product", "text": [ "TNFalpha" ], "offsets": [ [ 271, 279 ] ], "normalized": [] }, { "id": "PMID-22001530_T9", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 327, 336 ] ], "normalized": [] }, { "id": "PMID-22001530_T10", "type": "Gene_or_gene_product", "text": [ "retinoic acid receptors" ], "offsets": [ [ 389, 412 ] ], "normalized": [] }, { "id": "PMID-22001530_T11", "type": "Gene_or_gene_product", "text": [ "peroxisome proliferator-activated receptors" ], "offsets": [ [ 417, 460 ] ], "normalized": [] }, { "id": "PMID-22001530_T12", "type": "Gene_or_gene_product", "text": [ "PPAR" ], "offsets": [ [ 462, 466 ] ], "normalized": [] }, { "id": "PMID-22001530_T13", "type": "Gene_or_gene_product", "text": [ "TNIP1" ], "offsets": [ [ 501, 506 ] ], "normalized": [] }, { "id": "PMID-22001530_T14", "type": "Gene_or_gene_product", "text": [ "TNIP1" ], "offsets": [ [ 612, 617 ] ], "normalized": [] }, { "id": "PMID-22001530_T15", "type": "Gene_or_gene_product", "text": [ "TNIP1" ], "offsets": [ [ 731, 736 ] ], "normalized": [] }, { "id": "PMID-22001530_T16", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1244, 1253 ] ], "normalized": [] }, { "id": "PMID-22001530_T17", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1337, 1346 ] ], "normalized": [] }, { "id": "PMID-22001530_T18", "type": "Gene_or_gene_product", "text": [ "PPAR" ], "offsets": [ [ 1351, 1355 ] ], "normalized": [] }, { "id": "PMID-22001530_T19", "type": "Gene_or_gene_product", "text": [ "TNIP1" ], "offsets": [ [ 1385, 1390 ] ], "normalized": [] }, { "id": "PMID-22001530_T20", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 1482, 1491 ] ], "normalized": [] }, { "id": "PMID-22001530_T21", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1527, 1536 ] ], "normalized": [] }, { "id": "PMID-22001530_T22", "type": "Gene_or_gene_product", "text": [ "TNIP1" ], "offsets": [ [ 1550, 1555 ] ], "normalized": [] }, { "id": "PMID-22001530_T23", "type": "Gene_or_gene_product", "text": [ "TNIP1" ], "offsets": [ [ 1663, 1668 ] ], "normalized": [] }, { "id": "PMID-22001530_T24", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1786, 1795 ] ], "normalized": [] }, { "id": "PMID-22001530_T25", "type": "Gene_or_gene_product", "text": [ "PPAR" ], "offsets": [ [ 1800, 1804 ] ], "normalized": [] } ]

[ { "id": "PMID-22001530_E1", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 24, 32 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_E3" }, { "role": "Cause", "ref_id": "PMID-22001530_T1" } ] }, { "id": "PMID-22001530_E2", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 24, 32 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_E3" }, { "role": "Cause", "ref_id": "PMID-22001530_T2" } ] }, { "id": "PMID-22001530_E3", "type": "Negative_regulation", "trigger": { "text": [ "repressor" ], "offsets": [ [ 76, 85 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_T3" } ] }, { "id": "PMID-22001530_E4", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 210, 221 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_T6" }, { "role": "Theme", "ref_id": "PMID-22001530_T4" } ] }, { "id": "PMID-22001530_E5", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 258, 267 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_T8" }, { "role": "Cause", "ref_id": "PMID-22001530_E7" } ] }, { "id": "PMID-22001530_E6", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 310, 321 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_T9" }, { "role": "Theme", "ref_id": "PMID-22001530_T4" } ] }, { "id": "PMID-22001530_E7", "type": "Positive_regulation", "trigger": { "text": [ "interaction" ], "offsets": [ [ 310, 321 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_E6" }, { "role": "Cause", "ref_id": "PMID-22001530_T4" } ] }, { "id": "PMID-22001530_E8", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 337, 344 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22001530_T9" } ] }, { "id": "PMID-22001530_E9", "type": "Negative_regulation", "trigger": { "text": [ "corepression" ], "offsets": [ [ 359, 371 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22001530_T4" }, { "role": "Theme", "ref_id": "PMID-22001530_T10" } ] }, { "id": "PMID-22001530_E10", "type": "Negative_regulation", "trigger": { "text": [ "corepression" ], "offsets": [ [ 359, 371 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22001530_T4" }, { "role": "Theme", "ref_id": "PMID-22001530_T11" } ] }, { "id": "PMID-22001530_E11", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 601, 608 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_E12" } ] }, { "id": "PMID-22001530_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 618, 628 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_T14" } ] }, { "id": "PMID-22001530_E13", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1356, 1366 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22001530_T19" }, { "role": "Theme", "ref_id": "PMID-22001530_T17" } ] }, { "id": "PMID-22001530_E14", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1356, 1366 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22001530_T19" }, { "role": "Theme", "ref_id": "PMID-22001530_T18" } ] }, { "id": "PMID-22001530_E15", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 1648, 1655 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_T23" } ] }, { "id": "PMID-22001530_E16", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1767, 1777 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_T24" } ] }, { "id": "PMID-22001530_E17", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1767, 1777 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22001530_T25" } ] } ]

[ { "id": "PMID-22001530_1", "entity_ids": [ "PMID-22001530_T4", "PMID-22001530_T5" ] }, { "id": "PMID-22001530_2", "entity_ids": [ "PMID-22001530_T11", "PMID-22001530_T12" ] } ]

[]

[ { "id": "PMID-22021368__text", "type": "abstract", "text": [ "AML1/RUNX1 functions as a cytoplasmic attenuator of NF-kappaB signaling in the repression of myeloid tumors. \nFunctional deregulation of transcription factors has been found in many types of tumors. Transcription factor AML1/RUNX1 is one of the most frequent targets of chromosomal abnormalities in human leukemia and altered function of AML1 is closely associated with malignant transformation of hematopoietic cells. However, the molecular basis and therapeutic targets of AML1-related leukemia are still elusive. Here, we explored immediate target pathways of AML1 by in vitro synchronous inactivation in hematopoietic cells. We found that AML1 inhibits NF-kappaB signaling through interaction with IkappaB kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-kappaB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-kappaB signaling. Furthermore, inhibition of NF-kappaB signaling in leukemic cells with mutated AML1 efficiently blocks their growth and development of leukemia. These findings reveal a novel role for AML1 as a cytoplasmic attenuator of NF-kappaB signaling and indicate that NF-kappaB signaling is one of the promising therapeutic targets of hematologic malignancies with AML1 abnormality.\n" ], "offsets": [ [ 0, 1307 ] ] } ]

[ { "id": "PMID-22021368_T1", "type": "Gene_or_gene_product", "text": [ "AML1" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "PMID-22021368_T2", "type": "Gene_or_gene_product", "text": [ "RUNX1" ], "offsets": [ [ 5, 10 ] ], "normalized": [] }, { "id": "PMID-22021368_T3", "type": "Cellular_component", "text": [ "cytoplasmic" ], "offsets": [ [ 26, 37 ] ], "normalized": [] }, { "id": "PMID-22021368_T4", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 52, 61 ] ], "normalized": [] }, { "id": "PMID-22021368_T5", "type": "Gene_or_gene_product", "text": [ "AML1" ], "offsets": [ [ 220, 224 ] ], "normalized": [] }, { "id": "PMID-22021368_T6", "type": "Gene_or_gene_product", "text": [ "RUNX1" ], "offsets": [ [ 225, 230 ] ], "normalized": [] }, { "id": "PMID-22021368_T7", "type": "Cellular_component", "text": [ "chromosomal" ], "offsets": [ [ 270, 281 ] ], "normalized": [] }, { "id": "PMID-22021368_T8", "type": "Gene_or_gene_product", "text": [ "AML1" ], "offsets": [ [ 338, 342 ] ], "normalized": [] }, { "id": "PMID-22021368_T9", "type": "Gene_or_gene_product", "text": [ "AML1" ], "offsets": [ [ 475, 479 ] ], "normalized": [] }, { "id": "PMID-22021368_T10", "type": "Gene_or_gene_product", "text": [ "AML1" ], "offsets": [ [ 563, 567 ] ], "normalized": [] }, { "id": "PMID-22021368_T11", "type": "Gene_or_gene_product", "text": [ "AML1" ], "offsets": [ [ 643, 647 ] ], "normalized": [] }, { "id": "PMID-22021368_T12", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 657, 666 ] ], "normalized": [] }, { "id": "PMID-22021368_T13", "type": "Complex", "text": [ "IkappaB kinase" ], "offsets": [ [ 702, 716 ] ], "normalized": [] }, { "id": "PMID-22021368_T14", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 732, 741 ] ], "normalized": [] }, { "id": "PMID-22021368_T15", "type": "Gene_or_gene_product", "text": [ "AML1" ], "offsets": [ [ 755, 759 ] ], "normalized": [] }, { "id": "PMID-22021368_T16", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 820, 829 ] ], "normalized": [] }, { "id": "PMID-22021368_T17", "type": "Gene_or_gene_product", "text": [ "AML1" ], "offsets": [ [ 862, 866 ] ], "normalized": [] }, { "id": "PMID-22021368_T18", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 914, 923 ] ], "normalized": [] }, { "id": "PMID-22021368_T19", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 962, 971 ] ], "normalized": [] }, { "id": "PMID-22021368_T20", "type": "Gene_or_gene_product", "text": [ "AML1" ], "offsets": [ [ 1013, 1017 ] ], "normalized": [] }, { "id": "PMID-22021368_T21", "type": "Gene_or_gene_product", "text": [ "AML1" ], "offsets": [ [ 1118, 1122 ] ], "normalized": [] }, { "id": "PMID-22021368_T22", "type": "Cellular_component", "text": [ "cytoplasmic" ], "offsets": [ [ 1128, 1139 ] ], "normalized": [] }, { "id": "PMID-22021368_T23", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1154, 1163 ] ], "normalized": [] }, { "id": "PMID-22021368_T24", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1192, 1201 ] ], "normalized": [] }, { "id": "PMID-22021368_T25", "type": "Gene_or_gene_product", "text": [ "AML1" ], "offsets": [ [ 1289, 1293 ] ], "normalized": [] } ]

[ { "id": "PMID-22021368_E1", "type": "Negative_regulation", "trigger": { "text": [ "attenuator" ], "offsets": [ [ 38, 48 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22021368_E2" }, { "role": "Cause", "ref_id": "PMID-22021368_T1" } ] }, { "id": "PMID-22021368_E2", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 62, 71 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22021368_T4" } ] }, { "id": "PMID-22021368_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 648, 656 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22021368_E4" }, { "role": "Cause", "ref_id": "PMID-22021368_E5" } ] }, { "id": "PMID-22021368_E4", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 667, 676 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22021368_T12" } ] }, { "id": "PMID-22021368_E5", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 685, 696 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22021368_T13" }, { "role": "Theme", "ref_id": "PMID-22021368_T11" } ] }, { "id": "PMID-22021368_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 812, 819 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22021368_E7" } ] }, { "id": "PMID-22021368_E7", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 830, 839 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22021368_T16" } ] }, { "id": "PMID-22021368_E8", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 904, 913 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22021368_E9" } ] }, { "id": "PMID-22021368_E9", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 924, 933 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22021368_T18" } ] }, { "id": "PMID-22021368_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 948, 958 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22021368_E11" } ] }, { "id": "PMID-22021368_E11", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 972, 981 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22021368_T19" } ] }, { "id": "PMID-22021368_E12", "type": "Negative_regulation", "trigger": { "text": [ "attenuator" ], "offsets": [ [ 1140, 1150 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22021368_E13" }, { "role": "Cause", "ref_id": "PMID-22021368_T21" } ] }, { "id": "PMID-22021368_E13", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1164, 1173 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22021368_T23" } ] }, { "id": "PMID-22021368_E14", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1202, 1211 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22021368_T24" } ] } ]

[ { "id": "PMID-22021368_1", "entity_ids": [ "PMID-22021368_T1", "PMID-22021368_T2" ] }, { "id": "PMID-22021368_2", "entity_ids": [ "PMID-22021368_T5", "PMID-22021368_T6" ] } ]

[]

[ { "id": "PMID-22065579__text", "type": "abstract", "text": [ "Formation of ternary complex of human biliverdin reductase-protein kinase Cdelta-ERK2 protein is essential for ERK2-mediated activation of Elk1 protein, nuclear factor-kappaB, and inducible nitric-oxidase synthase (iNOS). \nGrowth factors, insulin, oxidative stress, and cytokines activate ERK1/2 by PKCdelta and MEK1/2. Human biliverdin reductase (hBVR), a Ser/Thr/Tyr kinase and intracellular scaffold/bridge/anchor, is a nuclear transporter of MEK1/2-stimulated ERK1/2 (Lerner-Marmarosh, N., Miralem, T., Gibbs, P. E., and Maines, M. D. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 6870-6875). hBVR, PKCdelta, and MEK1/2 overlap in their tissue expression profile and type of activators. Presently, we report on formation of an hBVR-PKCdelta-ERK2 ternary complex that is essential for ERK2 signal transduction and activation of genes linked to cell proliferation and cancer. MEK1/2 and the protein phosphatase PP2A were also present in the complex. When cells were stimulated with insulin-like growth factor-1 (IGF-1), an increased interaction between hBVR and PKCdelta was detected by FRET-fluorescence lifetime imaging microscopy. hBVR and ERK2 were phosphorylated by PKCdelta; however, the PKC was not a substrate for either ERK2 or hBVR. IGF-1 and phorbol ester increased hBVR/PKCdelta binding; hBVR was required for the activation of PKCdelta and its interaction with ERK2. The C-terminal phenylalanine residues of PKCdelta (Phe(660), Phe(663), and Phe(665)) were necessary for binding to ERK2 but not for hBVR binding. Formation of the hBVR-PKCdelta-ERK2 complex required the hBVR docking site for ERK, FXFP (DEF, C-box) and D(delta)-box (ILXXLXL) motifs. The hBVR-based peptide KKRILHCLGLA inhibited PKC activation and PKCdelta/ERK2 interaction. Phorbol ester- and TNF-alpha-dependent activation of the ERK-regulated transcription factors Elk1 and NF-kappaB and expression of the iNOS gene were suppressed by hBVR siRNA; those activities were rescued by hBVR. The findings reveal the direct input of hBVR in PKCdelta/ERK signaling and identify hBVR-based peptide regulators of ERK-mediated gene activation.\n" ], "offsets": [ [ 0, 2113 ] ] } ]

[ { "id": "PMID-22065579_T1", "type": "Gene_or_gene_product", "text": [ "biliverdin reductase" ], "offsets": [ [ 38, 58 ] ], "normalized": [] }, { "id": "PMID-22065579_T2", "type": "Gene_or_gene_product", "text": [ "protein kinase Cdelta" ], "offsets": [ [ 59, 80 ] ], "normalized": [] }, { "id": "PMID-22065579_T3", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 81, 85 ] ], "normalized": [] }, { "id": "PMID-22065579_T4", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 111, 115 ] ], "normalized": [] }, { "id": "PMID-22065579_T5", "type": "Gene_or_gene_product", "text": [ "Elk1" ], "offsets": [ [ 139, 143 ] ], "normalized": [] }, { "id": "PMID-22065579_T6", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 153, 174 ] ], "normalized": [] }, { "id": "PMID-22065579_T7", "type": "Gene_or_gene_product", "text": [ "nitric-oxidase synthase" ], "offsets": [ [ 190, 213 ] ], "normalized": [] }, { "id": "PMID-22065579_T8", "type": "Gene_or_gene_product", "text": [ "iNOS" ], "offsets": [ [ 215, 219 ] ], "normalized": [] }, { "id": "PMID-22065579_T9", "type": "Gene_or_gene_product", "text": [ "insulin" ], "offsets": [ [ 239, 246 ] ], "normalized": [] }, { "id": "PMID-22065579_T10", "type": "Gene_or_gene_product", "text": [ "ERK1/2" ], "offsets": [ [ 289, 295 ] ], "normalized": [] }, { "id": "PMID-22065579_T11", "type": "Gene_or_gene_product", "text": [ "PKCdelta" ], "offsets": [ [ 299, 307 ] ], "normalized": [] }, { "id": "PMID-22065579_T12", "type": "Gene_or_gene_product", "text": [ "MEK1/2" ], "offsets": [ [ 312, 318 ] ], "normalized": [] }, { "id": "PMID-22065579_T13", "type": "Gene_or_gene_product", "text": [ "biliverdin reductase" ], "offsets": [ [ 326, 346 ] ], "normalized": [] }, { "id": "PMID-22065579_T14", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 348, 352 ] ], "normalized": [] }, { "id": "PMID-22065579_T15", "type": "Simple_chemical", "text": [ "Ser" ], "offsets": [ [ 357, 360 ] ], "normalized": [] }, { "id": "PMID-22065579_T16", "type": "Simple_chemical", "text": [ "Thr" ], "offsets": [ [ 361, 364 ] ], "normalized": [] }, { "id": "PMID-22065579_T17", "type": "Simple_chemical", "text": [ "Tyr" ], "offsets": [ [ 365, 368 ] ], "normalized": [] }, { "id": "PMID-22065579_T18", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 380, 393 ] ], "normalized": [] }, { "id": "PMID-22065579_T19", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 423, 430 ] ], "normalized": [] }, { "id": "PMID-22065579_T20", "type": "Gene_or_gene_product", "text": [ "MEK1/2" ], "offsets": [ [ 446, 452 ] ], "normalized": [] }, { "id": "PMID-22065579_T21", "type": "Gene_or_gene_product", "text": [ "ERK1/2" ], "offsets": [ [ 464, 470 ] ], "normalized": [] }, { "id": "PMID-22065579_T22", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 593, 597 ] ], "normalized": [] }, { "id": "PMID-22065579_T23", "type": "Gene_or_gene_product", "text": [ "PKCdelta" ], "offsets": [ [ 599, 607 ] ], "normalized": [] }, { "id": "PMID-22065579_T24", "type": "Gene_or_gene_product", "text": [ "MEK1/2" ], "offsets": [ [ 613, 619 ] ], "normalized": [] }, { "id": "PMID-22065579_T25", "type": "Complex", "text": [ "hBVR-PKCdelta-ERK2" ], "offsets": [ [ 727, 745 ] ], "normalized": [] }, { "id": "PMID-22065579_T26", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 784, 788 ] ], "normalized": [] }, { "id": "PMID-22065579_T27", "type": "Gene_or_gene_product", "text": [ "MEK1/2" ], "offsets": [ [ 874, 880 ] ], "normalized": [] }, { "id": "PMID-22065579_T28", "type": "Gene_or_gene_product", "text": [ "PP2A" ], "offsets": [ [ 909, 913 ] ], "normalized": [] }, { "id": "PMID-22065579_T29", "type": "Gene_or_gene_product", "text": [ "insulin-like growth factor-1" ], "offsets": [ [ 980, 1008 ] ], "normalized": [] }, { "id": "PMID-22065579_T30", "type": "Gene_or_gene_product", "text": [ "IGF-1" ], "offsets": [ [ 1010, 1015 ] ], "normalized": [] }, { "id": "PMID-22065579_T31", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 1051, 1055 ] ], "normalized": [] }, { "id": "PMID-22065579_T32", "type": "Gene_or_gene_product", "text": [ "PKCdelta" ], "offsets": [ [ 1060, 1068 ] ], "normalized": [] }, { "id": "PMID-22065579_T33", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 1132, 1136 ] ], "normalized": [] }, { "id": "PMID-22065579_T34", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 1141, 1145 ] ], "normalized": [] }, { "id": "PMID-22065579_T35", "type": "Gene_or_gene_product", "text": [ "PKCdelta" ], "offsets": [ [ 1169, 1177 ] ], "normalized": [] }, { "id": "PMID-22065579_T36", "type": "Gene_or_gene_product", "text": [ "PKC" ], "offsets": [ [ 1192, 1195 ] ], "normalized": [] }, { "id": "PMID-22065579_T37", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 1227, 1231 ] ], "normalized": [] }, { "id": "PMID-22065579_T38", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 1235, 1239 ] ], "normalized": [] }, { "id": "PMID-22065579_T39", "type": "Gene_or_gene_product", "text": [ "IGF-1" ], "offsets": [ [ 1241, 1246 ] ], "normalized": [] }, { "id": "PMID-22065579_T40", "type": "Simple_chemical", "text": [ "phorbol ester" ], "offsets": [ [ 1251, 1264 ] ], "normalized": [] }, { "id": "PMID-22065579_T41", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 1275, 1279 ] ], "normalized": [] }, { "id": "PMID-22065579_T42", "type": "Gene_or_gene_product", "text": [ "PKCdelta" ], "offsets": [ [ 1280, 1288 ] ], "normalized": [] }, { "id": "PMID-22065579_T43", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 1298, 1302 ] ], "normalized": [] }, { "id": "PMID-22065579_T44", "type": "Gene_or_gene_product", "text": [ "PKCdelta" ], "offsets": [ [ 1338, 1346 ] ], "normalized": [] }, { "id": "PMID-22065579_T45", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 1372, 1376 ] ], "normalized": [] }, { "id": "PMID-22065579_T46", "type": "Gene_or_gene_product", "text": [ "PKCdelta" ], "offsets": [ [ 1419, 1427 ] ], "normalized": [] }, { "id": "PMID-22065579_T47", "type": "Simple_chemical", "text": [ "Phe(660)" ], "offsets": [ [ 1429, 1437 ] ], "normalized": [] }, { "id": "PMID-22065579_T48", "type": "Simple_chemical", "text": [ "Phe(663)" ], "offsets": [ [ 1439, 1447 ] ], "normalized": [] }, { "id": "PMID-22065579_T49", "type": "Simple_chemical", "text": [ "Phe(665)" ], "offsets": [ [ 1453, 1461 ] ], "normalized": [] }, { "id": "PMID-22065579_T50", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 1493, 1497 ] ], "normalized": [] }, { "id": "PMID-22065579_T51", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 1510, 1514 ] ], "normalized": [] }, { "id": "PMID-22065579_T52", "type": "Complex", "text": [ "hBVR-PKCdelta-ERK2" ], "offsets": [ [ 1541, 1559 ] ], "normalized": [] }, { "id": "PMID-22065579_T53", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 1581, 1585 ] ], "normalized": [] }, { "id": "PMID-22065579_T54", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 1603, 1606 ] ], "normalized": [] }, { "id": "PMID-22065579_T55", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 1665, 1669 ] ], "normalized": [] }, { "id": "PMID-22065579_T56", "type": "Gene_or_gene_product", "text": [ "PKC" ], "offsets": [ [ 1706, 1709 ] ], "normalized": [] }, { "id": "PMID-22065579_T57", "type": "Gene_or_gene_product", "text": [ "PKCdelta" ], "offsets": [ [ 1725, 1733 ] ], "normalized": [] }, { "id": "PMID-22065579_T58", "type": "Gene_or_gene_product", "text": [ "ERK2" ], "offsets": [ [ 1734, 1738 ] ], "normalized": [] }, { "id": "PMID-22065579_T59", "type": "Simple_chemical", "text": [ "Phorbol ester" ], "offsets": [ [ 1752, 1765 ] ], "normalized": [] }, { "id": "PMID-22065579_T60", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 1771, 1780 ] ], "normalized": [] }, { "id": "PMID-22065579_T61", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 1809, 1812 ] ], "normalized": [] }, { "id": "PMID-22065579_T62", "type": "Gene_or_gene_product", "text": [ "Elk1" ], "offsets": [ [ 1845, 1849 ] ], "normalized": [] }, { "id": "PMID-22065579_T63", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1854, 1863 ] ], "normalized": [] }, { "id": "PMID-22065579_T64", "type": "Gene_or_gene_product", "text": [ "iNOS" ], "offsets": [ [ 1886, 1890 ] ], "normalized": [] }, { "id": "PMID-22065579_T65", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 1915, 1919 ] ], "normalized": [] }, { "id": "PMID-22065579_T66", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 1960, 1964 ] ], "normalized": [] }, { "id": "PMID-22065579_T67", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 2006, 2010 ] ], "normalized": [] }, { "id": "PMID-22065579_T68", "type": "Gene_or_gene_product", "text": [ "PKCdelta" ], "offsets": [ [ 2014, 2022 ] ], "normalized": [] }, { "id": "PMID-22065579_T69", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 2023, 2026 ] ], "normalized": [] }, { "id": "PMID-22065579_T70", "type": "Gene_or_gene_product", "text": [ "hBVR" ], "offsets": [ [ 2050, 2054 ] ], "normalized": [] }, { "id": "PMID-22065579_T71", "type": "Gene_or_gene_product", "text": [ "ERK" ], "offsets": [ [ 2083, 2086 ] ], "normalized": [] } ]

[ { "id": "PMID-22065579_E1", "type": "Binding", "trigger": { "text": [ "Formation" ], "offsets": [ [ 0, 9 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T1" }, { "role": "Theme", "ref_id": "PMID-22065579_T2" }, { "role": "Theme", "ref_id": "PMID-22065579_T3" } ] }, { "id": "PMID-22065579_E2", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 97, 106 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_E1" }, { "role": "Theme", "ref_id": "PMID-22065579_E8" } ] }, { "id": "PMID-22065579_E3", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 97, 106 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_E1" }, { "role": "Theme", "ref_id": "PMID-22065579_E10" } ] }, { "id": "PMID-22065579_E4", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 97, 106 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_E1" }, { "role": "Theme", "ref_id": "PMID-22065579_E9" } ] }, { "id": "PMID-22065579_E5", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 116, 124 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T4" }, { "role": "Theme", "ref_id": "PMID-22065579_E8" } ] }, { "id": "PMID-22065579_E6", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 116, 124 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T4" }, { "role": "Theme", "ref_id": "PMID-22065579_E9" } ] }, { "id": "PMID-22065579_E7", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 116, 124 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T4" }, { "role": "Theme", "ref_id": "PMID-22065579_E10" } ] }, { "id": "PMID-22065579_E8", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 125, 135 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T5" } ] }, { "id": "PMID-22065579_E9", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 125, 135 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T6" } ] }, { "id": "PMID-22065579_E10", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 125, 135 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T7" } ] }, { "id": "PMID-22065579_E11", "type": "Activation", "trigger": { "text": [ "activate" ], "offsets": [ [ 280, 288 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T10" }, { "role": "Cause", "ref_id": "PMID-22065579_E12" } ] }, { "id": "PMID-22065579_E12", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 280, 288 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T9" }, { "role": "Theme", "ref_id": "PMID-22065579_T11" } ] }, { "id": "PMID-22065579_E13", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 280, 288 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T9" }, { "role": "Theme", "ref_id": "PMID-22065579_T12" } ] }, { "id": "PMID-22065579_E14", "type": "Activation", "trigger": { "text": [ "activate" ], "offsets": [ [ 280, 288 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T10" }, { "role": "Cause", "ref_id": "PMID-22065579_E13" } ] }, { "id": "PMID-22065579_E15", "type": "Transport", "trigger": { "text": [ "transporter" ], "offsets": [ [ 431, 442 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T21" }, { "role": "ToLoc", "ref_id": "PMID-22065579_T19" } ] }, { "id": "PMID-22065579_E16", "type": "Positive_regulation", "trigger": { "text": [ "transporter" ], "offsets": [ [ 431, 442 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T13" }, { "role": "Theme", "ref_id": "PMID-22065579_E15" } ] }, { "id": "PMID-22065579_E17", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 453, 463 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T20" }, { "role": "Theme", "ref_id": "PMID-22065579_T21" } ] }, { "id": "PMID-22065579_E18", "type": "Binding", "trigger": { "text": [ "formation" ], "offsets": [ [ 711, 720 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-22065579_T25" } ] }, { "id": "PMID-22065579_E19", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 770, 779 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_E20" }, { "role": "Cause", "ref_id": "PMID-22065579_E18" } ] }, { "id": "PMID-22065579_E20", "type": "Pathway", "trigger": { "text": [ "signal transduction" ], "offsets": [ [ 789, 808 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22065579_T26" } ] }, { "id": "PMID-22065579_E21", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 964, 974 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T29" } ] }, { "id": "PMID-22065579_E22", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1021, 1030 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_E23" } ] }, { "id": "PMID-22065579_E23", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1031, 1042 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T31" }, { "role": "Theme", "ref_id": "PMID-22065579_T32" } ] }, { "id": "PMID-22065579_E24", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 1151, 1165 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T35" }, { "role": "Theme", "ref_id": "PMID-22065579_T33" } ] }, { "id": "PMID-22065579_E25", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 1151, 1165 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T35" }, { "role": "Theme", "ref_id": "PMID-22065579_T34" } ] }, { "id": "PMID-22065579_E26", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1265, 1274 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_E28" }, { "role": "Cause", "ref_id": "PMID-22065579_T40" } ] }, { "id": "PMID-22065579_E27", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1265, 1274 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_E28" }, { "role": "Cause", "ref_id": "PMID-22065579_T39" } ] }, { "id": "PMID-22065579_E28", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1289, 1296 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T41" }, { "role": "Theme", "ref_id": "PMID-22065579_T42" } ] }, { "id": "PMID-22065579_E29", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1307, 1315 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T43" }, { "role": "Theme", "ref_id": "PMID-22065579_E31" } ] }, { "id": "PMID-22065579_E30", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1307, 1315 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T43" }, { "role": "Theme", "ref_id": "PMID-22065579_E32" } ] }, { "id": "PMID-22065579_E31", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1324, 1334 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T44" } ] }, { "id": "PMID-22065579_E32", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1355, 1366 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T43" }, { "role": "Theme", "ref_id": "PMID-22065579_T45" } ] }, { "id": "PMID-22065579_E33", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 1468, 1477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_E35" } ] }, { "id": "PMID-22065579_E34", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 1468, 1477 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_E36" } ] }, { "id": "PMID-22065579_E35", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1482, 1489 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T50" }, { "role": "Theme", "ref_id": "PMID-22065579_T46" } ] }, { "id": "PMID-22065579_E36", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1515, 1522 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T51" }, { "role": "Theme", "ref_id": "PMID-22065579_T46" } ] }, { "id": "PMID-22065579_E37", "type": "Binding", "trigger": { "text": [ "Formation" ], "offsets": [ [ 1524, 1533 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-22065579_T52" } ] }, { "id": "PMID-22065579_E38", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1568, 1576 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_E37" }, { "role": "Cause", "ref_id": "PMID-22065579_E39" } ] }, { "id": "PMID-22065579_E39", "type": "Binding", "trigger": { "text": [ "docking" ], "offsets": [ [ 1586, 1593 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T53" }, { "role": "Theme", "ref_id": "PMID-22065579_T54" } ] }, { "id": "PMID-22065579_E40", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1696, 1705 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_E43" } ] }, { "id": "PMID-22065579_E41", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1696, 1705 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_E42" } ] }, { "id": "PMID-22065579_E42", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1710, 1720 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T56" } ] }, { "id": "PMID-22065579_E43", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1739, 1750 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T57" }, { "role": "Theme", "ref_id": "PMID-22065579_T58" } ] }, { "id": "PMID-22065579_E44", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1781, 1790 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T60" }, { "role": "Theme", "ref_id": "PMID-22065579_E50" } ] }, { "id": "PMID-22065579_E45", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1781, 1790 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T59" }, { "role": "Theme", "ref_id": "PMID-22065579_E50" } ] }, { "id": "PMID-22065579_E46", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1781, 1790 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T59" }, { "role": "Theme", "ref_id": "PMID-22065579_E51" } ] }, { "id": "PMID-22065579_E47", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1781, 1790 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T60" }, { "role": "Theme", "ref_id": "PMID-22065579_E51" } ] }, { "id": "PMID-22065579_E48", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1781, 1790 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T59" }, { "role": "Theme", "ref_id": "PMID-22065579_E54" } ] }, { "id": "PMID-22065579_E49", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1781, 1790 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T60" }, { "role": "Theme", "ref_id": "PMID-22065579_E54" } ] }, { "id": "PMID-22065579_E50", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1791, 1801 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T62" } ] }, { "id": "PMID-22065579_E51", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1791, 1801 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T63" } ] }, { "id": "PMID-22065579_E52", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1813, 1822 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T61" }, { "role": "Theme", "ref_id": "PMID-22065579_T62" } ] }, { "id": "PMID-22065579_E53", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1813, 1822 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T61" }, { "role": "Theme", "ref_id": "PMID-22065579_T63" } ] }, { "id": "PMID-22065579_E54", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1868, 1878 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22065579_T64" } ] }, { "id": "PMID-22065579_E55", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1901, 1911 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T65" }, { "role": "Theme", "ref_id": "PMID-22065579_E54" } ] }, { "id": "PMID-22065579_E56", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1901, 1911 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T65" }, { "role": "Theme", "ref_id": "PMID-22065579_E50" } ] }, { "id": "PMID-22065579_E57", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1901, 1911 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T65" }, { "role": "Theme", "ref_id": "PMID-22065579_E51" } ] }, { "id": "PMID-22065579_E58", "type": "Positive_regulation", "trigger": { "text": [ "rescued" ], "offsets": [ [ 1949, 1956 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T66" }, { "role": "Theme", "ref_id": "PMID-22065579_E50" } ] }, { "id": "PMID-22065579_E59", "type": "Positive_regulation", "trigger": { "text": [ "rescued" ], "offsets": [ [ 1949, 1956 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T66" }, { "role": "Theme", "ref_id": "PMID-22065579_E51" } ] }, { "id": "PMID-22065579_E60", "type": "Positive_regulation", "trigger": { "text": [ "rescued" ], "offsets": [ [ 1949, 1956 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22065579_T66" }, { "role": "Theme", "ref_id": "PMID-22065579_E54" } ] }, { "id": "PMID-22065579_E61", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 2027, 2036 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22065579_T69" }, { "role": "Participant", "ref_id": "PMID-22065579_T68" } ] } ]

[ { "id": "PMID-22065579_1", "entity_ids": [ "PMID-22065579_T7", "PMID-22065579_T8" ] }, { "id": "PMID-22065579_2", "entity_ids": [ "PMID-22065579_T14", "PMID-22065579_T13" ] }, { "id": "PMID-22065579_3", "entity_ids": [ "PMID-22065579_T29", "PMID-22065579_T30" ] } ]

[]

[ { "id": "PMID-22139845__text", "type": "abstract", "text": [ "The p65 subunit of NF-kappaB inhibits COL1A1 gene transcription in human dermal and scleroderma fibroblasts through its recruitment on promoter by protein interaction with transcriptional activators (c-Krox, Sp1, and Sp3). \nTranscriptional mechanisms regulating type I collagen genes expression in physiopathological situations are not completely known. In this study, we have investigated the role of nuclear factor-kappaB (NF-kappaB) transcription factor on type I collagen expression in adult normal human (ANF) and scleroderma (SF) fibroblasts. We demonstrated that NF-kappaB, a master transcription factor playing a major role in immune response/apoptosis, down-regulates COL1A1 expression by a transcriptional control involving the -112/-61 bp sequence. This 51-bp region mediates the action of two zinc fingers, Sp1 (specific protein-1) and Sp3, acting as trans-activators of type I collagen expression in ANF and SF. Knockdown of each one of these trans factors by siRNA confirmed the trans-activating effect of Sp1/Sp3 and the p65 subunit of NF-kappaB trans-inhibiting effect on COL1A1 expression. Despite no existing kappaB consensus sequence in the COL1A1 promoter, we found that Sp1/Sp3/c-Krox and NF-kappaB bind and/or are recruited on the proximal promoter in chromatin immunoprecipitation (ChIP) assays. Attempts to elucidate whether interactions between Sp1/Sp3/c-Krox and p65 are necessary to mediate the NF-kappaB inhibitory effect on COL1A1 in ANF and SF were carried out; in this regard, immunoprecipitation assays revealed that they interact, and this was validated by re-ChIP. Finally, the knockdown of Sp1/Sp3/c-Krox prevents the p65 inhibitory effect on COL1A1 transcription in ANF, whereas only the siRNAs targeting Sp3 and c-Krox provoked the same effect in SF, suggesting that particular interactions are characteristic of the scleroderma phenotype. In conclusion, our findings highlight a new mechanism for COL1A1 transcriptional regulation by NF-kappaB, and these data could allow the development of new antifibrotic strategies.\n" ], "offsets": [ [ 0, 2058 ] ] } ]

[ { "id": "PMID-22139845_T1", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 4, 7 ] ], "normalized": [] }, { "id": "PMID-22139845_T2", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 19, 28 ] ], "normalized": [] }, { "id": "PMID-22139845_T3", "type": "Gene_or_gene_product", "text": [ "COL1A1" ], "offsets": [ [ 38, 44 ] ], "normalized": [] }, { "id": "PMID-22139845_T4", "type": "Gene_or_gene_product", "text": [ "c-Krox" ], "offsets": [ [ 200, 206 ] ], "normalized": [] }, { "id": "PMID-22139845_T5", "type": "Gene_or_gene_product", "text": [ "Sp1" ], "offsets": [ [ 208, 211 ] ], "normalized": [] }, { "id": "PMID-22139845_T6", "type": "Gene_or_gene_product", "text": [ "Sp3" ], "offsets": [ [ 217, 220 ] ], "normalized": [] }, { "id": "PMID-22139845_T7", "type": "Gene_or_gene_product", "text": [ "type I collagen" ], "offsets": [ [ 262, 277 ] ], "normalized": [] }, { "id": "PMID-22139845_T8", "type": "Complex", "text": [ "nuclear factor-kappaB" ], "offsets": [ [ 402, 423 ] ], "normalized": [] }, { "id": "PMID-22139845_T9", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 425, 434 ] ], "normalized": [] }, { "id": "PMID-22139845_T10", "type": "Gene_or_gene_product", "text": [ "type I collagen" ], "offsets": [ [ 460, 475 ] ], "normalized": [] }, { "id": "PMID-22139845_T11", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 570, 579 ] ], "normalized": [] }, { "id": "PMID-22139845_T12", "type": "Gene_or_gene_product", "text": [ "COL1A1" ], "offsets": [ [ 677, 683 ] ], "normalized": [] }, { "id": "PMID-22139845_T13", "type": "Simple_chemical", "text": [ "zinc" ], "offsets": [ [ 805, 809 ] ], "normalized": [] }, { "id": "PMID-22139845_T14", "type": "Gene_or_gene_product", "text": [ "Sp1" ], "offsets": [ [ 819, 822 ] ], "normalized": [] }, { "id": "PMID-22139845_T15", "type": "Gene_or_gene_product", "text": [ "specific protein-1" ], "offsets": [ [ 824, 842 ] ], "normalized": [] }, { "id": "PMID-22139845_T16", "type": "Gene_or_gene_product", "text": [ "Sp3" ], "offsets": [ [ 848, 851 ] ], "normalized": [] }, { "id": "PMID-22139845_T17", "type": "Gene_or_gene_product", "text": [ "type I collagen" ], "offsets": [ [ 883, 898 ] ], "normalized": [] }, { "id": "PMID-22139845_T18", "type": "Gene_or_gene_product", "text": [ "Sp1" ], "offsets": [ [ 1020, 1023 ] ], "normalized": [] }, { "id": "PMID-22139845_T19", "type": "Gene_or_gene_product", "text": [ "Sp3" ], "offsets": [ [ 1024, 1027 ] ], "normalized": [] }, { "id": "PMID-22139845_T20", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1036, 1039 ] ], "normalized": [] }, { "id": "PMID-22139845_T21", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1051, 1060 ] ], "normalized": [] }, { "id": "PMID-22139845_T22", "type": "Gene_or_gene_product", "text": [ "COL1A1" ], "offsets": [ [ 1088, 1094 ] ], "normalized": [] }, { "id": "PMID-22139845_T23", "type": "Complex", "text": [ "kappaB" ], "offsets": [ [ 1127, 1133 ] ], "normalized": [] }, { "id": "PMID-22139845_T24", "type": "Gene_or_gene_product", "text": [ "COL1A1" ], "offsets": [ [ 1160, 1166 ] ], "normalized": [] }, { "id": "PMID-22139845_T25", "type": "Gene_or_gene_product", "text": [ "Sp1" ], "offsets": [ [ 1191, 1194 ] ], "normalized": [] }, { "id": "PMID-22139845_T26", "type": "Gene_or_gene_product", "text": [ "Sp3" ], "offsets": [ [ 1195, 1198 ] ], "normalized": [] }, { "id": "PMID-22139845_T27", "type": "Gene_or_gene_product", "text": [ "c-Krox" ], "offsets": [ [ 1199, 1205 ] ], "normalized": [] }, { "id": "PMID-22139845_T28", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1210, 1219 ] ], "normalized": [] }, { "id": "PMID-22139845_T29", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 1274, 1283 ] ], "normalized": [] }, { "id": "PMID-22139845_T30", "type": "Gene_or_gene_product", "text": [ "Sp1" ], "offsets": [ [ 1370, 1373 ] ], "normalized": [] }, { "id": "PMID-22139845_T31", "type": "Gene_or_gene_product", "text": [ "Sp3" ], "offsets": [ [ 1374, 1377 ] ], "normalized": [] }, { "id": "PMID-22139845_T32", "type": "Gene_or_gene_product", "text": [ "c-Krox" ], "offsets": [ [ 1378, 1384 ] ], "normalized": [] }, { "id": "PMID-22139845_T33", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1389, 1392 ] ], "normalized": [] }, { "id": "PMID-22139845_T34", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1422, 1431 ] ], "normalized": [] }, { "id": "PMID-22139845_T35", "type": "Gene_or_gene_product", "text": [ "COL1A1" ], "offsets": [ [ 1453, 1459 ] ], "normalized": [] }, { "id": "PMID-22139845_T36", "type": "Gene_or_gene_product", "text": [ "Sp1" ], "offsets": [ [ 1625, 1628 ] ], "normalized": [] }, { "id": "PMID-22139845_T37", "type": "Gene_or_gene_product", "text": [ "Sp3" ], "offsets": [ [ 1629, 1632 ] ], "normalized": [] }, { "id": "PMID-22139845_T38", "type": "Gene_or_gene_product", "text": [ "c-Krox" ], "offsets": [ [ 1633, 1639 ] ], "normalized": [] }, { "id": "PMID-22139845_T39", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1653, 1656 ] ], "normalized": [] }, { "id": "PMID-22139845_T40", "type": "Gene_or_gene_product", "text": [ "COL1A1" ], "offsets": [ [ 1678, 1684 ] ], "normalized": [] }, { "id": "PMID-22139845_T41", "type": "Gene_or_gene_product", "text": [ "Sp3" ], "offsets": [ [ 1741, 1744 ] ], "normalized": [] }, { "id": "PMID-22139845_T42", "type": "Gene_or_gene_product", "text": [ "c-Krox" ], "offsets": [ [ 1749, 1755 ] ], "normalized": [] }, { "id": "PMID-22139845_T43", "type": "Gene_or_gene_product", "text": [ "COL1A1" ], "offsets": [ [ 1935, 1941 ] ], "normalized": [] }, { "id": "PMID-22139845_T44", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1972, 1981 ] ], "normalized": [] } ]

[ { "id": "PMID-22139845_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 29, 37 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E4" }, { "role": "Cause", "ref_id": "PMID-22139845_E8" } ] }, { "id": "PMID-22139845_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 29, 37 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E4" }, { "role": "Cause", "ref_id": "PMID-22139845_E9" } ] }, { "id": "PMID-22139845_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 29, 37 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E4" }, { "role": "Cause", "ref_id": "PMID-22139845_E10" } ] }, { "id": "PMID-22139845_E4", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 50, 63 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T3" } ] }, { "id": "PMID-22139845_E5", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 155, 166 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T4" } ] }, { "id": "PMID-22139845_E6", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 155, 166 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T5" } ] }, { "id": "PMID-22139845_E7", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 155, 166 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T6" } ] }, { "id": "PMID-22139845_E8", "type": "Positive_regulation", "trigger": { "text": [ "interaction" ], "offsets": [ [ 155, 166 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22139845_T1" }, { "role": "Theme", "ref_id": "PMID-22139845_E7" } ] }, { "id": "PMID-22139845_E9", "type": "Positive_regulation", "trigger": { "text": [ "interaction" ], "offsets": [ [ 155, 166 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22139845_T1" }, { "role": "Theme", "ref_id": "PMID-22139845_E6" } ] }, { "id": "PMID-22139845_E10", "type": "Positive_regulation", "trigger": { "text": [ "interaction" ], "offsets": [ [ 155, 166 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22139845_T1" }, { "role": "Theme", "ref_id": "PMID-22139845_E6" } ] }, { "id": "PMID-22139845_E11", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 251, 261 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E12" } ] }, { "id": "PMID-22139845_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 284, 294 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T7" } ] }, { "id": "PMID-22139845_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 476, 486 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T10" } ] }, { "id": "PMID-22139845_E14", "type": "Positive_regulation", "trigger": { "text": [ "playing a major role" ], "offsets": [ [ 611, 631 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22139845_T11" }, { "role": "Theme", "ref_id": "PMID-22139845_E15" } ] }, { "id": "PMID-22139845_E15", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 651, 660 ] ] }, "arguments": [] }, { "id": "PMID-22139845_E16", "type": "Negative_regulation", "trigger": { "text": [ "down-regulates" ], "offsets": [ [ 662, 676 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22139845_T11" }, { "role": "Theme", "ref_id": "PMID-22139845_E17" } ] }, { "id": "PMID-22139845_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 684, 694 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T12" } ] }, { "id": "PMID-22139845_E18", "type": "Positive_regulation", "trigger": { "text": [ "mediates" ], "offsets": [ [ 778, 786 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T14" } ] }, { "id": "PMID-22139845_E19", "type": "Positive_regulation", "trigger": { "text": [ "mediates" ], "offsets": [ [ 778, 786 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T16" } ] }, { "id": "PMID-22139845_E20", "type": "Positive_regulation", "trigger": { "text": [ "activators" ], "offsets": [ [ 869, 879 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E22" }, { "role": "Cause", "ref_id": "PMID-22139845_T14" } ] }, { "id": "PMID-22139845_E21", "type": "Positive_regulation", "trigger": { "text": [ "activators" ], "offsets": [ [ 869, 879 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E22" }, { "role": "Cause", "ref_id": "PMID-22139845_T16" } ] }, { "id": "PMID-22139845_E22", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 899, 909 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T17" } ] }, { "id": "PMID-22139845_E23", "type": "Negative_regulation", "trigger": { "text": [ "Knockdown" ], "offsets": [ [ 925, 934 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T14" } ] }, { "id": "PMID-22139845_E24", "type": "Negative_regulation", "trigger": { "text": [ "Knockdown" ], "offsets": [ [ 925, 934 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T16" } ] }, { "id": "PMID-22139845_E25", "type": "Positive_regulation", "trigger": { "text": [ "trans-activating" ], "offsets": [ [ 993, 1009 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E30" } ] }, { "id": "PMID-22139845_E26", "type": "Positive_regulation", "trigger": { "text": [ "trans-activating" ], "offsets": [ [ 993, 1009 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E29" } ] }, { "id": "PMID-22139845_E27", "type": "Positive_regulation", "trigger": { "text": [ "trans-activating" ], "offsets": [ [ 993, 1009 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E31" } ] }, { "id": "PMID-22139845_E28", "type": "Positive_regulation", "trigger": { "text": [ "trans-activating" ], "offsets": [ [ 993, 1009 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E32" } ] }, { "id": "PMID-22139845_E29", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1010, 1016 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T18" }, { "role": "Cause", "ref_id": "PMID-22139845_E24" } ] }, { "id": "PMID-22139845_E30", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1010, 1016 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T19" }, { "role": "Cause", "ref_id": "PMID-22139845_E23" } ] }, { "id": "PMID-22139845_E31", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1010, 1016 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T19" }, { "role": "Cause", "ref_id": "PMID-22139845_E24" } ] }, { "id": "PMID-22139845_E32", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1010, 1016 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T18" }, { "role": "Cause", "ref_id": "PMID-22139845_E23" } ] }, { "id": "PMID-22139845_E33", "type": "Negative_regulation", "trigger": { "text": [ "trans-inhibiting" ], "offsets": [ [ 1061, 1077 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E37" } ] }, { "id": "PMID-22139845_E34", "type": "Negative_regulation", "trigger": { "text": [ "trans-inhibiting" ], "offsets": [ [ 1061, 1077 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E38" } ] }, { "id": "PMID-22139845_E35", "type": "Negative_regulation", "trigger": { "text": [ "trans-inhibiting" ], "offsets": [ [ 1061, 1077 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E40" } ] }, { "id": "PMID-22139845_E36", "type": "Negative_regulation", "trigger": { "text": [ "trans-inhibiting" ], "offsets": [ [ 1061, 1077 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E39" } ] }, { "id": "PMID-22139845_E37", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1078, 1084 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T20" }, { "role": "Cause", "ref_id": "PMID-22139845_E23" } ] }, { "id": "PMID-22139845_E38", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1078, 1084 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T20" }, { "role": "Cause", "ref_id": "PMID-22139845_E23" } ] }, { "id": "PMID-22139845_E39", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1078, 1084 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T20" }, { "role": "Cause", "ref_id": "PMID-22139845_E24" } ] }, { "id": "PMID-22139845_E40", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1078, 1084 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T20" }, { "role": "Cause", "ref_id": "PMID-22139845_E24" } ] }, { "id": "PMID-22139845_E41", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1095, 1105 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T22" } ] }, { "id": "PMID-22139845_E42", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1220, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T25" }, { "role": "Theme", "ref_id": "PMID-22139845_T28" } ] }, { "id": "PMID-22139845_E43", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1220, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T26" }, { "role": "Theme", "ref_id": "PMID-22139845_T28" } ] }, { "id": "PMID-22139845_E44", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1220, 1224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T27" }, { "role": "Theme", "ref_id": "PMID-22139845_T28" } ] }, { "id": "PMID-22139845_E45", "type": "Transport", "trigger": { "text": [ "recruited" ], "offsets": [ [ 1236, 1245 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T25" } ] }, { "id": "PMID-22139845_E46", "type": "Transport", "trigger": { "text": [ "recruited" ], "offsets": [ [ 1236, 1245 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T26" } ] }, { "id": "PMID-22139845_E47", "type": "Transport", "trigger": { "text": [ "recruited" ], "offsets": [ [ 1236, 1245 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T27" } ] }, { "id": "PMID-22139845_E48", "type": "Transport", "trigger": { "text": [ "recruited" ], "offsets": [ [ 1236, 1245 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T28" } ] }, { "id": "PMID-22139845_E49", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 1349, 1361 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T30" }, { "role": "Theme", "ref_id": "PMID-22139845_T33" } ] }, { "id": "PMID-22139845_E50", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 1349, 1361 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T31" }, { "role": "Theme", "ref_id": "PMID-22139845_T33" } ] }, { "id": "PMID-22139845_E51", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 1349, 1361 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T32" }, { "role": "Theme", "ref_id": "PMID-22139845_T33" } ] }, { "id": "PMID-22139845_E52", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 1397, 1406 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E55" }, { "role": "Cause", "ref_id": "PMID-22139845_E50" } ] }, { "id": "PMID-22139845_E53", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 1397, 1406 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E55" }, { "role": "Cause", "ref_id": "PMID-22139845_E49" } ] }, { "id": "PMID-22139845_E54", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 1397, 1406 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E55" }, { "role": "Cause", "ref_id": "PMID-22139845_E51" } ] }, { "id": "PMID-22139845_E55", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 1410, 1417 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E57" } ] }, { "id": "PMID-22139845_E56", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 1432, 1442 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T34" } ] }, { "id": "PMID-22139845_E57", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1443, 1449 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E56" } ] }, { "id": "PMID-22139845_E58", "type": "Binding", "trigger": { "text": [ "interact" ], "offsets": [ [ 1554, 1562 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T30" }, { "role": "Theme", "ref_id": "PMID-22139845_T33" } ] }, { "id": "PMID-22139845_E59", "type": "Binding", "trigger": { "text": [ "interact" ], "offsets": [ [ 1554, 1562 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T31" }, { "role": "Theme", "ref_id": "PMID-22139845_T33" } ] }, { "id": "PMID-22139845_E60", "type": "Binding", "trigger": { "text": [ "interact" ], "offsets": [ [ 1554, 1562 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T32" }, { "role": "Theme", "ref_id": "PMID-22139845_T33" } ] }, { "id": "PMID-22139845_E61", "type": "Negative_regulation", "trigger": { "text": [ "knockdown" ], "offsets": [ [ 1612, 1621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T36" } ] }, { "id": "PMID-22139845_E62", "type": "Negative_regulation", "trigger": { "text": [ "knockdown" ], "offsets": [ [ 1612, 1621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T37" } ] }, { "id": "PMID-22139845_E63", "type": "Negative_regulation", "trigger": { "text": [ "knockdown" ], "offsets": [ [ 1612, 1621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T38" } ] }, { "id": "PMID-22139845_E64", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 1640, 1648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E68" }, { "role": "Cause", "ref_id": "PMID-22139845_E61" } ] }, { "id": "PMID-22139845_E65", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 1640, 1648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E68" }, { "role": "Cause", "ref_id": "PMID-22139845_E62" } ] }, { "id": "PMID-22139845_E66", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 1640, 1648 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E68" }, { "role": "Cause", "ref_id": "PMID-22139845_E63" } ] }, { "id": "PMID-22139845_E67", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 1657, 1667 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22139845_T39" }, { "role": "Theme", "ref_id": "PMID-22139845_E68" } ] }, { "id": "PMID-22139845_E68", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1668, 1674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E69" } ] }, { "id": "PMID-22139845_E69", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1685, 1698 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T40" } ] }, { "id": "PMID-22139845_E70", "type": "Regulation", "trigger": { "text": [ "targeting" ], "offsets": [ [ 1731, 1740 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T41" } ] }, { "id": "PMID-22139845_E71", "type": "Regulation", "trigger": { "text": [ "targeting" ], "offsets": [ [ 1731, 1740 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T42" } ] }, { "id": "PMID-22139845_E72", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 1942, 1957 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_T43" } ] }, { "id": "PMID-22139845_E73", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1958, 1968 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22139845_E72" }, { "role": "Cause", "ref_id": "PMID-22139845_T44" } ] } ]

[ { "id": "PMID-22139845_1", "entity_ids": [ "PMID-22139845_T8", "PMID-22139845_T9" ] }, { "id": "PMID-22139845_2", "entity_ids": [ "PMID-22139845_T14", "PMID-22139845_T15" ] } ]

[]

[ { "id": "PMID-22144899__text", "type": "abstract", "text": [ "The enteropathogenic E. coli (EPEC) Tir effector inhibits NF-kappaB activity by targeting TNFalpha receptor-associated factors. \nEnteropathogenic Escherichia coli (EPEC) disease depends on the transfer of effector proteins into epithelia lining the human small intestine. EPEC E2348/69 has at least 20 effector genes of which six are located with the effector-delivery system genes on the Locus of Enterocyte Effacement (LEE) Pathogenicity Island. Our previous work implied that non-LEE-encoded (Nle) effectors possess functions that inhibit epithelial anti-microbial and inflammation-inducing responses by blocking NF-kappaB transcription factor activity. Indeed, screens by us and others have identified novel inhibitory mechanisms for NleC and NleH, with key co-operative functions for NleB1 and NleE1. Here, we demonstrate that the LEE-encoded Translocated-intimin receptor (Tir) effector has a potent and specific ability to inhibit NF-kappaB activation. Indeed, biochemical, imaging and immunoprecipitation studies reveal a novel inhibitory mechanism whereby Tir interaction with cytoplasm-located TNFalpha receptor-associated factor (TRAF) adaptor proteins induces their proteasomal-independent degradation. Infection studies support this Tir-TRAF relationship but reveal that Tir, like NleC and NleH, has a non-essential contribution in EPEC's NF-kappaB inhibitory capacity linked to Tir's activity being suppressed by undefined EPEC factors. Infections in a disease-relevant intestinal model confirm key NF-kappaB inhibitory roles for the NleB1/NleE1 effectors, with other studies providing insights on host targets. The work not only reveals a second Intimin-independent property for Tir and a novel EPEC effector-mediated NF-kappaB inhibitory mechanism but also lends itself to speculations on the evolution of EPEC's capacity to inhibit NF-kappaB function.\n" ], "offsets": [ [ 0, 1869 ] ] } ]

[ { "id": "PMID-22144899_T1", "type": "Gene_or_gene_product", "text": [ "Tir" ], "offsets": [ [ 36, 39 ] ], "normalized": [] }, { "id": "PMID-22144899_T2", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 58, 67 ] ], "normalized": [] }, { "id": "PMID-22144899_T3", "type": "Gene_or_gene_product", "text": [ "TNFalpha receptor-associated factors" ], "offsets": [ [ 90, 126 ] ], "normalized": [] }, { "id": "PMID-22144899_T4", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 616, 625 ] ], "normalized": [] }, { "id": "PMID-22144899_T5", "type": "Gene_or_gene_product", "text": [ "NleC" ], "offsets": [ [ 738, 742 ] ], "normalized": [] }, { "id": "PMID-22144899_T6", "type": "Gene_or_gene_product", "text": [ "NleH" ], "offsets": [ [ 747, 751 ] ], "normalized": [] }, { "id": "PMID-22144899_T7", "type": "Gene_or_gene_product", "text": [ "NleB1" ], "offsets": [ [ 789, 794 ] ], "normalized": [] }, { "id": "PMID-22144899_T8", "type": "Gene_or_gene_product", "text": [ "NleE1" ], "offsets": [ [ 799, 804 ] ], "normalized": [] }, { "id": "PMID-22144899_T9", "type": "Gene_or_gene_product", "text": [ "Translocated-intimin receptor" ], "offsets": [ [ 848, 877 ] ], "normalized": [] }, { "id": "PMID-22144899_T10", "type": "Gene_or_gene_product", "text": [ "Tir" ], "offsets": [ [ 879, 882 ] ], "normalized": [] }, { "id": "PMID-22144899_T11", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 938, 947 ] ], "normalized": [] }, { "id": "PMID-22144899_T12", "type": "Gene_or_gene_product", "text": [ "Tir" ], "offsets": [ [ 1065, 1068 ] ], "normalized": [] }, { "id": "PMID-22144899_T13", "type": "Gene_or_gene_product", "text": [ "TNFalpha receptor-associated factor" ], "offsets": [ [ 1104, 1139 ] ], "normalized": [] }, { "id": "PMID-22144899_T14", "type": "Gene_or_gene_product", "text": [ "TRAF" ], "offsets": [ [ 1141, 1145 ] ], "normalized": [] }, { "id": "PMID-22144899_T15", "type": "Cellular_component", "text": [ "proteasomal" ], "offsets": [ [ 1178, 1189 ] ], "normalized": [] }, { "id": "PMID-22144899_T16", "type": "Gene_or_gene_product", "text": [ "Tir" ], "offsets": [ [ 1246, 1249 ] ], "normalized": [] }, { "id": "PMID-22144899_T17", "type": "Gene_or_gene_product", "text": [ "TRAF" ], "offsets": [ [ 1250, 1254 ] ], "normalized": [] }, { "id": "PMID-22144899_T18", "type": "Gene_or_gene_product", "text": [ "Tir" ], "offsets": [ [ 1284, 1287 ] ], "normalized": [] }, { "id": "PMID-22144899_T19", "type": "Gene_or_gene_product", "text": [ "NleC" ], "offsets": [ [ 1294, 1298 ] ], "normalized": [] }, { "id": "PMID-22144899_T20", "type": "Gene_or_gene_product", "text": [ "NleH" ], "offsets": [ [ 1303, 1307 ] ], "normalized": [] }, { "id": "PMID-22144899_T21", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1352, 1361 ] ], "normalized": [] }, { "id": "PMID-22144899_T22", "type": "Gene_or_gene_product", "text": [ "Tir" ], "offsets": [ [ 1392, 1395 ] ], "normalized": [] }, { "id": "PMID-22144899_T23", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1513, 1522 ] ], "normalized": [] }, { "id": "PMID-22144899_T24", "type": "Gene_or_gene_product", "text": [ "NleB1" ], "offsets": [ [ 1548, 1553 ] ], "normalized": [] }, { "id": "PMID-22144899_T25", "type": "Gene_or_gene_product", "text": [ "NleE1" ], "offsets": [ [ 1554, 1559 ] ], "normalized": [] }, { "id": "PMID-22144899_T26", "type": "Gene_or_gene_product", "text": [ "Tir" ], "offsets": [ [ 1694, 1697 ] ], "normalized": [] }, { "id": "PMID-22144899_T27", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1733, 1742 ] ], "normalized": [] }, { "id": "PMID-22144899_T28", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1849, 1858 ] ], "normalized": [] } ]

[ { "id": "PMID-22144899_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 49, 57 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T2" }, { "role": "Cause", "ref_id": "PMID-22144899_E2" } ] }, { "id": "PMID-22144899_E2", "type": "Regulation", "trigger": { "text": [ "targeting" ], "offsets": [ [ 80, 89 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T3" }, { "role": "Cause", "ref_id": "PMID-22144899_T1" } ] }, { "id": "PMID-22144899_E3", "type": "Negative_regulation", "trigger": { "text": [ "blocking" ], "offsets": [ [ 607, 615 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T4" } ] }, { "id": "PMID-22144899_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 930, 937 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_E5" }, { "role": "Cause", "ref_id": "PMID-22144899_T10" } ] }, { "id": "PMID-22144899_E5", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 948, 958 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T11" } ] }, { "id": "PMID-22144899_E6", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1069, 1080 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T12" }, { "role": "Theme", "ref_id": "PMID-22144899_T13" } ] }, { "id": "PMID-22144899_E7", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 1164, 1171 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_E9" }, { "role": "Cause", "ref_id": "PMID-22144899_E6" } ] }, { "id": "PMID-22144899_E8", "type": "Regulation", "trigger": { "text": [ "independent" ], "offsets": [ [ 1190, 1201 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22144899_T15" }, { "role": "Theme", "ref_id": "PMID-22144899_E9" } ] }, { "id": "PMID-22144899_E9", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1202, 1213 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T13" } ] }, { "id": "PMID-22144899_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 1362, 1372 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T21" } ] }, { "id": "PMID-22144899_E11", "type": "Regulation", "trigger": { "text": [ "linked" ], "offsets": [ [ 1382, 1388 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T22" }, { "role": "Cause", "ref_id": "PMID-22144899_E10" } ] }, { "id": "PMID-22144899_E12", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1413, 1423 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T22" } ] }, { "id": "PMID-22144899_E13", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 1523, 1533 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T23" }, { "role": "Cause", "ref_id": "PMID-22144899_T25" } ] }, { "id": "PMID-22144899_E14", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 1523, 1533 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T23" }, { "role": "Cause", "ref_id": "PMID-22144899_T24" } ] }, { "id": "PMID-22144899_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 1743, 1753 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T27" } ] }, { "id": "PMID-22144899_E16", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1841, 1848 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22144899_T28" } ] } ]

[ { "id": "PMID-22144899_1", "entity_ids": [ "PMID-22144899_T9", "PMID-22144899_T10" ] }, { "id": "PMID-22144899_2", "entity_ids": [ "PMID-22144899_T13", "PMID-22144899_T14" ] } ]

[]

[ { "id": "PMID-22337883__text", "type": "abstract", "text": [ "The transcription factor Erg controls endothelial cell quiescence by repressing activity of nuclear factor (NF)-kappaB p65. \nThe interaction of transcription factors with specific DNA sequences is critical for activation of gene expression programs. In endothelial cells (EC), the transcription factor NF-kappaB is important in the switch from quiescence to activation, and is tightly controlled to avoid excessive inflammation and organ damage. Here we describe a novel mechanism that controls the activation of NF-kappaB in EC. The transcription factor Erg, the most highly expressed ETS member in resting EC, controls quiescence by repressing proinflammatory gene expression. Focusing on intercellular adhesion molecule 1(ICAM)-1 as a model, we identify two ETS binding sites (EBS -118 and -181) within the ICAM-1 promoter required for Erg-mediated repression. We show that Erg binds to both EBS -118 and EBS -181, the latter located within the NF-kappaB binding site. Interestingly, inhibition of Erg expression in quiescent EC results in increased NF-kappaB-dependent ICAM-1 expression, indicating that Erg represses basal NF-kappaB activity. Erg prevents NF-kappaB p65 from binding to the ICAM-1 promoter, suggesting a direct mechanism of interference. Gene set enrichment analysis of transcriptome profiles of Erg and NF-kappaB-dependent genes, together with chromatin immunoprecipitation (ChIP) studies, reveals that this mechanism is common to other proinflammatory genes, including cIAP-2 and IL-8. These results identify a role for Erg as a gatekeeper controlling vascular inflammation, thus providing an important barrier to protect against inappropriate endothelial activation.\n" ], "offsets": [ [ 0, 1691 ] ] } ]

[ { "id": "PMID-22337883_T1", "type": "Gene_or_gene_product", "text": [ "Erg" ], "offsets": [ [ 25, 28 ] ], "normalized": [] }, { "id": "PMID-22337883_T2", "type": "Complex", "text": [ "nuclear factor (NF)-kappaB" ], "offsets": [ [ 92, 118 ] ], "normalized": [] }, { "id": "PMID-22337883_T3", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 119, 122 ] ], "normalized": [] }, { "id": "PMID-22337883_T4", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 302, 311 ] ], "normalized": [] }, { "id": "PMID-22337883_T5", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 513, 522 ] ], "normalized": [] }, { "id": "PMID-22337883_T6", "type": "Gene_or_gene_product", "text": [ "Erg" ], "offsets": [ [ 555, 558 ] ], "normalized": [] }, { "id": "PMID-22337883_T7", "type": "Gene_or_gene_product", "text": [ "ETS" ], "offsets": [ [ 586, 589 ] ], "normalized": [] }, { "id": "PMID-22337883_T8", "type": "Gene_or_gene_product", "text": [ "intercellular adhesion molecule 1(ICAM)-1" ], "offsets": [ [ 691, 732 ] ], "normalized": [] }, { "id": "PMID-22337883_T9", "type": "Gene_or_gene_product", "text": [ "ETS" ], "offsets": [ [ 761, 764 ] ], "normalized": [] }, { "id": "PMID-22337883_T10", "type": "Gene_or_gene_product", "text": [ "ICAM-1" ], "offsets": [ [ 810, 816 ] ], "normalized": [] }, { "id": "PMID-22337883_T11", "type": "Gene_or_gene_product", "text": [ "Erg" ], "offsets": [ [ 839, 842 ] ], "normalized": [] }, { "id": "PMID-22337883_T12", "type": "Gene_or_gene_product", "text": [ "Erg" ], "offsets": [ [ 877, 880 ] ], "normalized": [] }, { "id": "PMID-22337883_T13", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 948, 957 ] ], "normalized": [] }, { "id": "PMID-22337883_T14", "type": "Gene_or_gene_product", "text": [ "Erg" ], "offsets": [ [ 1001, 1004 ] ], "normalized": [] }, { "id": "PMID-22337883_T15", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1053, 1062 ] ], "normalized": [] }, { "id": "PMID-22337883_T16", "type": "Gene_or_gene_product", "text": [ "ICAM-1" ], "offsets": [ [ 1073, 1079 ] ], "normalized": [] }, { "id": "PMID-22337883_T17", "type": "Gene_or_gene_product", "text": [ "Erg" ], "offsets": [ [ 1108, 1111 ] ], "normalized": [] }, { "id": "PMID-22337883_T18", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1128, 1137 ] ], "normalized": [] }, { "id": "PMID-22337883_T19", "type": "Gene_or_gene_product", "text": [ "Erg" ], "offsets": [ [ 1148, 1151 ] ], "normalized": [] }, { "id": "PMID-22337883_T20", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1161, 1170 ] ], "normalized": [] }, { "id": "PMID-22337883_T21", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 1171, 1174 ] ], "normalized": [] }, { "id": "PMID-22337883_T22", "type": "Gene_or_gene_product", "text": [ "ICAM-1" ], "offsets": [ [ 1195, 1201 ] ], "normalized": [] }, { "id": "PMID-22337883_T23", "type": "Gene_or_gene_product", "text": [ "Erg" ], "offsets": [ [ 1317, 1320 ] ], "normalized": [] }, { "id": "PMID-22337883_T24", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1325, 1334 ] ], "normalized": [] }, { "id": "PMID-22337883_T25", "type": "Cellular_component", "text": [ "chromatin" ], "offsets": [ [ 1366, 1375 ] ], "normalized": [] }, { "id": "PMID-22337883_T26", "type": "Gene_or_gene_product", "text": [ "cIAP-2" ], "offsets": [ [ 1492, 1498 ] ], "normalized": [] }, { "id": "PMID-22337883_T27", "type": "Gene_or_gene_product", "text": [ "IL-8" ], "offsets": [ [ 1503, 1507 ] ], "normalized": [] }, { "id": "PMID-22337883_T28", "type": "Gene_or_gene_product", "text": [ "Erg" ], "offsets": [ [ 1543, 1546 ] ], "normalized": [] } ]

[ { "id": "PMID-22337883_E1", "type": "Negative_regulation", "trigger": { "text": [ "repressing" ], "offsets": [ [ 69, 79 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22337883_T1" }, { "role": "Theme", "ref_id": "PMID-22337883_T2" } ] }, { "id": "PMID-22337883_E2", "type": "Negative_regulation", "trigger": { "text": [ "repressing" ], "offsets": [ [ 69, 79 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22337883_T1" }, { "role": "Theme", "ref_id": "PMID-22337883_T3" } ] }, { "id": "PMID-22337883_E3", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 385, 395 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_T4" } ] }, { "id": "PMID-22337883_E4", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 486, 494 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_E5" } ] }, { "id": "PMID-22337883_E5", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 499, 509 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_T5" } ] }, { "id": "PMID-22337883_E6", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 576, 585 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_T7" } ] }, { "id": "PMID-22337883_E7", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 826, 834 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_E9" } ] }, { "id": "PMID-22337883_E8", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 843, 851 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22337883_T11" }, { "role": "Theme", "ref_id": "PMID-22337883_E9" } ] }, { "id": "PMID-22337883_E9", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 852, 862 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_T8" } ] }, { "id": "PMID-22337883_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 987, 997 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_E11" } ] }, { "id": "PMID-22337883_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1005, 1015 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_T14" } ] }, { "id": "PMID-22337883_E12", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 1032, 1039 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_E13" }, { "role": "Cause", "ref_id": "PMID-22337883_E10" } ] }, { "id": "PMID-22337883_E13", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1043, 1052 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_E15" } ] }, { "id": "PMID-22337883_E14", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1063, 1072 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22337883_T15" }, { "role": "Theme", "ref_id": "PMID-22337883_E15" } ] }, { "id": "PMID-22337883_E15", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1080, 1090 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_T16" } ] }, { "id": "PMID-22337883_E16", "type": "Negative_regulation", "trigger": { "text": [ "represses" ], "offsets": [ [ 1112, 1121 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22337883_T17" }, { "role": "Theme", "ref_id": "PMID-22337883_T18" } ] }, { "id": "PMID-22337883_E17", "type": "Negative_regulation", "trigger": { "text": [ "prevents" ], "offsets": [ [ 1152, 1160 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22337883_T19" }, { "role": "Theme", "ref_id": "PMID-22337883_E18" } ] }, { "id": "PMID-22337883_E18", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1180, 1187 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22337883_T22" }, { "role": "Theme", "ref_id": "PMID-22337883_T21" }, { "role": "Theme", "ref_id": "PMID-22337883_T20" } ] } ]

[]

[]

[ { "id": "PMID-22399319__text", "type": "abstract", "text": [ "Consequences of fuzziness in the NFkappaB/IkappaBalpha interaction. \nThis chapter provides a short review of various biophysical experiments that have been applied to the inhibitor of kappa B, IkappaBalpha and its binding partner, nuclear factor kappa B, or NFkappaB. The picture that emerges from amide hydrogen/deuterium exchange, NMR and binding kinetics experiments is one in which parts of both proteins are \"fuzzy\" in the free-state and some parts remain \"fuzzy\" in the NFkappaB-IkappaBalpha complex. The NFkappaB family of transcription factors responds to inflammatory cytokines with rapid transcriptional activation, in which NFkappaB enters the nucleus and binds DNA. Just as rapidly as transcription is activated, it is subsequently repressed by newly synthesized IkappaBalpha?that also enters the nucleus and removes NFkappaB from the DNA. Because IkappaBalpha?is an ankyrin repeat protein, it's \"fuzziness\" can be controlled by mutagenesis to stabilized the folded state. Experimental comparison with such stabilized mutants helps provide evidence that much of the system control depends on the \"fuzziness\" of IkappaBalpha.\n" ], "offsets": [ [ 0, 1137 ] ] } ]

[ { "id": "PMID-22399319_T1", "type": "Complex", "text": [ "NFkappaB" ], "offsets": [ [ 33, 41 ] ], "normalized": [] }, { "id": "PMID-22399319_T2", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 42, 54 ] ], "normalized": [] }, { "id": "PMID-22399319_T3", "type": "Complex", "text": [ "kappa B" ], "offsets": [ [ 184, 191 ] ], "normalized": [] }, { "id": "PMID-22399319_T4", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 193, 205 ] ], "normalized": [] }, { "id": "PMID-22399319_T5", "type": "Complex", "text": [ "nuclear factor kappa B" ], "offsets": [ [ 231, 253 ] ], "normalized": [] }, { "id": "PMID-22399319_T6", "type": "Complex", "text": [ "NFkappaB" ], "offsets": [ [ 258, 266 ] ], "normalized": [] }, { "id": "PMID-22399319_T7", "type": "Simple_chemical", "text": [ "amide" ], "offsets": [ [ 298, 303 ] ], "normalized": [] }, { "id": "PMID-22399319_T8", "type": "Simple_chemical", "text": [ "hydrogen" ], "offsets": [ [ 304, 312 ] ], "normalized": [] }, { "id": "PMID-22399319_T9", "type": "Simple_chemical", "text": [ "deuterium" ], "offsets": [ [ 313, 322 ] ], "normalized": [] }, { "id": "PMID-22399319_T10", "type": "Complex", "text": [ "NFkappaB-IkappaBalpha" ], "offsets": [ [ 476, 497 ] ], "normalized": [] }, { "id": "PMID-22399319_T11", "type": "Complex", "text": [ "NFkappaB" ], "offsets": [ [ 511, 519 ] ], "normalized": [] }, { "id": "PMID-22399319_T12", "type": "Complex", "text": [ "NFkappaB" ], "offsets": [ [ 635, 643 ] ], "normalized": [] }, { "id": "PMID-22399319_T13", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 655, 662 ] ], "normalized": [] }, { "id": "PMID-22399319_T14", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 775, 787 ] ], "normalized": [] }, { "id": "PMID-22399319_T15", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 809, 816 ] ], "normalized": [] }, { "id": "PMID-22399319_T16", "type": "Complex", "text": [ "NFkappaB" ], "offsets": [ [ 829, 837 ] ], "normalized": [] }, { "id": "PMID-22399319_T17", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 860, 872 ] ], "normalized": [] }, { "id": "PMID-22399319_T18", "type": "Gene_or_gene_product", "text": [ "ankyrin" ], "offsets": [ [ 879, 886 ] ], "normalized": [] }, { "id": "PMID-22399319_T19", "type": "Gene_or_gene_product", "text": [ "IkappaBalpha" ], "offsets": [ [ 1123, 1135 ] ], "normalized": [] } ]

[ { "id": "PMID-22399319_E1", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 55, 66 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22399319_T1" }, { "role": "Theme", "ref_id": "PMID-22399319_T2" } ] }, { "id": "PMID-22399319_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 171, 180 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22399319_T3" }, { "role": "Cause", "ref_id": "PMID-22399319_T4" } ] }, { "id": "PMID-22399319_E3", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 214, 221 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22399319_T5" }, { "role": "Theme", "ref_id": "PMID-22399319_T4" } ] }, { "id": "PMID-22399319_E4", "type": "Transport", "trigger": { "text": [ "enters" ], "offsets": [ [ 644, 650 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-22399319_T13" }, { "role": "Theme", "ref_id": "PMID-22399319_T12" } ] }, { "id": "PMID-22399319_E5", "type": "Gene_expression", "trigger": { "text": [ "synthesized" ], "offsets": [ [ 763, 774 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22399319_T14" } ] }, { "id": "PMID-22399319_E6", "type": "Transport", "trigger": { "text": [ "enters" ], "offsets": [ [ 798, 804 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-22399319_T15" }, { "role": "Theme", "ref_id": "PMID-22399319_T14" } ] }, { "id": "PMID-22399319_E7", "type": "Negative_regulation", "trigger": { "text": [ "removes" ], "offsets": [ [ 821, 828 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22399319_T16" }, { "role": "Cause", "ref_id": "PMID-22399319_T14" } ] } ]

[ { "id": "PMID-22399319_1", "entity_ids": [ "PMID-22399319_T5", "PMID-22399319_T6" ] } ]

[]

[ { "id": "PMID-22623799__text", "type": "abstract", "text": [ "Suppression of the interferon and NF-kappaB responses by severe fever with thrombocytopenia syndrome virus. \nSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease characterized by high fever, thrombocytopenia, multiorgan dysfunction, and a high fatality rate between 12 and 30%. It is caused by SFTS virus (SFTSV), a novel Phlebovirus in family Bunyaviridae. Although the viral pathogenesis remains largely unknown, hemopoietic cells appear to be targeted by the virus. In this study we report that human monocytes were susceptible to SFTSV, which replicated efficiently, as shown by an immunofluorescence assay and real-time reverse transcription-PCR. We examined host responses in the infected cells and found that antiviral interferon (IFN) and IFN-inducible proteins were induced upon infection. However, our data also indicated that downregulation of key molecules such as mitochondrial antiviral signaling protein (MAVS) or weakened activation of interferon regulatory factor (IRF) and NF-kappaB responses may contribute to a restricted innate immunity against the infection. NSs, the nonstructural protein encoded by the S segment, suppressed the beta interferon (IFN-beta) and NF-kappaB promoter activities, although NF-kappaB activation appears to facilitate SFTSV replication in human monocytes. NSs was found to be associated with TBK1 and may inhibit the activation of downstream IRF and NF-kappaB signaling through this interaction. Interestingly, we demonstrated that the nucleoprotein (N), also encoded by the S segment, exhibited a suppressive effect on the activation of IFN-beta and NF-kappaB signaling as well. Infected monocytes, mainly intact and free of apoptosis, may likely be implicated in persistent viral infection, spreading the virus to the circulation and causing primary viremia. Our findings provide the first evidence in dissecting the host responses in monocytes and understanding viral pathogenesis in humans infected with a novel deadly Bunyavirus.\n" ], "offsets": [ [ 0, 2016 ] ] } ]

[ { "id": "PMID-22623799_T1", "type": "Gene_or_gene_product", "text": [ "interferon" ], "offsets": [ [ 19, 29 ] ], "normalized": [] }, { "id": "PMID-22623799_T2", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 34, 43 ] ], "normalized": [] }, { "id": "PMID-22623799_T3", "type": "Gene_or_gene_product", "text": [ "interferon" ], "offsets": [ [ 758, 768 ] ], "normalized": [] }, { "id": "PMID-22623799_T4", "type": "Gene_or_gene_product", "text": [ "IFN" ], "offsets": [ [ 770, 773 ] ], "normalized": [] }, { "id": "PMID-22623799_T5", "type": "Gene_or_gene_product", "text": [ "IFN" ], "offsets": [ [ 779, 782 ] ], "normalized": [] }, { "id": "PMID-22623799_T6", "type": "Gene_or_gene_product", "text": [ "mitochondrial antiviral signaling protein" ], "offsets": [ [ 909, 950 ] ], "normalized": [] }, { "id": "PMID-22623799_T7", "type": "Gene_or_gene_product", "text": [ "MAVS" ], "offsets": [ [ 952, 956 ] ], "normalized": [] }, { "id": "PMID-22623799_T8", "type": "Gene_or_gene_product", "text": [ "interferon regulatory factor" ], "offsets": [ [ 984, 1012 ] ], "normalized": [] }, { "id": "PMID-22623799_T9", "type": "Gene_or_gene_product", "text": [ "IRF" ], "offsets": [ [ 1014, 1017 ] ], "normalized": [] }, { "id": "PMID-22623799_T10", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1023, 1032 ] ], "normalized": [] }, { "id": "PMID-22623799_T11", "type": "Gene_or_gene_product", "text": [ "NSs" ], "offsets": [ [ 1113, 1116 ] ], "normalized": [] }, { "id": "PMID-22623799_T12", "type": "Gene_or_gene_product", "text": [ "beta interferon" ], "offsets": [ [ 1185, 1200 ] ], "normalized": [] }, { "id": "PMID-22623799_T13", "type": "Gene_or_gene_product", "text": [ "IFN-beta" ], "offsets": [ [ 1202, 1210 ] ], "normalized": [] }, { "id": "PMID-22623799_T14", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1216, 1225 ] ], "normalized": [] }, { "id": "PMID-22623799_T15", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1256, 1265 ] ], "normalized": [] }, { "id": "PMID-22623799_T16", "type": "Gene_or_gene_product", "text": [ "NSs" ], "offsets": [ [ 1337, 1340 ] ], "normalized": [] }, { "id": "PMID-22623799_T17", "type": "Gene_or_gene_product", "text": [ "TBK1" ], "offsets": [ [ 1373, 1377 ] ], "normalized": [] }, { "id": "PMID-22623799_T18", "type": "Gene_or_gene_product", "text": [ "IRF" ], "offsets": [ [ 1423, 1426 ] ], "normalized": [] }, { "id": "PMID-22623799_T19", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1431, 1440 ] ], "normalized": [] }, { "id": "PMID-22623799_T20", "type": "Gene_or_gene_product", "text": [ "IFN-beta" ], "offsets": [ [ 1619, 1627 ] ], "normalized": [] }, { "id": "PMID-22623799_T21", "type": "Complex", "text": [ "NF-kappaB" ], "offsets": [ [ 1632, 1641 ] ], "normalized": [] } ]

[ { "id": "PMID-22623799_E1", "type": "Negative_regulation", "trigger": { "text": [ "Suppression" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_T1" } ] }, { "id": "PMID-22623799_E2", "type": "Negative_regulation", "trigger": { "text": [ "Suppression" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_T2" } ] }, { "id": "PMID-22623799_E3", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 807, 814 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_T3" } ] }, { "id": "PMID-22623799_E4", "type": "Negative_regulation", "trigger": { "text": [ "downregulation" ], "offsets": [ [ 869, 883 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_T6" } ] }, { "id": "PMID-22623799_E5", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 970, 980 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_T8" } ] }, { "id": "PMID-22623799_E6", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 970, 980 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_T10" } ] }, { "id": "PMID-22623799_E7", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1170, 1180 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22623799_T11" }, { "role": "Theme", "ref_id": "PMID-22623799_T12" } ] }, { "id": "PMID-22623799_E8", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1170, 1180 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22623799_T11" }, { "role": "Theme", "ref_id": "PMID-22623799_T14" } ] }, { "id": "PMID-22623799_E9", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1266, 1276 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_T15" } ] }, { "id": "PMID-22623799_E10", "type": "Binding", "trigger": { "text": [ "associated" ], "offsets": [ [ 1357, 1367 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_T16" }, { "role": "Theme", "ref_id": "PMID-22623799_T17" } ] }, { "id": "PMID-22623799_E11", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1386, 1393 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22623799_T16" }, { "role": "Theme", "ref_id": "PMID-22623799_E13" } ] }, { "id": "PMID-22623799_E12", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1386, 1393 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22623799_T16" }, { "role": "Theme", "ref_id": "PMID-22623799_E14" } ] }, { "id": "PMID-22623799_E13", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1398, 1408 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22623799_E16" }, { "role": "Theme", "ref_id": "PMID-22623799_T18" } ] }, { "id": "PMID-22623799_E14", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1398, 1408 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-22623799_E16" }, { "role": "Theme", "ref_id": "PMID-22623799_E15" } ] }, { "id": "PMID-22623799_E15", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1441, 1450 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22623799_T19" } ] }, { "id": "PMID-22623799_E16", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1464, 1475 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_T16" }, { "role": "Theme", "ref_id": "PMID-22623799_T17" } ] }, { "id": "PMID-22623799_E17", "type": "Negative_regulation", "trigger": { "text": [ "suppressive effect" ], "offsets": [ [ 1579, 1597 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_E19" } ] }, { "id": "PMID-22623799_E18", "type": "Negative_regulation", "trigger": { "text": [ "suppressive effect" ], "offsets": [ [ 1579, 1597 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_E20" } ] }, { "id": "PMID-22623799_E19", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1605, 1615 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_T20" } ] }, { "id": "PMID-22623799_E20", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1605, 1615 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-22623799_E21" } ] }, { "id": "PMID-22623799_E21", "type": "Pathway", "trigger": { "text": [ "signaling" ], "offsets": [ [ 1642, 1651 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-22623799_T21" } ] }, { "id": "PMID-22623799_E22", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1707, 1716 ] ] }, "arguments": [] } ]

[ { "id": "PMID-22623799_1", "entity_ids": [ "PMID-22623799_T3", "PMID-22623799_T4" ] }, { "id": "PMID-22623799_2", "entity_ids": [ "PMID-22623799_T6", "PMID-22623799_T7" ] }, { "id": "PMID-22623799_3", "entity_ids": [ "PMID-22623799_T8", "PMID-22623799_T9" ] }, { "id": "PMID-22623799_4", "entity_ids": [ "PMID-22623799_T12", "PMID-22623799_T13" ] } ]

[]

[ { "id": "PMID-2355012__text", "type": "abstract", "text": [ "Association of initiation factor eIF-4E in a cap binding protein complex (eIF-4F) is critical for and enhances phosphorylation by protein kinase C. \nPhosphorylation by protein kinase C of the mRNA cap binding protein purified as part of a cap binding protein complex (eIF-4F) or as a single protein (eIF-4E), has been examined. Significant phosphorylation (up to 1 mol of phosphate/mol of p25 subunit) occurs only when the protein is part of the eIF-4F complex. With purified eIF-4E, using the same conditions, up to 0.1 mol of phosphate can be incorporated. Tryptic phosphopeptide maps show that the site phosphorylated in the Mr 25,000 subunit of eIF-4F (eIF-4F p25) is the same as that modified in purified eIF-4E. Kinetic measurements obtained from initial rates indicate that the Km values for eIF-4F and eIF-4E are similar, although the Vmax is 5-6 times higher for the complex. Dephosphorylation of eIF-4F p25, previously phosphorylated with protein kinase C, occurs in reticulocyte lysate with a half-life of 15-20 min, whereas little dephosphorylation is observed after 15 min with the purified phosphorylated eIF-4E. Phosphorylation of eIF-4F on the p220 and p25 subunits does not affect the stability of the complex as indicated by gel filtration on Sephacryl S-300. However, addition of non-phosphorylated eIF-4E to the phosphorylated complex results in the dissociation of the complex. These results suggest that interaction of p25 with other subunits in the complex greatly affects phosphorylation/dephosphorylation of p25. Since the rate of phosphorylation/dephosphorylation is significantly greater in the complex, regulation of the cap binding protein by phosphorylation appears to occur primarily on eIF-4F. \n" ], "offsets": [ [ 0, 1727 ] ] } ]

[ { "id": "PMID-2355012_T1", "type": "Gene_or_gene_product", "text": [ "eIF-4E" ], "offsets": [ [ 33, 39 ] ], "normalized": [] }, { "id": "PMID-2355012_T2", "type": "Complex", "text": [ "eIF-4F" ], "offsets": [ [ 74, 80 ] ], "normalized": [] }, { "id": "PMID-2355012_T3", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 130, 146 ] ], "normalized": [] }, { "id": "PMID-2355012_T4", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 168, 184 ] ], "normalized": [] }, { "id": "PMID-2355012_T5", "type": "Complex", "text": [ "eIF-4F" ], "offsets": [ [ 268, 274 ] ], "normalized": [] }, { "id": "PMID-2355012_T6", "type": "Gene_or_gene_product", "text": [ "eIF-4E" ], "offsets": [ [ 300, 306 ] ], "normalized": [] }, { "id": "PMID-2355012_T7", "type": "Simple_chemical", "text": [ "phosphate" ], "offsets": [ [ 372, 381 ] ], "normalized": [] }, { "id": "PMID-2355012_T8", "type": "Gene_or_gene_product", "text": [ "p25" ], "offsets": [ [ 389, 392 ] ], "normalized": [] }, { "id": "PMID-2355012_T9", "type": "Complex", "text": [ "eIF-4F" ], "offsets": [ [ 446, 452 ] ], "normalized": [] }, { "id": "PMID-2355012_T10", "type": "Gene_or_gene_product", "text": [ "eIF-4E" ], "offsets": [ [ 476, 482 ] ], "normalized": [] }, { "id": "PMID-2355012_T11", "type": "Simple_chemical", "text": [ "phosphate" ], "offsets": [ [ 528, 537 ] ], "normalized": [] }, { "id": "PMID-2355012_T12", "type": "Complex", "text": [ "eIF-4F" ], "offsets": [ [ 649, 655 ] ], "normalized": [] }, { "id": "PMID-2355012_T13", "type": "Gene_or_gene_product", "text": [ "eIF-4F p25" ], "offsets": [ [ 657, 667 ] ], "normalized": [] }, { "id": "PMID-2355012_T14", "type": "Gene_or_gene_product", "text": [ "eIF-4E" ], "offsets": [ [ 710, 716 ] ], "normalized": [] }, { "id": "PMID-2355012_T15", "type": "Complex", "text": [ "eIF-4F" ], "offsets": [ [ 799, 805 ] ], "normalized": [] }, { "id": "PMID-2355012_T16", "type": "Gene_or_gene_product", "text": [ "eIF-4E" ], "offsets": [ [ 810, 816 ] ], "normalized": [] }, { "id": "PMID-2355012_T17", "type": "Gene_or_gene_product", "text": [ "eIF-4F p25" ], "offsets": [ [ 906, 916 ] ], "normalized": [] }, { "id": "PMID-2355012_T18", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 949, 965 ] ], "normalized": [] }, { "id": "PMID-2355012_T19", "type": "Gene_or_gene_product", "text": [ "eIF-4E" ], "offsets": [ [ 1119, 1125 ] ], "normalized": [] }, { "id": "PMID-2355012_T20", "type": "Complex", "text": [ "eIF-4F" ], "offsets": [ [ 1146, 1152 ] ], "normalized": [] }, { "id": "PMID-2355012_T21", "type": "Gene_or_gene_product", "text": [ "p220" ], "offsets": [ [ 1160, 1164 ] ], "normalized": [] }, { "id": "PMID-2355012_T22", "type": "Gene_or_gene_product", "text": [ "p25" ], "offsets": [ [ 1169, 1172 ] ], "normalized": [] }, { "id": "PMID-2355012_T23", "type": "Simple_chemical", "text": [ "Sephacryl S-300" ], "offsets": [ [ 1261, 1276 ] ], "normalized": [] }, { "id": "PMID-2355012_T24", "type": "Gene_or_gene_product", "text": [ "eIF-4E" ], "offsets": [ [ 1318, 1324 ] ], "normalized": [] }, { "id": "PMID-2355012_T25", "type": "Gene_or_gene_product", "text": [ "p25" ], "offsets": [ [ 1441, 1444 ] ], "normalized": [] }, { "id": "PMID-2355012_T26", "type": "Gene_or_gene_product", "text": [ "p25" ], "offsets": [ [ 1533, 1536 ] ], "normalized": [] }, { "id": "PMID-2355012_T27", "type": "Complex", "text": [ "eIF-4F" ], "offsets": [ [ 1718, 1724 ] ], "normalized": [] } ]

[ { "id": "PMID-2355012_E1", "type": "Binding", "trigger": { "text": [ "Association" ], "offsets": [ [ 0, 11 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T1" }, { "role": "Product", "ref_id": "PMID-2355012_T2" } ] }, { "id": "PMID-2355012_E2", "type": "Positive_regulation", "trigger": { "text": [ "critical" ], "offsets": [ [ 85, 93 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_E4" }, { "role": "Cause", "ref_id": "PMID-2355012_E1" } ] }, { "id": "PMID-2355012_E3", "type": "Positive_regulation", "trigger": { "text": [ "enhances" ], "offsets": [ [ 102, 110 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_E4" }, { "role": "Cause", "ref_id": "PMID-2355012_E1" } ] }, { "id": "PMID-2355012_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 111, 126 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T1" }, { "role": "Cause", "ref_id": "PMID-2355012_T3" } ] }, { "id": "PMID-2355012_E5", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 149, 164 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T5" }, { "role": "Cause", "ref_id": "PMID-2355012_T4" } ] }, { "id": "PMID-2355012_E6", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 149, 164 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T6" }, { "role": "Cause", "ref_id": "PMID-2355012_T4" } ] }, { "id": "PMID-2355012_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 340, 355 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T8" } ] }, { "id": "PMID-2355012_E8", "type": "Phosphorylation", "trigger": { "text": [ "incorporated" ], "offsets": [ [ 545, 557 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T10" } ] }, { "id": "PMID-2355012_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 606, 620 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T13" } ] }, { "id": "PMID-2355012_E10", "type": "Phosphorylation", "trigger": { "text": [ "modified" ], "offsets": [ [ 689, 697 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T14" } ] }, { "id": "PMID-2355012_E11", "type": "Dephosphorylation", "trigger": { "text": [ "Dephosphorylation" ], "offsets": [ [ 885, 902 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T17" } ] }, { "id": "PMID-2355012_E12", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 929, 943 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T17" }, { "role": "Cause", "ref_id": "PMID-2355012_T18" } ] }, { "id": "PMID-2355012_E13", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylation" ], "offsets": [ [ 1043, 1060 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T19" } ] }, { "id": "PMID-2355012_E14", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 1104, 1118 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T19" } ] }, { "id": "PMID-2355012_E15", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 1127, 1142 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T22" } ] }, { "id": "PMID-2355012_E16", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 1127, 1142 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T21" } ] }, { "id": "PMID-2355012_E17", "type": "Phosphorylation", "trigger": { "text": [ "Phosphorylation" ], "offsets": [ [ 1127, 1142 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T20" } ] }, { "id": "PMID-2355012_E18", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 1191, 1197 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T20" }, { "role": "Cause", "ref_id": "PMID-2355012_E17" } ] }, { "id": "PMID-2355012_E19", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 1191, 1197 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T20" }, { "role": "Cause", "ref_id": "PMID-2355012_E15" } ] }, { "id": "PMID-2355012_E20", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 1191, 1197 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T20" }, { "role": "Cause", "ref_id": "PMID-2355012_E16" } ] }, { "id": "PMID-2355012_E21", "type": "Phosphorylation", "trigger": { "text": [ "non-phosphorylated" ], "offsets": [ [ 1299, 1317 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T24" } ] }, { "id": "PMID-2355012_E22", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 1332, 1346 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T20" } ] }, { "id": "PMID-2355012_E23", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 1355, 1362 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_E24" } ] }, { "id": "PMID-2355012_E24", "type": "Dissociation", "trigger": { "text": [ "dissociation" ], "offsets": [ [ 1370, 1382 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T20" } ] }, { "id": "PMID-2355012_E25", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1426, 1437 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T25" } ] }, { "id": "PMID-2355012_E26", "type": "Regulation", "trigger": { "text": [ "affects" ], "offsets": [ [ 1488, 1495 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-2355012_E25" }, { "role": "Theme", "ref_id": "PMID-2355012_E29" } ] }, { "id": "PMID-2355012_E27", "type": "Regulation", "trigger": { "text": [ "affects" ], "offsets": [ [ 1488, 1495 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-2355012_E25" }, { "role": "Theme", "ref_id": "PMID-2355012_E28" } ] }, { "id": "PMID-2355012_E28", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1496, 1511 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T26" } ] }, { "id": "PMID-2355012_E29", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylation" ], "offsets": [ [ 1512, 1529 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T26" } ] }, { "id": "PMID-2355012_E30", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1556, 1571 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T26" } ] }, { "id": "PMID-2355012_E31", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylation" ], "offsets": [ [ 1572, 1589 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T26" } ] }, { "id": "PMID-2355012_E32", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1672, 1687 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2355012_T26" } ] } ]

[]

[]

[ { "id": "PMID-2377602__text", "type": "abstract", "text": [ "Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12-lipoxygenase. \nThe major pathway of arachidonic acid metabolism in human platelets proceeds via a 12-lipoxygenase enzyme; however, the biological role of the product of this reaction, 12-hydro(pero)xyeicosatetraenoic acid [12-H(P)ETE], is unknown. Using a combination of the polymerase chain reaction and conventional screening procedures, we have isolated cDNA clones encoding the human platelet/human erythroleukemia (HEL) cell 12-lipoxygenase. From the deduced primary structure, human platelet/HEL 12-lipoxygenase would encode a Mr 75,000 protein consisting of 663 amino acids. The cDNA encoding the full-length protein (pCDNA-121x) under the control of the cytomegalovirus promoter was expressed in simian COS-M6 cells. Intact cells and lysed-cell supernatants were able to synthesize 12-H(P)ETE from arachidonic acid, whereas no 12-H(P)ETE synthesis was detected in mock-transfected cells. A single 2.4-kilobase mRNA was detected in erythroleukemia cells but not in several other tissues and cell lines evaluated by Northern blot analysis. Comparison of the human platelet/HEL 12-lipoxygenase sequence with that of porcine leukocyte 12-lipoxygenase and human reticulocyte 15-lipoxygenase revealed 65% amino acid identity to both enzymes. By contrast, the leukocyte 12-lipoxygenase is 86% identical to human reticulocyte 15-lipoxygenase. Sequence data and previously demonstrated immunochemical and biochemical evidence support the existence of distinct 12-lipoxygenase isoforms. The availability of cDNA probes for human platelet/HEL cell 12-lipoxygenase should facilitate elucidation of the biological role of this pathway.\n" ], "offsets": [ [ 0, 1730 ] ] } ]

[ { "id": "PMID-2377602_T1", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 96, 111 ] ], "normalized": [] }, { "id": "PMID-2377602_T2", "type": "Simple_chemical", "text": [ "arachidonic acid" ], "offsets": [ [ 135, 151 ] ], "normalized": [] }, { "id": "PMID-2377602_T3", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 197, 212 ] ], "normalized": [] }, { "id": "PMID-2377602_T4", "type": "Simple_chemical", "text": [ "12-hydro(pero)xyeicosatetraenoic acid" ], "offsets": [ [ 283, 320 ] ], "normalized": [] }, { "id": "PMID-2377602_T5", "type": "Simple_chemical", "text": [ "12-H(P)ETE" ], "offsets": [ [ 322, 332 ] ], "normalized": [] }, { "id": "PMID-2377602_T6", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 529, 544 ] ], "normalized": [] }, { "id": "PMID-2377602_T7", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 601, 616 ] ], "normalized": [] }, { "id": "PMID-2377602_T8", "type": "Gene_or_gene_product", "text": [ "pCDNA-121x" ], "offsets": [ [ 724, 734 ] ], "normalized": [] }, { "id": "PMID-2377602_T9", "type": "Simple_chemical", "text": [ "12-H(P)ETE" ], "offsets": [ [ 889, 899 ] ], "normalized": [] }, { "id": "PMID-2377602_T10", "type": "Simple_chemical", "text": [ "arachidonic acid" ], "offsets": [ [ 905, 921 ] ], "normalized": [] }, { "id": "PMID-2377602_T11", "type": "Simple_chemical", "text": [ "12-H(P)ETE" ], "offsets": [ [ 934, 944 ] ], "normalized": [] }, { "id": "PMID-2377602_T12", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 1182, 1197 ] ], "normalized": [] }, { "id": "PMID-2377602_T13", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 1238, 1253 ] ], "normalized": [] }, { "id": "PMID-2377602_T14", "type": "Gene_or_gene_product", "text": [ "15-lipoxygenase" ], "offsets": [ [ 1277, 1292 ] ], "normalized": [] }, { "id": "PMID-2377602_T15", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 1370, 1385 ] ], "normalized": [] }, { "id": "PMID-2377602_T16", "type": "Gene_or_gene_product", "text": [ "15-lipoxygenase" ], "offsets": [ [ 1425, 1440 ] ], "normalized": [] }, { "id": "PMID-2377602_T17", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 1558, 1573 ] ], "normalized": [] }, { "id": "PMID-2377602_T18", "type": "Gene_or_gene_product", "text": [ "12-lipoxygenase" ], "offsets": [ [ 1644, 1659 ] ], "normalized": [] } ]

[ { "id": "PMID-2377602_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 42, 52 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2377602_T1" } ] }, { "id": "PMID-2377602_E2", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 124, 131 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-2377602_T2" } ] }, { "id": "PMID-2377602_E3", "type": "Conversion", "trigger": { "text": [ "metabolism" ], "offsets": [ [ 152, 162 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2377602_T2" }, { "role": "Product", "ref_id": "PMID-2377602_T4" } ] }, { "id": "PMID-2377602_E4", "type": "Positive_regulation", "trigger": { "text": [ "proceeds" ], "offsets": [ [ 182, 190 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2377602_E2" }, { "role": "Cause", "ref_id": "PMID-2377602_T3" } ] }, { "id": "PMID-2377602_E5", "type": "Conversion", "trigger": { "text": [ "synthesize" ], "offsets": [ [ 878, 888 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-2377602_T9" }, { "role": "Theme", "ref_id": "PMID-2377602_T10" } ] }, { "id": "PMID-2377602_E6", "type": "Conversion", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 945, 954 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-2377602_T11" } ] } ]

[ { "id": "PMID-2377602_1", "entity_ids": [ "PMID-2377602_T5", "PMID-2377602_T4" ] } ]

[]

[ { "id": "PMID-2581505__text", "type": "abstract", "text": [ "Kinetic properties of the plasma membrane Na+-H+ exchanger. \nThe plasma membrane Na+-H+ exchanger is a ubiquitous transport system that participates in diverse cell functions involving the cellular uptake of Na+ or extrusion of H+. It has a tightly coupled 1:1 stoichiometry, has affinity for Li+ and NH+4 in addition to Na+ and H+, and can function in multiple amiloride-sensitive exchange modes involving these cations. These general transport properties may be explained by kinetic models involving either cation-hydroxyl cotransport or actual cation-proton exchange. The most important kinetic property of the Na+-H+ exchanger is its greater than first-order dependence on [H+]i. This property enables the Na+-H+ exchanger to play an important role in the regulation of intracellular pH.\n" ], "offsets": [ [ 0, 792 ] ] } ]

[ { "id": "PMID-2581505_T1", "type": "Cellular_component", "text": [ "plasma membrane" ], "offsets": [ [ 26, 41 ] ], "normalized": [] }, { "id": "PMID-2581505_T2", "type": "Gene_or_gene_product", "text": [ "Na+-H+ exchanger" ], "offsets": [ [ 42, 58 ] ], "normalized": [] }, { "id": "PMID-2581505_T3", "type": "Cellular_component", "text": [ "plasma membrane" ], "offsets": [ [ 65, 80 ] ], "normalized": [] }, { "id": "PMID-2581505_T4", "type": "Gene_or_gene_product", "text": [ "Na+-H+ exchanger" ], "offsets": [ [ 81, 97 ] ], "normalized": [] }, { "id": "PMID-2581505_T5", "type": "Simple_chemical", "text": [ "Na+" ], "offsets": [ [ 208, 211 ] ], "normalized": [] }, { "id": "PMID-2581505_T6", "type": "Simple_chemical", "text": [ "H+" ], "offsets": [ [ 228, 230 ] ], "normalized": [] }, { "id": "PMID-2581505_T7", "type": "Simple_chemical", "text": [ "Li+" ], "offsets": [ [ 293, 296 ] ], "normalized": [] }, { "id": "PMID-2581505_T8", "type": "Simple_chemical", "text": [ "NH+4" ], "offsets": [ [ 301, 305 ] ], "normalized": [] }, { "id": "PMID-2581505_T9", "type": "Simple_chemical", "text": [ "Na+" ], "offsets": [ [ 321, 324 ] ], "normalized": [] }, { "id": "PMID-2581505_T10", "type": "Simple_chemical", "text": [ "H+" ], "offsets": [ [ 329, 331 ] ], "normalized": [] }, { "id": "PMID-2581505_T11", "type": "Simple_chemical", "text": [ "amiloride" ], "offsets": [ [ 362, 371 ] ], "normalized": [] }, { "id": "PMID-2581505_T12", "type": "Simple_chemical", "text": [ "cations" ], "offsets": [ [ 413, 420 ] ], "normalized": [] }, { "id": "PMID-2581505_T13", "type": "Simple_chemical", "text": [ "cation" ], "offsets": [ [ 509, 515 ] ], "normalized": [] }, { "id": "PMID-2581505_T14", "type": "Simple_chemical", "text": [ "hydroxyl" ], "offsets": [ [ 516, 524 ] ], "normalized": [] }, { "id": "PMID-2581505_T15", "type": "Simple_chemical", "text": [ "cation" ], "offsets": [ [ 547, 553 ] ], "normalized": [] }, { "id": "PMID-2581505_T16", "type": "Simple_chemical", "text": [ "proton" ], "offsets": [ [ 554, 560 ] ], "normalized": [] }, { "id": "PMID-2581505_T17", "type": "Gene_or_gene_product", "text": [ "Na+-H+ exchanger" ], "offsets": [ [ 614, 630 ] ], "normalized": [] }, { "id": "PMID-2581505_T18", "type": "Simple_chemical", "text": [ "[H+]i" ], "offsets": [ [ 677, 682 ] ], "normalized": [] }, { "id": "PMID-2581505_T19", "type": "Gene_or_gene_product", "text": [ "Na+-H+ exchanger" ], "offsets": [ [ 710, 726 ] ], "normalized": [] }, { "id": "PMID-2581505_T20", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 774, 787 ] ], "normalized": [] } ]

[ { "id": "PMID-2581505_E1", "type": "Regulation", "trigger": { "text": [ "participates" ], "offsets": [ [ 136, 148 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-2581505_T4" }, { "role": "Theme", "ref_id": "PMID-2581505_E3" } ] }, { "id": "PMID-2581505_E2", "type": "Regulation", "trigger": { "text": [ "participates" ], "offsets": [ [ 136, 148 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-2581505_T4" }, { "role": "Theme", "ref_id": "PMID-2581505_E4" } ] }, { "id": "PMID-2581505_E3", "type": "Regulation", "trigger": { "text": [ "involving" ], "offsets": [ [ 175, 184 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_E5" } ] }, { "id": "PMID-2581505_E4", "type": "Regulation", "trigger": { "text": [ "involving" ], "offsets": [ [ 175, 184 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_E6" } ] }, { "id": "PMID-2581505_E5", "type": "Transport", "trigger": { "text": [ "uptake" ], "offsets": [ [ 198, 204 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T5" } ] }, { "id": "PMID-2581505_E6", "type": "Transport", "trigger": { "text": [ "extrusion" ], "offsets": [ [ 215, 224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T6" } ] }, { "id": "PMID-2581505_E7", "type": "Binding", "trigger": { "text": [ "affinity" ], "offsets": [ [ 280, 288 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T4" }, { "role": "Theme", "ref_id": "PMID-2581505_T7" }, { "role": "Theme", "ref_id": "PMID-2581505_T8" } ] }, { "id": "PMID-2581505_E8", "type": "Binding", "trigger": { "text": [ "affinity" ], "offsets": [ [ 280, 288 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T4" }, { "role": "Theme", "ref_id": "PMID-2581505_T9" }, { "role": "Theme", "ref_id": "PMID-2581505_T10" } ] }, { "id": "PMID-2581505_E9", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 372, 381 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-2581505_T11" }, { "role": "Theme", "ref_id": "PMID-2581505_E14" } ] }, { "id": "PMID-2581505_E10", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 372, 381 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-2581505_T11" }, { "role": "Theme", "ref_id": "PMID-2581505_E15" } ] }, { "id": "PMID-2581505_E11", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 372, 381 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-2581505_T11" }, { "role": "Theme", "ref_id": "PMID-2581505_E16" } ] }, { "id": "PMID-2581505_E12", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 372, 381 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-2581505_T11" }, { "role": "Theme", "ref_id": "PMID-2581505_E17" } ] }, { "id": "PMID-2581505_E13", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 372, 381 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-2581505_T11" }, { "role": "Theme", "ref_id": "PMID-2581505_E18" } ] }, { "id": "PMID-2581505_E14", "type": "Transport", "trigger": { "text": [ "exchange" ], "offsets": [ [ 382, 390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T12" } ] }, { "id": "PMID-2581505_E15", "type": "Transport", "trigger": { "text": [ "exchange" ], "offsets": [ [ 382, 390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T7" } ] }, { "id": "PMID-2581505_E16", "type": "Transport", "trigger": { "text": [ "exchange" ], "offsets": [ [ 382, 390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T8" } ] }, { "id": "PMID-2581505_E17", "type": "Transport", "trigger": { "text": [ "exchange" ], "offsets": [ [ 382, 390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T9" } ] }, { "id": "PMID-2581505_E18", "type": "Transport", "trigger": { "text": [ "exchange" ], "offsets": [ [ 382, 390 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T10" } ] }, { "id": "PMID-2581505_E19", "type": "Transport", "trigger": { "text": [ "cotransport" ], "offsets": [ [ 525, 536 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T13" } ] }, { "id": "PMID-2581505_E20", "type": "Transport", "trigger": { "text": [ "cotransport" ], "offsets": [ [ 525, 536 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T14" } ] }, { "id": "PMID-2581505_E21", "type": "Transport", "trigger": { "text": [ "exchange" ], "offsets": [ [ 561, 569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T15" } ] }, { "id": "PMID-2581505_E22", "type": "Transport", "trigger": { "text": [ "exchange" ], "offsets": [ [ 561, 569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T16" } ] }, { "id": "PMID-2581505_E23", "type": "Positive_regulation", "trigger": { "text": [ "dependence" ], "offsets": [ [ 663, 673 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-2581505_T17" }, { "role": "Cause", "ref_id": "PMID-2581505_T18" } ] } ]

[]

[]

[ { "id": "PMID-3034602__text", "type": "abstract", "text": [ "Molecular cloning of the beta-subunit of human prolyl 4-hydroxylase. This subunit and protein disulphide isomerase are products of the same gene. \nProlyl 4-hydroxylase (EC 1.14.11.2), an alpha 2 beta 2 tetramer, catalyses the formation of 4-hydroxyproline in collagens by the hydroxylation of proline residues in peptide linkages. We report here the isolation of cDNA clones coding for the beta-subunit of prolyl 4-hydroxylase from a human hepatoma lambda gt11 library and a corresponding human placenta library. Five overlapping clones covering all the coding sequences and almost all the non-coding sequences were characterized. The size of the mRNA hybridizing with these clones in Northern blotting is approximately 2.5 kb. The clones encode a polypeptide of 508 amino acid residues, including a signal peptide of 17 amino acids. These human sequences were found to be very similar to those recently reported for rat protein disulphide isomerase (EC 5.3.4.1). The degree of homology between these two proteins was 84% at the level of nucleotide sequences or 94% at the level of amino acid sequences. Southern blot analyses of human genomic DNA with a cDNA probe for the beta-subunit indicated the presence of only one gene containing these sequences. The product of a single gene thus appears to possess two different enzymatic functions depending on whether it is present in cells in monomer form or in the prolyl 4-hydroxylase tetramer.\n" ], "offsets": [ [ 0, 1443 ] ] } ]

[ { "id": "PMID-3034602_T1", "type": "Complex", "text": [ "prolyl 4-hydroxylase" ], "offsets": [ [ 47, 67 ] ], "normalized": [] }, { "id": "PMID-3034602_T2", "type": "Gene_or_gene_product", "text": [ "protein disulphide isomerase" ], "offsets": [ [ 86, 114 ] ], "normalized": [] }, { "id": "PMID-3034602_T3", "type": "Complex", "text": [ "Prolyl 4-hydroxylase" ], "offsets": [ [ 147, 167 ] ], "normalized": [] }, { "id": "PMID-3034602_T4", "type": "Gene_or_gene_product", "text": [ "EC 1.14.11.2" ], "offsets": [ [ 169, 181 ] ], "normalized": [] }, { "id": "PMID-3034602_T5", "type": "Simple_chemical", "text": [ "4-hydroxyproline" ], "offsets": [ [ 239, 255 ] ], "normalized": [] }, { "id": "PMID-3034602_T6", "type": "Simple_chemical", "text": [ "collagens" ], "offsets": [ [ 259, 268 ] ], "normalized": [] }, { "id": "PMID-3034602_T7", "type": "Simple_chemical", "text": [ "proline" ], "offsets": [ [ 293, 300 ] ], "normalized": [] }, { "id": "PMID-3034602_T8", "type": "Complex", "text": [ "prolyl 4-hydroxylase" ], "offsets": [ [ 406, 426 ] ], "normalized": [] }, { "id": "PMID-3034602_T9", "type": "Gene_or_gene_product", "text": [ "protein disulphide isomerase" ], "offsets": [ [ 921, 949 ] ], "normalized": [] }, { "id": "PMID-3034602_T10", "type": "Gene_or_gene_product", "text": [ "EC 5.3.4.1" ], "offsets": [ [ 951, 961 ] ], "normalized": [] }, { "id": "PMID-3034602_T11", "type": "Complex", "text": [ "prolyl 4-hydroxylase" ], "offsets": [ [ 1412, 1432 ] ], "normalized": [] } ]

[ { "id": "PMID-3034602_E1", "type": "Positive_regulation", "trigger": { "text": [ "catalyses" ], "offsets": [ [ 212, 221 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-3034602_E4" }, { "role": "Cause", "ref_id": "PMID-3034602_T3" } ] }, { "id": "PMID-3034602_E2", "type": "Positive_regulation", "trigger": { "text": [ "catalyses" ], "offsets": [ [ 212, 221 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-3034602_E4" }, { "role": "Cause", "ref_id": "PMID-3034602_T4" } ] }, { "id": "PMID-3034602_E3", "type": "Positive_regulation", "trigger": { "text": [ "catalyses" ], "offsets": [ [ 212, 221 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-3034602_E4" }, { "role": "Cause", "ref_id": "PMID-3034602_E5" } ] }, { "id": "PMID-3034602_E4", "type": "Conversion", "trigger": { "text": [ "formation" ], "offsets": [ [ 226, 235 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-3034602_T5" }, { "role": "Theme", "ref_id": "PMID-3034602_T7" } ] }, { "id": "PMID-3034602_E5", "type": "Hydroxylation", "trigger": { "text": [ "hydroxylation" ], "offsets": [ [ 276, 289 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-3034602_T7" } ] }, { "id": "PMID-3034602_E6", "type": "Binding", "trigger": { "text": [ "tetramer" ], "offsets": [ [ 1433, 1441 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-3034602_T11" } ] } ]

[]

[]

[ { "id": "PMID-3759988__text", "type": "abstract", "text": [ "Quantitation of the efflux of acylcarnitines from rat heart, brain, and liver mitochondria. \nThe efflux of individual short-chain and medium-chain acylcarnitines from rat liver, heart, and brain mitochondria metabolizing several substrates has been measured. The acylcarnitine efflux profiles depend on the substrate, the source of mitochondria, and the incubation conditions. The largest amount of any acylcarnitine effluxing per mg of protein was acetylcarnitine produced by heart mitochondria from pyruvate. This efflux of acetylcarnitine from heart mitochondria is almost 5 times greater with 1 mM than 0.2 mM carnitine. Apparently the acetyl-CoA generated from pyruvate by pyruvate dehydrogenase is very accessible to carnitine acetyltransferase. Very little acetylcarnitine effluxes from heart mitochondria when octanoate is the substrate except in the presence of malonate. Acetylcarnitine production from some substrates peaks and then declines, indicating uptake and utilization. The unequivocal demonstration that considerable amounts of propionylcarnitine or isobutyrylcarnitine efflux from heart mitochondria metabolizing alpha-ketoisovalerate and alpha-keto-beta-methylvalerate provides evidence for a role (via removal of non-metabolizable propionyl-CoA or slowly metabolizable acyl-CoAs) for carnitine in tissues which have limited capacity to metabolize propionyl-CoA. These results also show propionyl-CoA must be formed during the metabolism of alpha-ketoisovalerate and that extra-mitochondrial free carnitine rapidly interacts with matrix short-chain aliphatic acyl-CoA generated from alpha-keto acids of branched-chain amino acids and pyruvate in the presence and absence of malate.\n" ], "offsets": [ [ 0, 1704 ] ] } ]

[ { "id": "PMID-3759988_T1", "type": "Simple_chemical", "text": [ "acylcarnitines" ], "offsets": [ [ 30, 44 ] ], "normalized": [] }, { "id": "PMID-3759988_T2", "type": "Cellular_component", "text": [ "mitochondria" ], "offsets": [ [ 78, 90 ] ], "normalized": [] }, { "id": "PMID-3759988_T3", "type": "Simple_chemical", "text": [ "acylcarnitines" ], "offsets": [ [ 147, 161 ] ], "normalized": [] }, { "id": "PMID-3759988_T4", "type": "Cellular_component", "text": [ "mitochondria" ], "offsets": [ [ 195, 207 ] ], "normalized": [] }, { "id": "PMID-3759988_T5", "type": "Simple_chemical", "text": [ "acylcarnitine" ], "offsets": [ [ 263, 276 ] ], "normalized": [] }, { "id": "PMID-3759988_T6", "type": "Cellular_component", "text": [ "mitochondria" ], "offsets": [ [ 332, 344 ] ], "normalized": [] }, { "id": "PMID-3759988_T7", "type": "Simple_chemical", "text": [ "acylcarnitine" ], "offsets": [ [ 403, 416 ] ], "normalized": [] }, { "id": "PMID-3759988_T8", "type": "Simple_chemical", "text": [ "acetylcarnitine" ], "offsets": [ [ 449, 464 ] ], "normalized": [] }, { "id": "PMID-3759988_T9", "type": "Cellular_component", "text": [ "mitochondria" ], "offsets": [ [ 483, 495 ] ], "normalized": [] }, { "id": "PMID-3759988_T10", "type": "Simple_chemical", "text": [ "pyruvate" ], "offsets": [ [ 501, 509 ] ], "normalized": [] }, { "id": "PMID-3759988_T11", "type": "Simple_chemical", "text": [ "acetylcarnitine" ], "offsets": [ [ 526, 541 ] ], "normalized": [] }, { "id": "PMID-3759988_T12", "type": "Cellular_component", "text": [ "mitochondria" ], "offsets": [ [ 553, 565 ] ], "normalized": [] }, { "id": "PMID-3759988_T13", "type": "Simple_chemical", "text": [ "carnitine" ], "offsets": [ [ 614, 623 ] ], "normalized": [] }, { "id": "PMID-3759988_T14", "type": "Simple_chemical", "text": [ "acetyl-CoA" ], "offsets": [ [ 640, 650 ] ], "normalized": [] }, { "id": "PMID-3759988_T15", "type": "Simple_chemical", "text": [ "pyruvate" ], "offsets": [ [ 666, 674 ] ], "normalized": [] }, { "id": "PMID-3759988_T16", "type": "Gene_or_gene_product", "text": [ "pyruvate dehydrogenase" ], "offsets": [ [ 678, 700 ] ], "normalized": [] }, { "id": "PMID-3759988_T17", "type": "Gene_or_gene_product", "text": [ "carnitine acetyltransferase" ], "offsets": [ [ 723, 750 ] ], "normalized": [] }, { "id": "PMID-3759988_T18", "type": "Simple_chemical", "text": [ "acetylcarnitine" ], "offsets": [ [ 764, 779 ] ], "normalized": [] }, { "id": "PMID-3759988_T19", "type": "Cellular_component", "text": [ "mitochondria" ], "offsets": [ [ 800, 812 ] ], "normalized": [] }, { "id": "PMID-3759988_T20", "type": "Simple_chemical", "text": [ "octanoate" ], "offsets": [ [ 818, 827 ] ], "normalized": [] }, { "id": "PMID-3759988_T21", "type": "Simple_chemical", "text": [ "malonate" ], "offsets": [ [ 871, 879 ] ], "normalized": [] }, { "id": "PMID-3759988_T22", "type": "Simple_chemical", "text": [ "Acetylcarnitine" ], "offsets": [ [ 881, 896 ] ], "normalized": [] }, { "id": "PMID-3759988_T23", "type": "Simple_chemical", "text": [ "propionylcarnitine" ], "offsets": [ [ 1048, 1066 ] ], "normalized": [] }, { "id": "PMID-3759988_T24", "type": "Simple_chemical", "text": [ "isobutyrylcarnitine" ], "offsets": [ [ 1070, 1089 ] ], "normalized": [] }, { "id": "PMID-3759988_T25", "type": "Cellular_component", "text": [ "mitochondria" ], "offsets": [ [ 1108, 1120 ] ], "normalized": [] }, { "id": "PMID-3759988_T26", "type": "Simple_chemical", "text": [ "alpha-ketoisovalerate" ], "offsets": [ [ 1134, 1155 ] ], "normalized": [] }, { "id": "PMID-3759988_T27", "type": "Simple_chemical", "text": [ "alpha-keto-beta-methylvalerate" ], "offsets": [ [ 1160, 1190 ] ], "normalized": [] }, { "id": "PMID-3759988_T28", "type": "Simple_chemical", "text": [ "propionyl-CoA" ], "offsets": [ [ 1254, 1267 ] ], "normalized": [] }, { "id": "PMID-3759988_T29", "type": "Simple_chemical", "text": [ "acyl-CoAs" ], "offsets": [ [ 1292, 1301 ] ], "normalized": [] }, { "id": "PMID-3759988_T30", "type": "Simple_chemical", "text": [ "carnitine" ], "offsets": [ [ 1307, 1316 ] ], "normalized": [] }, { "id": "PMID-3759988_T31", "type": "Simple_chemical", "text": [ "propionyl-CoA" ], "offsets": [ [ 1370, 1383 ] ], "normalized": [] }, { "id": "PMID-3759988_T32", "type": "Simple_chemical", "text": [ "propionyl-CoA" ], "offsets": [ [ 1409, 1422 ] ], "normalized": [] }, { "id": "PMID-3759988_T33", "type": "Simple_chemical", "text": [ "alpha-ketoisovalerate" ], "offsets": [ [ 1463, 1484 ] ], "normalized": [] }, { "id": "PMID-3759988_T34", "type": "Cellular_component", "text": [ "extra-mitochondrial" ], "offsets": [ [ 1494, 1513 ] ], "normalized": [] }, { "id": "PMID-3759988_T35", "type": "Simple_chemical", "text": [ "carnitine" ], "offsets": [ [ 1519, 1528 ] ], "normalized": [] }, { "id": "PMID-3759988_T36", "type": "Cellular_component", "text": [ "matrix" ], "offsets": [ [ 1552, 1558 ] ], "normalized": [] }, { "id": "PMID-3759988_T37", "type": "Simple_chemical", "text": [ "acyl-CoA" ], "offsets": [ [ 1581, 1589 ] ], "normalized": [] }, { "id": "PMID-3759988_T38", "type": "Simple_chemical", "text": [ "alpha-keto acids" ], "offsets": [ [ 1605, 1621 ] ], "normalized": [] }, { "id": "PMID-3759988_T39", "type": "Simple_chemical", "text": [ "pyruvate" ], "offsets": [ [ 1656, 1664 ] ], "normalized": [] }, { "id": "PMID-3759988_T40", "type": "Simple_chemical", "text": [ "malate" ], "offsets": [ [ 1696, 1702 ] ], "normalized": [] } ]

[ { "id": "PMID-3759988_E1", "type": "Conversion", "trigger": { "text": [ "produced" ], "offsets": [ [ 465, 473 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-3759988_T8" }, { "role": "Theme", "ref_id": "PMID-3759988_T10" } ] }, { "id": "PMID-3759988_E2", "type": "Conversion", "trigger": { "text": [ "generated" ], "offsets": [ [ 651, 660 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-3759988_T14" }, { "role": "Theme", "ref_id": "PMID-3759988_T15" } ] }, { "id": "PMID-3759988_E3", "type": "Positive_regulation", "trigger": { "text": [ "generated" ], "offsets": [ [ 651, 660 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-3759988_E2" }, { "role": "Cause", "ref_id": "PMID-3759988_T16" } ] }, { "id": "PMID-3759988_E4", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 1537, 1546 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-3759988_T37" }, { "role": "Theme", "ref_id": "PMID-3759988_T35" } ] }, { "id": "PMID-3759988_E5", "type": "Conversion", "trigger": { "text": [ "generated" ], "offsets": [ [ 1590, 1599 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-3759988_T37" }, { "role": "Theme", "ref_id": "PMID-3759988_T38" } ] }, { "id": "PMID-3759988_E6", "type": "Conversion", "trigger": { "text": [ "generated" ], "offsets": [ [ 1590, 1599 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-3759988_T37" }, { "role": "Theme", "ref_id": "PMID-3759988_T39" } ] } ]

[]

[]

[ { "id": "PMID-4019466__text", "type": "abstract", "text": [ "A sulfatase specific for glucuronic acid 2-sulfate residues in glycosaminoglycans. \nAlthough 2-O-sulfated L-iduronic acid (IdoA) residues have been known to occur in heparin, 2-O-sulfated D-glucuronic acid (GlcA) residues have been reported only recently (Bienkowski, M. J., and Conrad, H. E. (1985) J. Biol. Chem. 250, 356-365). Disaccharides prepared by cleavage of heparin and N-deacetylated chondroitin 6-sulfate with nitrous acid were used to demonstrate a new sulfatase that catalyzed the removal of the 2-O-sulfate substituents from GlcA but not IdoA residues. The deamination products were labeled by NaB3H4 reduction to give disaccharides from heparin and chondroitin sulfate which had reducing terminal 2,5-anhydro-D-mannitol ([3H]AManR) and 2,5-anhydro-D-talitol ([3H]ATalR) residues, respectively. IdoA(2-SO4)-[3H]AManR(6-SO4) from heparin and GlcA(2-SO4)-[3H]ATalR(6-SO4) from chondroitin sulfate were purified for use as substrates. GlcA(2-SO4)-[3H]AManR(6-SO4) was prepared by epimerization of IdoA(2-SO4)-[3H]AManR(6-SO4) with hydrazine at 100 degrees C. Lysosomal enzyme preparations from chick embryo chondrocytes and from two normal human fibroblast cell lines catalyzed the removal of the 2-O-SO4 substituent from the uronic acid residues of IdoA(2-SO4)-[3H]AManR(6-SO4), GlcA(2-SO4)-[3H] AManR(6-SO4), and GlcA(2-SO4)-[3H]ATalR(6-SO4). In contrast, a lysosomal enzyme preparation from a human fibroblast cell line deficient in idurono-2-sulfatase (Hunter's-syndrome), which had no activity on the IdoA(2-SO4)-[3H]AManR(6-SO4), converted GlcA(2-SO4)-[3H]AManR(6-SO4) to a mixture of GlcA-[3H] AManR(6-SO4) and [3H]AManR(6-SO4). This enzyme also converted GlcA(2-SO4)-[3H]ATalR(6-SO4) to a mixture of GlcA-[3H]ATalR(6-SO4) and [3H]ATalR(6-SO4). Digestion of both GlcA(2-SO4)-[3H]AManR(6-SO4) and GlcA(2-SO4)-[3H]ATalR(6-SO4) was inhibited by 35SO2-4 and was arrested at the monosulfated disaccharide stage by 1,4-saccharolactone. The glucurono-2-sulfatase exhibited a pH optimum of 4. The results indicate that there exists a separate sulfatase for the removal of sulfate substituents from C-2 of GlcA residues in glycosaminoglycans.\n" ], "offsets": [ [ 0, 2153 ] ] } ]

[ { "id": "PMID-4019466_T1", "type": "Simple_chemical", "text": [ "glucuronic acid 2-sulfate" ], "offsets": [ [ 25, 50 ] ], "normalized": [] }, { "id": "PMID-4019466_T2", "type": "Simple_chemical", "text": [ "glycosaminoglycans" ], "offsets": [ [ 63, 81 ] ], "normalized": [] }, { "id": "PMID-4019466_T3", "type": "Simple_chemical", "text": [ "L-iduronic acid" ], "offsets": [ [ 106, 121 ] ], "normalized": [] }, { "id": "PMID-4019466_T4", "type": "Simple_chemical", "text": [ "IdoA" ], "offsets": [ [ 123, 127 ] ], "normalized": [] }, { "id": "PMID-4019466_T5", "type": "Simple_chemical", "text": [ "heparin" ], "offsets": [ [ 166, 173 ] ], "normalized": [] }, { "id": "PMID-4019466_T6", "type": "Simple_chemical", "text": [ "D-glucuronic acid" ], "offsets": [ [ 188, 205 ] ], "normalized": [] }, { "id": "PMID-4019466_T7", "type": "Simple_chemical", "text": [ "GlcA" ], "offsets": [ [ 207, 211 ] ], "normalized": [] }, { "id": "PMID-4019466_T8", "type": "Simple_chemical", "text": [ "heparin" ], "offsets": [ [ 368, 375 ] ], "normalized": [] }, { "id": "PMID-4019466_T9", "type": "Simple_chemical", "text": [ "chondroitin 6-sulfate" ], "offsets": [ [ 395, 416 ] ], "normalized": [] }, { "id": "PMID-4019466_T10", "type": "Simple_chemical", "text": [ "nitrous acid" ], "offsets": [ [ 422, 434 ] ], "normalized": [] }, { "id": "PMID-4019466_T11", "type": "Simple_chemical", "text": [ "2-O-sulfate" ], "offsets": [ [ 510, 521 ] ], "normalized": [] }, { "id": "PMID-4019466_T12", "type": "Simple_chemical", "text": [ "GlcA" ], "offsets": [ [ 540, 544 ] ], "normalized": [] }, { "id": "PMID-4019466_T13", "type": "Simple_chemical", "text": [ "IdoA" ], "offsets": [ [ 553, 557 ] ], "normalized": [] }, { "id": "PMID-4019466_T14", "type": "Simple_chemical", "text": [ "NaB3H4" ], "offsets": [ [ 609, 615 ] ], "normalized": [] }, { "id": "PMID-4019466_T15", "type": "Simple_chemical", "text": [ "heparin" ], "offsets": [ [ 653, 660 ] ], "normalized": [] }, { "id": "PMID-4019466_T16", "type": "Simple_chemical", "text": [ "chondroitin sulfate" ], "offsets": [ [ 665, 684 ] ], "normalized": [] }, { "id": "PMID-4019466_T17", "type": "Simple_chemical", "text": [ "2,5-anhydro-D-mannitol" ], "offsets": [ [ 713, 735 ] ], "normalized": [] }, { "id": "PMID-4019466_T18", "type": "Simple_chemical", "text": [ "[3H]AManR" ], "offsets": [ [ 737, 746 ] ], "normalized": [] }, { "id": "PMID-4019466_T19", "type": "Simple_chemical", "text": [ "2,5-anhydro-D-talitol" ], "offsets": [ [ 752, 773 ] ], "normalized": [] }, { "id": "PMID-4019466_T20", "type": "Simple_chemical", "text": [ "[3H]ATalR" ], "offsets": [ [ 775, 784 ] ], "normalized": [] }, { "id": "PMID-4019466_T21", "type": "Simple_chemical", "text": [ "IdoA(2-SO4)-[3H]AManR(6-SO4)" ], "offsets": [ [ 810, 838 ] ], "normalized": [] }, { "id": "PMID-4019466_T22", "type": "Simple_chemical", "text": [ "heparin" ], "offsets": [ [ 844, 851 ] ], "normalized": [] }, { "id": "PMID-4019466_T23", "type": "Simple_chemical", "text": [ "GlcA(2-SO4)-[3H]ATalR(6-SO4)" ], "offsets": [ [ 856, 884 ] ], "normalized": [] }, { "id": "PMID-4019466_T24", "type": "Simple_chemical", "text": [ "chondroitin sulfate" ], "offsets": [ [ 890, 909 ] ], "normalized": [] }, { "id": "PMID-4019466_T25", "type": "Simple_chemical", "text": [ "GlcA(2-SO4)-[3H]AManR(6-SO4)" ], "offsets": [ [ 947, 975 ] ], "normalized": [] }, { "id": "PMID-4019466_T26", "type": "Simple_chemical", "text": [ "IdoA(2-SO4)-[3H]AManR(6-SO4)" ], "offsets": [ [ 1009, 1037 ] ], "normalized": [] }, { "id": "PMID-4019466_T27", "type": "Simple_chemical", "text": [ "hydrazine" ], "offsets": [ [ 1043, 1052 ] ], "normalized": [] }, { "id": "PMID-4019466_T28", "type": "Cellular_component", "text": [ "Lysosomal" ], "offsets": [ [ 1071, 1080 ] ], "normalized": [] }, { "id": "PMID-4019466_T29", "type": "Simple_chemical", "text": [ "2-O-SO4" ], "offsets": [ [ 1209, 1216 ] ], "normalized": [] }, { "id": "PMID-4019466_T30", "type": "Simple_chemical", "text": [ "uronic acid" ], "offsets": [ [ 1238, 1249 ] ], "normalized": [] }, { "id": "PMID-4019466_T31", "type": "Simple_chemical", "text": [ "IdoA(2-SO4)-[3H]AManR(6-SO4)" ], "offsets": [ [ 1262, 1290 ] ], "normalized": [] }, { "id": "PMID-4019466_T32", "type": "Simple_chemical", "text": [ "GlcA(2-SO4)-[3H] AManR(6-SO4)" ], "offsets": [ [ 1292, 1321 ] ], "normalized": [] }, { "id": "PMID-4019466_T33", "type": "Simple_chemical", "text": [ "GlcA(2-SO4)-[3H]ATalR(6-SO4)" ], "offsets": [ [ 1327, 1355 ] ], "normalized": [] }, { "id": "PMID-4019466_T34", "type": "Cellular_component", "text": [ "lysosomal" ], "offsets": [ [ 1372, 1381 ] ], "normalized": [] }, { "id": "PMID-4019466_T35", "type": "Gene_or_gene_product", "text": [ "idurono-2-sulfatase" ], "offsets": [ [ 1448, 1467 ] ], "normalized": [] }, { "id": "PMID-4019466_T36", "type": "Simple_chemical", "text": [ "IdoA(2-SO4)-[3H]AManR(6-SO4)" ], "offsets": [ [ 1518, 1546 ] ], "normalized": [] }, { "id": "PMID-4019466_T37", "type": "Simple_chemical", "text": [ "GlcA(2-SO4)-[3H]AManR(6-SO4)" ], "offsets": [ [ 1558, 1586 ] ], "normalized": [] }, { "id": "PMID-4019466_T38", "type": "Simple_chemical", "text": [ "GlcA-[3H] AManR(6-SO4)" ], "offsets": [ [ 1603, 1625 ] ], "normalized": [] }, { "id": "PMID-4019466_T39", "type": "Simple_chemical", "text": [ "[3H]AManR(6-SO4)" ], "offsets": [ [ 1630, 1646 ] ], "normalized": [] }, { "id": "PMID-4019466_T40", "type": "Simple_chemical", "text": [ "GlcA(2-SO4)-[3H]ATalR(6-SO4)" ], "offsets": [ [ 1675, 1703 ] ], "normalized": [] }, { "id": "PMID-4019466_T41", "type": "Simple_chemical", "text": [ "GlcA-[3H]ATalR(6-SO4)" ], "offsets": [ [ 1720, 1741 ] ], "normalized": [] }, { "id": "PMID-4019466_T42", "type": "Simple_chemical", "text": [ "[3H]ATalR(6-SO4)" ], "offsets": [ [ 1746, 1762 ] ], "normalized": [] }, { "id": "PMID-4019466_T43", "type": "Simple_chemical", "text": [ "GlcA(2-SO4)-[3H]AManR(6-SO4)" ], "offsets": [ [ 1782, 1810 ] ], "normalized": [] }, { "id": "PMID-4019466_T44", "type": "Simple_chemical", "text": [ "GlcA(2-SO4)-[3H]ATalR(6-SO4)" ], "offsets": [ [ 1815, 1843 ] ], "normalized": [] }, { "id": "PMID-4019466_T45", "type": "Simple_chemical", "text": [ "35SO2-4" ], "offsets": [ [ 1861, 1868 ] ], "normalized": [] }, { "id": "PMID-4019466_T46", "type": "Simple_chemical", "text": [ "monosulfated disaccharide" ], "offsets": [ [ 1893, 1918 ] ], "normalized": [] }, { "id": "PMID-4019466_T47", "type": "Simple_chemical", "text": [ "1,4-saccharolactone" ], "offsets": [ [ 1928, 1947 ] ], "normalized": [] }, { "id": "PMID-4019466_T48", "type": "Gene_or_gene_product", "text": [ "glucurono-2-sulfatase" ], "offsets": [ [ 1953, 1974 ] ], "normalized": [] }, { "id": "PMID-4019466_T49", "type": "Simple_chemical", "text": [ "sulfate" ], "offsets": [ [ 2083, 2090 ] ], "normalized": [] }, { "id": "PMID-4019466_T50", "type": "Simple_chemical", "text": [ "C-2" ], "offsets": [ [ 2109, 2112 ] ], "normalized": [] }, { "id": "PMID-4019466_T51", "type": "Simple_chemical", "text": [ "GlcA" ], "offsets": [ [ 2116, 2120 ] ], "normalized": [] }, { "id": "PMID-4019466_T52", "type": "Simple_chemical", "text": [ "glycosaminoglycans" ], "offsets": [ [ 2133, 2151 ] ], "normalized": [] } ]

[ { "id": "PMID-4019466_E1", "type": "Conversion", "trigger": { "text": [ "cleavage" ], "offsets": [ [ 356, 364 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T8" } ] }, { "id": "PMID-4019466_E2", "type": "Deacetylation", "trigger": { "text": [ "deacetylated" ], "offsets": [ [ 382, 394 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T9" } ] }, { "id": "PMID-4019466_E3", "type": "Positive_regulation", "trigger": { "text": [ "catalyzed" ], "offsets": [ [ 481, 490 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_E4" } ] }, { "id": "PMID-4019466_E4", "type": "Conversion", "trigger": { "text": [ "removal" ], "offsets": [ [ 495, 502 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T11" } ] }, { "id": "PMID-4019466_E5", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 616, 625 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T14" } ] }, { "id": "PMID-4019466_E6", "type": "Negative_regulation", "trigger": { "text": [ "reducing" ], "offsets": [ [ 695, 703 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T17" } ] }, { "id": "PMID-4019466_E7", "type": "Positive_regulation", "trigger": { "text": [ "catalyzed" ], "offsets": [ [ 1180, 1189 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_E8" } ] }, { "id": "PMID-4019466_E8", "type": "Conversion", "trigger": { "text": [ "removal" ], "offsets": [ [ 1194, 1201 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T29" } ] }, { "id": "PMID-4019466_E9", "type": "Inactivation", "trigger": { "text": [ "deficient" ], "offsets": [ [ 1435, 1444 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T35" } ] }, { "id": "PMID-4019466_E10", "type": "Regulation", "trigger": { "text": [ "no activity" ], "offsets": [ [ 1499, 1510 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T36" } ] }, { "id": "PMID-4019466_E11", "type": "Conversion", "trigger": { "text": [ "converted" ], "offsets": [ [ 1548, 1557 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T37" }, { "role": "Product", "ref_id": "PMID-4019466_T38" } ] }, { "id": "PMID-4019466_E12", "type": "Conversion", "trigger": { "text": [ "converted" ], "offsets": [ [ 1548, 1557 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T37" }, { "role": "Product", "ref_id": "PMID-4019466_T39" } ] }, { "id": "PMID-4019466_E13", "type": "Conversion", "trigger": { "text": [ "converted" ], "offsets": [ [ 1665, 1674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T40" }, { "role": "Product", "ref_id": "PMID-4019466_T41" } ] }, { "id": "PMID-4019466_E14", "type": "Positive_regulation", "trigger": { "text": [ "converted" ], "offsets": [ [ 1665, 1674 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-4019466_T35" }, { "role": "Theme", "ref_id": "PMID-4019466_E13" } ] }, { "id": "PMID-4019466_E15", "type": "Conversion", "trigger": { "text": [ "converted" ], "offsets": [ [ 1665, 1674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T40" }, { "role": "Product", "ref_id": "PMID-4019466_T42" } ] }, { "id": "PMID-4019466_E16", "type": "Positive_regulation", "trigger": { "text": [ "converted" ], "offsets": [ [ 1665, 1674 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-4019466_T35" }, { "role": "Theme", "ref_id": "PMID-4019466_E15" } ] }, { "id": "PMID-4019466_E17", "type": "Conversion", "trigger": { "text": [ "Digestion" ], "offsets": [ [ 1764, 1773 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T43" } ] }, { "id": "PMID-4019466_E18", "type": "Conversion", "trigger": { "text": [ "Digestion" ], "offsets": [ [ 1764, 1773 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T44" } ] }, { "id": "PMID-4019466_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1848, 1857 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-4019466_T45" }, { "role": "Theme", "ref_id": "PMID-4019466_E18" } ] }, { "id": "PMID-4019466_E20", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1848, 1857 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-4019466_T45" }, { "role": "Theme", "ref_id": "PMID-4019466_E17" } ] }, { "id": "PMID-4019466_E21", "type": "Negative_regulation", "trigger": { "text": [ "arrested" ], "offsets": [ [ 1877, 1885 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-4019466_T47" }, { "role": "Theme", "ref_id": "PMID-4019466_E18" } ] }, { "id": "PMID-4019466_E22", "type": "Negative_regulation", "trigger": { "text": [ "arrested" ], "offsets": [ [ 1877, 1885 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-4019466_T47" }, { "role": "Theme", "ref_id": "PMID-4019466_E17" } ] }, { "id": "PMID-4019466_E23", "type": "Conversion", "trigger": { "text": [ "removal" ], "offsets": [ [ 2072, 2079 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-4019466_T49" } ] } ]

[ { "id": "PMID-4019466_1", "entity_ids": [ "PMID-4019466_T3", "PMID-4019466_T4" ] }, { "id": "PMID-4019466_2", "entity_ids": [ "PMID-4019466_T7", "PMID-4019466_T6" ] }, { "id": "PMID-4019466_3", "entity_ids": [ "PMID-4019466_T17", "PMID-4019466_T18" ] }, { "id": "PMID-4019466_4", "entity_ids": [ "PMID-4019466_T19", "PMID-4019466_T20" ] } ]

[]

[ { "id": "PMID-7681363__text", "type": "abstract", "text": [ "Negative regulation of the wee1 protein kinase by direct action of the nim1/cdr1 mitotic inducer. \nThe wee1 protein kinase suppresses the entry into mitosis by mediating the inhibitory tyrosine phosphorylation of p34cdc2. Genetic studies have suggested that the nim1 protein kinase (also known as cdr1) acts as a positive regulator of mitosis by down-regulating the wee1 pathway in yeast cells. We have overexpressed the nim1 protein in both bacteria and insect cells. The recombinant nim1 protein autophosphorylates on both tyrosine and serine residues and can phosphorylate the isolated wee1 protein directly in a cell-free system. The nim1-catalyzed phosphorylation of the wee1 protein occurs in its C-terminal region and leads to a substantial drop in its activity as a cdc2-specific tyrosine kinase. This nim1-dependent inhibition of the wee1 protein kinase can be reversed readily in vitro by treatment with a protein phosphatase. These experiments provide direct biochemical evidence that the wee1 protein is subject to negative regulation by phosphorylation and indicate that the nim1 protein acts as an inhibitory, wee1-specific kinase.\n" ], "offsets": [ [ 0, 1146 ] ] } ]

[ { "id": "PMID-7681363_T1", "type": "Gene_or_gene_product", "text": [ "wee1" ], "offsets": [ [ 27, 31 ] ], "normalized": [] }, { "id": "PMID-7681363_T2", "type": "Gene_or_gene_product", "text": [ "nim1" ], "offsets": [ [ 71, 75 ] ], "normalized": [] }, { "id": "PMID-7681363_T3", "type": "Gene_or_gene_product", "text": [ "cdr1" ], "offsets": [ [ 76, 80 ] ], "normalized": [] }, { "id": "PMID-7681363_T4", "type": "Gene_or_gene_product", "text": [ "wee1" ], "offsets": [ [ 103, 107 ] ], "normalized": [] }, { "id": "PMID-7681363_T5", "type": "Simple_chemical", "text": [ "tyrosine" ], "offsets": [ [ 185, 193 ] ], "normalized": [] }, { "id": "PMID-7681363_T6", "type": "Gene_or_gene_product", "text": [ "p34cdc2" ], "offsets": [ [ 213, 220 ] ], "normalized": [] }, { "id": "PMID-7681363_T7", "type": "Gene_or_gene_product", "text": [ "nim1" ], "offsets": [ [ 262, 266 ] ], "normalized": [] }, { "id": "PMID-7681363_T8", "type": "Gene_or_gene_product", "text": [ "cdr1" ], "offsets": [ [ 297, 301 ] ], "normalized": [] }, { "id": "PMID-7681363_T9", "type": "Gene_or_gene_product", "text": [ "wee1" ], "offsets": [ [ 366, 370 ] ], "normalized": [] }, { "id": "PMID-7681363_T10", "type": "Gene_or_gene_product", "text": [ "nim1" ], "offsets": [ [ 421, 425 ] ], "normalized": [] }, { "id": "PMID-7681363_T11", "type": "Gene_or_gene_product", "text": [ "nim1" ], "offsets": [ [ 485, 489 ] ], "normalized": [] }, { "id": "PMID-7681363_T12", "type": "Simple_chemical", "text": [ "tyrosine" ], "offsets": [ [ 525, 533 ] ], "normalized": [] }, { "id": "PMID-7681363_T13", "type": "Simple_chemical", "text": [ "serine" ], "offsets": [ [ 538, 544 ] ], "normalized": [] }, { "id": "PMID-7681363_T14", "type": "Gene_or_gene_product", "text": [ "wee1" ], "offsets": [ [ 589, 593 ] ], "normalized": [] }, { "id": "PMID-7681363_T15", "type": "Gene_or_gene_product", "text": [ "nim1" ], "offsets": [ [ 638, 642 ] ], "normalized": [] }, { "id": "PMID-7681363_T16", "type": "Gene_or_gene_product", "text": [ "wee1" ], "offsets": [ [ 676, 680 ] ], "normalized": [] }, { "id": "PMID-7681363_T17", "type": "Gene_or_gene_product", "text": [ "cdc2" ], "offsets": [ [ 774, 778 ] ], "normalized": [] }, { "id": "PMID-7681363_T18", "type": "Simple_chemical", "text": [ "tyrosine" ], "offsets": [ [ 788, 796 ] ], "normalized": [] }, { "id": "PMID-7681363_T19", "type": "Gene_or_gene_product", "text": [ "nim1" ], "offsets": [ [ 810, 814 ] ], "normalized": [] }, { "id": "PMID-7681363_T20", "type": "Gene_or_gene_product", "text": [ "wee1" ], "offsets": [ [ 843, 847 ] ], "normalized": [] }, { "id": "PMID-7681363_T21", "type": "Gene_or_gene_product", "text": [ "wee1" ], "offsets": [ [ 1000, 1004 ] ], "normalized": [] }, { "id": "PMID-7681363_T22", "type": "Gene_or_gene_product", "text": [ "nim1" ], "offsets": [ [ 1088, 1092 ] ], "normalized": [] }, { "id": "PMID-7681363_T23", "type": "Gene_or_gene_product", "text": [ "wee1" ], "offsets": [ [ 1124, 1128 ] ], "normalized": [] } ]

[ { "id": "PMID-7681363_E1", "type": "Negative_regulation", "trigger": { "text": [ "Negative regulation" ], "offsets": [ [ 0, 19 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_T1" } ] }, { "id": "PMID-7681363_E2", "type": "Positive_regulation", "trigger": { "text": [ "mediating" ], "offsets": [ [ 160, 169 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_E3" }, { "role": "Cause", "ref_id": "PMID-7681363_T4" } ] }, { "id": "PMID-7681363_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 194, 209 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_T6" } ] }, { "id": "PMID-7681363_E4", "type": "Negative_regulation", "trigger": { "text": [ "down-regulating" ], "offsets": [ [ 346, 361 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_E5" }, { "role": "Cause", "ref_id": "PMID-7681363_T8" } ] }, { "id": "PMID-7681363_E5", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 371, 378 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-7681363_T9" } ] }, { "id": "PMID-7681363_E6", "type": "Phosphorylation", "trigger": { "text": [ "autophosphorylates" ], "offsets": [ [ 498, 516 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-7681363_T12" }, { "role": "Theme", "ref_id": "PMID-7681363_T11" } ] }, { "id": "PMID-7681363_E7", "type": "Phosphorylation", "trigger": { "text": [ "autophosphorylates" ], "offsets": [ [ 498, 516 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-7681363_T12" }, { "role": "Theme", "ref_id": "PMID-7681363_T13" } ] }, { "id": "PMID-7681363_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylate" ], "offsets": [ [ 562, 575 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_T14" }, { "role": "Cause", "ref_id": "PMID-7681363_T11" } ] }, { "id": "PMID-7681363_E9", "type": "Positive_regulation", "trigger": { "text": [ "catalyzed" ], "offsets": [ [ 643, 652 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7681363_T15" }, { "role": "Theme", "ref_id": "PMID-7681363_E10" } ] }, { "id": "PMID-7681363_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 653, 668 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_T16" } ] }, { "id": "PMID-7681363_E11", "type": "Positive_regulation", "trigger": { "text": [ "leads to" ], "offsets": [ [ 725, 733 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_E12" } ] }, { "id": "PMID-7681363_E12", "type": "Negative_regulation", "trigger": { "text": [ "drop" ], "offsets": [ [ 748, 752 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_T16" } ] }, { "id": "PMID-7681363_E13", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 815, 824 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7681363_T19" }, { "role": "Theme", "ref_id": "PMID-7681363_E14" } ] }, { "id": "PMID-7681363_E14", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 825, 835 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_T20" } ] }, { "id": "PMID-7681363_E15", "type": "Negative_regulation", "trigger": { "text": [ "reversed" ], "offsets": [ [ 870, 878 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_E14" } ] }, { "id": "PMID-7681363_E16", "type": "Negative_regulation", "trigger": { "text": [ "negative regulation" ], "offsets": [ [ 1027, 1046 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_T21" }, { "role": "Cause", "ref_id": "PMID-7681363_E17" } ] }, { "id": "PMID-7681363_E17", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1050, 1065 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7681363_T21" } ] }, { "id": "PMID-7681363_E18", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory" ], "offsets": [ [ 1112, 1122 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7681363_T22" }, { "role": "Theme", "ref_id": "PMID-7681363_T23" } ] } ]

[ { "id": "PMID-7681363_1", "entity_ids": [ "PMID-7681363_T2", "PMID-7681363_T3" ] }, { "id": "PMID-7681363_2", "entity_ids": [ "PMID-7681363_T8", "PMID-7681363_T7" ] } ]

[]

[ { "id": "PMID-7775431__text", "type": "abstract", "text": [ "Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. \nA monoclonal antibody (mAb) was isolated that blocked the binding and bioactivity of both human and murine interleukin 1 beta (IL-1 beta) on murine IL-1 receptor-bearing cells. This mAb recognized a protein that was distinct from the Type I and Type II IL-1 receptors, suggesting that an additional protein exists that is involved in IL-1 biological responses. By expression cloning in COS-7 cells, we have isolated a cDNA from mouse 3T3-LI cells encoding this putative auxiliary molecule, which we term the IL-1 receptor accessory protein (IL-1R AcP). Sequence analysis of the cDNA predicts an open reading frame that encodes a 570-amino acid protein with a molecular mass of approximately 66 kDa. The IL-1R AcP is a member of the Ig superfamily by analysis of its putative extracellular domain and also bears limited homology throughout the protein to both Type I and Type II IL-1 receptors. Northern analysis reveals that murine IL-1R AcP mRNA is expressed in many tissues and appears to be regulated by IL-1. In mammalian cells expressing natural or recombinant Type I IL-1R and IL-1R AcP, the accessory protein forms a complex with the Type I IL-1R and either IL-1 alpha or IL-1 beta but not IL-1ra. The recombinant accessory protein also increases the binding affinity of the recombinant Type I IL-1R for IL-1 beta when the two receptor proteins are coexpressed. Therefore, the functional IL-1 receptor appears to be a complex composed of at least two subunits.\n" ], "offsets": [ [ 0, 1567 ] ] } ]

[ { "id": "PMID-7775431_T1", "type": "Complex", "text": [ "interleukin 1 receptor" ], "offsets": [ [ 66, 88 ] ], "normalized": [] }, { "id": "PMID-7775431_T2", "type": "Gene_or_gene_product", "text": [ "interleukin 1 beta" ], "offsets": [ [ 206, 224 ] ], "normalized": [] }, { "id": "PMID-7775431_T3", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 226, 235 ] ], "normalized": [] }, { "id": "PMID-7775431_T4", "type": "Complex", "text": [ "IL-1 receptor" ], "offsets": [ [ 247, 260 ] ], "normalized": [] }, { "id": "PMID-7775431_T5", "type": "Gene_or_gene_product", "text": [ "Type I" ], "offsets": [ [ 333, 339 ] ], "normalized": [] }, { "id": "PMID-7775431_T6", "type": "Gene_or_gene_product", "text": [ "Type II IL-1 receptors" ], "offsets": [ [ 344, 366 ] ], "normalized": [] }, { "id": "PMID-7775431_T7", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 433, 437 ] ], "normalized": [] }, { "id": "PMID-7775431_T8", "type": "Gene_or_gene_product", "text": [ "IL-1 receptor accessory protein" ], "offsets": [ [ 607, 638 ] ], "normalized": [] }, { "id": "PMID-7775431_T9", "type": "Gene_or_gene_product", "text": [ "IL-1R AcP" ], "offsets": [ [ 640, 649 ] ], "normalized": [] }, { "id": "PMID-7775431_T10", "type": "Gene_or_gene_product", "text": [ "IL-1R AcP" ], "offsets": [ [ 802, 811 ] ], "normalized": [] }, { "id": "PMID-7775431_T11", "type": "Gene_or_gene_product", "text": [ "Ig" ], "offsets": [ [ 831, 833 ] ], "normalized": [] }, { "id": "PMID-7775431_T12", "type": "Cellular_component", "text": [ "extracellular" ], "offsets": [ [ 874, 887 ] ], "normalized": [] }, { "id": "PMID-7775431_T13", "type": "Gene_or_gene_product", "text": [ "Type I" ], "offsets": [ [ 958, 964 ] ], "normalized": [] }, { "id": "PMID-7775431_T14", "type": "Gene_or_gene_product", "text": [ "Type II IL-1 receptors" ], "offsets": [ [ 969, 991 ] ], "normalized": [] }, { "id": "PMID-7775431_T15", "type": "Gene_or_gene_product", "text": [ "IL-1R AcP" ], "offsets": [ [ 1031, 1040 ] ], "normalized": [] }, { "id": "PMID-7775431_T16", "type": "Gene_or_gene_product", "text": [ "IL-1" ], "offsets": [ [ 1106, 1110 ] ], "normalized": [] }, { "id": "PMID-7775431_T17", "type": "Gene_or_gene_product", "text": [ "Type I IL-1R" ], "offsets": [ [ 1165, 1177 ] ], "normalized": [] }, { "id": "PMID-7775431_T18", "type": "Gene_or_gene_product", "text": [ "IL-1R AcP" ], "offsets": [ [ 1182, 1191 ] ], "normalized": [] }, { "id": "PMID-7775431_T19", "type": "Gene_or_gene_product", "text": [ "Type I IL-1R" ], "offsets": [ [ 1240, 1252 ] ], "normalized": [] }, { "id": "PMID-7775431_T20", "type": "Gene_or_gene_product", "text": [ "IL-1 alpha" ], "offsets": [ [ 1264, 1274 ] ], "normalized": [] }, { "id": "PMID-7775431_T21", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 1278, 1287 ] ], "normalized": [] }, { "id": "PMID-7775431_T22", "type": "Gene_or_gene_product", "text": [ "IL-1ra" ], "offsets": [ [ 1296, 1302 ] ], "normalized": [] }, { "id": "PMID-7775431_T23", "type": "Gene_or_gene_product", "text": [ "Type I IL-1R" ], "offsets": [ [ 1393, 1405 ] ], "normalized": [] }, { "id": "PMID-7775431_T24", "type": "Gene_or_gene_product", "text": [ "IL-1 beta" ], "offsets": [ [ 1410, 1419 ] ], "normalized": [] }, { "id": "PMID-7775431_T25", "type": "Complex", "text": [ "IL-1 receptor" ], "offsets": [ [ 1494, 1507 ] ], "normalized": [] } ]

[ { "id": "PMID-7775431_E1", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 145, 152 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_E2" } ] }, { "id": "PMID-7775431_E2", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 157, 164 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_T2" } ] }, { "id": "PMID-7775431_E3", "type": "Transcription", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1049, 1058 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_T15" } ] }, { "id": "PMID-7775431_E4", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1093, 1102 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-7775431_T16" }, { "role": "Theme", "ref_id": "PMID-7775431_E3" } ] }, { "id": "PMID-7775431_E5", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 1131, 1141 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_T17" } ] }, { "id": "PMID-7775431_E6", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 1131, 1141 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_T18" } ] }, { "id": "PMID-7775431_E7", "type": "Binding", "trigger": { "text": [ "forms a complex" ], "offsets": [ [ 1215, 1230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_T19" }, { "role": "Theme", "ref_id": "PMID-7775431_T20" } ] }, { "id": "PMID-7775431_E8", "type": "Binding", "trigger": { "text": [ "forms a complex" ], "offsets": [ [ 1215, 1230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_T19" }, { "role": "Theme", "ref_id": "PMID-7775431_T21" } ] }, { "id": "PMID-7775431_E9", "type": "Binding", "trigger": { "text": [ "forms a complex" ], "offsets": [ [ 1215, 1230 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_T22" }, { "role": "Theme", "ref_id": "PMID-7775431_T19" } ] }, { "id": "PMID-7775431_E10", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 1343, 1352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_E11" } ] }, { "id": "PMID-7775431_E11", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1357, 1364 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_T23" }, { "role": "Theme", "ref_id": "PMID-7775431_T24" } ] }, { "id": "PMID-7775431_E12", "type": "Gene_expression", "trigger": { "text": [ "coexpressed" ], "offsets": [ [ 1455, 1466 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_T23" } ] }, { "id": "PMID-7775431_E13", "type": "Gene_expression", "trigger": { "text": [ "coexpressed" ], "offsets": [ [ 1455, 1466 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-7775431_T24" } ] }, { "id": "PMID-7775431_E14", "type": "Binding", "trigger": { "text": [ "be a complex" ], "offsets": [ [ 1519, 1531 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-7775431_T25" } ] } ]

[ { "id": "PMID-7775431_1", "entity_ids": [ "PMID-7775431_T2", "PMID-7775431_T3" ] }, { "id": "PMID-7775431_2", "entity_ids": [ "PMID-7775431_T8", "PMID-7775431_T9" ] } ]

[]

[ { "id": "PMID-8034624__text", "type": "abstract", "text": [ "Activation of phosphoinositide 3-kinase activity by Cdc42Hs binding to p85. \nThe Ras-like GTPase Cdc42 is essential for cell polarity and bud site assembly in Saccharomyces cerevisiae by regulating cell cycle-dependent reorganization of cortical cytoskeletal elements. However, its role in mammalian cells is unknown. To identify potential effectors of Cdc42Hs, we incubated lysates from NIH 3T3 fibroblasts or PC12 cells with immobilized glutathione S-transferase (GST)-Cdc42Hs fusion proteins bound to different guanine nucleotides and observed a specific association between the 85-kDa subunit (p85) of phosphatidylinositol 3-kinase (PI 3-kinase) and GTP gamma S (guanosine 5'-3-O-(thio)triphosphate)-bound GST-Cdc42Hs. Recombinant p85 formed a complex with GTP gamma S-bound GST-Cdc42Hs and with a GTPase-defective GTP-bound GST-Cdc42Hs-Q61L mutant, but not with a GTP gamma S-bound, effector domain GST-Cdc42HsT35A mutant. Both the Rho-GAP homology domain of p85 and the Cdc42Hs-GAP competitively inhibited the binding of recombinant p85 to Cdc42Hs. In addition, PI 3-kinase activity immunoprecipitated from cell lysates with anti-p85 antibody was stimulated 2-4-fold by GST-Cdc42-GTP gamma S. Similar interactions were observed between p85 and GST-Rac1-GTP gamma S but not between p85 and GST-RhoA-GTP gamma S. These findings suggest that PI 3-kinase, through the Rho-GAP homology domain of p85, can couple to the effector domain of Cdc42Hs and that p85 may be a target for the GTP-bound forms of Cdc42Hs and Rac1.\n" ], "offsets": [ [ 0, 1521 ] ] } ]

[ { "id": "PMID-8034624_T1", "type": "Gene_or_gene_product", "text": [ "phosphoinositide 3-kinase" ], "offsets": [ [ 14, 39 ] ], "normalized": [] }, { "id": "PMID-8034624_T2", "type": "Gene_or_gene_product", "text": [ "Cdc42Hs" ], "offsets": [ [ 52, 59 ] ], "normalized": [] }, { "id": "PMID-8034624_T3", "type": "Gene_or_gene_product", "text": [ "p85" ], "offsets": [ [ 71, 74 ] ], "normalized": [] }, { "id": "PMID-8034624_T4", "type": "Gene_or_gene_product", "text": [ "Ras" ], "offsets": [ [ 81, 84 ] ], "normalized": [] }, { "id": "PMID-8034624_T5", "type": "Gene_or_gene_product", "text": [ "Cdc42" ], "offsets": [ [ 97, 102 ] ], "normalized": [] }, { "id": "PMID-8034624_T6", "type": "Cellular_component", "text": [ "cytoskeletal elements" ], "offsets": [ [ 246, 267 ] ], "normalized": [] }, { "id": "PMID-8034624_T7", "type": "Gene_or_gene_product", "text": [ "Cdc42Hs" ], "offsets": [ [ 353, 360 ] ], "normalized": [] }, { "id": "PMID-8034624_T8", "type": "Gene_or_gene_product", "text": [ "glutathione S-transferase (GST)-Cdc42Hs" ], "offsets": [ [ 439, 478 ] ], "normalized": [] }, { "id": "PMID-8034624_T9", "type": "Simple_chemical", "text": [ "guanine" ], "offsets": [ [ 514, 521 ] ], "normalized": [] }, { "id": "PMID-8034624_T10", "type": "Gene_or_gene_product", "text": [ "p85" ], "offsets": [ [ 598, 601 ] ], "normalized": [] }, { "id": "PMID-8034624_T11", "type": "Gene_or_gene_product", "text": [ "phosphatidylinositol 3-kinase" ], "offsets": [ [ 606, 635 ] ], "normalized": [] }, { "id": "PMID-8034624_T12", "type": "Gene_or_gene_product", "text": [ "PI 3-kinase" ], "offsets": [ [ 637, 648 ] ], "normalized": [] }, { "id": "PMID-8034624_T13", "type": "Simple_chemical", "text": [ "GTP gamma S" ], "offsets": [ [ 654, 665 ] ], "normalized": [] }, { "id": "PMID-8034624_T14", "type": "Simple_chemical", "text": [ "guanosine 5'-3-O-(thio)triphosphate" ], "offsets": [ [ 667, 702 ] ], "normalized": [] }, { "id": "PMID-8034624_T15", "type": "Gene_or_gene_product", "text": [ "GST-Cdc42Hs" ], "offsets": [ [ 710, 721 ] ], "normalized": [] }, { "id": "PMID-8034624_T16", "type": "Gene_or_gene_product", "text": [ "p85" ], "offsets": [ [ 735, 738 ] ], "normalized": [] }, { "id": "PMID-8034624_T17", "type": "Simple_chemical", "text": [ "GTP gamma S" ], "offsets": [ [ 761, 772 ] ], "normalized": [] }, { "id": "PMID-8034624_T18", "type": "Gene_or_gene_product", "text": [ "GST-Cdc42Hs" ], "offsets": [ [ 779, 790 ] ], "normalized": [] }, { "id": "PMID-8034624_T19", "type": "Simple_chemical", "text": [ "GTP" ], "offsets": [ [ 819, 822 ] ], "normalized": [] }, { "id": "PMID-8034624_T20", "type": "Complex", "text": [ "GST-Cdc42Hs-Q61L" ], "offsets": [ [ 829, 845 ] ], "normalized": [] }, { "id": "PMID-8034624_T21", "type": "Simple_chemical", "text": [ "GTP gamma S" ], "offsets": [ [ 869, 880 ] ], "normalized": [] }, { "id": "PMID-8034624_T22", "type": "Gene_or_gene_product", "text": [ "GST-Cdc42HsT35A" ], "offsets": [ [ 904, 919 ] ], "normalized": [] }, { "id": "PMID-8034624_T23", "type": "Gene_or_gene_product", "text": [ "Rho-GAP" ], "offsets": [ [ 937, 944 ] ], "normalized": [] }, { "id": "PMID-8034624_T24", "type": "Gene_or_gene_product", "text": [ "p85" ], "offsets": [ [ 964, 967 ] ], "normalized": [] }, { "id": "PMID-8034624_T25", "type": "Gene_or_gene_product", "text": [ "Cdc42Hs-GAP" ], "offsets": [ [ 976, 987 ] ], "normalized": [] }, { "id": "PMID-8034624_T26", "type": "Gene_or_gene_product", "text": [ "p85" ], "offsets": [ [ 1039, 1042 ] ], "normalized": [] }, { "id": "PMID-8034624_T27", "type": "Gene_or_gene_product", "text": [ "Cdc42Hs" ], "offsets": [ [ 1046, 1053 ] ], "normalized": [] }, { "id": "PMID-8034624_T28", "type": "Gene_or_gene_product", "text": [ "PI 3-kinase" ], "offsets": [ [ 1068, 1079 ] ], "normalized": [] }, { "id": "PMID-8034624_T29", "type": "Gene_or_gene_product", "text": [ "p85" ], "offsets": [ [ 1136, 1139 ] ], "normalized": [] }, { "id": "PMID-8034624_T30", "type": "Complex", "text": [ "GST-Cdc42-GTP gamma S" ], "offsets": [ [ 1176, 1197 ] ], "normalized": [] }, { "id": "PMID-8034624_T31", "type": "Gene_or_gene_product", "text": [ "p85" ], "offsets": [ [ 1242, 1245 ] ], "normalized": [] }, { "id": "PMID-8034624_T32", "type": "Complex", "text": [ "GST-Rac1-GTP gamma S" ], "offsets": [ [ 1250, 1270 ] ], "normalized": [] }, { "id": "PMID-8034624_T33", "type": "Gene_or_gene_product", "text": [ "p85" ], "offsets": [ [ 1287, 1290 ] ], "normalized": [] }, { "id": "PMID-8034624_T34", "type": "Complex", "text": [ "GST-RhoA-GTP gamma S" ], "offsets": [ [ 1295, 1315 ] ], "normalized": [] }, { "id": "PMID-8034624_T35", "type": "Gene_or_gene_product", "text": [ "PI 3-kinase" ], "offsets": [ [ 1345, 1356 ] ], "normalized": [] }, { "id": "PMID-8034624_T36", "type": "Gene_or_gene_product", "text": [ "Rho-GAP" ], "offsets": [ [ 1370, 1377 ] ], "normalized": [] }, { "id": "PMID-8034624_T37", "type": "Gene_or_gene_product", "text": [ "p85" ], "offsets": [ [ 1397, 1400 ] ], "normalized": [] }, { "id": "PMID-8034624_T38", "type": "Gene_or_gene_product", "text": [ "Cdc42Hs" ], "offsets": [ [ 1439, 1446 ] ], "normalized": [] }, { "id": "PMID-8034624_T39", "type": "Gene_or_gene_product", "text": [ "p85" ], "offsets": [ [ 1456, 1459 ] ], "normalized": [] }, { "id": "PMID-8034624_T40", "type": "Simple_chemical", "text": [ "GTP" ], "offsets": [ [ 1484, 1487 ] ], "normalized": [] }, { "id": "PMID-8034624_T41", "type": "Gene_or_gene_product", "text": [ "Cdc42Hs" ], "offsets": [ [ 1503, 1510 ] ], "normalized": [] }, { "id": "PMID-8034624_T42", "type": "Gene_or_gene_product", "text": [ "Rac1" ], "offsets": [ [ 1515, 1519 ] ], "normalized": [] } ]

[ { "id": "PMID-8034624_E1", "type": "Positive_regulation", "trigger": { "text": [ "Activation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T1" }, { "role": "Cause", "ref_id": "PMID-8034624_E2" } ] }, { "id": "PMID-8034624_E2", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 60, 67 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T3" }, { "role": "Theme", "ref_id": "PMID-8034624_T2" } ] }, { "id": "PMID-8034624_E3", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 198, 208 ] ] }, "arguments": [] }, { "id": "PMID-8034624_E4", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 495, 500 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T8" }, { "role": "Theme", "ref_id": "PMID-8034624_T9" } ] }, { "id": "PMID-8034624_E5", "type": "Binding", "trigger": { "text": [ "association" ], "offsets": [ [ 558, 569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T11" }, { "role": "Theme", "ref_id": "PMID-8034624_T10" }, { "role": "Theme", "ref_id": "PMID-8034624_T15" } ] }, { "id": "PMID-8034624_E6", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 704, 709 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T15" }, { "role": "Theme", "ref_id": "PMID-8034624_T13" } ] }, { "id": "PMID-8034624_E7", "type": "Binding", "trigger": { "text": [ "formed a complex" ], "offsets": [ [ 739, 755 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T18" }, { "role": "Theme", "ref_id": "PMID-8034624_T16" } ] }, { "id": "PMID-8034624_E8", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 773, 778 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T18" }, { "role": "Theme", "ref_id": "PMID-8034624_T17" } ] }, { "id": "PMID-8034624_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1002, 1011 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_E11" }, { "role": "Cause", "ref_id": "PMID-8034624_T24" } ] }, { "id": "PMID-8034624_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1002, 1011 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_E11" }, { "role": "Cause", "ref_id": "PMID-8034624_T25" } ] }, { "id": "PMID-8034624_E11", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1016, 1023 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T26" }, { "role": "Theme", "ref_id": "PMID-8034624_T27" } ] }, { "id": "PMID-8034624_E12", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 1153, 1163 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8034624_T30" }, { "role": "Theme", "ref_id": "PMID-8034624_T28" } ] }, { "id": "PMID-8034624_E13", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 1207, 1219 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T31" }, { "role": "Theme", "ref_id": "PMID-8034624_T32" } ] }, { "id": "PMID-8034624_E14", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 1207, 1219 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T33" }, { "role": "Theme", "ref_id": "PMID-8034624_T34" } ] }, { "id": "PMID-8034624_E15", "type": "Regulation", "trigger": { "text": [ "couple" ], "offsets": [ [ 1406, 1412 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T38" }, { "role": "Cause", "ref_id": "PMID-8034624_T35" } ] }, { "id": "PMID-8034624_E16", "type": "Positive_regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 1469, 1475 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8034624_T39" }, { "role": "Theme", "ref_id": "PMID-8034624_E19" } ] }, { "id": "PMID-8034624_E17", "type": "Positive_regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 1469, 1475 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8034624_T39" }, { "role": "Theme", "ref_id": "PMID-8034624_E18" } ] }, { "id": "PMID-8034624_E18", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 1488, 1493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T40" }, { "role": "Theme", "ref_id": "PMID-8034624_T41" } ] }, { "id": "PMID-8034624_E19", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 1488, 1493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8034624_T40" }, { "role": "Theme", "ref_id": "PMID-8034624_T42" } ] } ]

[ { "id": "PMID-8034624_1", "entity_ids": [ "PMID-8034624_T11", "PMID-8034624_T12" ] }, { "id": "PMID-8034624_2", "entity_ids": [ "PMID-8034624_T14", "PMID-8034624_T13" ] } ]

[]

[ { "id": "PMID-8063807__text", "type": "abstract", "text": [ "Human liver arylacetamide deacetylase. Molecular cloning of a novel esterase involved in the metabolic activation of arylamine carcinogens with high sequence similarity to hormone-sensitive lipase. \nMicrosomal arylacetamide deacetylase (DAC) competes against the activity of cytosolic arylamine N-acetyltransferase, which catalyzes one of the initial biotransformation pathways for arylamine and heterocyclic amine carcinogens in many species and tissues. Activity determination and immunoblot analysis of DAC in human target tissues for arylamine carcinogens revealed that in extrahepatic tissues, additional enzymes are responsible for any deacetylation activity, whereas a single enzyme predominantly catalyzes this hydrolytic reaction in liver. We isolated and characterized a full-length cDNA from a human liver lambda gt11 library. This clone encodes an open reading frame of 400 amino acids with a deduced molecular mass of 45.7 kDa and contains two putative glycosylation sites. The 3'-untranslated region contains two putative polyadenylation signals. The cDNA was confirmed to be that for DAC in tryptic peptides from the purified human liver protein. Highest sequence similarity of DAC was found in a series of prokaryotic esterases encompassing the putative active site. Two extended regions of significant sequence homology with hormone-sensitive lipase and with lipase 2 from Moraxella TA144 were identified, whereas similarity to carboxyl esterases was restricted to the region encompassing the putative active site, indicating that DAC should be classified as esterase. This cDNA provides an important tool to study deacetylation and its effects on the metabolic activation of arylamine and heterocyclic amine carcinogens.\n" ], "offsets": [ [ 0, 1739 ] ] } ]

[ { "id": "PMID-8063807_T1", "type": "Gene_or_gene_product", "text": [ "arylacetamide deacetylase" ], "offsets": [ [ 12, 37 ] ], "normalized": [] }, { "id": "PMID-8063807_T2", "type": "Gene_or_gene_product", "text": [ "esterase" ], "offsets": [ [ 68, 76 ] ], "normalized": [] }, { "id": "PMID-8063807_T3", "type": "Simple_chemical", "text": [ "arylamine" ], "offsets": [ [ 117, 126 ] ], "normalized": [] }, { "id": "PMID-8063807_T4", "type": "Gene_or_gene_product", "text": [ "hormone-sensitive lipase" ], "offsets": [ [ 172, 196 ] ], "normalized": [] }, { "id": "PMID-8063807_T5", "type": "Gene_or_gene_product", "text": [ "arylacetamide deacetylase" ], "offsets": [ [ 210, 235 ] ], "normalized": [] }, { "id": "PMID-8063807_T6", "type": "Gene_or_gene_product", "text": [ "DAC" ], "offsets": [ [ 237, 240 ] ], "normalized": [] }, { "id": "PMID-8063807_T7", "type": "Cellular_component", "text": [ "cytosolic" ], "offsets": [ [ 275, 284 ] ], "normalized": [] }, { "id": "PMID-8063807_T8", "type": "Gene_or_gene_product", "text": [ "arylamine N-acetyltransferase" ], "offsets": [ [ 285, 314 ] ], "normalized": [] }, { "id": "PMID-8063807_T9", "type": "Simple_chemical", "text": [ "arylamine" ], "offsets": [ [ 382, 391 ] ], "normalized": [] }, { "id": "PMID-8063807_T10", "type": "Simple_chemical", "text": [ "heterocyclic amine" ], "offsets": [ [ 396, 414 ] ], "normalized": [] }, { "id": "PMID-8063807_T11", "type": "Gene_or_gene_product", "text": [ "DAC" ], "offsets": [ [ 506, 509 ] ], "normalized": [] }, { "id": "PMID-8063807_T12", "type": "Simple_chemical", "text": [ "arylamine" ], "offsets": [ [ 538, 547 ] ], "normalized": [] }, { "id": "PMID-8063807_T13", "type": "Gene_or_gene_product", "text": [ "DAC" ], "offsets": [ [ 1099, 1102 ] ], "normalized": [] }, { "id": "PMID-8063807_T14", "type": "Gene_or_gene_product", "text": [ "DAC" ], "offsets": [ [ 1193, 1196 ] ], "normalized": [] }, { "id": "PMID-8063807_T15", "type": "Gene_or_gene_product", "text": [ "hormone-sensitive lipase" ], "offsets": [ [ 1342, 1366 ] ], "normalized": [] }, { "id": "PMID-8063807_T16", "type": "Gene_or_gene_product", "text": [ "lipase 2" ], "offsets": [ [ 1376, 1384 ] ], "normalized": [] }, { "id": "PMID-8063807_T17", "type": "Gene_or_gene_product", "text": [ "carboxyl esterases" ], "offsets": [ [ 1445, 1463 ] ], "normalized": [] }, { "id": "PMID-8063807_T18", "type": "Gene_or_gene_product", "text": [ "DAC" ], "offsets": [ [ 1548, 1551 ] ], "normalized": [] }, { "id": "PMID-8063807_T19", "type": "Gene_or_gene_product", "text": [ "esterase" ], "offsets": [ [ 1576, 1584 ] ], "normalized": [] }, { "id": "PMID-8063807_T20", "type": "Simple_chemical", "text": [ "arylamine" ], "offsets": [ [ 1693, 1702 ] ], "normalized": [] }, { "id": "PMID-8063807_T21", "type": "Simple_chemical", "text": [ "heterocyclic amine" ], "offsets": [ [ 1707, 1725 ] ], "normalized": [] } ]

[ { "id": "PMID-8063807_E1", "type": "Positive_regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 77, 85 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8063807_E2" }, { "role": "Cause", "ref_id": "PMID-8063807_T2" } ] }, { "id": "PMID-8063807_E2", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 103, 113 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8063807_T3" } ] }, { "id": "PMID-8063807_E3", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1654, 1661 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8063807_T18" }, { "role": "Theme", "ref_id": "PMID-8063807_E5" } ] }, { "id": "PMID-8063807_E4", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1654, 1661 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8063807_T18" }, { "role": "Theme", "ref_id": "PMID-8063807_E6" } ] }, { "id": "PMID-8063807_E5", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1679, 1689 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8063807_T20" } ] }, { "id": "PMID-8063807_E6", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1679, 1689 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8063807_T21" } ] } ]

[ { "id": "PMID-8063807_1", "entity_ids": [ "PMID-8063807_T5", "PMID-8063807_T6" ] } ]

[]

[ { "id": "PMID-8078588__text", "type": "abstract", "text": [ "p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. \nTransforming growth factor-beta (TGF-beta) inhibits cell proliferation by inducing a G1-phase cell cycle arrest. Normal progression through G1 is promoted by the activity of the cyclin-dependent protein kinases CDK4 and CDK6 (ref. 2), which are inhibited by the protein p16INK4. We have isolated a new member of the p16INK4 family, p15INK4B. p15 expression is induced approximately 30-fold in human keratinocytes by treatment with TGF-beta, suggesting that p15 may act as an effector of TGF-beta-mediated cell cycle arrest. The gene encoding p15 is located on chromosome 9 adjacent to the p16 gene at a frequent site of chromosomal abnormality in human tumours (9p21).\n" ], "offsets": [ [ 0, 742 ] ] } ]

[ { "id": "PMID-8078588_T1", "type": "Gene_or_gene_product", "text": [ "p15INK4B" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "PMID-8078588_T2", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 36, 44 ] ], "normalized": [] }, { "id": "PMID-8078588_T3", "type": "Gene_or_gene_product", "text": [ "Transforming growth factor-beta" ], "offsets": [ [ 73, 104 ] ], "normalized": [] }, { "id": "PMID-8078588_T4", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 106, 114 ] ], "normalized": [] }, { "id": "PMID-8078588_T5", "type": "Gene_or_gene_product", "text": [ "cyclin-dependent protein kinases" ], "offsets": [ [ 251, 283 ] ], "normalized": [] }, { "id": "PMID-8078588_T6", "type": "Gene_or_gene_product", "text": [ "CDK4" ], "offsets": [ [ 284, 288 ] ], "normalized": [] }, { "id": "PMID-8078588_T7", "type": "Gene_or_gene_product", "text": [ "CDK6" ], "offsets": [ [ 293, 297 ] ], "normalized": [] }, { "id": "PMID-8078588_T8", "type": "Gene_or_gene_product", "text": [ "p16INK4" ], "offsets": [ [ 343, 350 ] ], "normalized": [] }, { "id": "PMID-8078588_T9", "type": "Gene_or_gene_product", "text": [ "p16INK4" ], "offsets": [ [ 389, 396 ] ], "normalized": [] }, { "id": "PMID-8078588_T10", "type": "Gene_or_gene_product", "text": [ "p15INK4B" ], "offsets": [ [ 405, 413 ] ], "normalized": [] }, { "id": "PMID-8078588_T11", "type": "Gene_or_gene_product", "text": [ "p15" ], "offsets": [ [ 415, 418 ] ], "normalized": [] }, { "id": "PMID-8078588_T12", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 504, 512 ] ], "normalized": [] }, { "id": "PMID-8078588_T13", "type": "Gene_or_gene_product", "text": [ "p15" ], "offsets": [ [ 530, 533 ] ], "normalized": [] }, { "id": "PMID-8078588_T14", "type": "Gene_or_gene_product", "text": [ "TGF-beta" ], "offsets": [ [ 560, 568 ] ], "normalized": [] }, { "id": "PMID-8078588_T15", "type": "Gene_or_gene_product", "text": [ "p15" ], "offsets": [ [ 615, 618 ] ], "normalized": [] }, { "id": "PMID-8078588_T16", "type": "Cellular_component", "text": [ "chromosome 9" ], "offsets": [ [ 633, 645 ] ], "normalized": [] }, { "id": "PMID-8078588_T17", "type": "Gene_or_gene_product", "text": [ "p16" ], "offsets": [ [ 662, 665 ] ], "normalized": [] }, { "id": "PMID-8078588_T18", "type": "Cellular_component", "text": [ "chromosomal" ], "offsets": [ [ 693, 704 ] ], "normalized": [] } ]

[ { "id": "PMID-8078588_E1", "type": "Regulation", "trigger": { "text": [ "effector" ], "offsets": [ [ 24, 32 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8078588_T1" }, { "role": "Theme", "ref_id": "PMID-8078588_E4" } ] }, { "id": "PMID-8078588_E2", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 45, 52 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8078588_T2" }, { "role": "Theme", "ref_id": "PMID-8078588_E4" } ] }, { "id": "PMID-8078588_E3", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 53, 63 ] ] }, "arguments": [] }, { "id": "PMID-8078588_E4", "type": "Negative_regulation", "trigger": { "text": [ "arrest" ], "offsets": [ [ 64, 70 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8078588_E3" } ] }, { "id": "PMID-8078588_E5", "type": "Positive_regulation", "trigger": { "text": [ "inducing" ], "offsets": [ [ 147, 155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8078588_E7" }, { "role": "Cause", "ref_id": "PMID-8078588_T4" } ] }, { "id": "PMID-8078588_E6", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 167, 177 ] ] }, "arguments": [] }, { "id": "PMID-8078588_E7", "type": "Negative_regulation", "trigger": { "text": [ "arrest" ], "offsets": [ [ 178, 184 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8078588_E6" } ] }, { "id": "PMID-8078588_E8", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 318, 327 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8078588_T8" }, { "role": "Theme", "ref_id": "PMID-8078588_T6" } ] }, { "id": "PMID-8078588_E9", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 318, 327 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8078588_T8" }, { "role": "Theme", "ref_id": "PMID-8078588_T7" } ] }, { "id": "PMID-8078588_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 419, 429 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8078588_T11" } ] }, { "id": "PMID-8078588_E11", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 433, 440 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8078588_E10" }, { "role": "Cause", "ref_id": "PMID-8078588_T12" } ] }, { "id": "PMID-8078588_E12", "type": "Regulation", "trigger": { "text": [ "effector" ], "offsets": [ [ 548, 556 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8078588_T13" }, { "role": "Theme", "ref_id": "PMID-8078588_E15" } ] }, { "id": "PMID-8078588_E13", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 569, 577 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8078588_T14" }, { "role": "Theme", "ref_id": "PMID-8078588_E15" } ] }, { "id": "PMID-8078588_E14", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 578, 588 ] ] }, "arguments": [] }, { "id": "PMID-8078588_E15", "type": "Negative_regulation", "trigger": { "text": [ "arrest" ], "offsets": [ [ 589, 595 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8078588_E14" } ] }, { "id": "PMID-8078588_E16", "type": "Localization", "trigger": { "text": [ "located" ], "offsets": [ [ 622, 629 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-8078588_T16" }, { "role": "Theme", "ref_id": "PMID-8078588_T15" } ] } ]

[ { "id": "PMID-8078588_1", "entity_ids": [ "PMID-8078588_T3", "PMID-8078588_T4" ] } ]

[]

[ { "id": "PMID-8105476__text", "type": "abstract", "text": [ "The t-complex polypeptide 1 complex is a chaperonin for tubulin and actin in vivo. \nA role in folding newly translated cytoskeletal proteins in the cytosol of eukaryotes has been proposed for t-complex polypeptide 1 (TCP1). In this study, we investigated tubulin and actin biogenesis in Chinese hamster ovary (CHO) cells. When extracts of pulse-labeled cells were analyzed by anion-exchange and size-exclusion chromatography, newly synthesized alpha-tubulin, beta-tubulin, and actin were observed to enter a large molecular mass complex (approximately 900 kDa). These proteins were released from this complex capable, in the case of tubulin, of forming heterodimers. The large molecular mass complexes coeluted with TCP1 and could be immunoprecipitated by using an anti-TCP1 antibody. These findings demonstrate that there is a cytosolic pathway for folding tubulin and actin in vivo that involves the TCP1 complex. \n" ], "offsets": [ [ 0, 917 ] ] } ]

[ { "id": "PMID-8105476_T1", "type": "Complex", "text": [ "t-complex polypeptide 1 complex" ], "offsets": [ [ 4, 35 ] ], "normalized": [] }, { "id": "PMID-8105476_T2", "type": "Gene_or_gene_product", "text": [ "tubulin" ], "offsets": [ [ 56, 63 ] ], "normalized": [] }, { "id": "PMID-8105476_T3", "type": "Gene_or_gene_product", "text": [ "actin" ], "offsets": [ [ 68, 73 ] ], "normalized": [] }, { "id": "PMID-8105476_T4", "type": "Cellular_component", "text": [ "cytoskeletal" ], "offsets": [ [ 119, 131 ] ], "normalized": [] }, { "id": "PMID-8105476_T5", "type": "Cellular_component", "text": [ "cytosol" ], "offsets": [ [ 148, 155 ] ], "normalized": [] }, { "id": "PMID-8105476_T6", "type": "Gene_or_gene_product", "text": [ "t-complex polypeptide 1" ], "offsets": [ [ 192, 215 ] ], "normalized": [] }, { "id": "PMID-8105476_T7", "type": "Gene_or_gene_product", "text": [ "TCP1" ], "offsets": [ [ 217, 221 ] ], "normalized": [] }, { "id": "PMID-8105476_T8", "type": "Gene_or_gene_product", "text": [ "tubulin" ], "offsets": [ [ 255, 262 ] ], "normalized": [] }, { "id": "PMID-8105476_T9", "type": "Gene_or_gene_product", "text": [ "actin" ], "offsets": [ [ 267, 272 ] ], "normalized": [] }, { "id": "PMID-8105476_T10", "type": "Simple_chemical", "text": [ "anion" ], "offsets": [ [ 376, 381 ] ], "normalized": [] }, { "id": "PMID-8105476_T11", "type": "Gene_or_gene_product", "text": [ "alpha-tubulin" ], "offsets": [ [ 444, 457 ] ], "normalized": [] }, { "id": "PMID-8105476_T12", "type": "Gene_or_gene_product", "text": [ "beta-tubulin" ], "offsets": [ [ 459, 471 ] ], "normalized": [] }, { "id": "PMID-8105476_T13", "type": "Gene_or_gene_product", "text": [ "actin" ], "offsets": [ [ 477, 482 ] ], "normalized": [] }, { "id": "PMID-8105476_T14", "type": "Gene_or_gene_product", "text": [ "tubulin" ], "offsets": [ [ 633, 640 ] ], "normalized": [] }, { "id": "PMID-8105476_T15", "type": "Gene_or_gene_product", "text": [ "TCP1" ], "offsets": [ [ 716, 720 ] ], "normalized": [] }, { "id": "PMID-8105476_T16", "type": "Gene_or_gene_product", "text": [ "anti-TCP1 antibody" ], "offsets": [ [ 765, 783 ] ], "normalized": [] }, { "id": "PMID-8105476_T17", "type": "Cellular_component", "text": [ "cytosolic" ], "offsets": [ [ 828, 837 ] ], "normalized": [] }, { "id": "PMID-8105476_T18", "type": "Gene_or_gene_product", "text": [ "tubulin" ], "offsets": [ [ 858, 865 ] ], "normalized": [] }, { "id": "PMID-8105476_T19", "type": "Gene_or_gene_product", "text": [ "actin" ], "offsets": [ [ 870, 875 ] ], "normalized": [] }, { "id": "PMID-8105476_T20", "type": "Complex", "text": [ "TCP1 complex" ], "offsets": [ [ 902, 914 ] ], "normalized": [] } ]

[ { "id": "PMID-8105476_E1", "type": "Gene_expression", "trigger": { "text": [ "biogenesis" ], "offsets": [ [ 273, 283 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8105476_T8" } ] }, { "id": "PMID-8105476_E2", "type": "Gene_expression", "trigger": { "text": [ "biogenesis" ], "offsets": [ [ 273, 283 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8105476_T9" } ] }, { "id": "PMID-8105476_E3", "type": "Gene_expression", "trigger": { "text": [ "synthesized" ], "offsets": [ [ 432, 443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8105476_T13" } ] }, { "id": "PMID-8105476_E4", "type": "Gene_expression", "trigger": { "text": [ "synthesized" ], "offsets": [ [ 432, 443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8105476_T12" } ] }, { "id": "PMID-8105476_E5", "type": "Gene_expression", "trigger": { "text": [ "synthesized" ], "offsets": [ [ 432, 443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8105476_T11" } ] }, { "id": "PMID-8105476_E6", "type": "Binding", "trigger": { "text": [ "enter a large molecular mass complex" ], "offsets": [ [ 500, 536 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8105476_T11" }, { "role": "Theme", "ref_id": "PMID-8105476_T12" }, { "role": "Theme", "ref_id": "PMID-8105476_T13" } ] }, { "id": "PMID-8105476_E7", "type": "Dissociation", "trigger": { "text": [ "released" ], "offsets": [ [ 582, 590 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-8105476_T11" }, { "role": "Product", "ref_id": "PMID-8105476_T12" }, { "role": "Product", "ref_id": "PMID-8105476_T13" } ] }, { "id": "PMID-8105476_E8", "type": "Binding", "trigger": { "text": [ "forming heterodimers" ], "offsets": [ [ 645, 665 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8105476_T14" } ] }, { "id": "PMID-8105476_E9", "type": "Binding", "trigger": { "text": [ "folding" ], "offsets": [ [ 850, 857 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8105476_T18" }, { "role": "Theme", "ref_id": "PMID-8105476_T19" } ] }, { "id": "PMID-8105476_E10", "type": "Regulation", "trigger": { "text": [ "involves" ], "offsets": [ [ 889, 897 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8105476_T20" }, { "role": "Theme", "ref_id": "PMID-8105476_E9" } ] } ]

[ { "id": "PMID-8105476_1", "entity_ids": [ "PMID-8105476_T6", "PMID-8105476_T7" ] } ]

[]

[ { "id": "PMID-8386367__text", "type": "abstract", "text": [ "Transactivation of gene expression by Myc is inhibited by mutation at the phosphorylation sites Thr-58 and Ser-62. \nThe product of the human c-myc protooncogene (Myc) is a sequence-specific DNA binding protein. Here, we demonstrate that the placement of the specific Myc DNA binding site CACGTG upstream of a luciferase reporter gene conferred Myc-stimulated expression that was inhibited by the overexpression of the basic-helix-loop-helix/leucine zipper protein Max. It was observed that Myc was phosphorylated in vivo within the NH2-terminal domain at Thr-58 and Ser-62. Replacement of these phosphorylation sites with Ala residues caused a marked decrease in Myc-stimulated reporter gene expression. In contrast, the replacement of Thr-58 or Ser-62 with an acidic residue (Glu) caused only a small inhibition of transactivation. Together, these data demonstrate that the NH2-terminal phosphorylation sites Thr-58 and Ser-62 are required for high levels of transactivation of gene expression by Myc.\n" ], "offsets": [ [ 0, 1003 ] ] } ]

[ { "id": "PMID-8386367_T1", "type": "Gene_or_gene_product", "text": [ "Myc" ], "offsets": [ [ 38, 41 ] ], "normalized": [] }, { "id": "PMID-8386367_T2", "type": "Simple_chemical", "text": [ "Thr-58" ], "offsets": [ [ 96, 102 ] ], "normalized": [] }, { "id": "PMID-8386367_T3", "type": "Simple_chemical", "text": [ "Ser-62" ], "offsets": [ [ 107, 113 ] ], "normalized": [] }, { "id": "PMID-8386367_T4", "type": "Gene_or_gene_product", "text": [ "c-myc" ], "offsets": [ [ 141, 146 ] ], "normalized": [] }, { "id": "PMID-8386367_T5", "type": "Gene_or_gene_product", "text": [ "Myc" ], "offsets": [ [ 162, 165 ] ], "normalized": [] }, { "id": "PMID-8386367_T6", "type": "Gene_or_gene_product", "text": [ "Myc" ], "offsets": [ [ 267, 270 ] ], "normalized": [] }, { "id": "PMID-8386367_T7", "type": "Gene_or_gene_product", "text": [ "luciferase" ], "offsets": [ [ 309, 319 ] ], "normalized": [] }, { "id": "PMID-8386367_T8", "type": "Gene_or_gene_product", "text": [ "Myc" ], "offsets": [ [ 344, 347 ] ], "normalized": [] }, { "id": "PMID-8386367_T9", "type": "Simple_chemical", "text": [ "leucine" ], "offsets": [ [ 441, 448 ] ], "normalized": [] }, { "id": "PMID-8386367_T10", "type": "Gene_or_gene_product", "text": [ "Max" ], "offsets": [ [ 464, 467 ] ], "normalized": [] }, { "id": "PMID-8386367_T11", "type": "Gene_or_gene_product", "text": [ "Myc" ], "offsets": [ [ 490, 493 ] ], "normalized": [] }, { "id": "PMID-8386367_T12", "type": "Simple_chemical", "text": [ "Thr-58" ], "offsets": [ [ 555, 561 ] ], "normalized": [] }, { "id": "PMID-8386367_T13", "type": "Simple_chemical", "text": [ "Ser-62" ], "offsets": [ [ 566, 572 ] ], "normalized": [] }, { "id": "PMID-8386367_T14", "type": "Simple_chemical", "text": [ "Ala" ], "offsets": [ [ 622, 625 ] ], "normalized": [] }, { "id": "PMID-8386367_T15", "type": "Gene_or_gene_product", "text": [ "Myc" ], "offsets": [ [ 663, 666 ] ], "normalized": [] }, { "id": "PMID-8386367_T16", "type": "Simple_chemical", "text": [ "Thr-58" ], "offsets": [ [ 736, 742 ] ], "normalized": [] }, { "id": "PMID-8386367_T17", "type": "Simple_chemical", "text": [ "Ser-62" ], "offsets": [ [ 746, 752 ] ], "normalized": [] }, { "id": "PMID-8386367_T18", "type": "Simple_chemical", "text": [ "Glu" ], "offsets": [ [ 777, 780 ] ], "normalized": [] }, { "id": "PMID-8386367_T19", "type": "Simple_chemical", "text": [ "Thr-58" ], "offsets": [ [ 910, 916 ] ], "normalized": [] }, { "id": "PMID-8386367_T20", "type": "Simple_chemical", "text": [ "Ser-62" ], "offsets": [ [ 921, 927 ] ], "normalized": [] }, { "id": "PMID-8386367_T21", "type": "Gene_or_gene_product", "text": [ "Myc" ], "offsets": [ [ 998, 1001 ] ], "normalized": [] } ]

[ { "id": "PMID-8386367_E1", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 74, 89 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-8386367_T2" }, { "role": "Theme", "ref_id": "PMID-8386367_T1" } ] }, { "id": "PMID-8386367_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 74, 89 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-8386367_T3" }, { "role": "Theme", "ref_id": "PMID-8386367_T1" } ] }, { "id": "PMID-8386367_E3", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 194, 201 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8386367_T4" } ] }, { "id": "PMID-8386367_E4", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 396, 410 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8386367_T10" } ] }, { "id": "PMID-8386367_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 498, 512 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8386367_T11" }, { "role": "Site", "ref_id": "PMID-8386367_T12" } ] }, { "id": "PMID-8386367_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 498, 512 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8386367_T11" }, { "role": "Site", "ref_id": "PMID-8386367_T13" } ] }, { "id": "PMID-8386367_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 888, 903 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8386367_T21" }, { "role": "Site", "ref_id": "PMID-8386367_T19" } ] }, { "id": "PMID-8386367_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 888, 903 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8386367_T21" }, { "role": "Site", "ref_id": "PMID-8386367_T20" } ] } ]

[ { "id": "PMID-8386367_1", "entity_ids": [ "PMID-8386367_T4", "PMID-8386367_T5" ] } ]

[]

[ { "id": "PMID-8428580__text", "type": "abstract", "text": [ "The NF-kappa B precursor p105 and the proto-oncogene product Bcl-3 are I kappa B molecules and control nuclear translocation of NF-kappa B. \nWe have examined the interaction of the NF-kappa B precursor p105 with NF-kappa B subunits. Similar to an I kappa B molecule, p105 associates in the cytoplasm with p50 or p65. Through this assembly, p105 efficiently blocks nuclear transfer of either subunit. Moreover, the p105 protein inhibits DNA binding of dimeric NF-kappa B subunits in a similar, but not identical, manner to its isolated C-terminal domain, which contains an ankyrin-like repeat domain (ARD). The proto-oncogene product Bcl-3 also controls nuclear translocation of p50, but not of p65. Hence, p50 can be retained in the cytoplasm via at least three distinct interactions: through direct interactions either with its own precursor, with Bcl-3 or indirectly through I kappa B alpha or -beta when attached to p65. We discuss a function of p105 as a cytoplasmic assembly unit for homo- and heteromeric NF-kappa B complexes and of Bcl-3 as an I kappa B with novel subunit specificity.\n" ], "offsets": [ [ 0, 1093 ] ] } ]

[ { "id": "PMID-8428580_T1", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 4, 14 ] ], "normalized": [] }, { "id": "PMID-8428580_T2", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 25, 29 ] ], "normalized": [] }, { "id": "PMID-8428580_T3", "type": "Gene_or_gene_product", "text": [ "Bcl-3" ], "offsets": [ [ 61, 66 ] ], "normalized": [] }, { "id": "PMID-8428580_T4", "type": "Gene_or_gene_product", "text": [ "I kappa B" ], "offsets": [ [ 71, 80 ] ], "normalized": [] }, { "id": "PMID-8428580_T5", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 103, 110 ] ], "normalized": [] }, { "id": "PMID-8428580_T6", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 128, 138 ] ], "normalized": [] }, { "id": "PMID-8428580_T7", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 181, 191 ] ], "normalized": [] }, { "id": "PMID-8428580_T8", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 202, 206 ] ], "normalized": [] }, { "id": "PMID-8428580_T9", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 212, 222 ] ], "normalized": [] }, { "id": "PMID-8428580_T10", "type": "Gene_or_gene_product", "text": [ "I kappa B" ], "offsets": [ [ 247, 256 ] ], "normalized": [] }, { "id": "PMID-8428580_T11", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 267, 271 ] ], "normalized": [] }, { "id": "PMID-8428580_T12", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 290, 299 ] ], "normalized": [] }, { "id": "PMID-8428580_T13", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 305, 308 ] ], "normalized": [] }, { "id": "PMID-8428580_T14", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 312, 315 ] ], "normalized": [] }, { "id": "PMID-8428580_T15", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 340, 344 ] ], "normalized": [] }, { "id": "PMID-8428580_T16", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 364, 371 ] ], "normalized": [] }, { "id": "PMID-8428580_T17", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 414, 418 ] ], "normalized": [] }, { "id": "PMID-8428580_T18", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 459, 469 ] ], "normalized": [] }, { "id": "PMID-8428580_T19", "type": "Gene_or_gene_product", "text": [ "ankyrin" ], "offsets": [ [ 572, 579 ] ], "normalized": [] }, { "id": "PMID-8428580_T20", "type": "Gene_or_gene_product", "text": [ "Bcl-3" ], "offsets": [ [ 633, 638 ] ], "normalized": [] }, { "id": "PMID-8428580_T21", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 653, 660 ] ], "normalized": [] }, { "id": "PMID-8428580_T22", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 678, 681 ] ], "normalized": [] }, { "id": "PMID-8428580_T23", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 694, 697 ] ], "normalized": [] }, { "id": "PMID-8428580_T24", "type": "Gene_or_gene_product", "text": [ "p50" ], "offsets": [ [ 706, 709 ] ], "normalized": [] }, { "id": "PMID-8428580_T25", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 733, 742 ] ], "normalized": [] }, { "id": "PMID-8428580_T26", "type": "Gene_or_gene_product", "text": [ "Bcl-3" ], "offsets": [ [ 849, 854 ] ], "normalized": [] }, { "id": "PMID-8428580_T27", "type": "Gene_or_gene_product", "text": [ "I kappa B alpha" ], "offsets": [ [ 877, 892 ] ], "normalized": [] }, { "id": "PMID-8428580_T28", "type": "Gene_or_gene_product", "text": [ "-beta" ], "offsets": [ [ 896, 901 ] ], "normalized": [] }, { "id": "PMID-8428580_T29", "type": "Gene_or_gene_product", "text": [ "p65" ], "offsets": [ [ 919, 922 ] ], "normalized": [] }, { "id": "PMID-8428580_T30", "type": "Gene_or_gene_product", "text": [ "p105" ], "offsets": [ [ 949, 953 ] ], "normalized": [] }, { "id": "PMID-8428580_T31", "type": "Cellular_component", "text": [ "cytoplasmic" ], "offsets": [ [ 959, 970 ] ], "normalized": [] }, { "id": "PMID-8428580_T32", "type": "Complex", "text": [ "NF-kappa B" ], "offsets": [ [ 1011, 1021 ] ], "normalized": [] }, { "id": "PMID-8428580_T33", "type": "Gene_or_gene_product", "text": [ "Bcl-3" ], "offsets": [ [ 1039, 1044 ] ], "normalized": [] }, { "id": "PMID-8428580_T34", "type": "Gene_or_gene_product", "text": [ "I kappa B" ], "offsets": [ [ 1051, 1060 ] ], "normalized": [] } ]

[ { "id": "PMID-8428580_E1", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 95, 102 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_E3" }, { "role": "Cause", "ref_id": "PMID-8428580_T2" } ] }, { "id": "PMID-8428580_E2", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 95, 102 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_E3" }, { "role": "Cause", "ref_id": "PMID-8428580_T3" } ] }, { "id": "PMID-8428580_E3", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 111, 124 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-8428580_T5" }, { "role": "ToLoc", "ref_id": "PMID-8428580_T5" }, { "role": "Theme", "ref_id": "PMID-8428580_T6" } ] }, { "id": "PMID-8428580_E4", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 162, 173 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_T8" } ] }, { "id": "PMID-8428580_E5", "type": "Binding", "trigger": { "text": [ "associates" ], "offsets": [ [ 272, 282 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_T14" }, { "role": "Theme", "ref_id": "PMID-8428580_T11" } ] }, { "id": "PMID-8428580_E6", "type": "Binding", "trigger": { "text": [ "associates" ], "offsets": [ [ 272, 282 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_T11" }, { "role": "Theme", "ref_id": "PMID-8428580_T13" } ] }, { "id": "PMID-8428580_E7", "type": "Binding", "trigger": { "text": [ "assembly" ], "offsets": [ [ 330, 338 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_T11" }, { "role": "Theme", "ref_id": "PMID-8428580_T13" } ] }, { "id": "PMID-8428580_E8", "type": "Binding", "trigger": { "text": [ "assembly" ], "offsets": [ [ 330, 338 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_T11" }, { "role": "Theme", "ref_id": "PMID-8428580_T14" } ] }, { "id": "PMID-8428580_E9", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 644, 652 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8428580_T20" }, { "role": "Theme", "ref_id": "PMID-8428580_E11" } ] }, { "id": "PMID-8428580_E10", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 644, 652 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8428580_T20" }, { "role": "Theme", "ref_id": "PMID-8428580_E12" } ] }, { "id": "PMID-8428580_E11", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 661, 674 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-8428580_T21" }, { "role": "ToLoc", "ref_id": "PMID-8428580_T21" }, { "role": "Theme", "ref_id": "PMID-8428580_T23" } ] }, { "id": "PMID-8428580_E12", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 661, 674 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-8428580_T21" }, { "role": "ToLoc", "ref_id": "PMID-8428580_T21" }, { "role": "Theme", "ref_id": "PMID-8428580_T22" } ] }, { "id": "PMID-8428580_E13", "type": "Localization", "trigger": { "text": [ "retained" ], "offsets": [ [ 717, 725 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-8428580_T25" }, { "role": "Theme", "ref_id": "PMID-8428580_T24" } ] }, { "id": "PMID-8428580_E14", "type": "Positive_regulation", "trigger": { "text": [ "retained" ], "offsets": [ [ 717, 725 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_E13" }, { "role": "Cause", "ref_id": "PMID-8428580_E19" } ] }, { "id": "PMID-8428580_E15", "type": "Positive_regulation", "trigger": { "text": [ "retained" ], "offsets": [ [ 717, 725 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_E13" }, { "role": "Cause", "ref_id": "PMID-8428580_E18" } ] }, { "id": "PMID-8428580_E16", "type": "Positive_regulation", "trigger": { "text": [ "retained" ], "offsets": [ [ 717, 725 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_E13" }, { "role": "Cause", "ref_id": "PMID-8428580_E17" } ] }, { "id": "PMID-8428580_E17", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 800, 812 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_T26" } ] }, { "id": "PMID-8428580_E18", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 800, 812 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_T27" }, { "role": "Theme", "ref_id": "PMID-8428580_T29" } ] }, { "id": "PMID-8428580_E19", "type": "Binding", "trigger": { "text": [ "interactions" ], "offsets": [ [ 800, 812 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_T28" }, { "role": "Theme", "ref_id": "PMID-8428580_T29" } ] }, { "id": "PMID-8428580_E20", "type": "Binding", "trigger": { "text": [ "assembly" ], "offsets": [ [ 971, 979 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_T30" }, { "role": "Theme", "ref_id": "PMID-8428580_T32" } ] }, { "id": "PMID-8428580_E21", "type": "Binding", "trigger": { "text": [ "assembly" ], "offsets": [ [ 971, 979 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8428580_T30" }, { "role": "Theme", "ref_id": "PMID-8428580_T33" } ] } ]

[]

[]

[ { "id": "PMID-8497280__text", "type": "abstract", "text": [ "Multiple SWI6-dependent cis-acting elements control SWI4 transcription through the cell cycle. \nThe Saccharomyces cerevisiae SWI4 gene encodes an essential transcription factor which controls gene expression at the G1/S transition of the cell cycle. SWI4 transcription itself is cell cycle regulated, and this periodicity is crucial for the normal cell cycle regulation of HO and at least two of the G1 cyclins. Since the regulation of SWI4 is required for normal cell cycle progression, we have characterized cis- and trans-acting regulators of SWI4 transcription. Deletion analysis of the SWI4 promoter has defined a 140-bp region which is absolutely required for transcription and can function as a cell cycle-regulated upstream activating sequence (UAS). The SWI4 UAS contains three potential MluI cell cycle boxes (MCBs), which are known cell cycle-regulated promoter elements. Deletion of all three MCBs in the SWI4 UAS decreases the level of SWI4 mRNA 10-fold in asynchronous cultures but does not abolish periodicity. These data suggest that MCBs are involved in SWI4 UAS activity, but at least one other periodically regulated element must be present. Since SWI6 is known to bind to MCBs and regulate their activity, the role of SWI6 in SWI4 expression was analyzed. Although the MCBs cannot account for the full cell cycle regulation of SWI4, mutations in SWI6 eliminate the normal periodicity of SWI4 transcription. This suggests that the novel cell cycle-regulated element within the SWI4 promoter is also SWI6 dependent. The constitutive transcription of SWI4 in SWI6 mutant cells occurs at an intermediate level, which indicates that SWI6 is required for the full activation and repression of SWI4 transcription through the cell cycle. It also suggests that there is another pathway which can activate SWI4 transcription in the absence of SWI6. The second activator may also target MCB elements, since SWI4 transcription drops dramatically when they are deleted.\n" ], "offsets": [ [ 0, 1977 ] ] } ]

[ { "id": "PMID-8497280_T1", "type": "Gene_or_gene_product", "text": [ "SWI6" ], "offsets": [ [ 9, 13 ] ], "normalized": [] }, { "id": "PMID-8497280_T2", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 52, 56 ] ], "normalized": [] }, { "id": "PMID-8497280_T3", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 125, 129 ] ], "normalized": [] }, { "id": "PMID-8497280_T4", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 250, 254 ] ], "normalized": [] }, { "id": "PMID-8497280_T5", "type": "Gene_or_gene_product", "text": [ "HO" ], "offsets": [ [ 373, 375 ] ], "normalized": [] }, { "id": "PMID-8497280_T6", "type": "Gene_or_gene_product", "text": [ "G1 cyclins" ], "offsets": [ [ 400, 410 ] ], "normalized": [] }, { "id": "PMID-8497280_T7", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 436, 440 ] ], "normalized": [] }, { "id": "PMID-8497280_T8", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 546, 550 ] ], "normalized": [] }, { "id": "PMID-8497280_T9", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 591, 595 ] ], "normalized": [] }, { "id": "PMID-8497280_T10", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 763, 767 ] ], "normalized": [] }, { "id": "PMID-8497280_T11", "type": "Gene_or_gene_product", "text": [ "MluI" ], "offsets": [ [ 797, 801 ] ], "normalized": [] }, { "id": "PMID-8497280_T12", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 917, 921 ] ], "normalized": [] }, { "id": "PMID-8497280_T13", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 949, 953 ] ], "normalized": [] }, { "id": "PMID-8497280_T14", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 1071, 1075 ] ], "normalized": [] }, { "id": "PMID-8497280_T15", "type": "Gene_or_gene_product", "text": [ "SWI6" ], "offsets": [ [ 1167, 1171 ] ], "normalized": [] }, { "id": "PMID-8497280_T16", "type": "Gene_or_gene_product", "text": [ "SWI6" ], "offsets": [ [ 1238, 1242 ] ], "normalized": [] }, { "id": "PMID-8497280_T17", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 1246, 1250 ] ], "normalized": [] }, { "id": "PMID-8497280_T18", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 1347, 1351 ] ], "normalized": [] }, { "id": "PMID-8497280_T19", "type": "Gene_or_gene_product", "text": [ "SWI6" ], "offsets": [ [ 1366, 1370 ] ], "normalized": [] }, { "id": "PMID-8497280_T20", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 1407, 1411 ] ], "normalized": [] }, { "id": "PMID-8497280_T21", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 1496, 1500 ] ], "normalized": [] }, { "id": "PMID-8497280_T22", "type": "Gene_or_gene_product", "text": [ "SWI6" ], "offsets": [ [ 1518, 1522 ] ], "normalized": [] }, { "id": "PMID-8497280_T23", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 1568, 1572 ] ], "normalized": [] }, { "id": "PMID-8497280_T24", "type": "Gene_or_gene_product", "text": [ "SWI6" ], "offsets": [ [ 1576, 1580 ] ], "normalized": [] }, { "id": "PMID-8497280_T25", "type": "Gene_or_gene_product", "text": [ "SWI6" ], "offsets": [ [ 1648, 1652 ] ], "normalized": [] }, { "id": "PMID-8497280_T26", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 1707, 1711 ] ], "normalized": [] }, { "id": "PMID-8497280_T27", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 1816, 1820 ] ], "normalized": [] }, { "id": "PMID-8497280_T28", "type": "Gene_or_gene_product", "text": [ "SWI6" ], "offsets": [ [ 1853, 1857 ] ], "normalized": [] }, { "id": "PMID-8497280_T29", "type": "Gene_or_gene_product", "text": [ "SWI4" ], "offsets": [ [ 1916, 1920 ] ], "normalized": [] } ]

[ { "id": "PMID-8497280_E1", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 44, 51 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E2" }, { "role": "Cause", "ref_id": "PMID-8497280_E3" } ] }, { "id": "PMID-8497280_E2", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 57, 70 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T2" } ] }, { "id": "PMID-8497280_E3", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 83, 93 ] ] }, "arguments": [] }, { "id": "PMID-8497280_E4", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 238, 248 ] ] }, "arguments": [] }, { "id": "PMID-8497280_E5", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 255, 268 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T4" } ] }, { "id": "PMID-8497280_E6", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 279, 289 ] ] }, "arguments": [] }, { "id": "PMID-8497280_E7", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 290, 299 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8497280_E6" }, { "role": "Theme", "ref_id": "PMID-8497280_E5" } ] }, { "id": "PMID-8497280_E8", "type": "Positive_regulation", "trigger": { "text": [ "crucial" ], "offsets": [ [ 325, 332 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E9" } ] }, { "id": "PMID-8497280_E9", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 348, 358 ] ] }, "arguments": [] }, { "id": "PMID-8497280_E10", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 359, 369 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8497280_E9" }, { "role": "Theme", "ref_id": "PMID-8497280_T5" } ] }, { "id": "PMID-8497280_E11", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 359, 369 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8497280_E9" }, { "role": "Theme", "ref_id": "PMID-8497280_T6" } ] }, { "id": "PMID-8497280_E12", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 422, 432 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T7" } ] }, { "id": "PMID-8497280_E13", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 444, 452 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8497280_E12" }, { "role": "Theme", "ref_id": "PMID-8497280_E14" } ] }, { "id": "PMID-8497280_E14", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 464, 474 ] ] }, "arguments": [] }, { "id": "PMID-8497280_E15", "type": "Regulation", "trigger": { "text": [ "regulators" ], "offsets": [ [ 532, 542 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E16" } ] }, { "id": "PMID-8497280_E16", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 551, 564 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T8" } ] }, { "id": "PMID-8497280_E17", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 653, 661 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E18" } ] }, { "id": "PMID-8497280_E18", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 666, 679 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T9" } ] }, { "id": "PMID-8497280_E19", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 702, 712 ] ] }, "arguments": [] }, { "id": "PMID-8497280_E20", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 843, 853 ] ] }, "arguments": [] }, { "id": "PMID-8497280_E21", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 854, 863 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8497280_E20" }, { "role": "Theme", "ref_id": "PMID-8497280_T11" } ] }, { "id": "PMID-8497280_E22", "type": "Negative_regulation", "trigger": { "text": [ "decreases" ], "offsets": [ [ 926, 935 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T13" } ] }, { "id": "PMID-8497280_E23", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 1184, 1188 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T15" } ] }, { "id": "PMID-8497280_E24", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1230, 1234 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8497280_T16" }, { "role": "Theme", "ref_id": "PMID-8497280_E25" } ] }, { "id": "PMID-8497280_E25", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1251, 1261 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T17" } ] }, { "id": "PMID-8497280_E26", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1322, 1332 ] ] }, "arguments": [] }, { "id": "PMID-8497280_E27", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1333, 1343 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8497280_E26" }, { "role": "Theme", "ref_id": "PMID-8497280_T18" } ] }, { "id": "PMID-8497280_E28", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1412, 1425 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T20" } ] }, { "id": "PMID-8497280_E29", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1456, 1466 ] ] }, "arguments": [] }, { "id": "PMID-8497280_E30", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1467, 1476 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8497280_E29" }, { "role": "Theme", "ref_id": "PMID-8497280_T21" } ] }, { "id": "PMID-8497280_E31", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1523, 1532 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8497280_T22" }, { "role": "Theme", "ref_id": "PMID-8497280_T21" } ] }, { "id": "PMID-8497280_E32", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1551, 1564 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T23" } ] }, { "id": "PMID-8497280_E33", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1656, 1664 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E37" }, { "role": "Cause", "ref_id": "PMID-8497280_T25" } ] }, { "id": "PMID-8497280_E34", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1656, 1664 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E38" }, { "role": "Cause", "ref_id": "PMID-8497280_T25" } ] }, { "id": "PMID-8497280_E35", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1656, 1664 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E38" }, { "role": "Cause", "ref_id": "PMID-8497280_E40" } ] }, { "id": "PMID-8497280_E36", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1656, 1664 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E37" }, { "role": "Cause", "ref_id": "PMID-8497280_E40" } ] }, { "id": "PMID-8497280_E37", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1678, 1688 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E39" } ] }, { "id": "PMID-8497280_E38", "type": "Negative_regulation", "trigger": { "text": [ "repression" ], "offsets": [ [ 1693, 1703 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E39" } ] }, { "id": "PMID-8497280_E39", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1712, 1725 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T26" } ] }, { "id": "PMID-8497280_E40", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 1738, 1748 ] ] }, "arguments": [] }, { "id": "PMID-8497280_E41", "type": "Positive_regulation", "trigger": { "text": [ "activate" ], "offsets": [ [ 1807, 1815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E42" } ] }, { "id": "PMID-8497280_E42", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1821, 1834 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T27" } ] }, { "id": "PMID-8497280_E43", "type": "Positive_regulation", "trigger": { "text": [ "absence" ], "offsets": [ [ 1842, 1849 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E41" }, { "role": "Cause", "ref_id": "PMID-8497280_T28" } ] }, { "id": "PMID-8497280_E44", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1921, 1934 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_T29" } ] }, { "id": "PMID-8497280_E45", "type": "Negative_regulation", "trigger": { "text": [ "drops" ], "offsets": [ [ 1935, 1940 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8497280_E44" } ] } ]

[]

[]

[ { "id": "PMID-8530346__text", "type": "abstract", "text": [ "Human ADP-ribosylation factor-activated phosphatidylcholine-specific phospholipase D defines a new and highly conserved gene family. \nActivation of phosphatidylcholine-specific phospholipase D (PLD) has been implicated as a critical step in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. We report here the identification of the first human PLD cDNA, which defines a new and highly conserved gene family. Characterization of recombinant human PLD1 reveals that it is membrane-associated, selective for phosphatidylcholine, stimulated by phosphatidylinositol 4,5-bisphosphate, activated by the monomeric G-protein ADP-ribosylation factor-1, and inhibited by oleate. PLD1 likely encodes the gene product responsible for the most widely studied endogenous PLD activity.\n" ], "offsets": [ [ 0, 832 ] ] } ]

[ { "id": "PMID-8530346_T1", "type": "Gene_or_gene_product", "text": [ "ADP-ribosylation factor" ], "offsets": [ [ 6, 29 ] ], "normalized": [] }, { "id": "PMID-8530346_T2", "type": "Gene_or_gene_product", "text": [ "phosphatidylcholine-specific phospholipase D" ], "offsets": [ [ 40, 84 ] ], "normalized": [] }, { "id": "PMID-8530346_T3", "type": "Gene_or_gene_product", "text": [ "phosphatidylcholine-specific phospholipase D" ], "offsets": [ [ 148, 192 ] ], "normalized": [] }, { "id": "PMID-8530346_T4", "type": "Gene_or_gene_product", "text": [ "PLD" ], "offsets": [ [ 194, 197 ] ], "normalized": [] }, { "id": "PMID-8530346_T5", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 300, 308 ] ], "normalized": [] }, { "id": "PMID-8530346_T6", "type": "Gene_or_gene_product", "text": [ "PLD" ], "offsets": [ [ 406, 409 ] ], "normalized": [] }, { "id": "PMID-8530346_T7", "type": "Gene_or_gene_product", "text": [ "PLD1" ], "offsets": [ [ 508, 512 ] ], "normalized": [] }, { "id": "PMID-8530346_T8", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 532, 540 ] ], "normalized": [] }, { "id": "PMID-8530346_T9", "type": "Simple_chemical", "text": [ "phosphatidylcholine" ], "offsets": [ [ 567, 586 ] ], "normalized": [] }, { "id": "PMID-8530346_T10", "type": "Simple_chemical", "text": [ "phosphatidylinositol 4,5-bisphosphate" ], "offsets": [ [ 602, 639 ] ], "normalized": [] }, { "id": "PMID-8530346_T11", "type": "Gene_or_gene_product", "text": [ "G-protein" ], "offsets": [ [ 668, 677 ] ], "normalized": [] }, { "id": "PMID-8530346_T12", "type": "Gene_or_gene_product", "text": [ "ADP-ribosylation factor-1" ], "offsets": [ [ 678, 703 ] ], "normalized": [] }, { "id": "PMID-8530346_T13", "type": "Simple_chemical", "text": [ "oleate" ], "offsets": [ [ 722, 728 ] ], "normalized": [] }, { "id": "PMID-8530346_T14", "type": "Gene_or_gene_product", "text": [ "PLD1" ], "offsets": [ [ 730, 734 ] ], "normalized": [] }, { "id": "PMID-8530346_T15", "type": "Gene_or_gene_product", "text": [ "PLD" ], "offsets": [ [ 818, 821 ] ], "normalized": [] } ]

[ { "id": "PMID-8530346_E1", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 30, 39 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8530346_T1" }, { "role": "Theme", "ref_id": "PMID-8530346_T2" } ] }, { "id": "PMID-8530346_E2", "type": "Activation", "trigger": { "text": [ "Activation" ], "offsets": [ [ 134, 144 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8530346_T3" } ] }, { "id": "PMID-8530346_E3", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 588, 598 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8530346_T10" }, { "role": "Theme", "ref_id": "PMID-8530346_T7" } ] }, { "id": "PMID-8530346_E4", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 641, 650 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8530346_T12" }, { "role": "Theme", "ref_id": "PMID-8530346_T7" } ] }, { "id": "PMID-8530346_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 709, 718 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8530346_T13" }, { "role": "Theme", "ref_id": "PMID-8530346_T7" } ] }, { "id": "PMID-8530346_E6", "type": "Positive_regulation", "trigger": { "text": [ "responsible" ], "offsets": [ [ 767, 778 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8530346_T15" } ] } ]

[ { "id": "PMID-8530346_1", "entity_ids": [ "PMID-8530346_T3", "PMID-8530346_T4" ] } ]

[]

[ { "id": "PMID-8749392__text", "type": "abstract", "text": [ "Protein kinase C is regulated in vivo by three functionally distinct phosphorylations. \nBACKGROUND: Protein kinase Cs are a family of enzymes that transduce the plethora of signals promoting lipid hydrolysis. Here, we show that protein kinase C must first be processed by three distinct phosphorylations before it is competent to respond to second messengers. RESULTS: We have identified the positions and functions of the in vivo phosphorylation sites of protein kinase C by mass spectrometry and peptide sequencing of native and phosphatase-treated kinase from the detergent-soluble fraction of cells. Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. Biochemical analysis reveals that protein kinase C autophosphorylates on S660, that autophosphorylation on S660 follows T641 autophosphorylation, that autophosphorylation on S660 is accompanied by the release of protein kinase C into the cytosol, and that T500 is not an autophosphorylation site. CONCLUSIONS: Structural and biochemical analyses of native and phosphatase-treated protein kinase C indicate that protein kinase C is processed by three phosphorylations. Firstly, trans-phosphorylation on the activation loop (T500) renders it catalytically competent to autophosphorylate. Secondly, a subsequent autophosphorylation on the carboxyl terminus (T641) maintains catalytic competence. Thirdly, a second autophosphorylation on the carboxyl terminus (S660) regulates the enzyme's subcellular localization. The conservation of each of these residues (or an acidic residue) in conventional, novel and atypical protein kinase Cs underscores the essential role for each in regulating the protein kinase C family.\n" ], "offsets": [ [ 0, 2049 ] ] } ]

[ { "id": "PMID-8749392_T1", "type": "Gene_or_gene_product", "text": [ "Protein kinase C" ], "offsets": [ [ 0, 16 ] ], "normalized": [] }, { "id": "PMID-8749392_T2", "type": "Gene_or_gene_product", "text": [ "Protein kinase Cs" ], "offsets": [ [ 100, 117 ] ], "normalized": [] }, { "id": "PMID-8749392_T3", "type": "Simple_chemical", "text": [ "lipid" ], "offsets": [ [ 191, 196 ] ], "normalized": [] }, { "id": "PMID-8749392_T4", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 228, 244 ] ], "normalized": [] }, { "id": "PMID-8749392_T5", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 456, 472 ] ], "normalized": [] }, { "id": "PMID-8749392_T6", "type": "Simple_chemical", "text": [ "threonine at position 500" ], "offsets": [ [ 622, 647 ] ], "normalized": [] }, { "id": "PMID-8749392_T7", "type": "Simple_chemical", "text": [ "T500" ], "offsets": [ [ 649, 653 ] ], "normalized": [] }, { "id": "PMID-8749392_T8", "type": "Simple_chemical", "text": [ "T641" ], "offsets": [ [ 683, 687 ] ], "normalized": [] }, { "id": "PMID-8749392_T9", "type": "Simple_chemical", "text": [ "S660" ], "offsets": [ [ 692, 696 ] ], "normalized": [] }, { "id": "PMID-8749392_T10", "type": "Gene_or_gene_product", "text": [ "protein kinase C beta II" ], "offsets": [ [ 725, 749 ] ], "normalized": [] }, { "id": "PMID-8749392_T11", "type": "Simple_chemical", "text": [ "T500" ], "offsets": [ [ 778, 782 ] ], "normalized": [] }, { "id": "PMID-8749392_T12", "type": "Simple_chemical", "text": [ "S660" ], "offsets": [ [ 787, 791 ] ], "normalized": [] }, { "id": "PMID-8749392_T13", "type": "Gene_or_gene_product", "text": [ "protein phosphatase 2A" ], "offsets": [ [ 837, 859 ] ], "normalized": [] }, { "id": "PMID-8749392_T14", "type": "Simple_chemical", "text": [ "lipid" ], "offsets": [ [ 904, 909 ] ], "normalized": [] }, { "id": "PMID-8749392_T15", "type": "Gene_or_gene_product", "text": [ "protein phosphatase 1" ], "offsets": [ [ 983, 1004 ] ], "normalized": [] }, { "id": "PMID-8749392_T16", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 1068, 1084 ] ], "normalized": [] }, { "id": "PMID-8749392_T17", "type": "Simple_chemical", "text": [ "S660" ], "offsets": [ [ 1107, 1111 ] ], "normalized": [] }, { "id": "PMID-8749392_T18", "type": "Simple_chemical", "text": [ "S660" ], "offsets": [ [ 1141, 1145 ] ], "normalized": [] }, { "id": "PMID-8749392_T19", "type": "Simple_chemical", "text": [ "T641" ], "offsets": [ [ 1154, 1158 ] ], "normalized": [] }, { "id": "PMID-8749392_T20", "type": "Simple_chemical", "text": [ "S660" ], "offsets": [ [ 1208, 1212 ] ], "normalized": [] }, { "id": "PMID-8749392_T21", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 1246, 1262 ] ], "normalized": [] }, { "id": "PMID-8749392_T22", "type": "Cellular_component", "text": [ "cytosol" ], "offsets": [ [ 1272, 1279 ] ], "normalized": [] }, { "id": "PMID-8749392_T23", "type": "Simple_chemical", "text": [ "T500" ], "offsets": [ [ 1290, 1294 ] ], "normalized": [] }, { "id": "PMID-8749392_T24", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 1414, 1430 ] ], "normalized": [] }, { "id": "PMID-8749392_T25", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 1445, 1461 ] ], "normalized": [] }, { "id": "PMID-8749392_T26", "type": "Simple_chemical", "text": [ "T500" ], "offsets": [ [ 1557, 1561 ] ], "normalized": [] }, { "id": "PMID-8749392_T27", "type": "Simple_chemical", "text": [ "T641" ], "offsets": [ [ 1689, 1693 ] ], "normalized": [] }, { "id": "PMID-8749392_T28", "type": "Simple_chemical", "text": [ "S660" ], "offsets": [ [ 1791, 1795 ] ], "normalized": [] }, { "id": "PMID-8749392_T29", "type": "Cellular_component", "text": [ "subcellular" ], "offsets": [ [ 1820, 1831 ] ], "normalized": [] }, { "id": "PMID-8749392_T30", "type": "Gene_or_gene_product", "text": [ "protein kinase Cs" ], "offsets": [ [ 1948, 1965 ] ], "normalized": [] }, { "id": "PMID-8749392_T31", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 2024, 2040 ] ], "normalized": [] } ]

[ { "id": "PMID-8749392_E1", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 20, 29 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T1" }, { "role": "Cause", "ref_id": "PMID-8749392_E2" } ] }, { "id": "PMID-8749392_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylations" ], "offsets": [ [ 69, 85 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T1" } ] }, { "id": "PMID-8749392_E3", "type": "Positive_regulation", "trigger": { "text": [ "transduce" ], "offsets": [ [ 147, 156 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_E4" }, { "role": "Cause", "ref_id": "PMID-8749392_T2" } ] }, { "id": "PMID-8749392_E4", "type": "Positive_regulation", "trigger": { "text": [ "promoting" ], "offsets": [ [ 181, 190 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_E5" } ] }, { "id": "PMID-8749392_E5", "type": "Conversion", "trigger": { "text": [ "hydrolysis" ], "offsets": [ [ 197, 207 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T3" } ] }, { "id": "PMID-8749392_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylations" ], "offsets": [ [ 287, 303 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T4" } ] }, { "id": "PMID-8749392_E7", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 754, 768 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T10" }, { "role": "Site", "ref_id": "PMID-8749392_T7" } ] }, { "id": "PMID-8749392_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 754, 768 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T10" }, { "role": "Site", "ref_id": "PMID-8749392_T8" } ] }, { "id": "PMID-8749392_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 754, 768 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T10" }, { "role": "Site", "ref_id": "PMID-8749392_T9" } ] }, { "id": "PMID-8749392_E10", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylated" ], "offsets": [ [ 808, 824 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8749392_T13" }, { "role": "Theme", "ref_id": "PMID-8749392_T10" }, { "role": "Site", "ref_id": "PMID-8749392_T11" } ] }, { "id": "PMID-8749392_E11", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylated" ], "offsets": [ [ 808, 824 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8749392_T13" }, { "role": "Theme", "ref_id": "PMID-8749392_T10" }, { "role": "Site", "ref_id": "PMID-8749392_T12" } ] }, { "id": "PMID-8749392_E12", "type": "Positive_regulation", "trigger": { "text": [ "yield" ], "offsets": [ [ 863, 868 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T10" }, { "role": "Cause", "ref_id": "PMID-8749392_E10" } ] }, { "id": "PMID-8749392_E13", "type": "Positive_regulation", "trigger": { "text": [ "yield" ], "offsets": [ [ 863, 868 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T10" }, { "role": "Cause", "ref_id": "PMID-8749392_E11" } ] }, { "id": "PMID-8749392_E14", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 910, 919 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8749392_T14" }, { "role": "Theme", "ref_id": "PMID-8749392_E15" } ] }, { "id": "PMID-8749392_E15", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 920, 930 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T10" } ] }, { "id": "PMID-8749392_E16", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylated" ], "offsets": [ [ 963, 979 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8749392_T15" }, { "role": "Site", "ref_id": "PMID-8749392_T12" }, { "role": "Theme", "ref_id": "PMID-8749392_T10" } ] }, { "id": "PMID-8749392_E17", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylated" ], "offsets": [ [ 963, 979 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8749392_T15" }, { "role": "Site", "ref_id": "PMID-8749392_T11" }, { "role": "Theme", "ref_id": "PMID-8749392_T10" } ] }, { "id": "PMID-8749392_E18", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylated" ], "offsets": [ [ 963, 979 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8749392_T15" }, { "role": "Site", "ref_id": "PMID-8749392_T8" }, { "role": "Theme", "ref_id": "PMID-8749392_T10" } ] }, { "id": "PMID-8749392_E19", "type": "Positive_regulation", "trigger": { "text": [ "yield" ], "offsets": [ [ 1008, 1013 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T10" }, { "role": "Cause", "ref_id": "PMID-8749392_E16" } ] }, { "id": "PMID-8749392_E20", "type": "Positive_regulation", "trigger": { "text": [ "yield" ], "offsets": [ [ 1008, 1013 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T10" }, { "role": "Cause", "ref_id": "PMID-8749392_E17" } ] }, { "id": "PMID-8749392_E21", "type": "Positive_regulation", "trigger": { "text": [ "yield" ], "offsets": [ [ 1008, 1013 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8749392_E18" }, { "role": "Theme", "ref_id": "PMID-8749392_T10" } ] }, { "id": "PMID-8749392_E22", "type": "Inactivation", "trigger": { "text": [ "inactive" ], "offsets": [ [ 1017, 1025 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T10" } ] }, { "id": "PMID-8749392_E23", "type": "Phosphorylation", "trigger": { "text": [ "autophosphorylates" ], "offsets": [ [ 1085, 1103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T16" }, { "role": "Site", "ref_id": "PMID-8749392_T17" }, { "role": "Cause", "ref_id": "PMID-8749392_T16" } ] }, { "id": "PMID-8749392_E24", "type": "Phosphorylation", "trigger": { "text": [ "autophosphorylation" ], "offsets": [ [ 1118, 1137 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-8749392_T18" }, { "role": "Theme", "ref_id": "PMID-8749392_T16" }, { "role": "Cause", "ref_id": "PMID-8749392_T16" } ] }, { "id": "PMID-8749392_E25", "type": "Positive_regulation", "trigger": { "text": [ "follows" ], "offsets": [ [ 1146, 1153 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_E26" }, { "role": "Cause", "ref_id": "PMID-8749392_E24" } ] }, { "id": "PMID-8749392_E26", "type": "Phosphorylation", "trigger": { "text": [ "autophosphorylation" ], "offsets": [ [ 1159, 1178 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-8749392_T19" }, { "role": "Theme", "ref_id": "PMID-8749392_T16" }, { "role": "Cause", "ref_id": "PMID-8749392_T16" } ] }, { "id": "PMID-8749392_E27", "type": "Phosphorylation", "trigger": { "text": [ "autophosphorylation" ], "offsets": [ [ 1185, 1204 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T16" }, { "role": "Cause", "ref_id": "PMID-8749392_T16" }, { "role": "Site", "ref_id": "PMID-8749392_T20" } ] }, { "id": "PMID-8749392_E28", "type": "Positive_regulation", "trigger": { "text": [ "accompanied" ], "offsets": [ [ 1216, 1227 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8749392_E27" }, { "role": "Theme", "ref_id": "PMID-8749392_E29" } ] }, { "id": "PMID-8749392_E29", "type": "Transport", "trigger": { "text": [ "release" ], "offsets": [ [ 1235, 1242 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T21" }, { "role": "ToLoc", "ref_id": "PMID-8749392_T22" } ] }, { "id": "PMID-8749392_E30", "type": "Phosphorylation", "trigger": { "text": [ "autophosphorylation" ], "offsets": [ [ 1305, 1324 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T16" }, { "role": "Cause", "ref_id": "PMID-8749392_T16" }, { "role": "Site", "ref_id": "PMID-8749392_T23" } ] }, { "id": "PMID-8749392_E31", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylations" ], "offsets": [ [ 1484, 1500 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T25" } ] }, { "id": "PMID-8749392_E32", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1517, 1532 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T25" }, { "role": "Site", "ref_id": "PMID-8749392_T26" } ] }, { "id": "PMID-8749392_E33", "type": "Positive_regulation", "trigger": { "text": [ "renders" ], "offsets": [ [ 1563, 1570 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8749392_E32" }, { "role": "Theme", "ref_id": "PMID-8749392_E34" } ] }, { "id": "PMID-8749392_E34", "type": "Positive_regulation", "trigger": { "text": [ "competent" ], "offsets": [ [ 1588, 1597 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_E35" } ] }, { "id": "PMID-8749392_E35", "type": "Phosphorylation", "trigger": { "text": [ "autophosphorylate" ], "offsets": [ [ 1601, 1618 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_T25" }, { "role": "Cause", "ref_id": "PMID-8749392_T25" } ] }, { "id": "PMID-8749392_E36", "type": "Phosphorylation", "trigger": { "text": [ "autophosphorylation" ], "offsets": [ [ 1643, 1662 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-8749392_T27" }, { "role": "Theme", "ref_id": "PMID-8749392_T25" }, { "role": "Cause", "ref_id": "PMID-8749392_T25" } ] }, { "id": "PMID-8749392_E37", "type": "Phosphorylation", "trigger": { "text": [ "autophosphorylation" ], "offsets": [ [ 1745, 1764 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-8749392_T28" }, { "role": "Theme", "ref_id": "PMID-8749392_T25" }, { "role": "Cause", "ref_id": "PMID-8749392_T25" } ] }, { "id": "PMID-8749392_E38", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 1797, 1806 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8749392_E39" }, { "role": "Cause", "ref_id": "PMID-8749392_E37" } ] }, { "id": "PMID-8749392_E39", "type": "Localization", "trigger": { "text": [ "localization" ], "offsets": [ [ 1832, 1844 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-8749392_T29" }, { "role": "Theme", "ref_id": "PMID-8749392_T25" } ] } ]

[ { "id": "PMID-8749392_1", "entity_ids": [ "PMID-8749392_T6", "PMID-8749392_T7" ] } ]

[]

[ { "id": "PMID-8815811__text", "type": "abstract", "text": [ "Molecular mechanisms of renal apical Na/phosphate cotransport. \nIn the proximal tubule, sodium-dependent transport of phosphate (Pi) through the brush-border membrane represents the initial step in Pi reabsorption. cDNAs encoding several renal proximal tubule apical Na/Pi cotransport systems have been identified. These Na/Pi cotransporters are subdivided into type I (NaPi-1) and a type II (NaPi-2). Electrophysiological studies reveal that Pi transport by Na/Pi cotransporters is electrogenic. Regulation of proximal Pi reabsorption by dietary Pi intake and parathyroid hormone is primarily due to an alteration of apical type II Na/Pi cotransport; a rapid change of brush-border Na/Pi cotransport most likely occurs via an endo/exocytic mechanism. No evidence for physiological control of type I cotransporters has been obtained. Altered Pi reabsorption as observed in X-linked hypophosphatemia is largely via the type II Na/Pi cotransporter.\n" ], "offsets": [ [ 0, 947 ] ] } ]

[ { "id": "PMID-8815811_T1", "type": "Simple_chemical", "text": [ "Na" ], "offsets": [ [ 37, 39 ] ], "normalized": [] }, { "id": "PMID-8815811_T2", "type": "Simple_chemical", "text": [ "phosphate" ], "offsets": [ [ 40, 49 ] ], "normalized": [] }, { "id": "PMID-8815811_T3", "type": "Simple_chemical", "text": [ "sodium" ], "offsets": [ [ 88, 94 ] ], "normalized": [] }, { "id": "PMID-8815811_T4", "type": "Simple_chemical", "text": [ "phosphate" ], "offsets": [ [ 118, 127 ] ], "normalized": [] }, { "id": "PMID-8815811_T5", "type": "Simple_chemical", "text": [ "Pi" ], "offsets": [ [ 129, 131 ] ], "normalized": [] }, { "id": "PMID-8815811_T6", "type": "Simple_chemical", "text": [ "Pi" ], "offsets": [ [ 198, 200 ] ], "normalized": [] }, { "id": "PMID-8815811_T7", "type": "Simple_chemical", "text": [ "Na" ], "offsets": [ [ 267, 269 ] ], "normalized": [] }, { "id": "PMID-8815811_T8", "type": "Simple_chemical", "text": [ "Pi" ], "offsets": [ [ 270, 272 ] ], "normalized": [] }, { "id": "PMID-8815811_T9", "type": "Gene_or_gene_product", "text": [ "Na/Pi cotransporters" ], "offsets": [ [ 321, 341 ] ], "normalized": [] }, { "id": "PMID-8815811_T10", "type": "Gene_or_gene_product", "text": [ "NaPi-1" ], "offsets": [ [ 370, 376 ] ], "normalized": [] }, { "id": "PMID-8815811_T11", "type": "Gene_or_gene_product", "text": [ "NaPi-2" ], "offsets": [ [ 393, 399 ] ], "normalized": [] }, { "id": "PMID-8815811_T12", "type": "Simple_chemical", "text": [ "Pi" ], "offsets": [ [ 443, 445 ] ], "normalized": [] }, { "id": "PMID-8815811_T13", "type": "Gene_or_gene_product", "text": [ "Na/Pi cotransporters" ], "offsets": [ [ 459, 479 ] ], "normalized": [] }, { "id": "PMID-8815811_T14", "type": "Simple_chemical", "text": [ "Pi" ], "offsets": [ [ 520, 522 ] ], "normalized": [] }, { "id": "PMID-8815811_T15", "type": "Simple_chemical", "text": [ "Pi" ], "offsets": [ [ 547, 549 ] ], "normalized": [] }, { "id": "PMID-8815811_T16", "type": "Gene_or_gene_product", "text": [ "parathyroid hormone" ], "offsets": [ [ 561, 580 ] ], "normalized": [] }, { "id": "PMID-8815811_T17", "type": "Gene_or_gene_product", "text": [ "type II Na/Pi cotransport" ], "offsets": [ [ 625, 650 ] ], "normalized": [] }, { "id": "PMID-8815811_T18", "type": "Simple_chemical", "text": [ "Na" ], "offsets": [ [ 683, 685 ] ], "normalized": [] }, { "id": "PMID-8815811_T19", "type": "Simple_chemical", "text": [ "Pi" ], "offsets": [ [ 686, 688 ] ], "normalized": [] }, { "id": "PMID-8815811_T20", "type": "Gene_or_gene_product", "text": [ "type I cotransporters" ], "offsets": [ [ 793, 814 ] ], "normalized": [] }, { "id": "PMID-8815811_T21", "type": "Simple_chemical", "text": [ "Pi" ], "offsets": [ [ 842, 844 ] ], "normalized": [] }, { "id": "PMID-8815811_T22", "type": "Gene_or_gene_product", "text": [ "type II Na/Pi cotransporter" ], "offsets": [ [ 918, 945 ] ], "normalized": [] } ]

[ { "id": "PMID-8815811_E1", "type": "Transport", "trigger": { "text": [ "cotransport" ], "offsets": [ [ 50, 61 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T1" } ] }, { "id": "PMID-8815811_E2", "type": "Transport", "trigger": { "text": [ "cotransport" ], "offsets": [ [ 50, 61 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T2" } ] }, { "id": "PMID-8815811_E3", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 95, 104 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8815811_T3" }, { "role": "Theme", "ref_id": "PMID-8815811_E4" } ] }, { "id": "PMID-8815811_E4", "type": "Transport", "trigger": { "text": [ "transport" ], "offsets": [ [ 105, 114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T4" } ] }, { "id": "PMID-8815811_E5", "type": "Transport", "trigger": { "text": [ "reabsorption" ], "offsets": [ [ 201, 213 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T6" } ] }, { "id": "PMID-8815811_E6", "type": "Transport", "trigger": { "text": [ "cotransport" ], "offsets": [ [ 273, 284 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T7" } ] }, { "id": "PMID-8815811_E7", "type": "Transport", "trigger": { "text": [ "cotransport" ], "offsets": [ [ 273, 284 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T8" } ] }, { "id": "PMID-8815811_E8", "type": "Transport", "trigger": { "text": [ "transport" ], "offsets": [ [ 446, 455 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T12" } ] }, { "id": "PMID-8815811_E9", "type": "Positive_regulation", "trigger": { "text": [ "transport" ], "offsets": [ [ 446, 455 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8815811_T13" }, { "role": "Theme", "ref_id": "PMID-8815811_E8" } ] }, { "id": "PMID-8815811_E10", "type": "Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 497, 507 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_E11" }, { "role": "Cause", "ref_id": "PMID-8815811_T16" } ] }, { "id": "PMID-8815811_E11", "type": "Transport", "trigger": { "text": [ "reabsorption" ], "offsets": [ [ 523, 535 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T14" } ] }, { "id": "PMID-8815811_E12", "type": "Positive_regulation", "trigger": { "text": [ "due to" ], "offsets": [ [ 594, 600 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8815811_E13" }, { "role": "Theme", "ref_id": "PMID-8815811_E10" } ] }, { "id": "PMID-8815811_E13", "type": "Regulation", "trigger": { "text": [ "alteration" ], "offsets": [ [ 604, 614 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T17" } ] }, { "id": "PMID-8815811_E14", "type": "Transport", "trigger": { "text": [ "cotransport" ], "offsets": [ [ 689, 700 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T18" } ] }, { "id": "PMID-8815811_E15", "type": "Transport", "trigger": { "text": [ "cotransport" ], "offsets": [ [ 689, 700 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T19" } ] }, { "id": "PMID-8815811_E16", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 782, 789 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T20" } ] }, { "id": "PMID-8815811_E17", "type": "Regulation", "trigger": { "text": [ "Altered" ], "offsets": [ [ 834, 841 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_E18" } ] }, { "id": "PMID-8815811_E18", "type": "Transport", "trigger": { "text": [ "reabsorption" ], "offsets": [ [ 845, 857 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8815811_T21" } ] } ]

[ { "id": "PMID-8815811_1", "entity_ids": [ "PMID-8815811_T4", "PMID-8815811_T5" ] } ]

[]

[ { "id": "PMID-8833915__text", "type": "abstract", "text": [ "Regional expression of sodium pump subunits isoforms and Na+-Ca++ exchanger in the human heart. \nCardiac glycosides exert a positive inotropic effect by inhibiting sodium pump (Na,K-ATPase) activity, decreasing the driving force for Na+-Ca++ exchange, and increasing cellular content and release of Ca++ during depolarization. Since the inotropic response will be a function of the level of expression of sodium pumps, which are alpha(beta) heterodimers, and of Na+-Ca++ exchangers, this study aimed to determine the regional pattern of expression of these transporters in the heart. Immunoblot assays of homogenate from atria, ventricles, and septa of 14 nonfailing human hearts established expression of Na,K-ATPase alpha1, alpha2, alpha3, beta1, and Na+-Ca++ exchangers in all regions. Na,K-ATPase beta2 expression is negligible, indicating that the human cardiac glycoside receptors are alpha1beta1, alpha2beta1, and alpha3beta1. alpha3, beta1, sodium pump activity, and Na+-Ca++ exchanger levels were 30-50% lower in atria compared to ventricles and/or septum; differences between ventricles and septum were insignificant. Functionally, the EC50 of the sodium channel activator BDF 9148 to increase force of contraction was lower in atria than ventricle muscle strips (0.36 vs. 1.54 microM). These results define the distribution of the cardiac glycoside receptor isoforms in the human heart and they demonstrate that atria have fewer sodium pumps, fewer Na+-Ca++ exchangers, and enhanced sensitivity to inotropic stimulation compared to ventricles.\n" ], "offsets": [ [ 0, 1555 ] ] } ]

[ { "id": "PMID-8833915_T1", "type": "Complex", "text": [ "sodium pump" ], "offsets": [ [ 23, 34 ] ], "normalized": [] }, { "id": "PMID-8833915_T2", "type": "Gene_or_gene_product", "text": [ "Na+-Ca++ exchanger" ], "offsets": [ [ 57, 75 ] ], "normalized": [] }, { "id": "PMID-8833915_T3", "type": "Simple_chemical", "text": [ "glycosides" ], "offsets": [ [ 105, 115 ] ], "normalized": [] }, { "id": "PMID-8833915_T4", "type": "Complex", "text": [ "sodium pump" ], "offsets": [ [ 164, 175 ] ], "normalized": [] }, { "id": "PMID-8833915_T5", "type": "Complex", "text": [ "Na,K-ATPase" ], "offsets": [ [ 177, 188 ] ], "normalized": [] }, { "id": "PMID-8833915_T6", "type": "Simple_chemical", "text": [ "Na+" ], "offsets": [ [ 233, 236 ] ], "normalized": [] }, { "id": "PMID-8833915_T7", "type": "Simple_chemical", "text": [ "Ca++" ], "offsets": [ [ 237, 241 ] ], "normalized": [] }, { "id": "PMID-8833915_T8", "type": "Simple_chemical", "text": [ "Ca++" ], "offsets": [ [ 299, 303 ] ], "normalized": [] }, { "id": "PMID-8833915_T9", "type": "Complex", "text": [ "sodium pumps" ], "offsets": [ [ 405, 417 ] ], "normalized": [] }, { "id": "PMID-8833915_T10", "type": "Gene_or_gene_product", "text": [ "Na+-Ca++ exchangers" ], "offsets": [ [ 462, 481 ] ], "normalized": [] }, { "id": "PMID-8833915_T11", "type": "Gene_or_gene_product", "text": [ "Na,K-ATPase alpha1" ], "offsets": [ [ 706, 724 ] ], "normalized": [] }, { "id": "PMID-8833915_T12", "type": "Gene_or_gene_product", "text": [ "alpha2" ], "offsets": [ [ 726, 732 ] ], "normalized": [] }, { "id": "PMID-8833915_T13", "type": "Gene_or_gene_product", "text": [ "alpha3" ], "offsets": [ [ 734, 740 ] ], "normalized": [] }, { "id": "PMID-8833915_T14", "type": "Gene_or_gene_product", "text": [ "beta1" ], "offsets": [ [ 742, 747 ] ], "normalized": [] }, { "id": "PMID-8833915_T15", "type": "Gene_or_gene_product", "text": [ "Na+-Ca++ exchangers" ], "offsets": [ [ 753, 772 ] ], "normalized": [] }, { "id": "PMID-8833915_T16", "type": "Gene_or_gene_product", "text": [ "Na,K-ATPase beta2" ], "offsets": [ [ 789, 806 ] ], "normalized": [] }, { "id": "PMID-8833915_T17", "type": "Simple_chemical", "text": [ "glycoside" ], "offsets": [ [ 867, 876 ] ], "normalized": [] }, { "id": "PMID-8833915_T18", "type": "Complex", "text": [ "alpha1beta1" ], "offsets": [ [ 891, 902 ] ], "normalized": [] }, { "id": "PMID-8833915_T19", "type": "Complex", "text": [ "alpha2beta1" ], "offsets": [ [ 904, 915 ] ], "normalized": [] }, { "id": "PMID-8833915_T20", "type": "Complex", "text": [ "alpha3beta1" ], "offsets": [ [ 921, 932 ] ], "normalized": [] }, { "id": "PMID-8833915_T21", "type": "Gene_or_gene_product", "text": [ "alpha3" ], "offsets": [ [ 934, 940 ] ], "normalized": [] }, { "id": "PMID-8833915_T22", "type": "Gene_or_gene_product", "text": [ "beta1" ], "offsets": [ [ 942, 947 ] ], "normalized": [] }, { "id": "PMID-8833915_T23", "type": "Complex", "text": [ "sodium pump" ], "offsets": [ [ 949, 960 ] ], "normalized": [] }, { "id": "PMID-8833915_T24", "type": "Gene_or_gene_product", "text": [ "Na+-Ca++ exchanger" ], "offsets": [ [ 975, 993 ] ], "normalized": [] }, { "id": "PMID-8833915_T25", "type": "Simple_chemical", "text": [ "sodium" ], "offsets": [ [ 1158, 1164 ] ], "normalized": [] }, { "id": "PMID-8833915_T26", "type": "Simple_chemical", "text": [ "BDF 9148" ], "offsets": [ [ 1183, 1191 ] ], "normalized": [] }, { "id": "PMID-8833915_T27", "type": "Complex", "text": [ "glycoside receptor" ], "offsets": [ [ 1350, 1368 ] ], "normalized": [] }, { "id": "PMID-8833915_T28", "type": "Complex", "text": [ "sodium pumps" ], "offsets": [ [ 1440, 1452 ] ], "normalized": [] }, { "id": "PMID-8833915_T29", "type": "Gene_or_gene_product", "text": [ "Na+-Ca++ exchangers" ], "offsets": [ [ 1460, 1479 ] ], "normalized": [] } ]

[ { "id": "PMID-8833915_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 9, 19 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T2" } ] }, { "id": "PMID-8833915_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting" ], "offsets": [ [ 153, 163 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8833915_T3" }, { "role": "Theme", "ref_id": "PMID-8833915_T5" } ] }, { "id": "PMID-8833915_E3", "type": "Negative_regulation", "trigger": { "text": [ "decreasing" ], "offsets": [ [ 200, 210 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8833915_E2" }, { "role": "Theme", "ref_id": "PMID-8833915_E5" } ] }, { "id": "PMID-8833915_E4", "type": "Negative_regulation", "trigger": { "text": [ "decreasing" ], "offsets": [ [ 200, 210 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-8833915_E2" }, { "role": "Theme", "ref_id": "PMID-8833915_E6" } ] }, { "id": "PMID-8833915_E5", "type": "Transport", "trigger": { "text": [ "exchange" ], "offsets": [ [ 242, 250 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T6" } ] }, { "id": "PMID-8833915_E6", "type": "Transport", "trigger": { "text": [ "exchange" ], "offsets": [ [ 242, 250 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T7" } ] }, { "id": "PMID-8833915_E7", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 256, 266 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_E8" }, { "role": "Cause", "ref_id": "PMID-8833915_E2" } ] }, { "id": "PMID-8833915_E8", "type": "Transport", "trigger": { "text": [ "release" ], "offsets": [ [ 288, 295 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T8" } ] }, { "id": "PMID-8833915_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 391, 401 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T10" } ] }, { "id": "PMID-8833915_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 537, 547 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T10" } ] }, { "id": "PMID-8833915_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 692, 702 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T11" } ] }, { "id": "PMID-8833915_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 692, 702 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T12" } ] }, { "id": "PMID-8833915_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 692, 702 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T13" } ] }, { "id": "PMID-8833915_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 692, 702 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T14" } ] }, { "id": "PMID-8833915_E15", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 692, 702 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T15" } ] }, { "id": "PMID-8833915_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 807, 817 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T16" } ] }, { "id": "PMID-8833915_E17", "type": "Localization", "trigger": { "text": [ "distribution" ], "offsets": [ [ 1322, 1334 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-8833915_T27" } ] } ]

[ { "id": "PMID-8833915_1", "entity_ids": [ "PMID-8833915_T5", "PMID-8833915_T4" ] } ]

[]

[ { "id": "PMID-9070863__text", "type": "abstract", "text": [ "Cloning and expression of the adenosine kinase gene from rat and human tissues. \nAdenosine kinase is ubiquitous in eukaryotes and is a key enzyme in the regulation of the intracellular levels of adenosine, an important physiological effector of many cells and tissues. In this paper we report the cloning of cDNAs encoding adenosine kinase from both rat and human tissues. Two distinct forms of adenosine kinase mRNA were identified in human tissues. Sequence variation between the two forms is restricted to the extreme 5'-end of the adenosine kinase mRNA, including a portion of the coding region, and is consistent with differential splicing of a single transcriptional product. We have expressed both forms in E. coli and produced soluble active enzyme which catalyzes the phosphorylation of adenosine with high specific activity in vitro and is susceptible to known adenosine kinase inhibitors.\n" ], "offsets": [ [ 0, 900 ] ] } ]

[ { "id": "PMID-9070863_T1", "type": "Gene_or_gene_product", "text": [ "adenosine kinase" ], "offsets": [ [ 30, 46 ] ], "normalized": [] }, { "id": "PMID-9070863_T2", "type": "Gene_or_gene_product", "text": [ "Adenosine kinase" ], "offsets": [ [ 81, 97 ] ], "normalized": [] }, { "id": "PMID-9070863_T3", "type": "Cellular_component", "text": [ "intracellular" ], "offsets": [ [ 171, 184 ] ], "normalized": [] }, { "id": "PMID-9070863_T4", "type": "Simple_chemical", "text": [ "adenosine" ], "offsets": [ [ 195, 204 ] ], "normalized": [] }, { "id": "PMID-9070863_T5", "type": "Gene_or_gene_product", "text": [ "adenosine kinase" ], "offsets": [ [ 323, 339 ] ], "normalized": [] }, { "id": "PMID-9070863_T6", "type": "Gene_or_gene_product", "text": [ "adenosine kinase" ], "offsets": [ [ 395, 411 ] ], "normalized": [] }, { "id": "PMID-9070863_T7", "type": "Gene_or_gene_product", "text": [ "adenosine kinase" ], "offsets": [ [ 535, 551 ] ], "normalized": [] }, { "id": "PMID-9070863_T8", "type": "Simple_chemical", "text": [ "adenosine" ], "offsets": [ [ 796, 805 ] ], "normalized": [] }, { "id": "PMID-9070863_T9", "type": "Gene_or_gene_product", "text": [ "adenosine kinase" ], "offsets": [ [ 871, 887 ] ], "normalized": [] } ]

[ { "id": "PMID-9070863_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 12, 22 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9070863_T1" } ] }, { "id": "PMID-9070863_E2", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 153, 163 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9070863_T4" }, { "role": "Cause", "ref_id": "PMID-9070863_T2" } ] }, { "id": "PMID-9070863_E3", "type": "Positive_regulation", "trigger": { "text": [ "catalyzes" ], "offsets": [ [ 763, 772 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9070863_E4" } ] }, { "id": "PMID-9070863_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 777, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9070863_T8" } ] } ]

[]

[]

[ { "id": "PMID-9268380__text", "type": "abstract", "text": [ "Human Myt1 is a cell cycle-regulated kinase that inhibits Cdc2 but not Cdk2 activity. \nActivation of the Cdc2.cyclin B kinase is a pivotal step of mitotic initiation. This step is mediated principally by the dephosphorylation of residues threonine 14 (Thr14) and tyrosine 15 (Tyr15) on the Cdc2 catalytic subunit. In several organisms homologs of the Wee1 kinase have been shown to be the major activity responsible for phosphorylating the Tyr15 inhibitory site. A membrane-bound kinase capable of phosphorylating residue Thr14, the Myt1 kinase, has been identified in the frog Xenopus laevis and more recently in human. In this study, we have examined the substrate specificity and cell cycle regulation of the human Myt1 kinase. We find that human Myt1 phosphorylates and inactivates Cdc2-containing cyclin complexes but not complexes containing Cdk2 or Cdk4. Analysis of endogenous Myt1 demonstrates that it remains membrane-bound throughout the cell cycle, but its kinase activity decreased during M phase arrest, when Myt1 became hyperphosphorylated. Further, Cdc2. cyclin B1 was capable of phosphorylating Myt1 in vitro, but this phosphorylation did not affect Myt1 kinase activity. These findings suggest that human Myt1 is negatively regulated by an M phase-activated kinase and that Myt1 inhibits mitosis due to its specificity for Cdc2.cyclin complexes.\n" ], "offsets": [ [ 0, 1364 ] ] } ]

[ { "id": "PMID-9268380_T1", "type": "Gene_or_gene_product", "text": [ "Myt1" ], "offsets": [ [ 6, 10 ] ], "normalized": [] }, { "id": "PMID-9268380_T2", "type": "Gene_or_gene_product", "text": [ "Cdc2" ], "offsets": [ [ 58, 62 ] ], "normalized": [] }, { "id": "PMID-9268380_T3", "type": "Gene_or_gene_product", "text": [ "Cdk2" ], "offsets": [ [ 71, 75 ] ], "normalized": [] }, { "id": "PMID-9268380_T4", "type": "Complex", "text": [ "Cdc2.cyclin B" ], "offsets": [ [ 105, 118 ] ], "normalized": [] }, { "id": "PMID-9268380_T5", "type": "Simple_chemical", "text": [ "threonine 14" ], "offsets": [ [ 238, 250 ] ], "normalized": [] }, { "id": "PMID-9268380_T6", "type": "Simple_chemical", "text": [ "Thr14" ], "offsets": [ [ 252, 257 ] ], "normalized": [] }, { "id": "PMID-9268380_T7", "type": "Simple_chemical", "text": [ "tyrosine 15" ], "offsets": [ [ 263, 274 ] ], "normalized": [] }, { "id": "PMID-9268380_T8", "type": "Simple_chemical", "text": [ "Tyr15" ], "offsets": [ [ 276, 281 ] ], "normalized": [] }, { "id": "PMID-9268380_T9", "type": "Gene_or_gene_product", "text": [ "Cdc2" ], "offsets": [ [ 290, 294 ] ], "normalized": [] }, { "id": "PMID-9268380_T10", "type": "Gene_or_gene_product", "text": [ "Wee1" ], "offsets": [ [ 351, 355 ] ], "normalized": [] }, { "id": "PMID-9268380_T11", "type": "Simple_chemical", "text": [ "Tyr15" ], "offsets": [ [ 440, 445 ] ], "normalized": [] }, { "id": "PMID-9268380_T12", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 465, 473 ] ], "normalized": [] }, { "id": "PMID-9268380_T13", "type": "Simple_chemical", "text": [ "Thr14" ], "offsets": [ [ 522, 527 ] ], "normalized": [] }, { "id": "PMID-9268380_T14", "type": "Gene_or_gene_product", "text": [ "Myt1" ], "offsets": [ [ 533, 537 ] ], "normalized": [] }, { "id": "PMID-9268380_T15", "type": "Gene_or_gene_product", "text": [ "Myt1" ], "offsets": [ [ 718, 722 ] ], "normalized": [] }, { "id": "PMID-9268380_T16", "type": "Gene_or_gene_product", "text": [ "Myt1" ], "offsets": [ [ 750, 754 ] ], "normalized": [] }, { "id": "PMID-9268380_T17", "type": "Gene_or_gene_product", "text": [ "Cdc2" ], "offsets": [ [ 786, 790 ] ], "normalized": [] }, { "id": "PMID-9268380_T18", "type": "Complex", "text": [ "cyclin complexes" ], "offsets": [ [ 802, 818 ] ], "normalized": [] }, { "id": "PMID-9268380_T19", "type": "Gene_or_gene_product", "text": [ "Cdk2" ], "offsets": [ [ 848, 852 ] ], "normalized": [] }, { "id": "PMID-9268380_T20", "type": "Gene_or_gene_product", "text": [ "Cdk4" ], "offsets": [ [ 856, 860 ] ], "normalized": [] }, { "id": "PMID-9268380_T21", "type": "Gene_or_gene_product", "text": [ "Myt1" ], "offsets": [ [ 885, 889 ] ], "normalized": [] }, { "id": "PMID-9268380_T22", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 919, 927 ] ], "normalized": [] }, { "id": "PMID-9268380_T23", "type": "Gene_or_gene_product", "text": [ "Myt1" ], "offsets": [ [ 1023, 1027 ] ], "normalized": [] }, { "id": "PMID-9268380_T24", "type": "Complex", "text": [ "Cdc2. cyclin B1" ], "offsets": [ [ 1065, 1080 ] ], "normalized": [] }, { "id": "PMID-9268380_T25", "type": "Gene_or_gene_product", "text": [ "Myt1" ], "offsets": [ [ 1112, 1116 ] ], "normalized": [] }, { "id": "PMID-9268380_T26", "type": "Gene_or_gene_product", "text": [ "Myt1" ], "offsets": [ [ 1167, 1171 ] ], "normalized": [] }, { "id": "PMID-9268380_T27", "type": "Gene_or_gene_product", "text": [ "Myt1" ], "offsets": [ [ 1223, 1227 ] ], "normalized": [] }, { "id": "PMID-9268380_T28", "type": "Gene_or_gene_product", "text": [ "Myt1" ], "offsets": [ [ 1292, 1296 ] ], "normalized": [] }, { "id": "PMID-9268380_T29", "type": "Complex", "text": [ "Cdc2.cyclin" ], "offsets": [ [ 1341, 1352 ] ], "normalized": [] } ]

[ { "id": "PMID-9268380_E1", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 16, 26 ] ] }, "arguments": [] }, { "id": "PMID-9268380_E2", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 27, 36 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9268380_E1" }, { "role": "Theme", "ref_id": "PMID-9268380_T1" } ] }, { "id": "PMID-9268380_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 49, 57 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9268380_T1" }, { "role": "Theme", "ref_id": "PMID-9268380_T2" } ] }, { "id": "PMID-9268380_E4", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 49, 57 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9268380_T1" }, { "role": "Theme", "ref_id": "PMID-9268380_T3" } ] }, { "id": "PMID-9268380_E5", "type": "Activation", "trigger": { "text": [ "Activation" ], "offsets": [ [ 87, 97 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_T4" } ] }, { "id": "PMID-9268380_E6", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 180, 188 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_E5" }, { "role": "Cause", "ref_id": "PMID-9268380_E8" } ] }, { "id": "PMID-9268380_E7", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 180, 188 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_E5" }, { "role": "Cause", "ref_id": "PMID-9268380_E9" } ] }, { "id": "PMID-9268380_E8", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylation" ], "offsets": [ [ 208, 225 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_T9" }, { "role": "Site", "ref_id": "PMID-9268380_T6" } ] }, { "id": "PMID-9268380_E9", "type": "Dephosphorylation", "trigger": { "text": [ "dephosphorylation" ], "offsets": [ [ 208, 225 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_T9" }, { "role": "Site", "ref_id": "PMID-9268380_T8" } ] }, { "id": "PMID-9268380_E10", "type": "Positive_regulation", "trigger": { "text": [ "responsible" ], "offsets": [ [ 404, 415 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_E11" }, { "role": "Cause", "ref_id": "PMID-9268380_T10" } ] }, { "id": "PMID-9268380_E11", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylating" ], "offsets": [ [ 420, 435 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-9268380_T11" }, { "role": "Theme", "ref_id": "PMID-9268380_T9" } ] }, { "id": "PMID-9268380_E12", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylating" ], "offsets": [ [ 498, 513 ] ] }, "arguments": [ { "role": "Site", "ref_id": "PMID-9268380_T13" }, { "role": "Theme", "ref_id": "PMID-9268380_T9" }, { "role": "Cause", "ref_id": "PMID-9268380_T14" } ] }, { "id": "PMID-9268380_E13", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 683, 693 ] ] }, "arguments": [] }, { "id": "PMID-9268380_E14", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 694, 704 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_E13" }, { "role": "Cause", "ref_id": "PMID-9268380_T15" } ] }, { "id": "PMID-9268380_E15", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 755, 769 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_T18" }, { "role": "Cause", "ref_id": "PMID-9268380_T16" } ] }, { "id": "PMID-9268380_E16", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 755, 769 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9268380_T16" }, { "role": "Theme", "ref_id": "PMID-9268380_T19" } ] }, { "id": "PMID-9268380_E17", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 755, 769 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9268380_T16" }, { "role": "Theme", "ref_id": "PMID-9268380_T20" } ] }, { "id": "PMID-9268380_E18", "type": "Inactivation", "trigger": { "text": [ "inactivates" ], "offsets": [ [ 774, 785 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_T18" }, { "role": "Cause", "ref_id": "PMID-9268380_T16" } ] }, { "id": "PMID-9268380_E19", "type": "Inactivation", "trigger": { "text": [ "inactivates" ], "offsets": [ [ 774, 785 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9268380_T16" }, { "role": "Theme", "ref_id": "PMID-9268380_T19" } ] }, { "id": "PMID-9268380_E20", "type": "Inactivation", "trigger": { "text": [ "inactivates" ], "offsets": [ [ 774, 785 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9268380_T16" }, { "role": "Theme", "ref_id": "PMID-9268380_T20" } ] }, { "id": "PMID-9268380_E21", "type": "Binding", "trigger": { "text": [ "containing" ], "offsets": [ [ 791, 801 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_T17" }, { "role": "Theme", "ref_id": "PMID-9268380_T18" } ] }, { "id": "PMID-9268380_E22", "type": "Binding", "trigger": { "text": [ "containing" ], "offsets": [ [ 837, 847 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_T18" }, { "role": "Theme", "ref_id": "PMID-9268380_T19" } ] }, { "id": "PMID-9268380_E23", "type": "Binding", "trigger": { "text": [ "containing" ], "offsets": [ [ 837, 847 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_T18" }, { "role": "Theme", "ref_id": "PMID-9268380_T20" } ] }, { "id": "PMID-9268380_E24", "type": "Pathway", "trigger": { "text": [ "cell cycle" ], "offsets": [ [ 949, 959 ] ] }, "arguments": [] }, { "id": "PMID-9268380_E25", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 985, 994 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_T21" } ] }, { "id": "PMID-9268380_E26", "type": "Phosphorylation", "trigger": { "text": [ "hyperphosphorylated" ], "offsets": [ [ 1035, 1054 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_T23" } ] }, { "id": "PMID-9268380_E27", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylating" ], "offsets": [ [ 1096, 1111 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9268380_T24" }, { "role": "Theme", "ref_id": "PMID-9268380_T25" } ] }, { "id": "PMID-9268380_E28", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 1160, 1166 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9268380_E27" }, { "role": "Theme", "ref_id": "PMID-9268380_T26" } ] }, { "id": "PMID-9268380_E29", "type": "Negative_regulation", "trigger": { "text": [ "negatively regulated" ], "offsets": [ [ 1231, 1251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9268380_T27" } ] } ]

[ { "id": "PMID-9268380_1", "entity_ids": [ "PMID-9268380_T5", "PMID-9268380_T6" ] }, { "id": "PMID-9268380_2", "entity_ids": [ "PMID-9268380_T7", "PMID-9268380_T8" ] } ]

[]

[ { "id": "PMID-9337861__text", "type": "abstract", "text": [ "Cloning of a human phosphoinositide 3-kinase with a C2 domain that displays reduced sensitivity to the inhibitor wortmannin. \nThe generation of phosphatidylinositide 3-phosphates has been observed in a variety of cellular responses. The enzymes that mediate synthesis are the phosphoinositide 3-kinases (PI3-Ks) that form a family of structurally diverse enzymes with distinct substrate specificities. In this paper, we describe the cloning of a novel human PI3-K, namely PI3-K-C2 alpha, which contains a C-terminal C2 domain. This enzyme can be assigned to the class II PI3-Ks, which was defined by characterization of the Drosophila 68D enzyme and includes the recently described murine enzymes m-cpk and p170. Despite the overall similarity in the amino acid sequence of the murine and human enzymes, which suggests that they are encoded by closely related genes, these molecules show marked sequence heterogeneity at their N-termini. Biochemical analysis of recombinant PI3-K-C2 alpha demonstrates a restricted lipid substrate specificity. As reported for other members of this class, the enzyme only phosphorylates PtdIns and PtdIns4P when the lipids are presented alone. However, when lipids were presented together with phosphatidylserine acting as a carrier, phosphorylation of PtdIns(4,5)P2 was also observed. The catalytic activity of PI3-K-C2 alpha is refractory to concentrations of wortmannin and LY294002 which inhibit the PI3-K activity of other family members. The comparative insensitivity of PI3-K-C2 alpha to these inhibitors suggests that their use should be reevaluated in the study of PI3-Ks.\n" ], "offsets": [ [ 0, 1615 ] ] } ]

[ { "id": "PMID-9337861_T1", "type": "Gene_or_gene_product", "text": [ "human phosphoinositide 3-kinase" ], "offsets": [ [ 13, 44 ] ], "normalized": [] }, { "id": "PMID-9337861_T2", "type": "Simple_chemical", "text": [ "wortmannin" ], "offsets": [ [ 113, 123 ] ], "normalized": [] }, { "id": "PMID-9337861_T3", "type": "Simple_chemical", "text": [ "phosphatidylinositide 3-phosphates" ], "offsets": [ [ 144, 178 ] ], "normalized": [] }, { "id": "PMID-9337861_T4", "type": "Gene_or_gene_product", "text": [ "phosphoinositide 3-kinases" ], "offsets": [ [ 276, 302 ] ], "normalized": [] }, { "id": "PMID-9337861_T5", "type": "Gene_or_gene_product", "text": [ "PI3-Ks" ], "offsets": [ [ 304, 310 ] ], "normalized": [] }, { "id": "PMID-9337861_T6", "type": "Gene_or_gene_product", "text": [ "PI3-K" ], "offsets": [ [ 458, 463 ] ], "normalized": [] }, { "id": "PMID-9337861_T7", "type": "Gene_or_gene_product", "text": [ "PI3-K-C2 alpha" ], "offsets": [ [ 472, 486 ] ], "normalized": [] }, { "id": "PMID-9337861_T8", "type": "Gene_or_gene_product", "text": [ "class II PI3-Ks" ], "offsets": [ [ 562, 577 ] ], "normalized": [] }, { "id": "PMID-9337861_T9", "type": "Gene_or_gene_product", "text": [ "68D" ], "offsets": [ [ 635, 638 ] ], "normalized": [] }, { "id": "PMID-9337861_T10", "type": "Gene_or_gene_product", "text": [ "m-cpk" ], "offsets": [ [ 697, 702 ] ], "normalized": [] }, { "id": "PMID-9337861_T11", "type": "Gene_or_gene_product", "text": [ "p170" ], "offsets": [ [ 707, 711 ] ], "normalized": [] }, { "id": "PMID-9337861_T12", "type": "Gene_or_gene_product", "text": [ "PI3-K-C2 alpha" ], "offsets": [ [ 974, 988 ] ], "normalized": [] }, { "id": "PMID-9337861_T13", "type": "Simple_chemical", "text": [ "lipid" ], "offsets": [ [ 1015, 1020 ] ], "normalized": [] }, { "id": "PMID-9337861_T14", "type": "Simple_chemical", "text": [ "PtdIns" ], "offsets": [ [ 1120, 1126 ] ], "normalized": [] }, { "id": "PMID-9337861_T15", "type": "Simple_chemical", "text": [ "PtdIns4P" ], "offsets": [ [ 1131, 1139 ] ], "normalized": [] }, { "id": "PMID-9337861_T16", "type": "Simple_chemical", "text": [ "lipids" ], "offsets": [ [ 1149, 1155 ] ], "normalized": [] }, { "id": "PMID-9337861_T17", "type": "Simple_chemical", "text": [ "lipids" ], "offsets": [ [ 1191, 1197 ] ], "normalized": [] }, { "id": "PMID-9337861_T18", "type": "Simple_chemical", "text": [ "phosphatidylserine" ], "offsets": [ [ 1227, 1245 ] ], "normalized": [] }, { "id": "PMID-9337861_T19", "type": "Simple_chemical", "text": [ "PtdIns(4,5)P2" ], "offsets": [ [ 1286, 1299 ] ], "normalized": [] }, { "id": "PMID-9337861_T20", "type": "Gene_or_gene_product", "text": [ "PI3-K-C2 alpha" ], "offsets": [ [ 1345, 1359 ] ], "normalized": [] }, { "id": "PMID-9337861_T21", "type": "Simple_chemical", "text": [ "wortmannin" ], "offsets": [ [ 1395, 1405 ] ], "normalized": [] }, { "id": "PMID-9337861_T22", "type": "Simple_chemical", "text": [ "LY294002" ], "offsets": [ [ 1410, 1418 ] ], "normalized": [] }, { "id": "PMID-9337861_T23", "type": "Gene_or_gene_product", "text": [ "PI3-K" ], "offsets": [ [ 1437, 1442 ] ], "normalized": [] }, { "id": "PMID-9337861_T24", "type": "Gene_or_gene_product", "text": [ "PI3-K-C2 alpha" ], "offsets": [ [ 1510, 1524 ] ], "normalized": [] }, { "id": "PMID-9337861_T25", "type": "Gene_or_gene_product", "text": [ "PI3-Ks" ], "offsets": [ [ 1607, 1613 ] ], "normalized": [] } ]

[ { "id": "PMID-9337861_E1", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 76, 83 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9337861_E2" }, { "role": "Cause", "ref_id": "PMID-9337861_T1" } ] }, { "id": "PMID-9337861_E2", "type": "Regulation", "trigger": { "text": [ "sensitivity" ], "offsets": [ [ 84, 95 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9337861_T2" } ] }, { "id": "PMID-9337861_E3", "type": "Conversion", "trigger": { "text": [ "generation" ], "offsets": [ [ 130, 140 ] ] }, "arguments": [ { "role": "Product", "ref_id": "PMID-9337861_T3" } ] }, { "id": "PMID-9337861_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 1105, 1119 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9337861_T14" } ] }, { "id": "PMID-9337861_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 1105, 1119 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9337861_T15" } ] }, { "id": "PMID-9337861_E6", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1267, 1282 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9337861_T19" } ] }, { "id": "PMID-9337861_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1425, 1432 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9337861_T23" }, { "role": "Cause", "ref_id": "PMID-9337861_T21" } ] }, { "id": "PMID-9337861_E8", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1425, 1432 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9337861_T23" }, { "role": "Cause", "ref_id": "PMID-9337861_T22" } ] } ]

[ { "id": "PMID-9337861_1", "entity_ids": [ "PMID-9337861_T4", "PMID-9337861_T5" ] } ]

[]

[ { "id": "PMID-9430701__text", "type": "abstract", "text": [ "Crystal structure of a calcium-phospholipid binding domain from cytosolic phospholipase A2. \nCytosolic phospholipase A2 (cPLA2) is a calcium-sensitive 85-kDa enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an N-terminal C2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. The 2.4-A x-ray crystal structure of this C2 domain was solved by multiple isomorphous replacement and reveals a beta-sandwich with the same topology as the C2 domain from phosphoinositide-specific phospholipase C delta 1. Two clusters of exposed hydrophobic residues surround two adjacent calcium binding sites. This region, along with an adjoining strip of basic residues, appear to constitute the membrane binding motif. The structure provides a striking insight into the relative importance of hydrophobic and electrostatic components of membrane binding for cPLA2. Although hydrophobic interactions predominate for cPLA2, for other C2 domains such as in \"conventional\" protein kinase C and synaptotagmins, electrostatic forces prevail.\n" ], "offsets": [ [ 0, 1329 ] ] } ]

[ { "id": "PMID-9430701_T1", "type": "Simple_chemical", "text": [ "calcium" ], "offsets": [ [ 23, 30 ] ], "normalized": [] }, { "id": "PMID-9430701_T2", "type": "Simple_chemical", "text": [ "phospholipid" ], "offsets": [ [ 31, 43 ] ], "normalized": [] }, { "id": "PMID-9430701_T3", "type": "Cellular_component", "text": [ "cytosolic" ], "offsets": [ [ 64, 73 ] ], "normalized": [] }, { "id": "PMID-9430701_T4", "type": "Gene_or_gene_product", "text": [ "phospholipase A2" ], "offsets": [ [ 74, 90 ] ], "normalized": [] }, { "id": "PMID-9430701_T5", "type": "Gene_or_gene_product", "text": [ "Cytosolic phospholipase A2" ], "offsets": [ [ 93, 119 ] ], "normalized": [] }, { "id": "PMID-9430701_T6", "type": "Gene_or_gene_product", "text": [ "cPLA2" ], "offsets": [ [ 121, 126 ] ], "normalized": [] }, { "id": "PMID-9430701_T7", "type": "Simple_chemical", "text": [ "calcium" ], "offsets": [ [ 133, 140 ] ], "normalized": [] }, { "id": "PMID-9430701_T8", "type": "Simple_chemical", "text": [ "arachidonic acid" ], "offsets": [ [ 181, 197 ] ], "normalized": [] }, { "id": "PMID-9430701_T9", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 209, 217 ] ], "normalized": [] }, { "id": "PMID-9430701_T10", "type": "Simple_chemical", "text": [ "phospholipids" ], "offsets": [ [ 218, 231 ] ], "normalized": [] }, { "id": "PMID-9430701_T11", "type": "Simple_chemical", "text": [ "eicosanoids" ], "offsets": [ [ 264, 275 ] ], "normalized": [] }, { "id": "PMID-9430701_T12", "type": "Simple_chemical", "text": [ "platelet-activating factor" ], "offsets": [ [ 280, 306 ] ], "normalized": [] }, { "id": "PMID-9430701_T13", "type": "Simple_chemical", "text": [ "calcium" ], "offsets": [ [ 343, 350 ] ], "normalized": [] }, { "id": "PMID-9430701_T14", "type": "Simple_chemical", "text": [ "calcium" ], "offsets": [ [ 451, 458 ] ], "normalized": [] }, { "id": "PMID-9430701_T15", "type": "Cellular_component", "text": [ "membranes" ], "offsets": [ [ 500, 509 ] ], "normalized": [] }, { "id": "PMID-9430701_T16", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 558, 566 ] ], "normalized": [] }, { "id": "PMID-9430701_T17", "type": "Simple_chemical", "text": [ "phosphoinositide" ], "offsets": [ [ 760, 776 ] ], "normalized": [] }, { "id": "PMID-9430701_T18", "type": "Gene_or_gene_product", "text": [ "phospholipase C delta 1" ], "offsets": [ [ 786, 809 ] ], "normalized": [] }, { "id": "PMID-9430701_T19", "type": "Simple_chemical", "text": [ "calcium" ], "offsets": [ [ 878, 885 ] ], "normalized": [] }, { "id": "PMID-9430701_T20", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 988, 996 ] ], "normalized": [] }, { "id": "PMID-9430701_T21", "type": "Cellular_component", "text": [ "membrane" ], "offsets": [ [ 1130, 1138 ] ], "normalized": [] }, { "id": "PMID-9430701_T22", "type": "Gene_or_gene_product", "text": [ "cPLA2" ], "offsets": [ [ 1151, 1156 ] ], "normalized": [] }, { "id": "PMID-9430701_T23", "type": "Gene_or_gene_product", "text": [ "cPLA2" ], "offsets": [ [ 1208, 1213 ] ], "normalized": [] }, { "id": "PMID-9430701_T24", "type": "Gene_or_gene_product", "text": [ "protein kinase C" ], "offsets": [ [ 1262, 1278 ] ], "normalized": [] }, { "id": "PMID-9430701_T25", "type": "Gene_or_gene_product", "text": [ "synaptotagmins" ], "offsets": [ [ 1283, 1297 ] ], "normalized": [] } ]

[ { "id": "PMID-9430701_E1", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 141, 150 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9430701_T7" }, { "role": "Theme", "ref_id": "PMID-9430701_T6" } ] }, { "id": "PMID-9430701_E2", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 170, 180 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_T10" }, { "role": "Product", "ref_id": "PMID-9430701_T11" } ] }, { "id": "PMID-9430701_E3", "type": "Positive_regulation", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 170, 180 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9430701_T6" }, { "role": "Theme", "ref_id": "PMID-9430701_E2" } ] }, { "id": "PMID-9430701_E4", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 170, 180 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_T10" }, { "role": "Product", "ref_id": "PMID-9430701_T12" } ] }, { "id": "PMID-9430701_E5", "type": "Positive_regulation", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 170, 180 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9430701_T6" }, { "role": "Theme", "ref_id": "PMID-9430701_E4" } ] }, { "id": "PMID-9430701_E6", "type": "Binding", "trigger": { "text": [ "containing" ], "offsets": [ [ 198, 208 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_T8" }, { "role": "Theme", "ref_id": "PMID-9430701_T10" } ] }, { "id": "PMID-9430701_E7", "type": "Positive_regulation", "trigger": { "text": [ "initiate" ], "offsets": [ [ 235, 243 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_E11" }, { "role": "Cause", "ref_id": "PMID-9430701_E2" } ] }, { "id": "PMID-9430701_E8", "type": "Positive_regulation", "trigger": { "text": [ "initiate" ], "offsets": [ [ 235, 243 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_E12" }, { "role": "Cause", "ref_id": "PMID-9430701_E2" } ] }, { "id": "PMID-9430701_E9", "type": "Positive_regulation", "trigger": { "text": [ "initiate" ], "offsets": [ [ 235, 243 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_E12" }, { "role": "Cause", "ref_id": "PMID-9430701_E4" } ] }, { "id": "PMID-9430701_E10", "type": "Positive_regulation", "trigger": { "text": [ "initiate" ], "offsets": [ [ 235, 243 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_E11" }, { "role": "Cause", "ref_id": "PMID-9430701_E4" } ] }, { "id": "PMID-9430701_E11", "type": "Conversion", "trigger": { "text": [ "biosynthesis" ], "offsets": [ [ 248, 260 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_T10" }, { "role": "Product", "ref_id": "PMID-9430701_T11" } ] }, { "id": "PMID-9430701_E12", "type": "Conversion", "trigger": { "text": [ "biosynthesis" ], "offsets": [ [ 248, 260 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_T10" }, { "role": "Product", "ref_id": "PMID-9430701_T12" } ] }, { "id": "PMID-9430701_E13", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 351, 360 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9430701_T13" }, { "role": "Theme", "ref_id": "PMID-9430701_E14" } ] }, { "id": "PMID-9430701_E14", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 361, 371 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_T6" } ] }, { "id": "PMID-9430701_E15", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 389, 397 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_E14" } ] }, { "id": "PMID-9430701_E16", "type": "Positive_regulation", "trigger": { "text": [ "responsible" ], "offsets": [ [ 435, 446 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_E18" }, { "role": "Cause", "ref_id": "PMID-9430701_E15" } ] }, { "id": "PMID-9430701_E17", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 459, 468 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9430701_T14" }, { "role": "Theme", "ref_id": "PMID-9430701_E18" } ] }, { "id": "PMID-9430701_E18", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 469, 482 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_T6" }, { "role": "ToLoc", "ref_id": "PMID-9430701_T15" } ] }, { "id": "PMID-9430701_E19", "type": "Localization", "trigger": { "text": [ "binding" ], "offsets": [ [ 1139, 1146 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9430701_T22" }, { "role": "AtLoc", "ref_id": "PMID-9430701_T21" } ] } ]

[ { "id": "PMID-9430701_1", "entity_ids": [ "PMID-9430701_T5", "PMID-9430701_T6" ] } ]

[]

[ { "id": "PMID-9564042__text", "type": "abstract", "text": [ "Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. \nApoptosis signal-regulating kinase (ASK) 1 was recently identified as a mitogen-activated protein (MAP) kinase kinase kinase which activates the c-Jun N-terminal kinase (JNK) and p38 MAP kinase pathways and is required for tumor necrosis factor (TNF)-alpha-induced apoptosis; however, the mechanism regulating ASK1 activity is unknown. Through genetic screening for ASK1-binding proteins, thioredoxin (Trx), a reduction/oxidation (redox)-regulatory protein thought to have anti-apoptotic effects, was identified as an interacting partner of ASK1. Trx associated with the N-terminal portion of ASK1 in vitro and in vivo. Expression of Trx inhibited ASK1 kinase activity and the subsequent ASK1-dependent apoptosis. Treatment of cells with N-acetyl-L-cysteine also inhibited serum withdrawal-, TNF-alpha- and hydrogen peroxide-induced activation of ASK1 as well as apoptosis. The interaction between Trx and ASK1 was found to be highly dependent on the redox status of Trx. Moreover, inhibition of Trx resulted in activation of endogenous ASK1 activity, suggesting that Trx is a physiological inhibitor of ASK1. The evidence that Trx is a negative regulator of ASK1 suggests possible mechanisms for redox regulation of the apoptosis signal transduction pathway as well as the effects of antioxidants against cytokine- and stress-induced apoptosis.\n" ], "offsets": [ [ 0, 1438 ] ] } ]

[ { "id": "PMID-9564042_T1", "type": "Gene_or_gene_product", "text": [ "thioredoxin" ], "offsets": [ [ 10, 21 ] ], "normalized": [] }, { "id": "PMID-9564042_T2", "type": "Gene_or_gene_product", "text": [ "apoptosis signal-regulating kinase (ASK) 1" ], "offsets": [ [ 47, 89 ] ], "normalized": [] }, { "id": "PMID-9564042_T3", "type": "Gene_or_gene_product", "text": [ "Apoptosis signal-regulating kinase (ASK) 1" ], "offsets": [ [ 92, 134 ] ], "normalized": [] }, { "id": "PMID-9564042_T4", "type": "Gene_or_gene_product", "text": [ "mitogen-activated protein (MAP) kinase kinase kinase" ], "offsets": [ [ 164, 216 ] ], "normalized": [] }, { "id": "PMID-9564042_T5", "type": "Gene_or_gene_product", "text": [ "c-Jun N-terminal kinase" ], "offsets": [ [ 237, 260 ] ], "normalized": [] }, { "id": "PMID-9564042_T6", "type": "Gene_or_gene_product", "text": [ "JNK" ], "offsets": [ [ 262, 265 ] ], "normalized": [] }, { "id": "PMID-9564042_T7", "type": "Gene_or_gene_product", "text": [ "p38 MAP kinase" ], "offsets": [ [ 271, 285 ] ], "normalized": [] }, { "id": "PMID-9564042_T8", "type": "Gene_or_gene_product", "text": [ "tumor necrosis factor (TNF)-alpha" ], "offsets": [ [ 315, 348 ] ], "normalized": [] }, { "id": "PMID-9564042_T9", "type": "Gene_or_gene_product", "text": [ "ASK1" ], "offsets": [ [ 402, 406 ] ], "normalized": [] }, { "id": "PMID-9564042_T10", "type": "Gene_or_gene_product", "text": [ "ASK1" ], "offsets": [ [ 458, 462 ] ], "normalized": [] }, { "id": "PMID-9564042_T11", "type": "Gene_or_gene_product", "text": [ "thioredoxin" ], "offsets": [ [ 481, 492 ] ], "normalized": [] }, { "id": "PMID-9564042_T12", "type": "Gene_or_gene_product", "text": [ "Trx" ], "offsets": [ [ 494, 497 ] ], "normalized": [] }, { "id": "PMID-9564042_T13", "type": "Gene_or_gene_product", "text": [ "ASK1" ], "offsets": [ [ 633, 637 ] ], "normalized": [] }, { "id": "PMID-9564042_T14", "type": "Gene_or_gene_product", "text": [ "Trx" ], "offsets": [ [ 639, 642 ] ], "normalized": [] }, { "id": "PMID-9564042_T15", "type": "Gene_or_gene_product", "text": [ "ASK1" ], "offsets": [ [ 685, 689 ] ], "normalized": [] }, { "id": "PMID-9564042_T16", "type": "Gene_or_gene_product", "text": [ "Trx" ], "offsets": [ [ 726, 729 ] ], "normalized": [] }, { "id": "PMID-9564042_T17", "type": "Gene_or_gene_product", "text": [ "ASK1" ], "offsets": [ [ 740, 744 ] ], "normalized": [] }, { "id": "PMID-9564042_T18", "type": "Gene_or_gene_product", "text": [ "ASK1" ], "offsets": [ [ 780, 784 ] ], "normalized": [] }, { "id": "PMID-9564042_T19", "type": "Simple_chemical", "text": [ "N-acetyl-L-cysteine" ], "offsets": [ [ 830, 849 ] ], "normalized": [] }, { "id": "PMID-9564042_T20", "type": "Gene_or_gene_product", "text": [ "TNF-alpha" ], "offsets": [ [ 884, 893 ] ], "normalized": [] }, { "id": "PMID-9564042_T21", "type": "Simple_chemical", "text": [ "hydrogen peroxide" ], "offsets": [ [ 899, 916 ] ], "normalized": [] }, { "id": "PMID-9564042_T22", "type": "Gene_or_gene_product", "text": [ "ASK1" ], "offsets": [ [ 939, 943 ] ], "normalized": [] }, { "id": "PMID-9564042_T23", "type": "Gene_or_gene_product", "text": [ "Trx" ], "offsets": [ [ 990, 993 ] ], "normalized": [] }, { "id": "PMID-9564042_T24", "type": "Gene_or_gene_product", "text": [ "ASK1" ], "offsets": [ [ 998, 1002 ] ], "normalized": [] }, { "id": "PMID-9564042_T25", "type": "Gene_or_gene_product", "text": [ "Trx" ], "offsets": [ [ 1059, 1062 ] ], "normalized": [] }, { "id": "PMID-9564042_T26", "type": "Gene_or_gene_product", "text": [ "Trx" ], "offsets": [ [ 1088, 1091 ] ], "normalized": [] }, { "id": "PMID-9564042_T27", "type": "Gene_or_gene_product", "text": [ "ASK1" ], "offsets": [ [ 1129, 1133 ] ], "normalized": [] }, { "id": "PMID-9564042_T28", "type": "Gene_or_gene_product", "text": [ "Trx" ], "offsets": [ [ 1160, 1163 ] ], "normalized": [] }, { "id": "PMID-9564042_T29", "type": "Gene_or_gene_product", "text": [ "ASK1" ], "offsets": [ [ 1196, 1200 ] ], "normalized": [] }, { "id": "PMID-9564042_T30", "type": "Gene_or_gene_product", "text": [ "Trx" ], "offsets": [ [ 1220, 1223 ] ], "normalized": [] }, { "id": "PMID-9564042_T31", "type": "Gene_or_gene_product", "text": [ "ASK1" ], "offsets": [ [ 1251, 1255 ] ], "normalized": [] } ]

[ { "id": "PMID-9564042_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 34, 43 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9564042_T1" }, { "role": "Theme", "ref_id": "PMID-9564042_T2" } ] }, { "id": "PMID-9564042_E2", "type": "Positive_regulation", "trigger": { "text": [ "activates" ], "offsets": [ [ 223, 232 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9564042_T3" }, { "role": "Theme", "ref_id": "PMID-9564042_E4" } ] }, { "id": "PMID-9564042_E3", "type": "Positive_regulation", "trigger": { "text": [ "activates" ], "offsets": [ [ 223, 232 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9564042_T3" }, { "role": "Theme", "ref_id": "PMID-9564042_E5" } ] }, { "id": "PMID-9564042_E4", "type": "Pathway", "trigger": { "text": [ "pathways" ], "offsets": [ [ 286, 294 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-9564042_T5" } ] }, { "id": "PMID-9564042_E5", "type": "Pathway", "trigger": { "text": [ "pathways" ], "offsets": [ [ 286, 294 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-9564042_T7" } ] }, { "id": "PMID-9564042_E6", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 302, 310 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_E9" }, { "role": "Cause", "ref_id": "PMID-9564042_E2" } ] }, { "id": "PMID-9564042_E7", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 302, 310 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_E9" }, { "role": "Cause", "ref_id": "PMID-9564042_E3" } ] }, { "id": "PMID-9564042_E8", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 349, 356 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9564042_T8" }, { "role": "Theme", "ref_id": "PMID-9564042_E9" } ] }, { "id": "PMID-9564042_E9", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 357, 366 ] ] }, "arguments": [] }, { "id": "PMID-9564042_E10", "type": "Regulation", "trigger": { "text": [ "regulating" ], "offsets": [ [ 391, 401 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_T9" } ] }, { "id": "PMID-9564042_E11", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 463, 470 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_T10" }, { "role": "Theme", "ref_id": "PMID-9564042_T11" } ] }, { "id": "PMID-9564042_E12", "type": "Binding", "trigger": { "text": [ "interacting" ], "offsets": [ [ 610, 621 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_T13" }, { "role": "Theme", "ref_id": "PMID-9564042_T11" } ] }, { "id": "PMID-9564042_E13", "type": "Binding", "trigger": { "text": [ "associated" ], "offsets": [ [ 643, 653 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_T14" }, { "role": "Theme", "ref_id": "PMID-9564042_T15" } ] }, { "id": "PMID-9564042_E14", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 712, 722 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_T16" } ] }, { "id": "PMID-9564042_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 730, 739 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9564042_E14" }, { "role": "Theme", "ref_id": "PMID-9564042_T17" } ] }, { "id": "PMID-9564042_E16", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 730, 739 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9564042_E14" }, { "role": "Theme", "ref_id": "PMID-9564042_E18" } ] }, { "id": "PMID-9564042_E17", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 785, 794 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9564042_T18" }, { "role": "Theme", "ref_id": "PMID-9564042_E18" } ] }, { "id": "PMID-9564042_E18", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 795, 804 ] ] }, "arguments": [] }, { "id": "PMID-9564042_E19", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 855, 864 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9564042_T19" }, { "role": "Theme", "ref_id": "PMID-9564042_E23" } ] }, { "id": "PMID-9564042_E20", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 855, 864 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9564042_T19" }, { "role": "Theme", "ref_id": "PMID-9564042_E24" } ] }, { "id": "PMID-9564042_E21", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 917, 924 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_E23" }, { "role": "Cause", "ref_id": "PMID-9564042_T21" } ] }, { "id": "PMID-9564042_E22", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 917, 924 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_E23" }, { "role": "Cause", "ref_id": "PMID-9564042_T20" } ] }, { "id": "PMID-9564042_E23", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 925, 935 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_T22" } ] }, { "id": "PMID-9564042_E24", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 955, 964 ] ] }, "arguments": [] }, { "id": "PMID-9564042_E25", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 970, 981 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_T23" }, { "role": "Theme", "ref_id": "PMID-9564042_T24" } ] }, { "id": "PMID-9564042_E26", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1026, 1035 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9564042_T25" }, { "role": "Theme", "ref_id": "PMID-9564042_E25" } ] }, { "id": "PMID-9564042_E27", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1074, 1084 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_T26" } ] }, { "id": "PMID-9564042_E28", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 1092, 1100 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9564042_E27" }, { "role": "Theme", "ref_id": "PMID-9564042_E29" } ] }, { "id": "PMID-9564042_E29", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1104, 1114 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_T27" } ] }, { "id": "PMID-9564042_E30", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 1183, 1192 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_T29" }, { "role": "Cause", "ref_id": "PMID-9564042_T28" } ] }, { "id": "PMID-9564042_E31", "type": "Negative_regulation", "trigger": { "text": [ "negative regulator" ], "offsets": [ [ 1229, 1247 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_T31" }, { "role": "Cause", "ref_id": "PMID-9564042_T30" } ] }, { "id": "PMID-9564042_E32", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1295, 1305 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9564042_E33" } ] }, { "id": "PMID-9564042_E33", "type": "Pathway", "trigger": { "text": [ "apoptosis signal transduction pathway" ], "offsets": [ [ 1313, 1350 ] ] }, "arguments": [] }, { "id": "PMID-9564042_E34", "type": "Pathway", "trigger": { "text": [ "apoptosis" ], "offsets": [ [ 1427, 1436 ] ] }, "arguments": [] } ]

[ { "id": "PMID-9564042_1", "entity_ids": [ "PMID-9564042_T5", "PMID-9564042_T6" ] }, { "id": "PMID-9564042_2", "entity_ids": [ "PMID-9564042_T11", "PMID-9564042_T12" ] } ]

[]

[ { "id": "PMID-9676430__text", "type": "abstract", "text": [ "The CD39-like gene family: identification of three new human members (CD39L2, CD39L3, and CD39L4), their murine homologues, and a member of the gene family from Drosophila melanogaster. \nThe human lymphoid cell activation antigen CD39 is a known E-type apyrase that hydrolyzes extracellular ATP and ADP, a function important in homotypic adhesion, platelet aggregation, and removal by activated lymphocytes of the lytic effect of ATP. The recently identified putative rat homologue of CD39L1 has been shown to have E-type ecto-ATPase activity, by hydrolyzing extracellular ATP. We have characterized three novel CD39-like transcripts, CD39L2, CD39L3, and CD39L4, which share extensive amino acid homology with other nucleotide triphosphatases in vertebrates, invertebrates, and plants, suggesting that these genes also encode proteins with ecto-nucleotidase activity. Isolation and sequencing of full-length cDNA clones for each gene identified putative proteins of 485, 529, and 429 amino acids. The expression pattern of all five human members of the gene family was analyzed. CD39L2, CD39L3, and CD39L4 were mapped on the human genome, and the murine homologues identified with the putative map locations were assigned on the basis of regions of conserved gene order between human and mouse chromosomes. The map location of mcd39l4 places the gene within a region associated with audiogenic seizure susceptibility in mouse. This disorder is characterized by convulsions induced by loud high-frequency sound and has been shown to be associated with increased nucleotide triphosphatase activity.\n" ], "offsets": [ [ 0, 1597 ] ] } ]

[ { "id": "PMID-9676430_T1", "type": "Gene_or_gene_product", "text": [ "CD39" ], "offsets": [ [ 4, 8 ] ], "normalized": [] }, { "id": "PMID-9676430_T2", "type": "Gene_or_gene_product", "text": [ "CD39L2" ], "offsets": [ [ 70, 76 ] ], "normalized": [] }, { "id": "PMID-9676430_T3", "type": "Gene_or_gene_product", "text": [ "CD39L3" ], "offsets": [ [ 78, 84 ] ], "normalized": [] }, { "id": "PMID-9676430_T4", "type": "Gene_or_gene_product", "text": [ "CD39L4" ], "offsets": [ [ 90, 96 ] ], "normalized": [] }, { "id": "PMID-9676430_T5", "type": "Gene_or_gene_product", "text": [ "CD39" ], "offsets": [ [ 230, 234 ] ], "normalized": [] }, { "id": "PMID-9676430_T6", "type": "Gene_or_gene_product", "text": [ "E-type apyrase" ], "offsets": [ [ 246, 260 ] ], "normalized": [] }, { "id": "PMID-9676430_T7", "type": "Cellular_component", "text": [ "extracellular" ], "offsets": [ [ 277, 290 ] ], "normalized": [] }, { "id": "PMID-9676430_T8", "type": "Simple_chemical", "text": [ "ATP" ], "offsets": [ [ 291, 294 ] ], "normalized": [] }, { "id": "PMID-9676430_T9", "type": "Simple_chemical", "text": [ "ADP" ], "offsets": [ [ 299, 302 ] ], "normalized": [] }, { "id": "PMID-9676430_T10", "type": "Simple_chemical", "text": [ "ATP" ], "offsets": [ [ 430, 433 ] ], "normalized": [] }, { "id": "PMID-9676430_T11", "type": "Gene_or_gene_product", "text": [ "CD39L1" ], "offsets": [ [ 485, 491 ] ], "normalized": [] }, { "id": "PMID-9676430_T12", "type": "Gene_or_gene_product", "text": [ "E-type ecto-ATPase" ], "offsets": [ [ 515, 533 ] ], "normalized": [] }, { "id": "PMID-9676430_T13", "type": "Cellular_component", "text": [ "extracellular" ], "offsets": [ [ 559, 572 ] ], "normalized": [] }, { "id": "PMID-9676430_T14", "type": "Simple_chemical", "text": [ "ATP" ], "offsets": [ [ 573, 576 ] ], "normalized": [] }, { "id": "PMID-9676430_T15", "type": "Gene_or_gene_product", "text": [ "CD39" ], "offsets": [ [ 612, 616 ] ], "normalized": [] }, { "id": "PMID-9676430_T16", "type": "Gene_or_gene_product", "text": [ "CD39L2" ], "offsets": [ [ 635, 641 ] ], "normalized": [] }, { "id": "PMID-9676430_T17", "type": "Gene_or_gene_product", "text": [ "CD39L3" ], "offsets": [ [ 643, 649 ] ], "normalized": [] }, { "id": "PMID-9676430_T18", "type": "Gene_or_gene_product", "text": [ "CD39L4" ], "offsets": [ [ 655, 661 ] ], "normalized": [] }, { "id": "PMID-9676430_T19", "type": "Gene_or_gene_product", "text": [ "nucleotide triphosphatases" ], "offsets": [ [ 716, 742 ] ], "normalized": [] }, { "id": "PMID-9676430_T20", "type": "Gene_or_gene_product", "text": [ "ecto-nucleotidase" ], "offsets": [ [ 840, 857 ] ], "normalized": [] }, { "id": "PMID-9676430_T21", "type": "Gene_or_gene_product", "text": [ "CD39L2" ], "offsets": [ [ 1079, 1085 ] ], "normalized": [] }, { "id": "PMID-9676430_T22", "type": "Gene_or_gene_product", "text": [ "CD39L3" ], "offsets": [ [ 1087, 1093 ] ], "normalized": [] }, { "id": "PMID-9676430_T23", "type": "Gene_or_gene_product", "text": [ "CD39L4" ], "offsets": [ [ 1099, 1105 ] ], "normalized": [] }, { "id": "PMID-9676430_T24", "type": "Cellular_component", "text": [ "chromosomes" ], "offsets": [ [ 1294, 1305 ] ], "normalized": [] }, { "id": "PMID-9676430_T25", "type": "Gene_or_gene_product", "text": [ "nucleotide triphosphatase" ], "offsets": [ [ 1561, 1586 ] ], "normalized": [] } ]

[ { "id": "PMID-9676430_E1", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 266, 276 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9676430_T8" } ] }, { "id": "PMID-9676430_E2", "type": "Positive_regulation", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 266, 276 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9676430_T6" }, { "role": "Theme", "ref_id": "PMID-9676430_E1" } ] }, { "id": "PMID-9676430_E3", "type": "Conversion", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 266, 276 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9676430_T9" } ] }, { "id": "PMID-9676430_E4", "type": "Positive_regulation", "trigger": { "text": [ "hydrolyzes" ], "offsets": [ [ 266, 276 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9676430_T6" }, { "role": "Theme", "ref_id": "PMID-9676430_E3" } ] }, { "id": "PMID-9676430_E5", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 420, 426 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9676430_T10" } ] }, { "id": "PMID-9676430_E6", "type": "Conversion", "trigger": { "text": [ "hydrolyzing" ], "offsets": [ [ 547, 558 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9676430_T14" } ] }, { "id": "PMID-9676430_E7", "type": "Regulation", "trigger": { "text": [ "associated" ], "offsets": [ [ 1535, 1545 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9676430_T25" } ] }, { "id": "PMID-9676430_E8", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1551, 1560 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9676430_T25" } ] } ]

[]

[]

[ { "id": "PMID-9733515__text", "type": "abstract", "text": [ "Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. \nThe p53 tumor suppressor protein is activated and phosphorylated on serine-15 in response to various DNA damaging agents. The gene product mutated in ataxia telangiectasia, ATM, acts upstream of p53 in a signal transduction pathway initiated by ionizing radiation. Immunoprecipitated ATM had intrinsic protein kinase activity and phosphorylated p53 on serine-15 in a manganese-dependent manner. Ionizing radiation, but not ultraviolet radiation, rapidly enhanced this p53-directed kinase activity of endogenous ATM. These observations, along with the fact that phosphorylation of p53 on serine-15 in response to ionizing radiation is reduced in ataxia telangiectasia cells, suggest that ATM is a protein kinase that phosphorylates p53 in vivo.\n" ], "offsets": [ [ 0, 824 ] ] } ]

[ { "id": "PMID-9733515_T1", "type": "Gene_or_gene_product", "text": [ "ATM" ], "offsets": [ [ 18, 21 ] ], "normalized": [] }, { "id": "PMID-9733515_T2", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 74, 77 ] ], "normalized": [] }, { "id": "PMID-9733515_T3", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 84, 87 ] ], "normalized": [] }, { "id": "PMID-9733515_T4", "type": "Simple_chemical", "text": [ "serine-15" ], "offsets": [ [ 148, 157 ] ], "normalized": [] }, { "id": "PMID-9733515_T5", "type": "Gene_or_gene_product", "text": [ "mutated in ataxia telangiectasia" ], "offsets": [ [ 219, 251 ] ], "normalized": [] }, { "id": "PMID-9733515_T6", "type": "Gene_or_gene_product", "text": [ "ATM" ], "offsets": [ [ 253, 256 ] ], "normalized": [] }, { "id": "PMID-9733515_T7", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 275, 278 ] ], "normalized": [] }, { "id": "PMID-9733515_T8", "type": "Gene_or_gene_product", "text": [ "ATM" ], "offsets": [ [ 364, 367 ] ], "normalized": [] }, { "id": "PMID-9733515_T9", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 425, 428 ] ], "normalized": [] }, { "id": "PMID-9733515_T10", "type": "Simple_chemical", "text": [ "serine-15" ], "offsets": [ [ 432, 441 ] ], "normalized": [] }, { "id": "PMID-9733515_T11", "type": "Simple_chemical", "text": [ "manganese" ], "offsets": [ [ 447, 456 ] ], "normalized": [] }, { "id": "PMID-9733515_T12", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 548, 551 ] ], "normalized": [] }, { "id": "PMID-9733515_T13", "type": "Gene_or_gene_product", "text": [ "ATM" ], "offsets": [ [ 591, 594 ] ], "normalized": [] }, { "id": "PMID-9733515_T14", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 660, 663 ] ], "normalized": [] }, { "id": "PMID-9733515_T15", "type": "Simple_chemical", "text": [ "serine-15" ], "offsets": [ [ 667, 676 ] ], "normalized": [] }, { "id": "PMID-9733515_T16", "type": "Gene_or_gene_product", "text": [ "ATM" ], "offsets": [ [ 767, 770 ] ], "normalized": [] }, { "id": "PMID-9733515_T17", "type": "Gene_or_gene_product", "text": [ "p53" ], "offsets": [ [ 811, 814 ] ], "normalized": [] } ]

[ { "id": "PMID-9733515_E1", "type": "Activation", "trigger": { "text": [ "Activation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9733515_T1" } ] }, { "id": "PMID-9733515_E2", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 55, 70 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9733515_T2" }, { "role": "Cause", "ref_id": "PMID-9733515_T1" } ] }, { "id": "PMID-9733515_E3", "type": "Activation", "trigger": { "text": [ "activated" ], "offsets": [ [ 116, 125 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9733515_T3" } ] }, { "id": "PMID-9733515_E4", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 130, 144 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9733515_T3" }, { "role": "Site", "ref_id": "PMID-9733515_T4" } ] }, { "id": "PMID-9733515_E5", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 410, 424 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9733515_T8" }, { "role": "Theme", "ref_id": "PMID-9733515_T9" }, { "role": "Site", "ref_id": "PMID-9733515_T10" } ] }, { "id": "PMID-9733515_E6", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 457, 466 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9733515_T11" }, { "role": "Theme", "ref_id": "PMID-9733515_E5" } ] }, { "id": "PMID-9733515_E7", "type": "Positive_regulation", "trigger": { "text": [ "enhanced" ], "offsets": [ [ 534, 542 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9733515_T13" } ] }, { "id": "PMID-9733515_E8", "type": "Positive_regulation", "trigger": { "text": [ "directed" ], "offsets": [ [ 552, 560 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9733515_T12" }, { "role": "Theme", "ref_id": "PMID-9733515_T13" } ] }, { "id": "PMID-9733515_E9", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 641, 656 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9733515_T14" }, { "role": "Site", "ref_id": "PMID-9733515_T15" } ] }, { "id": "PMID-9733515_E10", "type": "Positive_regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 680, 688 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9733515_E9" } ] }, { "id": "PMID-9733515_E11", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 714, 721 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9733515_E9" } ] }, { "id": "PMID-9733515_E12", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylates" ], "offsets": [ [ 796, 810 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9733515_T16" }, { "role": "Theme", "ref_id": "PMID-9733515_T17" } ] } ]

[ { "id": "PMID-9733515_1", "entity_ids": [ "PMID-9733515_T5", "PMID-9733515_T6" ] } ]

[]

[ { "id": "PMID-9736735__text", "type": "abstract", "text": [ "Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21(CIP1/WAF1) and cyclin D proteins. \nDeregulation of cell proliferation is a hallmark of cancer. In many transformed cells, the cyclin A/CDK2 complex that contains S-phase kinase associated proteins 1 and 2 (SKP1 and SKP2) is highly induced. To determine the roles of this complex in the cell cycle regulation and transformation, we have examined the composition of this complex. We report here that this complex contained an additional protein, human CUL-1, a member of the cullin/CDC53 family. The identification of CUL-1 as a member of the complex raises the possibility that the p19(SKP1)/p45(SKP2)/CUL-1 complex may function as the yeast SKP1-CDC53-F-box (SCF) protein complex that acts as a ubiquitin E3 ligase to regulate the G1/S transition. In mammalian cells, cyclin D, p21(CIP1/WAF1), and p27(KIP1) are short-lived proteins that are controlled by ubiquitin-dependent proteolysis. To determine the potential in vivo targets of the p19(SKP1)/p45(SKP2)/CUL-1 complex, we have used the specific antisense oligodeoxynucleotides against either SKP1, SKP2, or CUL-1 RNA to inhibit their expression. Treatment of cells with these oligonucleotides caused the selective accumulation of p21 and cyclin D proteins. The protein level of p27 was not affected. These data suggest that the human p19(SKP1)/p45(SKP2)/CUL-1 complex is likely to function as an E3 ligase to selectively target cyclin D and p21 for the ubiquitin-dependent protein degradation. Aberrant expression of human p19(SKP1)/p45(SKP2)/CUL-1 complex thus may contribute to tumorigenesis by regulating the protein levels of G1 cell cycle regulators.\n" ], "offsets": [ [ 0, 1679 ] ] } ]

[ { "id": "PMID-9736735_T1", "type": "Gene_or_gene_product", "text": [ "CUL-1" ], "offsets": [ [ 6, 11 ] ], "normalized": [] }, { "id": "PMID-9736735_T2", "type": "Complex", "text": [ "SKP1/SKP2" ], "offsets": [ [ 32, 41 ] ], "normalized": [] }, { "id": "PMID-9736735_T3", "type": "Gene_or_gene_product", "text": [ "p21" ], "offsets": [ [ 64, 67 ] ], "normalized": [] }, { "id": "PMID-9736735_T4", "type": "Gene_or_gene_product", "text": [ "CIP1" ], "offsets": [ [ 68, 72 ] ], "normalized": [] }, { "id": "PMID-9736735_T5", "type": "Gene_or_gene_product", "text": [ "WAF1" ], "offsets": [ [ 73, 77 ] ], "normalized": [] }, { "id": "PMID-9736735_T6", "type": "Gene_or_gene_product", "text": [ "cyclin D" ], "offsets": [ [ 83, 91 ] ], "normalized": [] }, { "id": "PMID-9736735_T7", "type": "Complex", "text": [ "cyclin A/CDK2" ], "offsets": [ [ 194, 207 ] ], "normalized": [] }, { "id": "PMID-9736735_T8", "type": "Gene_or_gene_product", "text": [ "S-phase kinase associated proteins 1" ], "offsets": [ [ 230, 266 ] ], "normalized": [] }, { "id": "PMID-9736735_T9", "type": "Gene_or_gene_product", "text": [ "2" ], "offsets": [ [ 271, 272 ] ], "normalized": [] }, { "id": "PMID-9736735_T10", "type": "Gene_or_gene_product", "text": [ "SKP1" ], "offsets": [ [ 274, 278 ] ], "normalized": [] }, { "id": "PMID-9736735_T11", "type": "Gene_or_gene_product", "text": [ "SKP2" ], "offsets": [ [ 283, 287 ] ], "normalized": [] }, { "id": "PMID-9736735_T12", "type": "Gene_or_gene_product", "text": [ "CUL-1" ], "offsets": [ [ 518, 523 ] ], "normalized": [] }, { "id": "PMID-9736735_T13", "type": "Gene_or_gene_product", "text": [ "cullin" ], "offsets": [ [ 541, 547 ] ], "normalized": [] }, { "id": "PMID-9736735_T14", "type": "Gene_or_gene_product", "text": [ "CDC53" ], "offsets": [ [ 548, 553 ] ], "normalized": [] }, { "id": "PMID-9736735_T15", "type": "Gene_or_gene_product", "text": [ "CUL-1" ], "offsets": [ [ 584, 589 ] ], "normalized": [] }, { "id": "PMID-9736735_T16", "type": "Complex", "text": [ "p19(SKP1)/p45(SKP2)/CUL-1" ], "offsets": [ [ 649, 674 ] ], "normalized": [] }, { "id": "PMID-9736735_T17", "type": "Complex", "text": [ "SKP1-CDC53-F-box" ], "offsets": [ [ 709, 725 ] ], "normalized": [] }, { "id": "PMID-9736735_T18", "type": "Complex", "text": [ "SCF" ], "offsets": [ [ 727, 730 ] ], "normalized": [] }, { "id": "PMID-9736735_T19", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 763, 772 ] ], "normalized": [] }, { "id": "PMID-9736735_T20", "type": "Gene_or_gene_product", "text": [ "cyclin D" ], "offsets": [ [ 836, 844 ] ], "normalized": [] }, { "id": "PMID-9736735_T21", "type": "Gene_or_gene_product", "text": [ "p21" ], "offsets": [ [ 846, 849 ] ], "normalized": [] }, { "id": "PMID-9736735_T22", "type": "Gene_or_gene_product", "text": [ "CIP1" ], "offsets": [ [ 850, 854 ] ], "normalized": [] }, { "id": "PMID-9736735_T23", "type": "Gene_or_gene_product", "text": [ "WAF1" ], "offsets": [ [ 855, 859 ] ], "normalized": [] }, { "id": "PMID-9736735_T24", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 866, 869 ] ], "normalized": [] }, { "id": "PMID-9736735_T25", "type": "Gene_or_gene_product", "text": [ "KIP1" ], "offsets": [ [ 870, 874 ] ], "normalized": [] }, { "id": "PMID-9736735_T26", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 924, 933 ] ], "normalized": [] }, { "id": "PMID-9736735_T27", "type": "Complex", "text": [ "p19(SKP1)/p45(SKP2)/CUL-1" ], "offsets": [ [ 1007, 1032 ] ], "normalized": [] }, { "id": "PMID-9736735_T28", "type": "Gene_or_gene_product", "text": [ "SKP1" ], "offsets": [ [ 1115, 1119 ] ], "normalized": [] }, { "id": "PMID-9736735_T29", "type": "Gene_or_gene_product", "text": [ "SKP2" ], "offsets": [ [ 1121, 1125 ] ], "normalized": [] }, { "id": "PMID-9736735_T30", "type": "Gene_or_gene_product", "text": [ "CUL-1" ], "offsets": [ [ 1130, 1135 ] ], "normalized": [] }, { "id": "PMID-9736735_T31", "type": "Gene_or_gene_product", "text": [ "p21" ], "offsets": [ [ 1253, 1256 ] ], "normalized": [] }, { "id": "PMID-9736735_T32", "type": "Gene_or_gene_product", "text": [ "cyclin D" ], "offsets": [ [ 1261, 1269 ] ], "normalized": [] }, { "id": "PMID-9736735_T33", "type": "Gene_or_gene_product", "text": [ "p27" ], "offsets": [ [ 1301, 1304 ] ], "normalized": [] }, { "id": "PMID-9736735_T34", "type": "Complex", "text": [ "p19(SKP1)/p45(SKP2)/CUL-1" ], "offsets": [ [ 1357, 1382 ] ], "normalized": [] }, { "id": "PMID-9736735_T35", "type": "Gene_or_gene_product", "text": [ "cyclin D" ], "offsets": [ [ 1451, 1459 ] ], "normalized": [] }, { "id": "PMID-9736735_T36", "type": "Gene_or_gene_product", "text": [ "p21" ], "offsets": [ [ 1464, 1467 ] ], "normalized": [] }, { "id": "PMID-9736735_T37", "type": "Gene_or_gene_product", "text": [ "ubiquitin" ], "offsets": [ [ 1476, 1485 ] ], "normalized": [] }, { "id": "PMID-9736735_T38", "type": "Complex", "text": [ "p19(SKP1)/p45(SKP2)/CUL-1" ], "offsets": [ [ 1546, 1571 ] ], "normalized": [] } ]

[ { "id": "PMID-9736735_E1", "type": "Binding", "trigger": { "text": [ "associates" ], "offsets": [ [ 12, 22 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T1" }, { "role": "Theme", "ref_id": "PMID-9736735_T2" } ] }, { "id": "PMID-9736735_E2", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 54, 63 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9736735_T1" }, { "role": "Theme", "ref_id": "PMID-9736735_T3" } ] }, { "id": "PMID-9736735_E3", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 54, 63 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9736735_T1" }, { "role": "Theme", "ref_id": "PMID-9736735_T6" } ] }, { "id": "PMID-9736735_E4", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 299, 306 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T8" } ] }, { "id": "PMID-9736735_E5", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 299, 306 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T9" } ] }, { "id": "PMID-9736735_E6", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 910, 920 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T20" }, { "role": "Cause", "ref_id": "PMID-9736735_E12" } ] }, { "id": "PMID-9736735_E7", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 910, 920 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T21" }, { "role": "Cause", "ref_id": "PMID-9736735_E13" } ] }, { "id": "PMID-9736735_E8", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 910, 920 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T24" }, { "role": "Cause", "ref_id": "PMID-9736735_E14" } ] }, { "id": "PMID-9736735_E9", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 934, 943 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9736735_T26" }, { "role": "Theme", "ref_id": "PMID-9736735_E12" } ] }, { "id": "PMID-9736735_E10", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 934, 943 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9736735_T26" }, { "role": "Theme", "ref_id": "PMID-9736735_E13" } ] }, { "id": "PMID-9736735_E11", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 934, 943 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9736735_T26" }, { "role": "Theme", "ref_id": "PMID-9736735_E14" } ] }, { "id": "PMID-9736735_E12", "type": "Degradation", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 944, 955 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T20" } ] }, { "id": "PMID-9736735_E13", "type": "Degradation", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 944, 955 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T21" } ] }, { "id": "PMID-9736735_E14", "type": "Degradation", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 944, 955 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T24" } ] }, { "id": "PMID-9736735_E15", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1143, 1150 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_E18" } ] }, { "id": "PMID-9736735_E16", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1143, 1150 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_E19" } ] }, { "id": "PMID-9736735_E17", "type": "Negative_regulation", "trigger": { "text": [ "inhibit" ], "offsets": [ [ 1143, 1150 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_E20" } ] }, { "id": "PMID-9736735_E18", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1157, 1167 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T28" } ] }, { "id": "PMID-9736735_E19", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1157, 1167 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T29" } ] }, { "id": "PMID-9736735_E20", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1157, 1167 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T30" } ] }, { "id": "PMID-9736735_E21", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 1216, 1222 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_E23" } ] }, { "id": "PMID-9736735_E22", "type": "Positive_regulation", "trigger": { "text": [ "caused" ], "offsets": [ [ 1216, 1222 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_E24" } ] }, { "id": "PMID-9736735_E23", "type": "Positive_regulation", "trigger": { "text": [ "accumulation" ], "offsets": [ [ 1237, 1249 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T31" } ] }, { "id": "PMID-9736735_E24", "type": "Positive_regulation", "trigger": { "text": [ "accumulation" ], "offsets": [ [ 1237, 1249 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T32" } ] }, { "id": "PMID-9736735_E25", "type": "Regulation", "trigger": { "text": [ "affected" ], "offsets": [ [ 1313, 1321 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T33" } ] }, { "id": "PMID-9736735_E26", "type": "Positive_regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 1444, 1450 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9736735_T34" }, { "role": "Theme", "ref_id": "PMID-9736735_E30" } ] }, { "id": "PMID-9736735_E27", "type": "Positive_regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 1444, 1450 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9736735_T34" }, { "role": "Theme", "ref_id": "PMID-9736735_E31" } ] }, { "id": "PMID-9736735_E28", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1486, 1495 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9736735_T37" }, { "role": "Theme", "ref_id": "PMID-9736735_E30" } ] }, { "id": "PMID-9736735_E29", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1486, 1495 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9736735_T37" }, { "role": "Theme", "ref_id": "PMID-9736735_E31" } ] }, { "id": "PMID-9736735_E30", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1504, 1515 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T35" } ] }, { "id": "PMID-9736735_E31", "type": "Degradation", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1504, 1515 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9736735_T36" } ] } ]

[ { "id": "PMID-9736735_1", "entity_ids": [ "PMID-9736735_T3", "PMID-9736735_T4", "PMID-9736735_T5" ] }, { "id": "PMID-9736735_2", "entity_ids": [ "PMID-9736735_T8", "PMID-9736735_T10" ] }, { "id": "PMID-9736735_3", "entity_ids": [ "PMID-9736735_T9", "PMID-9736735_T11" ] }, { "id": "PMID-9736735_4", "entity_ids": [ "PMID-9736735_T13", "PMID-9736735_T14" ] }, { "id": "PMID-9736735_5", "entity_ids": [ "PMID-9736735_T17", "PMID-9736735_T18" ] }, { "id": "PMID-9736735_6", "entity_ids": [ "PMID-9736735_T21", "PMID-9736735_T22", "PMID-9736735_T23" ] }, { "id": "PMID-9736735_7", "entity_ids": [ "PMID-9736735_T24", "PMID-9736735_T25" ] } ]

[]

[ { "id": "PMID-9768359__text", "type": "abstract", "text": [ "Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. \nBACKGROUND: Mitogen-activated protein (MAP) kinases (or extracellular signal regulated kinases; Erks) and stress-activated protein (SAP) kinases mediate cellular responses to a wide variety of signals. In the Erk MAP kinase pathway, activation of MAP kinases takes place in the cytoplasm and the activated enzyme moves to the nucleus. This translocation to the nucleus is essential to MAP kinase signalling because it enables the kinase to phosphorylate transcription factors. Whether components of the pathway mediated by the SAP kinase p38 change their cellular location on activation is not clear; we have therefore studied the cellular localisation of components of this pathway before and after stimulation. RESULTS: The p38 SAP kinase substrate MAP-kinase-activated protein kinase-2 (MAPKAP kinase-2) contains a putative nuclear localisation signal which we show is functional and required for activation by a variety of stimuli. Following phosphorylation of MAPKAP kinase-2, nuclear p38 was exported to the cytoplasm in a complex with MAPKAP kinase-2. Export of MAPKAP kinase-2 required phosphorylation by p38 but did not appear to require the kinase activity of MAPKAP kinase-2. The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the nucleus. CONCLUSIONS: In the p38 SAP kinase pathway, MAPKAP kinase-2 serves both as an effector of p38 by phosphorylating substrates and as a determinant of cellular localisation of p38. Nuclear export of p38 and MAPKAP kinase-2 may permit them to phosphorylate substrates in the cytoplasm.\n" ], "offsets": [ [ 0, 1713 ] ] } ]

[ { "id": "PMID-9768359_T1", "type": "Cellular_component", "text": [ "Nuclear" ], "offsets": [ [ 0, 7 ] ], "normalized": [] }, { "id": "PMID-9768359_T2", "type": "Gene_or_gene_product", "text": [ "stress-activated protein kinase" ], "offsets": [ [ 22, 53 ] ], "normalized": [] }, { "id": "PMID-9768359_T3", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 54, 57 ] ], "normalized": [] }, { "id": "PMID-9768359_T4", "type": "Gene_or_gene_product", "text": [ "MAPKAP kinase-2" ], "offsets": [ [ 84, 99 ] ], "normalized": [] }, { "id": "PMID-9768359_T5", "type": "Gene_or_gene_product", "text": [ "Mitogen-activated protein (MAP) kinases" ], "offsets": [ [ 114, 153 ] ], "normalized": [] }, { "id": "PMID-9768359_T6", "type": "Gene_or_gene_product", "text": [ "extracellular signal regulated kinases" ], "offsets": [ [ 158, 196 ] ], "normalized": [] }, { "id": "PMID-9768359_T7", "type": "Gene_or_gene_product", "text": [ "Erks" ], "offsets": [ [ 198, 202 ] ], "normalized": [] }, { "id": "PMID-9768359_T8", "type": "Gene_or_gene_product", "text": [ "stress-activated protein (SAP) kinases" ], "offsets": [ [ 208, 246 ] ], "normalized": [] }, { "id": "PMID-9768359_T9", "type": "Gene_or_gene_product", "text": [ "Erk" ], "offsets": [ [ 311, 314 ] ], "normalized": [] }, { "id": "PMID-9768359_T10", "type": "Gene_or_gene_product", "text": [ "MAP kinase" ], "offsets": [ [ 315, 325 ] ], "normalized": [] }, { "id": "PMID-9768359_T11", "type": "Gene_or_gene_product", "text": [ "MAP kinases" ], "offsets": [ [ 349, 360 ] ], "normalized": [] }, { "id": "PMID-9768359_T12", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 380, 389 ] ], "normalized": [] }, { "id": "PMID-9768359_T13", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 428, 435 ] ], "normalized": [] }, { "id": "PMID-9768359_T14", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 463, 470 ] ], "normalized": [] }, { "id": "PMID-9768359_T15", "type": "Gene_or_gene_product", "text": [ "MAP kinase" ], "offsets": [ [ 487, 497 ] ], "normalized": [] }, { "id": "PMID-9768359_T16", "type": "Gene_or_gene_product", "text": [ "SAP kinase p38" ], "offsets": [ [ 629, 643 ] ], "normalized": [] }, { "id": "PMID-9768359_T17", "type": "Gene_or_gene_product", "text": [ "p38 SAP kinase" ], "offsets": [ [ 828, 842 ] ], "normalized": [] }, { "id": "PMID-9768359_T18", "type": "Gene_or_gene_product", "text": [ "MAP-kinase-activated protein kinase-2" ], "offsets": [ [ 853, 890 ] ], "normalized": [] }, { "id": "PMID-9768359_T19", "type": "Gene_or_gene_product", "text": [ "MAPKAP kinase-2" ], "offsets": [ [ 892, 907 ] ], "normalized": [] }, { "id": "PMID-9768359_T20", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 929, 936 ] ], "normalized": [] }, { "id": "PMID-9768359_T21", "type": "Gene_or_gene_product", "text": [ "MAPKAP kinase-2" ], "offsets": [ [ 1067, 1082 ] ], "normalized": [] }, { "id": "PMID-9768359_T22", "type": "Cellular_component", "text": [ "nuclear" ], "offsets": [ [ 1084, 1091 ] ], "normalized": [] }, { "id": "PMID-9768359_T23", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1092, 1095 ] ], "normalized": [] }, { "id": "PMID-9768359_T24", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 1116, 1125 ] ], "normalized": [] }, { "id": "PMID-9768359_T25", "type": "Gene_or_gene_product", "text": [ "MAPKAP kinase-2" ], "offsets": [ [ 1144, 1159 ] ], "normalized": [] }, { "id": "PMID-9768359_T26", "type": "Gene_or_gene_product", "text": [ "MAPKAP kinase-2" ], "offsets": [ [ 1171, 1186 ] ], "normalized": [] }, { "id": "PMID-9768359_T27", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1215, 1218 ] ], "normalized": [] }, { "id": "PMID-9768359_T28", "type": "Gene_or_gene_product", "text": [ "MAPKAP kinase-2" ], "offsets": [ [ 1272, 1287 ] ], "normalized": [] }, { "id": "PMID-9768359_T29", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1293, 1296 ] ], "normalized": [] }, { "id": "PMID-9768359_T30", "type": "Gene_or_gene_product", "text": [ "MKK3" ], "offsets": [ [ 1308, 1312 ] ], "normalized": [] }, { "id": "PMID-9768359_T31", "type": "Gene_or_gene_product", "text": [ "MKK6" ], "offsets": [ [ 1317, 1321 ] ], "normalized": [] }, { "id": "PMID-9768359_T32", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 1347, 1354 ] ], "normalized": [] }, { "id": "PMID-9768359_T33", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 1363, 1372 ] ], "normalized": [] }, { "id": "PMID-9768359_T34", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1411, 1414 ] ], "normalized": [] }, { "id": "PMID-9768359_T35", "type": "Cellular_component", "text": [ "nucleus" ], "offsets": [ [ 1422, 1429 ] ], "normalized": [] }, { "id": "PMID-9768359_T36", "type": "Gene_or_gene_product", "text": [ "p38 SAP kinase" ], "offsets": [ [ 1451, 1465 ] ], "normalized": [] }, { "id": "PMID-9768359_T37", "type": "Gene_or_gene_product", "text": [ "MAPKAP kinase-2" ], "offsets": [ [ 1475, 1490 ] ], "normalized": [] }, { "id": "PMID-9768359_T38", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1521, 1524 ] ], "normalized": [] }, { "id": "PMID-9768359_T39", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1604, 1607 ] ], "normalized": [] }, { "id": "PMID-9768359_T40", "type": "Cellular_component", "text": [ "Nuclear" ], "offsets": [ [ 1609, 1616 ] ], "normalized": [] }, { "id": "PMID-9768359_T41", "type": "Gene_or_gene_product", "text": [ "p38" ], "offsets": [ [ 1627, 1630 ] ], "normalized": [] }, { "id": "PMID-9768359_T42", "type": "Gene_or_gene_product", "text": [ "MAPKAP kinase-2" ], "offsets": [ [ 1635, 1650 ] ], "normalized": [] }, { "id": "PMID-9768359_T43", "type": "Cellular_component", "text": [ "cytoplasm" ], "offsets": [ [ 1702, 1711 ] ], "normalized": [] } ]

[ { "id": "PMID-9768359_E1", "type": "Transport", "trigger": { "text": [ "export" ], "offsets": [ [ 8, 14 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-9768359_T1" }, { "role": "Theme", "ref_id": "PMID-9768359_T2" } ] }, { "id": "PMID-9768359_E2", "type": "Transport", "trigger": { "text": [ "export" ], "offsets": [ [ 8, 14 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-9768359_T1" }, { "role": "Theme", "ref_id": "PMID-9768359_T3" } ] }, { "id": "PMID-9768359_E3", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 58, 66 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9768359_T4" }, { "role": "Theme", "ref_id": "PMID-9768359_E1" } ] }, { "id": "PMID-9768359_E4", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 58, 66 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9768359_T4" }, { "role": "Theme", "ref_id": "PMID-9768359_E2" } ] }, { "id": "PMID-9768359_E5", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 326, 333 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-9768359_T9" }, { "role": "Participant", "ref_id": "PMID-9768359_T10" } ] }, { "id": "PMID-9768359_E6", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 335, 345 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T11" } ] }, { "id": "PMID-9768359_E7", "type": "Transport", "trigger": { "text": [ "moves" ], "offsets": [ [ 415, 420 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T11" }, { "role": "ToLoc", "ref_id": "PMID-9768359_T13" }, { "role": "FromLoc", "ref_id": "PMID-9768359_T12" } ] }, { "id": "PMID-9768359_E8", "type": "Transport", "trigger": { "text": [ "translocation" ], "offsets": [ [ 442, 455 ] ] }, "arguments": [ { "role": "ToLoc", "ref_id": "PMID-9768359_T14" }, { "role": "Theme", "ref_id": "PMID-9768359_T11" } ] }, { "id": "PMID-9768359_E9", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 474, 483 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_E10" }, { "role": "Cause", "ref_id": "PMID-9768359_E8" } ] }, { "id": "PMID-9768359_E10", "type": "Pathway", "trigger": { "text": [ "signalling" ], "offsets": [ [ 498, 508 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-9768359_T15" } ] }, { "id": "PMID-9768359_E11", "type": "Localization", "trigger": { "text": [ "localisation" ], "offsets": [ [ 937, 949 ] ] }, "arguments": [ { "role": "AtLoc", "ref_id": "PMID-9768359_T20" }, { "role": "Theme", "ref_id": "PMID-9768359_T19" } ] }, { "id": "PMID-9768359_E12", "type": "Regulation", "trigger": { "text": [ "signal" ], "offsets": [ [ 950, 956 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_E11" } ] }, { "id": "PMID-9768359_E13", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 989, 997 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_E14" }, { "role": "Cause", "ref_id": "PMID-9768359_E12" } ] }, { "id": "PMID-9768359_E14", "type": "Activation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1002, 1012 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T19" } ] }, { "id": "PMID-9768359_E15", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1048, 1063 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T21" } ] }, { "id": "PMID-9768359_E16", "type": "Transport", "trigger": { "text": [ "exported" ], "offsets": [ [ 1100, 1108 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T23" }, { "role": "ToLoc", "ref_id": "PMID-9768359_T24" }, { "role": "FromLoc", "ref_id": "PMID-9768359_T22" } ] }, { "id": "PMID-9768359_E17", "type": "Binding", "trigger": { "text": [ "complex" ], "offsets": [ [ 1131, 1138 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T23" }, { "role": "Theme", "ref_id": "PMID-9768359_T25" } ] }, { "id": "PMID-9768359_E18", "type": "Transport", "trigger": { "text": [ "Export" ], "offsets": [ [ 1161, 1167 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T26" } ] }, { "id": "PMID-9768359_E19", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1187, 1195 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_E18" }, { "role": "Cause", "ref_id": "PMID-9768359_E20" } ] }, { "id": "PMID-9768359_E20", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1196, 1211 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T26" }, { "role": "Cause", "ref_id": "PMID-9768359_T27" } ] }, { "id": "PMID-9768359_E21", "type": "Positive_regulation", "trigger": { "text": [ "require" ], "offsets": [ [ 1241, 1248 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_E18" } ] }, { "id": "PMID-9768359_E22", "type": "Activation", "trigger": { "text": [ "activators" ], "offsets": [ [ 1297, 1307 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T29" }, { "role": "Cause", "ref_id": "PMID-9768359_T30" } ] }, { "id": "PMID-9768359_E23", "type": "Activation", "trigger": { "text": [ "activators" ], "offsets": [ [ 1297, 1307 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T29" }, { "role": "Cause", "ref_id": "PMID-9768359_T31" } ] }, { "id": "PMID-9768359_E24", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1392, 1396 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_E26" }, { "role": "Cause", "ref_id": "PMID-9768359_T30" } ] }, { "id": "PMID-9768359_E25", "type": "Regulation", "trigger": { "text": [ "role" ], "offsets": [ [ 1392, 1396 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_E26" }, { "role": "Cause", "ref_id": "PMID-9768359_T31" } ] }, { "id": "PMID-9768359_E26", "type": "Activation", "trigger": { "text": [ "activating" ], "offsets": [ [ 1400, 1410 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T34" } ] }, { "id": "PMID-9768359_E27", "type": "Pathway", "trigger": { "text": [ "pathway" ], "offsets": [ [ 1466, 1473 ] ] }, "arguments": [ { "role": "Participant", "ref_id": "PMID-9768359_T36" } ] }, { "id": "PMID-9768359_E28", "type": "Regulation", "trigger": { "text": [ "effector" ], "offsets": [ [ 1509, 1517 ] ] }, "arguments": [ { "role": "Cause", "ref_id": "PMID-9768359_T37" }, { "role": "Theme", "ref_id": "PMID-9768359_T38" } ] }, { "id": "PMID-9768359_E29", "type": "Regulation", "trigger": { "text": [ "determinant" ], "offsets": [ [ 1564, 1575 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_E30" }, { "role": "Cause", "ref_id": "PMID-9768359_T37" } ] }, { "id": "PMID-9768359_E30", "type": "Localization", "trigger": { "text": [ "localisation" ], "offsets": [ [ 1588, 1600 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "PMID-9768359_T39" } ] }, { "id": "PMID-9768359_E31", "type": "Transport", "trigger": { "text": [ "export" ], "offsets": [ [ 1617, 1623 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-9768359_T40" }, { "role": "Theme", "ref_id": "PMID-9768359_T41" } ] }, { "id": "PMID-9768359_E32", "type": "Transport", "trigger": { "text": [ "export" ], "offsets": [ [ 1617, 1623 ] ] }, "arguments": [ { "role": "FromLoc", "ref_id": "PMID-9768359_T40" }, { "role": "Theme", "ref_id": "PMID-9768359_T42" } ] } ]

[ { "id": "PMID-9768359_1", "entity_ids": [ "PMID-9768359_T5", "PMID-9768359_T6", "PMID-9768359_T7" ] }, { "id": "PMID-9768359_2", "entity_ids": [ "PMID-9768359_T18", "PMID-9768359_T19" ] } ]

[]