Datasets:

bigbio

/

bionlp_shared_task_2009

like 2

[ { "id": "10102628__text", "type": "abstract", "text": [ "Expression of IkappaBalpha in the nucleus of human peripheral blood T lymphocytes. \nAccording to current models the inhibitory capacity of I(kappa)B(alpha) would be mediated through the retention of Rel/NF-kappaB proteins in the cytosol. However, I(kappa)B(alpha) has also been detected in the nucleus of cell lines and when overexpressed by transient transfection. To gain better insight into the potential role of nuclear I(kappa)B(alpha) in a physiological context we have analysed its presence in the nucleus of human peripheral blood T lymphocytes (PBL). We demonstrate the nuclear localization of I(kappa)B(alpha) in PBL by different techniques: Western blot, indirect immunofluorescence and electron microscopy. Low levels of nuclear I(kappa)B(alpha) were detected in resting cells whereas a superinduction was obtained after PMA activation. The nuclear pool of I(kappa)B(alpha) showed a higher stability than cytosolic I(kappa)B(alpha) and was partially independent of the resynthesis of the protein. Unexpectedly, the presence of nuclear I(kappa)B(alpha) did not inhibit NF-kappaB binding to DNA and this phenomenon was not due to the presence of IkappaBbeta at the nuclear level. Immunoprecipitation experiments failed to demonstrate an association between nuclear I(kappa)B(alpha) and NF-kappaB proteins. Our results demonstrate that in resting and PMA-activated human PBL, I(kappa)B(alpha) is present in the nucleus in an apparently inactive form unable to disrupt NF-kappaB binding from DNA. " ], "offsets": [ [ 0, 1505 ] ] } ]

[ { "id": "10102628_T1", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 14, 26 ] ], "normalized": [] }, { "id": "10102628_T2", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 139, 155 ] ], "normalized": [] }, { "id": "10102628_T3", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 247, 263 ] ], "normalized": [] }, { "id": "10102628_T4", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 424, 440 ] ], "normalized": [] }, { "id": "10102628_T5", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 603, 619 ] ], "normalized": [] }, { "id": "10102628_T6", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 741, 757 ] ], "normalized": [] }, { "id": "10102628_T7", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 869, 885 ] ], "normalized": [] }, { "id": "10102628_T8", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 927, 943 ] ], "normalized": [] }, { "id": "10102628_T9", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 1047, 1063 ] ], "normalized": [] }, { "id": "10102628_T10", "type": "Protein", "text": [ "IkappaBbeta" ], "offsets": [ [ 1156, 1167 ] ], "normalized": [] }, { "id": "10102628_T11", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 1275, 1291 ] ], "normalized": [] }, { "id": "10102628_T12", "type": "Protein", "text": [ "I(kappa)B(alpha)" ], "offsets": [ [ 1385, 1401 ] ], "normalized": [] }, { "id": "10102628_T19", "type": "Entity", "text": [ "nuclear" ], "offsets": [ [ 579, 586 ] ], "normalized": [] }, { "id": "10102628_T27", "type": "Entity", "text": [ "nuclear" ], "offsets": [ [ 1039, 1046 ] ], "normalized": [] }, { "id": "10102628_T30", "type": "Entity", "text": [ "nuclear" ], "offsets": [ [ 1175, 1182 ] ], "normalized": [] }, { "id": "10102628_T32", "type": "Entity", "text": [ "nucleus" ], "offsets": [ [ 1420, 1427 ] ], "normalized": [] } ]

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[ { "id": "8151786__text", "type": "abstract", "text": [ "Human immunodeficiency virus type 1 Nef protein down-regulates transcription factors NF-kappa B and AP-1 in human T cells in vitro after T-cell receptor stimulation. \nHuman immunodeficiency virus type 1 (HIV-1) negative factor (Nef) has been shown to down-regulate the transcription factors NF-kappa B and AP-1 in vitro. To define the mechanism of action of the Nef protein, the signal transduction pathways which may be affected in T cells by constitutive expression of the nef gene were examined. Stimulation of T cells with tumor necrosis factor, interleukin-1, or lipopolysaccharide resulted in the recruitment of transcriptional factors to a similar level whether or not the cells expressed the nef gene. On the other hand, stimulation of T cells by mitogens or antibodies to the T-cell receptor (TCR)-CD3 complex resulted in the down-regulation of transcriptional factors NF-kappa B and AP-1 in cells expressing the nef gene compared with cells not expressing the nef gene. Because the Nef protein does not affect the surface expression of the CD3-TCR complex, we conclude that the Nef protein down-regulates the transcriptional factors NF-kappa B and AP-1 in T cells in vitro through an effect on the TCR-dependent signal transduction pathway. " ], "offsets": [ [ 0, 1251 ] ] } ]

[ { "id": "8151786_T1", "type": "Protein", "text": [ "Nef" ], "offsets": [ [ 36, 39 ] ], "normalized": [] }, { "id": "8151786_T2", "type": "Protein", "text": [ "negative factor" ], "offsets": [ [ 211, 226 ] ], "normalized": [] }, { "id": "8151786_T3", "type": "Protein", "text": [ "Nef" ], "offsets": [ [ 228, 231 ] ], "normalized": [] }, { "id": "8151786_T4", "type": "Protein", "text": [ "Nef" ], "offsets": [ [ 362, 365 ] ], "normalized": [] }, { "id": "8151786_T5", "type": "Protein", "text": [ "nef" ], "offsets": [ [ 475, 478 ] ], "normalized": [] }, { "id": "8151786_T6", "type": "Protein", "text": [ "nef" ], "offsets": [ [ 922, 925 ] ], "normalized": [] }, { "id": "8151786_T7", "type": "Protein", "text": [ "Nef" ], "offsets": [ [ 992, 995 ] ], "normalized": [] }, { "id": "8151786_T8", "type": "Protein", "text": [ "Nef" ], "offsets": [ [ 1088, 1091 ] ], "normalized": [] } ]

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[ { "id": "8151786_1", "entity_ids": [ "8151786_T2", "8151786_T3" ] } ]

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[ { "id": "9840924__text", "type": "abstract", "text": [ "Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-kappaB. \nThe Tpl-2 kinase activates the nuclear factor of activated T cells (NFAT) and induces IL-2 expression in T-cell lines. Here we show that the activation of the IL-2 promoter by Tpl-2 is inhibited by mutant signaling molecules that inhibit the mitogen-activated protein kinase (MAPK) or the calcineurin/NFAT pathways and is promoted by combinations of signaling molecules that activate these pathways. We, therefore, conclude that signals generated by the convergence of the MAPK and the calcineurin/NFAT pathway are necessary and sufficient for the activation of the IL-2 promoter by Tpl-2. The activation of both the IL-2 promoter and an NFAT-driven minimal promoter were shown to depend on signals transduced by Raf1. However, it was only the IL-2 promoter whose activation by Tpl-2 was fully blocked by the dominant negative mutant MEK1S218/222A and the MEK1/MEK2 inhibitor PD098059. Since the activation of NFAT is MAPK-dependent these findings suggested that the activation of MAPK by Tpl-2 is either independent or only partially dependent on MEK1 and MEK2. In addition, they suggested that the activation of the IL-2 promoter is under the control of not only NFAT but also a second factor whose activation is MEK-dependent. Experiments in COS-1 and EL-4 cells confirmed both hypotheses and revealed that the second factor activated by Tpl-2 is NF-kappaB. While the activation of the IL-2 promoter and an NFAT-driven minimal promoter by Tpl-2 was fully blocked by the dominant negative mutant NFAT delta418, it was only partially blocked by the calcineurin inhibitor cyclosporin A suggesting that the Tpl-2-mediated NFAT activation is under the control of a combination of calcineurin-dependent and independent pathways. Both pathways were fully blocked by Bcl-2 or Bcl-X(L). " ], "offsets": [ [ 0, 1904 ] ] } ]

[ { "id": "9840924_T1", "type": "Protein", "text": [ "Tpl-2" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "9840924_T2", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 14, 18 ] ], "normalized": [] }, { "id": "9840924_T3", "type": "Protein", "text": [ "Tpl-2" ], "offsets": [ [ 127, 132 ] ], "normalized": [] }, { "id": "9840924_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 209, 213 ] ], "normalized": [] }, { "id": "9840924_T5", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 282, 286 ] ], "normalized": [] }, { "id": "9840924_T6", "type": "Protein", "text": [ "Tpl-2" ], "offsets": [ [ 299, 304 ] ], "normalized": [] }, { "id": "9840924_T7", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 689, 693 ] ], "normalized": [] }, { "id": "9840924_T8", "type": "Protein", "text": [ "Tpl-2" ], "offsets": [ [ 706, 711 ] ], "normalized": [] }, { "id": "9840924_T9", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 740, 744 ] ], "normalized": [] }, { "id": "9840924_T10", "type": "Protein", "text": [ "Raf1" ], "offsets": [ [ 836, 840 ] ], "normalized": [] }, { "id": "9840924_T11", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 867, 871 ] ], "normalized": [] }, { "id": "9840924_T12", "type": "Protein", "text": [ "Tpl-2" ], "offsets": [ [ 901, 906 ] ], "normalized": [] }, { "id": "9840924_T13", "type": "Protein", "text": [ "MEK1" ], "offsets": [ [ 979, 983 ] ], "normalized": [] }, { "id": "9840924_T14", "type": "Protein", "text": [ "MEK2" ], "offsets": [ [ 984, 988 ] ], "normalized": [] }, { "id": "9840924_T15", "type": "Protein", "text": [ "Tpl-2" ], "offsets": [ [ 1112, 1117 ] ], "normalized": [] }, { "id": "9840924_T16", "type": "Protein", "text": [ "MEK1" ], "offsets": [ [ 1171, 1175 ] ], "normalized": [] }, { "id": "9840924_T17", "type": "Protein", "text": [ "MEK2" ], "offsets": [ [ 1180, 1184 ] ], "normalized": [] }, { "id": "9840924_T18", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1241, 1245 ] ], "normalized": [] }, { "id": "9840924_T19", "type": "Protein", "text": [ "Tpl-2" ], "offsets": [ [ 1464, 1469 ] ], "normalized": [] }, { "id": "9840924_T20", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1512, 1516 ] ], "normalized": [] }, { "id": "9840924_T21", "type": "Protein", "text": [ "Tpl-2" ], "offsets": [ [ 1565, 1570 ] ], "normalized": [] }, { "id": "9840924_T22", "type": "Protein", "text": [ "Tpl-2" ], "offsets": [ [ 1729, 1734 ] ], "normalized": [] }, { "id": "9840924_T23", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1885, 1890 ] ], "normalized": [] }, { "id": "9840924_T24", "type": "Protein", "text": [ "Bcl-X(L)" ], "offsets": [ [ 1894, 1902 ] ], "normalized": [] }, { "id": "9840924_T30", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 287, 295 ] ], "normalized": [] }, { "id": "9840924_T35", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 694, 702 ] ], "normalized": [] }, { "id": "9840924_T37", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 745, 753 ] ], "normalized": [] }, { "id": "9840924_T39", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 872, 880 ] ], "normalized": [] }, { "id": "9840924_T44", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1246, 1254 ] ], "normalized": [] }, { "id": "9840924_T47", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1517, 1525 ] ], "normalized": [] } ]

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[ { "id": "8605359__text", "type": "abstract", "text": [ "Transactivation of the interleukin-1alpha promoter by human T-cell leukemia virus type I and type II Tax proteins. \nHuman T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of interleukin-1alpha (IL-1alpha). To analyze the mechanisms that lead to the expression of IL-1alpha in HTLV-I-infected cell lines, we studied regulatory regions of the human IL-1alpha promoter involved in activation of the IL-1alpha gene. IL-1alpha promoter constructs drive transcription of the chloramphenicol acetyltransferase (CAT) reporter gene in HTLV-I-positive MT-2 cells, which constitutively produce IL-1alpha. In a cotransfection assay, the Tax protein of both HTLV-I and HTLV-II specifically activated transcription from the IL-1alpha promoter in an uninfected Jurkat cell line. A mutant Tax protein deficient in transactivation of genes by the nuclear factor (NF)-kappaB pathway was unable to induce transcriptional activity of IL-1alpha promoter-CAT constructs, but was rescued by exogenous provision of p65/p50 NF-kappaB. We found that two IL-1alpha kappaB-like sites (positions -1,065 to -1,056 and +646 to +655) specifically formed a complex with NF-kappaB-containing nuclear extract from MT-2 cells and that NF-kappaB bound with higher affinity to the 3' NF-kappaB binding site than to the 5' NF-kappaB site. Moreover, deletion of either 5' or 3' NF-kappaB sites reduced IL-1alpha promoter activity in MT-2 cells and transactivation of the IL-1alpha promoter by exogenous NF-kappaB and Tax in Jurkat cells. These data suggest a general role for Tax induction of IL-1alpha gene transcription by the NF-kappaB pathway. Expression of IL-1alpha by HTLV-I productively infected cells may be important in the hypercalcemia, osteolytic bone lesions, neutrophilia, elevation of C-reactive protein, and fever frequently seen in patients with HTLV-I-induced adult T-cell leukemia/lymphoma. " ], "offsets": [ [ 0, 1917 ] ] } ]

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[ { "id": "10425206__text", "type": "abstract", "text": [ "PPARgamma activation induces the expression of the adipocyte fatty acid binding protein gene in human monocytes. \nThe peroxisome-proliferator activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily of ligand activated transcription factors, plays a key role in the anti-diabetic actions of the thiazolidinediones (TZDs). PPARgamma induces the expression of many genes involved in lipid anabolism, including the adipocyte fatty acid binding protein (aP2), and is a key regulator of adipocyte differentiation. PPARgamma is also expressed in hematopoietic cells and is up-regulated in activated monocytes/macrophages. Activation of PPARgamma may play a role in the induction of differentiation of macrophages to foam cells that are associated with atherosclerotic lesions. We report that both natural and synthetic PPARgamma agonists induce time- and dose-dependent increases in aP2 mRNA in both primary human monocytes and the monocytic cell line, THP-1. These data suggest that PPARgamma activation may play a role in monocyte differentiation and function analogous to its well-characterized role in adipocytes. " ], "offsets": [ [ 0, 1138 ] ] } ]

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[ { "id": "9078381__text", "type": "abstract", "text": [ "Differentiation of T-helper lymphocytes: selective regulation by members of the STAT family of transcription factors. \nInterleukin-4 (IL-4) and interleukin-12 (IL-12) control the differentiation of T-helper cells. Here we summarize studies which investigate the mechanism by which these cytokines selectively reprogramme gene expression in T-lymphocytes. Cytokine stimulation leads to the phosphorylation of specific tyrosine residues within the intracellular domain of the corresponding cytokine receptor. These phosphotyrosines serve as docking sites for latent, cytoplasmic transcription factors known as signal transducers and activators of transcription (Stat) proteins. Receptor/Stat interaction is mediated by the src homology 2 (SH2) domain of the corresponding Stat protein. Although Stat binding to the intracellular domain of the cytokine receptor strongly depends on the phosphotyrosine residue, the recruitment of a specific Stat protein is dictated by amino acid residues C-terminal to the phosphotyrosine. Specific docking sites within individual cytokine receptors have been identified for almost all Stat proteins. The direct coupling between cytokine receptor and transcription factor helps to explain how different cytokines elicit distinct patterns of gene expression. " ], "offsets": [ [ 0, 1289 ] ] } ]

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[ { "id": "9199305__text", "type": "abstract", "text": [ "The immediate-early gene product Egr-1 regulates the human interleukin-2 receptor beta-chain promoter through noncanonical Egr and Sp1 binding sites. \nThe interleukin-2 IL-2 receptor beta-chain (IL-2Rbeta) is an essential component of the receptors for IL-2 and IL-15. Although IL-2Rbeta is constitutively expressed by lymphocytes, its expression can be further induced by a number of stimuli, including phorbol 12-myristate 13-acetate (PMA). We have now characterized factors that bind to an enhancer region located between nucleotides -170 and -139 of the human IL-2Rbeta promoter. Both Sp1 and Sp3 bound to the 5' portion of this region, whereas a PMA-inducible factor (PIF) mainly bound to its 3' portion and bound to the Sp binding motifs as well. In Jurkat T cells, induction of PIF DNA binding activity was rapidly induced, required de novo protein synthesis, and was sustained at a high level for at least 23 h. Interestingly, PIF was constitutively activated in human T-cell leukemia virus type 1-transformed MT-2 cells. In this paper, we demonstrate that PIF is Egr-1 based on its recognition by anti-Egr-1 antisera in gel mobility shift assays, even though the IL-2Rbeta DNA binding motif differed substantially from the canonical Egr-1 binding site. In addition, Egr-1 bound to the Sp binding site. In Jurkat cells, both sites were required for maximal IL-2Rbeta promoter activity, and in HeLaS3 cells, transfection of Egr-1 could drive activity of a reporter construct containing both sites. Moreover, Sp1 and Egr-1 could form a complex with kinetics that correlated with the production of Egr-1 in Jurkat cells upon PMA stimulation. Thus, Sp1 and Egr-1 physically and functionally cooperate to mediate maximal IL-2Rbeta promoter activity. " ], "offsets": [ [ 0, 1753 ] ] } ]

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[ { "id": "9625770__text", "type": "abstract", "text": [ "The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). \nThe human homologue of Drosophila Toll (hToll) is a recently cloned receptor of the interleukin 1 receptor (IL-1R) superfamily, and has been implicated in the activation of adaptive immunity. Signaling by hToll is shown to occur through sequential recruitment of the adapter molecule MyD88 and the IL-1R-associated kinase. Tumor necrosis factor receptor-activated factor 6 (TRAF6) and the nuclear factor kappaB (NF-kappaB)-inducing kinase (NIK) are both involved in subsequent steps of NF-kappaB activation. Conversely, a dominant negative version of TRAF6 failed to block hToll-induced activation of stress-activated protein kinase/c-Jun NH2-terminal kinases, thus suggesting an early divergence of the two pathways. " ], "offsets": [ [ 0, 885 ] ] } ]

[ { "id": "9625770_T1", "type": "Protein", "text": [ "tumor necrosis factor receptor-associated factor 6" ], "offsets": [ [ 106, 156 ] ], "normalized": [] }, { "id": "9625770_T2", "type": "Protein", "text": [ "TRAF6" ], "offsets": [ [ 158, 163 ] ], "normalized": [] }, { "id": "9625770_T3", "type": "Protein", "text": [ "MyD88" ], "offsets": [ [ 451, 456 ] ], "normalized": [] }, { "id": "9625770_T4", "type": "Protein", "text": [ "Tumor necrosis factor receptor-activated factor 6" ], "offsets": [ [ 490, 539 ] ], "normalized": [] }, { "id": "9625770_T5", "type": "Protein", "text": [ "TRAF6" ], "offsets": [ [ 541, 546 ] ], "normalized": [] }, { "id": "9625770_T6", "type": "Protein", "text": [ "nuclear factor kappaB (NF-kappaB)-inducing kinase" ], "offsets": [ [ 556, 605 ] ], "normalized": [] }, { "id": "9625770_T7", "type": "Protein", "text": [ "NIK" ], "offsets": [ [ 607, 610 ] ], "normalized": [] }, { "id": "9625770_T8", "type": "Protein", "text": [ "TRAF6" ], "offsets": [ [ 718, 723 ] ], "normalized": [] } ]

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[]

[ { "id": "9182556__text", "type": "abstract", "text": [ "Overexpression of HSF2-beta inhibits hemin-induced heat shock gene expression and erythroid differentiation in K562 cells. \nAcquisition of heat shock factor 2 (HSF2) DNA binding activity is accompanied by induced transcription of heat shock genes in hemin-treated K562 cells undergoing erythroid differentiation. Previous studies revealed that HSF2 consists of two alternatively spliced isoforms, HSF2-alpha and HSF2-beta, whose relative abundance is developmentally regulated and varies between different tissues. To investigate whether the molar ratio of HSF2-alpha and HSF2-beta isoforms is crucial for the activation of HSF2 and whether the HSF2 isoforms play functionally distinct roles during the hemin-mediated erythroid differentiation, we generated cell clones expressing different levels of HSF2-alpha and HSF2-beta. We show that in parental K562 cells, the HSF2-alpha isoform is predominantly expressed and HSF2 can be activated upon hemin treatment. In contrast, when HSF2-beta is expressed at levels exceeding those of endogenous HSF2-alpha, the hemin-induced DNA binding activity and transcription of heat shock genes are repressed, whereas overexpression of HSF2-alpha results in an enhanced hemin response. Furthermore, the hemin-induced accumulation of globin, known as a marker of erythroid differentiation, is decreased in cells overexpressing HSF2-beta. We suggest that HSF2-beta acts as a negative regulator of HSF2 activity during hemin-mediated erythroid differentiation of K562 cells. " ], "offsets": [ [ 0, 1509 ] ] } ]

[ { "id": "9182556_T1", "type": "Protein", "text": [ "HSF2-beta" ], "offsets": [ [ 18, 27 ] ], "normalized": [] }, { "id": "9182556_T2", "type": "Protein", "text": [ "heat shock factor 2" ], "offsets": [ [ 139, 158 ] ], "normalized": [] }, { "id": "9182556_T3", "type": "Protein", "text": [ "HSF2" ], "offsets": [ [ 160, 164 ] ], "normalized": [] }, { "id": "9182556_T4", "type": "Protein", "text": [ "HSF2" ], "offsets": [ [ 344, 348 ] ], "normalized": [] }, { "id": "9182556_T5", "type": "Protein", "text": [ "HSF2-alpha" ], "offsets": [ [ 397, 407 ] ], "normalized": [] }, { "id": "9182556_T6", "type": "Protein", "text": [ "HSF2-beta" ], "offsets": [ [ 412, 421 ] ], "normalized": [] }, { "id": "9182556_T7", "type": "Protein", "text": [ "HSF2-alpha" ], "offsets": [ [ 557, 567 ] ], "normalized": [] }, { "id": "9182556_T8", "type": "Protein", "text": [ "HSF2-beta" ], "offsets": [ [ 572, 581 ] ], "normalized": [] }, { "id": "9182556_T9", "type": "Protein", "text": [ "HSF2" ], "offsets": [ [ 624, 628 ] ], "normalized": [] }, { "id": "9182556_T10", "type": "Protein", "text": [ "HSF2" ], "offsets": [ [ 645, 649 ] ], "normalized": [] }, { "id": "9182556_T11", "type": "Protein", "text": [ "HSF2-alpha" ], "offsets": [ [ 801, 811 ] ], "normalized": [] }, { "id": "9182556_T12", "type": "Protein", "text": [ "HSF2-beta" ], "offsets": [ [ 816, 825 ] ], "normalized": [] }, { "id": "9182556_T13", "type": "Protein", "text": [ "HSF2-alpha" ], "offsets": [ [ 868, 878 ] ], "normalized": [] }, { "id": "9182556_T14", "type": "Protein", "text": [ "HSF2" ], "offsets": [ [ 918, 922 ] ], "normalized": [] }, { "id": "9182556_T15", "type": "Protein", "text": [ "HSF2-beta" ], "offsets": [ [ 980, 989 ] ], "normalized": [] }, { "id": "9182556_T16", "type": "Protein", "text": [ "HSF2-alpha" ], "offsets": [ [ 1043, 1053 ] ], "normalized": [] }, { "id": "9182556_T17", "type": "Protein", "text": [ "HSF2-alpha" ], "offsets": [ [ 1173, 1183 ] ], "normalized": [] }, { "id": "9182556_T18", "type": "Protein", "text": [ "HSF2-beta" ], "offsets": [ [ 1363, 1372 ] ], "normalized": [] }, { "id": "9182556_T19", "type": "Protein", "text": [ "HSF2-beta" ], "offsets": [ [ 1390, 1399 ] ], "normalized": [] }, { "id": "9182556_T20", "type": "Protein", "text": [ "HSF2" ], "offsets": [ [ 1432, 1436 ] ], "normalized": [] } ]

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[ { "id": "9182556_1", "entity_ids": [ "9182556_T2", "9182556_T3" ] } ]

[]

[ { "id": "9729045__text", "type": "abstract", "text": [ "CD30 is a CD40-inducible molecule that negatively regulates CD40-mediated immunoglobulin class switching in non-antigen-selected human B cells. \nWe used our monoclonal model of germinal center maturation, CL-01 B cells, to investigate the role of CD30 in human B cell differentiation. CL-01 cells are IgM+ IgD+ CD30+ and switch to IgG, IgA, and IgE when exposed to CD40L and IL-4. Switching is hampered by CD30 coengagement, possibly through interference with the CD40-mediated NF-kappaB-dependent transcriptional activation of downstream C(H) genes. The physiological relevance of this phenomenon is emphasized by similar CD30-mediated effects in naive B cells. Expression of CD30 by these cells is induced by CD40L but is inhibited by B cell receptor coengagement and/or exposure to IL-6 and IL-12. Our data suggest that CD30 critically regulates the CD40-mediated differentiation of non-antigen-selected human B cells. " ], "offsets": [ [ 0, 922 ] ] } ]

[ { "id": "9729045_T1", "type": "Protein", "text": [ "CD30" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "9729045_T2", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 10, 14 ] ], "normalized": [] }, { "id": "9729045_T3", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 60, 64 ] ], "normalized": [] }, { "id": "9729045_T4", "type": "Protein", "text": [ "CD30" ], "offsets": [ [ 247, 251 ] ], "normalized": [] }, { "id": "9729045_T5", "type": "Protein", "text": [ "CD30" ], "offsets": [ [ 311, 315 ] ], "normalized": [] }, { "id": "9729045_T6", "type": "Protein", "text": [ "CD40L" ], "offsets": [ [ 365, 370 ] ], "normalized": [] }, { "id": "9729045_T7", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 375, 379 ] ], "normalized": [] }, { "id": "9729045_T8", "type": "Protein", "text": [ "CD30" ], "offsets": [ [ 406, 410 ] ], "normalized": [] }, { "id": "9729045_T9", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 464, 468 ] ], "normalized": [] }, { "id": "9729045_T10", "type": "Protein", "text": [ "CD30" ], "offsets": [ [ 623, 627 ] ], "normalized": [] }, { "id": "9729045_T11", "type": "Protein", "text": [ "CD30" ], "offsets": [ [ 677, 681 ] ], "normalized": [] }, { "id": "9729045_T12", "type": "Protein", "text": [ "CD40L" ], "offsets": [ [ 711, 716 ] ], "normalized": [] }, { "id": "9729045_T13", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 785, 789 ] ], "normalized": [] }, { "id": "9729045_T14", "type": "Protein", "text": [ "CD30" ], "offsets": [ [ 823, 827 ] ], "normalized": [] }, { "id": "9729045_T15", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 853, 857 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "1380242__text", "type": "abstract", "text": [ "SRC-related proto-oncogenes and transcription factors in primary human T cells: modulation by cyclosporin A and FK506. \nActivation of T lymphocytes induces transcription of genes encoding for lymphokines. Interleukin-2 (IL-2) gene expression is controlled transcriptionally by the cooperative activity of specific trans-activating factors that bind to the IL-2 enhancer. Cyclosporin A (CsA) and FK506 inhibit the production of IL-2 in T lymphocytes at the level of gene transcription. A member of the src gene family, the lymphocyte-specific protein tyrosine kinase, p56lck, has been implicated in IL-2 production. CsA was found not to inhibit lck gene expression, nor the activity of the lck gene product. However, CsA and FK506 inhibit the appearance of DNA binding activity of factors that bind to the NF-AT and AP-1 sites in the IL-2 enhancer. Since the induction of NF-AT and AP-1 is induced by the same stimuli that stimulate IL-2 production, these results indicate that the immunosuppressant action of CsA and FK506 is exerted at the level of these trans-activating factors. " ], "offsets": [ [ 0, 1082 ] ] } ]

[ { "id": "1380242_T1", "type": "Protein", "text": [ "Interleukin-2" ], "offsets": [ [ 205, 218 ] ], "normalized": [] }, { "id": "1380242_T2", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 220, 224 ] ], "normalized": [] }, { "id": "1380242_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 356, 360 ] ], "normalized": [] }, { "id": "1380242_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 427, 431 ] ], "normalized": [] }, { "id": "1380242_T5", "type": "Protein", "text": [ "p56lck" ], "offsets": [ [ 567, 573 ] ], "normalized": [] }, { "id": "1380242_T6", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 598, 602 ] ], "normalized": [] }, { "id": "1380242_T7", "type": "Protein", "text": [ "lck" ], "offsets": [ [ 644, 647 ] ], "normalized": [] }, { "id": "1380242_T8", "type": "Protein", "text": [ "lck" ], "offsets": [ [ 689, 692 ] ], "normalized": [] }, { "id": "1380242_T9", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 833, 837 ] ], "normalized": [] }, { "id": "1380242_T10", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 932, 936 ] ], "normalized": [] }, { "id": "1380242_T14", "type": "Entity", "text": [ "enhancer" ], "offsets": [ [ 361, 369 ] ], "normalized": [] } ]

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[ { "id": "1380242_1", "entity_ids": [ "1380242_T1", "1380242_T2" ] } ]

[]

[ { "id": "7650486__text", "type": "abstract", "text": [ "Activation and expression of the nuclear factors of activated T cells, NFATp and NFATc, in human natural killer cells: regulation upon CD16 ligand binding. \nThe putative factors that couple the signal transduction from surface receptors to the activation of cytokine synthesis in natural killer (NK) cells have not been elucidated. We report here that the nuclear factor of activated T cells (NFATp), a cyclosporin A (CsA)-sensitive factor that regulates the transcription of several cytokines, mediates CD16-induced activation of cytokine genes in human NK cells. CD16 (Fc gamma RIIIA)-induced expression of cytokine mRNA in NK cells occurs via a CsA-sensitive and Ca(2+)-dependent mechanism. Stimulation of NK cells with CD16 ligands induces NFAT-like DNA binding activity in the nuclear extracts from these cells, as detected in electrophoretic mobility shift assays. This occurs with fast kinetics after stimulation, via a CsA-sensitive and Ca(2+)-dependent mechanism that does not require de novo protein synthesis. NK cell NFAT is present in the cytosol of nonstimulated cells, migrates to the nucleus upon stimulation, and can associate with AP-1. Two distinct molecules, NFATp and NFATc, have been reported to mediate NFAT activity. The results of supershift assays using NFATp- and NFATc- specific antibodies indicate that NK cell activation early after CD16 ligand binding involves primarily, if not exclusively, NFATp, and Western blot analysis shows that this has the same electrophoretic mobility (approximately 120 kD) as that of T lymphocytes. NK cells do not express NFATc constitutively, but NFATc mRNA accumulation is induced in these cells within 2 h of stimulation with CD16 ligands. However, supershift assays using the available mAb recognizing the T cell NFATc revealed no detectable NFATc protein in nuclear and cytoplasmic extracts from CD16- or phorbol ester-stimulated cells at any time tested, up to 4 h. These results provide the first direct evidence that both CsA-sensitive transcription factors, NFATp and NFATc, are expressed in human NK cells, and that their activation and/or expression can be regulated in primary cells by a single stimulus, that, in the case of CD16 in NK cells, results in early activation of NFATp and subsequently induced expression of NFATc mRNA. " ], "offsets": [ [ 0, 2305 ] ] } ]

[ { "id": "7650486_T1", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 71, 76 ] ], "normalized": [] }, { "id": "7650486_T2", "type": "Protein", "text": [ "NFATc" ], "offsets": [ [ 81, 86 ] ], "normalized": [] }, { "id": "7650486_T3", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 393, 398 ] ], "normalized": [] }, { "id": "7650486_T4", "type": "Protein", "text": [ "Fc gamma RIIIA" ], "offsets": [ [ 571, 585 ] ], "normalized": [] }, { "id": "7650486_T5", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 1179, 1184 ] ], "normalized": [] }, { "id": "7650486_T6", "type": "Protein", "text": [ "NFATc" ], "offsets": [ [ 1189, 1194 ] ], "normalized": [] }, { "id": "7650486_T7", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 1280, 1285 ] ], "normalized": [] }, { "id": "7650486_T8", "type": "Protein", "text": [ "NFATc" ], "offsets": [ [ 1291, 1296 ] ], "normalized": [] }, { "id": "7650486_T9", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 1423, 1428 ] ], "normalized": [] }, { "id": "7650486_T10", "type": "Protein", "text": [ "NFATc" ], "offsets": [ [ 1583, 1588 ] ], "normalized": [] }, { "id": "7650486_T11", "type": "Protein", "text": [ "NFATc" ], "offsets": [ [ 1609, 1614 ] ], "normalized": [] }, { "id": "7650486_T12", "type": "Protein", "text": [ "NFATc" ], "offsets": [ [ 1778, 1783 ] ], "normalized": [] }, { "id": "7650486_T13", "type": "Protein", "text": [ "NFATc" ], "offsets": [ [ 1807, 1812 ] ], "normalized": [] }, { "id": "7650486_T14", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 2028, 2033 ] ], "normalized": [] }, { "id": "7650486_T15", "type": "Protein", "text": [ "NFATc" ], "offsets": [ [ 2038, 2043 ] ], "normalized": [] }, { "id": "7650486_T16", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 2248, 2253 ] ], "normalized": [] }, { "id": "7650486_T17", "type": "Protein", "text": [ "NFATc" ], "offsets": [ [ 2293, 2298 ] ], "normalized": [] } ]

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] }, { "id": "7650486_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1636, 1643 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E11" } ] }, { "id": "7650486_E13", "type": "Gene_expression", "trigger": { "text": [ "detectable" ], "offsets": [ [ 1796, 1806 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_T13" } ] }, { "id": "7650486_E14", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 1995, 2004 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_T14" } ] }, { "id": "7650486_E15", "type": "Regulation", "trigger": { "text": [ "sensitive" ], "offsets": [ [ 1995, 2004 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_T15" } ] }, { "id": "7650486_E16", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 2049, 2058 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_T14" } ] }, { "id": "7650486_E17", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 2049, 2058 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_T15" } ] }, { "id": "7650486_E18", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 2093, 2103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_T15" } ] }, { "id": "7650486_E19", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 2093, 2103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_T14" } ] }, { "id": "7650486_E20", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2111, 2121 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_T14" } ] }, { "id": "7650486_E21", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 2111, 2121 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_T15" } ] }, { "id": "7650486_E22", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 2129, 2138 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E18" } ] }, { "id": "7650486_E23", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 2129, 2138 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E19" } ] }, { "id": "7650486_E24", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 2129, 2138 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E21" } ] }, { "id": "7650486_E25", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 2129, 2138 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E20" } ] }, { "id": "7650486_E26", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 2217, 2224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E30" }, { "role": "Cause", "ref_id": "7650486_E22" } ] }, { "id": "7650486_E27", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 2217, 2224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E30" }, { "role": "Cause", "ref_id": "7650486_E23" } ] }, { "id": "7650486_E28", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 2217, 2224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E30" }, { "role": "Cause", "ref_id": "7650486_E25" } ] }, { "id": "7650486_E29", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 2217, 2224 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E30" }, { "role": "Cause", "ref_id": "7650486_E24" } ] }, { "id": "7650486_E30", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 2234, 2244 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_T16" } ] }, { "id": "7650486_E31", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 2271, 2278 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E35" }, { "role": "Cause", "ref_id": "7650486_E27" } ] }, { "id": "7650486_E32", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 2271, 2278 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E35" }, { "role": "Cause", "ref_id": "7650486_E29" } ] }, { "id": "7650486_E33", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 2271, 2278 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E35" }, { "role": "Cause", "ref_id": "7650486_E26" } ] }, { "id": "7650486_E34", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 2271, 2278 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_E35" }, { "role": "Cause", "ref_id": "7650486_E28" } ] }, { "id": "7650486_E35", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 2279, 2289 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7650486_T17" } ] } ]

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[ { "id": "10068588__text", "type": "abstract", "text": [ "Activation of human immunodeficiency virus type 1 expression by Gardnerella vaginalis. \nBacterial vaginosis (BV) is associated with an increased rate of sexual transmission of human immunodeficiency virus (HIV) type 1, and Gardnerella vaginalis is frequently isolated from the genital tracts of women with BV. G. vaginalis lysates were found to significantly stimulate HIV expression in monocytoid cells. Stimulation was significantly higher when lysates were heated at 100 degrees C for 5 min but was reduced by treatment with lysozyme or protease. G. vaginalis lysates also activated HIV expression in certain T cell lines. G. vaginalis lysates activated HIV long-terminal repeat transcription in HIV-infected cells and increased NF-kappaB binding activity, indicating an effect by G. vaginalis on HIV transcription. The activation of HIV production by G. vaginalis suggests that genital tract infection with G. vaginalis increases the risk of HIV transmission by increasing HIV expression in the genital tract. This may explain, at least in part, the increased rate of HIV transmission in women with BV. " ], "offsets": [ [ 0, 1107 ] ] } ]

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[ { "id": "8507862__text", "type": "abstract", "text": [ "Expression of mRNA for the GATA-binding proteins in human eosinophils and basophils: potential role in gene transcription. \nThe expression of the hematopoietic transcription factors GATA-1, GATA-2, and GATA-3 was studied in eosinophils and basophils. Eosinophils express mRNA for GATA-1, GATA-2, and GATA-3. Basophils express GATA-2 and GATA-3. Treatment of HL-60 eosinophilic sublines with either interleukin-5 or butyric acid increased the expression of GATA-1 mRNA concomitant with the expression of eosinophil-specific genes, whereas levels of GATA-2 mRNA remained relatively constant. The presence of mRNA for these proteins in eosinophils and basophils suggests that gene transcription in these lineages may be regulated by GATA-binding proteins. " ], "offsets": [ [ 0, 753 ] ] } ]

[ { "id": "8507862_T1", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 182, 188 ] ], "normalized": [] }, { "id": "8507862_T2", "type": "Protein", "text": [ "GATA-2" ], "offsets": [ [ 190, 196 ] ], "normalized": [] }, { "id": "8507862_T3", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 202, 208 ] ], "normalized": [] }, { "id": "8507862_T4", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 280, 286 ] ], "normalized": [] }, { "id": "8507862_T5", "type": "Protein", "text": [ "GATA-2" ], "offsets": [ [ 288, 294 ] ], "normalized": [] }, { "id": "8507862_T6", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 300, 306 ] ], "normalized": [] }, { "id": "8507862_T7", "type": "Protein", "text": [ "GATA-2" ], "offsets": [ [ 326, 332 ] ], "normalized": [] }, { "id": "8507862_T8", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 337, 343 ] ], "normalized": [] }, { "id": "8507862_T9", "type": "Protein", "text": [ "interleukin-5" ], "offsets": [ [ 398, 411 ] ], "normalized": [] }, { "id": "8507862_T10", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 456, 462 ] ], "normalized": [] }, { "id": "8507862_T11", "type": "Protein", "text": [ "GATA-2" ], "offsets": [ [ 548, 554 ] ], "normalized": [] } ]

[ { "id": "8507862_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 128, 138 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T2" } ] }, { "id": "8507862_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 128, 138 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T3" } ] }, { "id": "8507862_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 128, 138 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T1" } ] }, { "id": "8507862_E4", "type": "Transcription", "trigger": { "text": [ "express mRNA" ], "offsets": [ [ 263, 275 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T6" } ] }, { "id": "8507862_E5", "type": "Transcription", "trigger": { "text": [ "express mRNA" ], "offsets": [ [ 263, 275 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T5" } ] }, { "id": "8507862_E6", "type": "Transcription", "trigger": { "text": [ "express mRNA" ], "offsets": [ [ 263, 275 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T4" } ] }, { "id": "8507862_E7", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 318, 325 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T7" } ] }, { "id": "8507862_E8", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 318, 325 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T8" } ] }, { "id": "8507862_E9", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 428, 437 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_E10" } ] }, { "id": "8507862_E10", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 442, 452 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T10" } ] }, { "id": "8507862_E11", "type": "Positive_regulation", "trigger": { "text": [ "constant" ], "offsets": [ [ 580, 588 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T11" } ] }, { "id": "8507862_E12", "type": "Localization", "trigger": { "text": [ "presence" ], "offsets": [ [ 594, 602 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T6" } ] }, { "id": "8507862_E13", "type": "Localization", "trigger": { "text": [ "presence" ], "offsets": [ [ 594, 602 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T4" } ] }, { "id": "8507862_E14", "type": "Localization", "trigger": { "text": [ "presence" ], "offsets": [ [ 594, 602 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8507862_T5" } ] } ]

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[ { "id": "7540578__text", "type": "abstract", "text": [ "Danazol decreases transcription of estrogen receptor gene in human monocytes. \n1. Administration of danazol for over one month reduced the levels of estrogen receptor (ER) and its mRNA to approximately 50 and 20%, respectively in monocytes. 2. Danazol did not alter the degradation rate of ER mRNA in monocytes. 3. Danazol decreased the transcription rate of ER gene to approximately 50% in monocytes in a run-on assay. 4. Danazol may release estrogen predominance via the reduction of transcription for ER gene, which leads to the reduction of ER mRNA and ER expressions in monocytes. " ], "offsets": [ [ 0, 586 ] ] } ]

[ { "id": "7540578_T1", "type": "Protein", "text": [ "estrogen receptor" ], "offsets": [ [ 35, 52 ] ], "normalized": [] }, { "id": "7540578_T2", "type": "Protein", "text": [ "estrogen receptor" ], "offsets": [ [ 149, 166 ] ], "normalized": [] }, { "id": "7540578_T3", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 168, 170 ] ], "normalized": [] }, { "id": "7540578_T4", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 290, 292 ] ], "normalized": [] }, { "id": "7540578_T5", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 359, 361 ] ], "normalized": [] }, { "id": "7540578_T6", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 504, 506 ] ], "normalized": [] }, { "id": "7540578_T7", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 545, 547 ] ], "normalized": [] }, { "id": "7540578_T8", "type": "Protein", "text": [ "ER" ], "offsets": [ [ 557, 559 ] ], "normalized": [] } ]

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[ { "id": "7540578_1", "entity_ids": [ "7540578_T2", "7540578_T3" ] } ]

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[ { "id": "2314899__text", "type": "abstract", "text": [ "Tax-independent binding of multiple cellular factors to Tax-response element DNA of HTLV-I. \nThe human T-cell leukemia virus type I (HTLV-I) promoter contains three copies of imperfect repeats of a 21-base pair sequence designated here as TRE (Tax-response element) that is responsive to the virally encoded transactivator protein Tax. We have identified and separated four nuclear proteins from C81-66-45 cells, an HTLV-I immortalized Tax-expressing human T-lymphocyte line (Salahuddin et al., 1983), that interact with the TRE-DNA, none of which are identical with the Tax-protein. The proteins identified have molecular weights of about 32, 36 to 42, 50 and 110 kD. Four different methods were used to identify the proteins. First, from different cell lines three or all four of the nuclear proteins were specifically cross-linked by UV irradiation to the radioactively labeled TRE-DNA fragment. Second, TRE-DNA binding proteins sedimented through a glycerol density gradient at rates corresponding to proteins of native molecular weights of 35 to 50 kD and 110 kD. Third, only the 50 kD protein was retained on a biotinylated DNA-streptavidin matrix when the DNA fragment contained the TRE-DNA. Fourth, extensive purification by several cycles of TRE-DNA affinity chromatography resulted in the 32, 36 to 42 and 110 kD proteins and to less extent the 50 kD factor. Two abundant proteins of 75 and 80 kD were competed out by poly[d(I-C)] in all reactions. The cAMP-response element CRE, TGACGTCA, present in the 21 base-pair sequence, appears to be essential for specific protein-TRE-DNA interactions because mutation of the two G's destroys this complex. This result suggests that the cAMP response element binding protein, CREB, is involved in the protein-TRE-DNA complex and in mediating the Tax response. " ], "offsets": [ [ 0, 1812 ] ] } ]

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[ { "id": "8441379__text", "type": "abstract", "text": [ "The human prointerleukin 1 beta gene requires DNA sequences both proximal and distal to the transcription start site for tissue-specific induction. \nIn these studies, we have identified DNA sequences and specific protein interactions necessary for transcriptional regulation of the human prointerleukin 1 beta (proIL-1 beta) gene. A cell-type-independent lipopolysaccharide (LPS)-responsive enhancer element located between -3757 and -2729 bp upstream from the transcription start site (cap site) consisted of at least six discrete subregions which were essential to the maximal induction by LPS in transfected monocytes. The enhancer also appeared to mediate phorbol myristate acetate induction in monocytes and IL-1 responsiveness in fibroblasts. Deletion and base substitution mutations along with DNA binding studies demonstrated that the enhancer contained a minimum of three functional protein binding sequences, two of which appeared to be important for gene induction. One of the essential proteins which bound to the enhancer was similar or identical to members of the C/EBP family of transcription factors required for both IL-1- and LPS-specific induction of the IL-6 gene (i.e., the NF-IL6 proteins). When ligated to the proIL-1 beta cap site-proximal region (located between -131 to +12), both the proIL-1 beta and the simian virus 40 enhancer elements functioned more efficiently in monocytes than in HeLa cells, which are not normally competent for IL-1 beta expression. When ligated to the murine c-fos promoter, however, the proIL-1 beta enhancer was inducible in phorbol myristate acetate-stimulated HeLa cells, suggesting the existence of a proIL-1 beta promoter-proximal requirement for tissue specificity. " ], "offsets": [ [ 0, 1727 ] ] } ]

[ { "id": "8441379_T1", "type": "Protein", "text": [ "human prointerleukin 1 beta" ], "offsets": [ [ 4, 31 ] ], "normalized": [] }, { "id": "8441379_T2", "type": "Protein", "text": [ "human prointerleukin 1 beta" ], "offsets": [ [ 282, 309 ] ], "normalized": [] }, { "id": "8441379_T3", "type": "Protein", "text": [ "proIL-1 beta" ], "offsets": [ [ 311, 323 ] ], "normalized": [] }, { "id": "8441379_T4", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 1174, 1178 ] ], "normalized": [] }, { "id": "8441379_T5", "type": "Protein", "text": [ "NF-IL6" ], "offsets": [ [ 1195, 1201 ] ], "normalized": [] }, { "id": "8441379_T6", "type": "Protein", "text": [ "proIL-1 beta" ], "offsets": [ [ 1233, 1245 ] ], "normalized": [] }, { "id": "8441379_T7", "type": "Protein", "text": [ "IL-1 beta" ], "offsets": [ [ 1464, 1473 ] ], "normalized": [] }, { "id": "8441379_T8", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 1513, 1518 ] ], "normalized": [] }, { "id": "8441379_T9", "type": "Protein", "text": [ "proIL-1 beta" ], "offsets": [ [ 1542, 1554 ] ], "normalized": [] }, { "id": "8441379_T10", "type": "Protein", "text": [ "proIL-1 beta" ], "offsets": [ [ 1660, 1672 ] ], "normalized": [] }, { "id": "8441379_T21", "type": "Entity", "text": [ "enhancer" ], "offsets": [ [ 1555, 1563 ] ], "normalized": [] }, { "id": "8441379_T23", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1673, 1681 ] ], "normalized": [] } ]

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[ { "id": "1492121__text", "type": "abstract", "text": [ "Activation of lymphokine genes in T cells: role of cis-acting DNA elements that respond to T cell activation signals. \nActivation of T cells is initiated by the recognition of antigen on antigen presenting cells to exert the effector functions in immune and inflammatory responses. Two types of helper T cell (Th) clones (Th1 and Th2) are defined on the basis of different patterns of cytokine (lymphokine) secretion. They determine the outcome of an antigenic response toward humoral or cell-mediated immunity. Although lymphokine genes are coordinately regulated upon antigen stimulation, they are regulated by the mechanisms common to all as well as those which are unique to each gene. For most lymphokine genes, a combination of phorbol esters (phorbol 12-myristate 13 acetate, PMA) and calcium ionophores (A23187) is required for their maximal induction. Yet phorbol ester alone or calcium ionophore alone produce several lymphokines. The production of the granulocyte-macrophage colony stimulating factor (GM-CSF) is completely dependent on the two signals. We have previously found a cis-acting region spanning the GM-CSF promoter region (positions -95 to +27) that confers inducibility to reporter genes in transient transfection assays. Further analysis identified three elements required for efficient induction, referred to as GM2, GC-box and conserved lymphokine element (CLE0). GM2 defines a binding site for protein(s) whose binding is inducible by PMA. One protein, NF-GM2 is similar to the transcription factor NF-kB. GC-box is a binding site for constitutively bound proteins. CLEO defines a binding site for protein(s) whose optimum binding is stimulated by PMA and A23187. Viral trans-activators such as Tax (human T cell leukemia virus-1, HTLV-1) and E2 (bovine papilloma virus, BPV) proteins are other agents which activate lymphokine gene expression by bypassing T cell receptor (TCR) mediated signaling. The trans-activation domain of E2 and Tax is interchangeable although they have no obvious sequence homology between them. The viral trans-activators appear to target specific DNA binding protein such as NF-kB and Sp1 to cis-acting DNA site and promote lymphokine gene expression without TCR-mediated stimulation. " ], "offsets": [ [ 0, 2242 ] ] } ]

[ { "id": "1492121_T1", "type": "Protein", "text": [ "granulocyte-macrophage colony stimulating factor" ], "offsets": [ [ 963, 1011 ] ], "normalized": [] }, { "id": "1492121_T2", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 1013, 1019 ] ], "normalized": [] }, { "id": "1492121_T3", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 1123, 1129 ] ], "normalized": [] }, { "id": "1492121_T4", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 1724, 1727 ] ], "normalized": [] }, { "id": "1492121_T5", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 1772, 1774 ] ], "normalized": [] }, { "id": "1492121_T6", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 1959, 1961 ] ], "normalized": [] }, { "id": "1492121_T7", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 1966, 1969 ] ], "normalized": [] }, { "id": "1492121_T8", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 2142, 2145 ] ], "normalized": [] } ]

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[ { "id": "8083467__text", "type": "abstract", "text": [ "Signals and nuclear factors that regulate the expression of interleukin-4 and interleukin-5 genes in helper T cells. \nMouse thymoma line EL-4 cells produce cytokines such as interleukin (IL)-2, IL-3, IL-4, IL-10, and granulocyte-macrophage colony-stimulating factor in response to phorbol 12-myristate 13-acetate (PMA). EL-4 cells also produce low levels of IL-5 when stimulated by PMA alone; however, cAMP greatly augments PMA-dependent IL-5 production. A transient transfection assay revealed that two signals, PMA and cAMP, are required for optimal activation of the IL-5 promoter. In contrast, cAMP almost completely inhibited the PMA-dependent activation of the endogenous IL-2 gene, as well as the transfected IL-2 promoter. These results indicate that the IL-5 gene is positively regulated by cAMP in a manner opposite to that for the IL-2 gene. One of the nuclear factors (NFs) that regulates the response of the IL-5 promoter to cAMP and PMA has properties similar to NF for activated t cell. The P sequence of the IL-4 gene, defined as a responsive element for PMA and calcium ionophore (A23187), shares sequence similarity with the NF kappa B and the NF-activated T cell binding sites. We attempted to determine whether NF(P), a nuclear factor specific for the P sequence, is related to NF-kappa B and nuclear factor for activated T cell (NF-AT). In electromobility shift assays both NF-kappa B (P65 or P65/P50 heterodimer) and NF-AT bound to the P sequence. However, sequence specificity of NF-AT was more similar to that of NF(P), and only a small amount of P65 was detected in NF(P). These results indicate that a component or components of NF-AT have the potential to reconstitute NF(P), whereas NF-kappa B alone does not account for NF(P) in Jurkat crude extract. Taken together, these results suggest that NF-AT-like factors are involved in the regulation of IL-4 and IL-5 genes. " ], "offsets": [ [ 0, 1897 ] ] } ]

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"augments" ], "offsets": [ [ 415, 423 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_E18" } ] }, { "id": "8083467_E18", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 428, 437 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_E19" } ] }, { "id": "8083467_E19", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 443, 453 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T9" } ] }, { "id": "8083467_E20", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 531, 539 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_E21" } ] }, { "id": "8083467_E21", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 552, 562 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T10" }, { "role": "Site", "ref_id": "8083467_T34" } ] }, { "id": "8083467_E22", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 621, 630 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_E24" } ] }, { "id": "8083467_E23", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 621, 630 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_E25" } ] }, { "id": "8083467_E24", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 649, 659 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T11" } ] }, { "id": "8083467_E25", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 649, 659 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T12" }, { "role": "Site", "ref_id": "8083467_T37" } ] }, { "id": "8083467_E26", "type": "Positive_regulation", "trigger": { "text": [ "positively regulated" ], "offsets": [ [ 776, 796 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T13" } ] }, { "id": "8083467_E27", "type": "Negative_regulation", "trigger": { "text": [ "opposite" ], "offsets": [ [ 817, 825 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T14" } ] }, { "id": "8083467_E28", "type": "Regulation", "trigger": { "text": [ "regulates" ], "offsets": [ [ 891, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_E29" } ] }, { "id": "8083467_E29", "type": "Regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 905, 913 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T15" }, { "role": "Site", "ref_id": "8083467_T42" } ] }, { "id": "8083467_E30", "type": "Regulation", "trigger": { "text": [ "defined as a responsive element" ], "offsets": [ [ 1035, 1066 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T16" }, { "role": "Site", "ref_id": "8083467_T43" } ] }, { "id": "8083467_E31", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 1445, 1450 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T17" } ] }, { "id": "8083467_E32", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 1445, 1450 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T19" } ] }, { "id": "8083467_E33", "type": "Binding", "trigger": { "text": [ "bound" ], "offsets": [ [ 1445, 1450 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T18" } ] }, { "id": "8083467_E34", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1862, 1872 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T22" } ] }, { "id": "8083467_E35", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1862, 1872 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8083467_T21" } ] } ]

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[ { "id": "7862157__text", "type": "abstract", "text": [ "Expression of the Runt domain-encoding PEBP2 alpha genes in T cells during thymic development. \nThe PEBP2 alpha A and PEBP2 alpha B genes encode the DNA-binding subunit of a murine transcription factor, PEBP2, which is implicated as a T-cell-specific transcriptional regulator. These two related genes share the evolutionarily conserved region encoding the Runt domain. PEBP2 alpha B is the murine counterpart of human AML1, which is located at the breakpoints of the 8;21 and 3;21 chromosome translocations associated with acute myeloid leukemia. Northern (RNA) blots of various adult mouse tissues revealed that the levels of expression of both genes were most prominent in the thymus. Furthermore, transcripts of PEBP2 alpha A and mouse AML1/PEBP2 alpha B were detected in T lymphocytes in the thymuses from day 16 embryos and newborns, as well as 4-week-old adult mice, by in situ hybridization. The expression of the genes persisted in peripheral lymph nodes of adult mice. The transcripts were detected in all the CD4- CD8-, CD4+ CD8+, CD4+ CD8-, and CD4- CD8+ cell populations. The results indicated that both genes are expressed in T cells throughout their development, supporting the notion that PEBP2 is a T-cell-specific transcription factor. Transcripts of mouse AML1/PEBP2 alpha B were also detected in day 12 fetal hematopoietic liver and in the bone marrow cells of newborn mice. The implication of mouse AML1/PEBP2 alpha B expression in hematopoietic cells other than those of T-cell lineage is discussed in relation to myeloid leukemogenesis. " ], "offsets": [ [ 0, 1560 ] ] } ]

[ { "id": "7862157_T1", "type": "Protein", "text": [ "PEBP2 alpha A" ], "offsets": [ [ 100, 113 ] ], "normalized": [] }, { "id": "7862157_T2", "type": "Protein", "text": [ "PEBP2 alpha B" ], "offsets": [ [ 118, 131 ] ], "normalized": [] }, { "id": "7862157_T3", "type": "Protein", "text": [ "PEBP2 alpha B" ], "offsets": [ [ 370, 383 ] ], "normalized": [] }, { "id": "7862157_T4", "type": "Protein", "text": [ "AML1" ], "offsets": [ [ 419, 423 ] ], "normalized": [] }, { "id": "7862157_T5", "type": "Protein", "text": [ "PEBP2 alpha A" ], "offsets": [ [ 716, 729 ] ], "normalized": [] }, { "id": "7862157_T6", "type": "Protein", "text": [ "AML1/PEBP2 alpha B" ], "offsets": [ [ 740, 758 ] ], "normalized": [] }, { "id": "7862157_T7", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1020, 1023 ] ], "normalized": [] }, { "id": "7862157_T8", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1031, 1034 ] ], "normalized": [] }, { "id": "7862157_T9", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1042, 1045 ] ], "normalized": [] }, { "id": "7862157_T10", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1057, 1060 ] ], "normalized": [] }, { "id": "7862157_T11", "type": "Protein", "text": [ "AML1/PEBP2 alpha B" ], "offsets": [ [ 1275, 1293 ] ], "normalized": [] }, { "id": "7862157_T12", "type": "Protein", "text": [ "AML1/PEBP2 alpha B" ], "offsets": [ [ 1420, 1438 ] ], "normalized": [] } ]

[ { "id": "7862157_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 628, 638 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T2" } ] }, { "id": "7862157_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 628, 638 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T1" } ] }, { "id": "7862157_E3", "type": "Positive_regulation", "trigger": { "text": [ "prominent" ], "offsets": [ [ 663, 672 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_E2" } ] }, { "id": "7862157_E4", "type": "Positive_regulation", "trigger": { "text": [ "prominent" ], "offsets": [ [ 663, 672 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_E1" } ] }, { "id": "7862157_E5", "type": "Transcription", "trigger": { "text": [ "detected" ], "offsets": [ [ 764, 772 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T6" } ] }, { "id": "7862157_E6", "type": "Transcription", "trigger": { "text": [ "detected" ], "offsets": [ [ 764, 772 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T5" } ] }, { "id": "7862157_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 904, 914 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T6" } ] }, { "id": "7862157_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 904, 914 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T5" } ] }, { "id": "7862157_E9", "type": "Positive_regulation", "trigger": { "text": [ "persisted" ], "offsets": [ [ 928, 937 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_E7" } ] }, { "id": "7862157_E10", "type": "Positive_regulation", "trigger": { "text": [ "persisted" ], "offsets": [ [ 928, 937 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_E8" } ] }, { "id": "7862157_E11", "type": "Transcription", "trigger": { "text": [ "detected" ], "offsets": [ [ 1000, 1008 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T6" } ] }, { "id": "7862157_E12", "type": "Transcription", "trigger": { "text": [ "detected" ], "offsets": [ [ 1000, 1008 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T5" } ] }, { "id": "7862157_E13", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1127, 1136 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T5" } ] }, { "id": "7862157_E14", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 1127, 1136 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T6" } ] }, { "id": "7862157_E15", "type": "Transcription", "trigger": { "text": [ "detected" ], "offsets": [ [ 1304, 1312 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T11" } ] }, { "id": "7862157_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1439, 1449 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7862157_T12" } ] } ]

[]

[]

[ { "id": "9442395__text", "type": "abstract", "text": [ "Temporal control of IgH gene expression in developing B cells by the 3' locus control region. \nThe suggested roles of the downstream 3' regions acting as a Locus Control Region (LCR), have allowed comparisons to be made between the regulation of the IgH locus with other model systems whose gene expression is governed by LCR activity. Here we summarize the importance of the IgH 3'LCR and its putative functional role in IgH gene expression and compare it with the 5'LCR regulatory region of the human beta-globin locus. " ], "offsets": [ [ 0, 522 ] ] } ]

[ { "id": "9442395_T1", "type": "Protein", "text": [ "IgH" ], "offsets": [ [ 20, 23 ] ], "normalized": [] }, { "id": "9442395_T2", "type": "Protein", "text": [ "IgH" ], "offsets": [ [ 250, 253 ] ], "normalized": [] }, { "id": "9442395_T3", "type": "Protein", "text": [ "IgH" ], "offsets": [ [ 376, 379 ] ], "normalized": [] }, { "id": "9442395_T4", "type": "Protein", "text": [ "IgH" ], "offsets": [ [ 422, 425 ] ], "normalized": [] }, { "id": "9442395_T5", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 503, 514 ] ], "normalized": [] } ]

[ { "id": "9442395_E1", "type": "Regulation", "trigger": { "text": [ "control" ], "offsets": [ [ 9, 16 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9442395_E2" } ] }, { "id": "9442395_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 29, 39 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9442395_T1" } ] }, { "id": "9442395_E3", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 232, 242 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9442395_T2" } ] }, { "id": "9442395_E4", "type": "Regulation", "trigger": { "text": [ "functional role" ], "offsets": [ [ 403, 418 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9442395_E5" } ] }, { "id": "9442395_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 431, 441 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9442395_T4" } ] } ]

[]

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[ { "id": "7706727__text", "type": "abstract", "text": [ "cDNA cloning of a NGFI-B/nur77-related transcription factor from an apoptotic human T cell line. \nA human T lymphoid cell line, PEER, dies by apoptosis in the presence of PMA and calcium ionophore. A new gene, TINUR, was cloned from apoptotic PEER cells. The expression of the TINUR gene is induced within 1 h after the cross-linking of the T cell Ag receptor complex. TINUR belongs to the NGFI-B/nur77 family of the steroid receptor superfamily and is an orphan receptor. TINUR binds to the same DNA sequence as NGFI-B/nur77. We also propose that the NGFI-B/nur77 family can be classified into two subtypes. " ], "offsets": [ [ 0, 609 ] ] } ]

[ { "id": "7706727_T1", "type": "Protein", "text": [ "NGFI-B" ], "offsets": [ [ 18, 24 ] ], "normalized": [] }, { "id": "7706727_T2", "type": "Protein", "text": [ "nur77" ], "offsets": [ [ 25, 30 ] ], "normalized": [] }, { "id": "7706727_T3", "type": "Protein", "text": [ "TINUR" ], "offsets": [ [ 210, 215 ] ], "normalized": [] }, { "id": "7706727_T4", "type": "Protein", "text": [ "TINUR" ], "offsets": [ [ 277, 282 ] ], "normalized": [] }, { "id": "7706727_T5", "type": "Protein", "text": [ "TINUR" ], "offsets": [ [ 369, 374 ] ], "normalized": [] }, { "id": "7706727_T6", "type": "Protein", "text": [ "NGFI-B" ], "offsets": [ [ 390, 396 ] ], "normalized": [] }, { "id": "7706727_T7", "type": "Protein", "text": [ "nur77" ], "offsets": [ [ 397, 402 ] ], "normalized": [] }, { "id": "7706727_T8", "type": "Protein", "text": [ "TINUR" ], "offsets": [ [ 473, 478 ] ], "normalized": [] }, { "id": "7706727_T9", "type": "Protein", "text": [ "NGFI-B" ], "offsets": [ [ 513, 519 ] ], "normalized": [] }, { "id": "7706727_T10", "type": "Protein", "text": [ "nur77" ], "offsets": [ [ 520, 525 ] ], "normalized": [] }, { "id": "7706727_T11", "type": "Protein", "text": [ "NGFI-B" ], "offsets": [ [ 552, 558 ] ], "normalized": [] }, { "id": "7706727_T12", "type": "Protein", "text": [ "nur77" ], "offsets": [ [ 559, 564 ] ], "normalized": [] } ]

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[ { "id": "7706727_1", "entity_ids": [ "7706727_T1", "7706727_T2" ] }, { "id": "7706727_2", "entity_ids": [ "7706727_T11", "7706727_T12" ] }, { "id": "7706727_3", "entity_ids": [ "7706727_T9", "7706727_T10" ] }, { "id": "7706727_4", "entity_ids": [ "7706727_T6", "7706727_T7" ] } ]

[]

[ { "id": "9893043__text", "type": "abstract", "text": [ "CD2 signalling induces phosphorylation of CREB in primary lymphocytes. \nPromoter sequences responsive to cyclic AMP (cAMP) are found in a number of cellular genes, and bind transcription factors of the cAMP response element binding protein (CREB)/activating transcription factor-1 (ATF-1) family. We have used a human T-lymphotropic virus type 1 (HTLV-1) model of cAMP response element (CRE) transcription to investigate the influence of lymphocyte activation on transcription from homologous regions in the viral promoter. We previously demonstrated increased HTLV-1 transcription following CD2 but not CD3 receptor cross-linking. We hypothesized that this increased viral transcription was mediated, in part, through the phosphorylation of CREB. Therefore, we investigated CD2 and CD3 receptor-mediated signalling in primary human peripheral blood mononuclear cells (PBMC). CD2, but not CD3, cross-linking increased cAMP detected by competitive enzyme-linked immunosorbent assay (ELISA) approximately fourfold. CD2 cross-linking concurrently increased phosphorylation of CREB detected by immunoblot assay eightfold. Consistent with post-translational regulation, no change in total level of CREB protein was observed. Phosphorylation of CREB occurred through a herbimycin A and Rp-cAMP- sensitive pathway, suggesting phosphorylation required antecedent activation of both protein tyrosine kinases (PTK) and protein kinase A (PKA). Both CD2 and CD3 cross-linking increased binding of nuclear proteins to a radiolabelled CRE oligonucleotide probe in electrophoretic mobility shift assays suggesting that lymphocyte activation enhances binding independently of phosphorylation of CREB at serine 133. These data indicate specific modulation of the CREB/ATF-1 family of transcription factors by the CD2 signalling pathway and suggest CD2 receptor modulation of CRE-mediated transcription following ligand engagement (e.g. cell-to-cell contact). " ], "offsets": [ [ 0, 1942 ] ] } ]

[ { "id": "9893043_T1", "type": "Protein", "text": [ "CREB" ], "offsets": [ [ 42, 46 ] ], "normalized": [] }, { "id": "9893043_T2", "type": "Protein", "text": [ "cAMP response element binding protein" ], "offsets": [ [ 202, 239 ] ], "normalized": [] }, { "id": "9893043_T3", "type": "Protein", "text": [ "CREB" ], "offsets": [ [ 241, 245 ] ], "normalized": [] }, { "id": "9893043_T4", "type": "Protein", "text": [ "activating transcription factor-1" ], "offsets": [ [ 247, 280 ] ], "normalized": [] }, { "id": "9893043_T5", "type": "Protein", "text": [ "ATF-1" ], "offsets": [ [ 282, 287 ] ], "normalized": [] }, { "id": "9893043_T6", "type": "Protein", "text": [ "CD2" ], "offsets": [ [ 592, 595 ] ], "normalized": [] }, { "id": "9893043_T7", "type": "Protein", "text": [ "CREB" ], "offsets": [ [ 742, 746 ] ], "normalized": [] }, { "id": "9893043_T8", "type": "Protein", "text": [ "CD2" ], "offsets": [ [ 775, 778 ] ], "normalized": [] }, { "id": "9893043_T9", "type": "Protein", "text": [ "CD2" ], "offsets": [ [ 876, 879 ] ], "normalized": [] }, { "id": "9893043_T10", "type": "Protein", "text": [ "CD2" ], "offsets": [ [ 1013, 1016 ] ], "normalized": [] }, { "id": "9893043_T11", "type": "Protein", "text": [ "CREB" ], "offsets": [ [ 1073, 1077 ] ], "normalized": [] }, { "id": "9893043_T12", "type": "Protein", "text": [ "CREB" ], "offsets": [ [ 1193, 1197 ] ], "normalized": [] }, { "id": "9893043_T13", "type": "Protein", "text": [ "CREB" ], "offsets": [ [ 1239, 1243 ] ], "normalized": [] }, { "id": "9893043_T14", "type": "Protein", "text": [ "CD2" ], "offsets": [ [ 1438, 1441 ] ], "normalized": [] }, { "id": "9893043_T15", "type": "Protein", "text": [ "CREB" ], "offsets": [ [ 1679, 1683 ] ], "normalized": [] }, { "id": "9893043_T16", "type": "Protein", "text": [ "CREB" ], "offsets": [ [ 1746, 1750 ] ], "normalized": [] }, { "id": "9893043_T17", "type": "Protein", "text": [ "ATF-1" ], "offsets": [ [ 1751, 1756 ] ], "normalized": [] }, { "id": "9893043_T18", "type": "Protein", "text": [ "CD2" ], "offsets": [ [ 1796, 1799 ] ], "normalized": [] }, { "id": "9893043_T19", "type": "Protein", "text": [ "CD2 receptor" ], "offsets": [ [ 1831, 1843 ] ], "normalized": [] }, { "id": "9893043_T33", "type": "Entity", "text": [ "serine 133" ], "offsets": [ [ 1687, 1697 ] ], "normalized": [] } ]

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[]

[ { "id": "10330274__text", "type": "abstract", "text": [ "Paradoxical priming effects of IL-10 on cytokine production. \nIL-10 is a well-known immunosuppressive and/or anti-inflammatory cytokine. However, we report in vitro experimental studies in which IL-10 primed leukocytes and led to an enhanced production of tumor necrosis factor (TNF) upon further stimulation by lipopolysaccharide (LPS). Monocytes and peripheral blood mononuclear cells (PBMC) prepared from whole blood maintained for 20 h at 37 degrees C in the presence of recombinant human IL-10 had an enhanced capacity to produce TNF in response to LPS. In addition to TNF, LPS-induced IL-6 and spontaneous IL-1ra production were also enhanced. When isolated PBMC were first cultured for 20 h in the presence of IL-10 on Teflon to prevent adherence, washed to remove IL-10 and then further cultured in plastic dishes for an additional 20 h in the presence of LPS or IL-1beta, an enhanced release of TNF was observed. This was not the case when PBMC were pre-cultured in plastic multidishes in the presence of IL-10. TNF mRNA expression induced by LPS was decreased when the pre-treatment of PBMC with IL-10 was performed on plastic, whereas this was not the case when cells were pre-cultured with IL-10 on Teflon. Furthermore, NFkappaB translocation following LPS activation was higher after IL-10 pre-treatment on Teflon than on plastic. Interestingly, an enhanced frequency of CD16 and CD68(+) cells among the CD14(+) cells was observed in the presence of IL-10, independently of the pre-culture conditions of the PBMC. Altogether, these results indicate that the IL-10-induced up-regulation of cytokine production depends on the prevention of monocyte adherence by red cells in the whole blood assays or by cultures of PBMC on Teflon. In contrast, the adherence parameter has no effect on the IL-10-induced modulation of some monocyte surface markers. " ], "offsets": [ [ 0, 1860 ] ] } ]

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[ { "id": "1964088__text", "type": "abstract", "text": [ "Suppression of signals required for activation of transcription factor NF-kappa B in cells constitutively expressing the HTLV-I Tax protein. \nTransient short-term expression of the Tax protein of human T-cell leukemia virus type-I (HTLV-I) leads to activation of the pleiotropic transcription factor NF-kappa B. Consistent with findings obtained with transient expression assays, we observed marked accumulation of the transcription factor NF-kappa B in the nucleus of Namalwa B lymphoid cells, which constitutively express Tax. In contrast, NF-kappa B activity was not detected in the nucleus following long-term expression of Tax in Jurkat T lymphocytes. The ability of both mitogens and cytokines to activate NF-kappa B was also blocked in Jurkat cells constitutively expressing Tax. However, the activation of other mitogen-inducible transcription factors, such as Fos and Jun, was unaffected. Thus, depending on the cellular environment, the short- and long-term effects of Tax expression can be quite different. Consequently, one function of Tax in cells infected with HTLV-I might involve cell-type-specific suppression, as opposed to activation, of distinct signal pathways. The cells lines described here should be useful for the delineation of signaling pathways utilized in the selective regulation of gene expression. " ], "offsets": [ [ 0, 1330 ] ] } ]

[ { "id": "1964088_T1", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 128, 131 ] ], "normalized": [] }, { "id": "1964088_T2", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 181, 184 ] ], "normalized": [] }, { "id": "1964088_T3", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 524, 527 ] ], "normalized": [] }, { "id": "1964088_T4", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 628, 631 ] ], "normalized": [] }, { "id": "1964088_T5", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 782, 785 ] ], "normalized": [] }, { "id": "1964088_T6", "type": "Protein", "text": [ "Fos" ], "offsets": [ [ 869, 872 ] ], "normalized": [] }, { "id": "1964088_T7", "type": "Protein", "text": [ "Jun" ], "offsets": [ [ 877, 880 ] ], "normalized": [] }, { "id": "1964088_T8", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 979, 982 ] ], "normalized": [] }, { "id": "1964088_T9", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 1048, 1051 ] ], "normalized": [] } ]

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[ { "id": "8641467__text", "type": "abstract", "text": [ "Involvement of intracellular Ca2+ in oxidant-induced NF-kappa B activation. \nIn human Jurkat T cells and its subclone Wurzburg cells oxidant challenge elevated [Ca2+]i by mobilizing Ca2+ from intracellular stores. In Jurkat cells this effect was rapid and transient, but in Wurzburg cells the response was slow and sustained. H2O2-induced NF-kappaB activation in Wurzburg cells was not influenced by the presence of extracellular EGTA but was totally inhibited in cells that were loaded with esterified EGTA. In Jurkat cells that are not sensitive to H2O2-induced NF-kappaB activation, H2O2 potentiated NF-kappaB activation in the presence of sustained high [Ca2+]i following thapsigargin treatment. NF-kappaB regulatory effect of alpha-lipoate and N-acetylcysteine appeared to be, at least in part, due to their ability to stabilize elevation of [Ca2+]i following oxidant challenge. Results of this study indicate that a sustained elevated [Ca2+]i is a significant factor in oxidant-induced NF-kappaB activation. " ], "offsets": [ [ 0, 1014 ] ] } ]

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[ { "id": "7590249__text", "type": "abstract", "text": [ "Constitutive NF-kappa B activation, enhanced granulopoiesis, and neonatal lethality in I kappa B alpha-deficient mice. \nTranscription factors belonging to the NF-kappa B family are controlled by inhibitory I kappa B proteins, mainly I kappa B alpha and I kappa B beta. Apparently normal at birth, I kappa B alpha-/- mice exhibit severe runting, skin defects, and extensive granulopoiesis postnatally, typically dying by 8 days. Hematopoietic tissues from these mice display elevated levels of both nuclear NF-kappa B and mRNAs of some, but not all, genes thought to be regulated by NF-kappa B. NF-kappa B elevation results in these phenotypic abnormalities because mice lacking both I kappa B alpha and the p50 subunit of NF-kappa B show a dramatically delayed onset of abnormalities. In contrast to hematopoietic cells, I kappa B alpha-/- embryonic fibroblasts show minimal constitutive NF-kappa B, as well as normal signal-dependent NF-kappa B activation that is concomitant with I kappa B beta degradation. Our results indicate that I kappa b beta, but not I kappa B alpha, is required for the signal-dependent activation of NF-kappa B in fibroblasts. However, I kappa B alpha is required for the postinduction repression of NF-kappa B in fibroblasts. These results define distinct roles for the two forms of I kappa B and demonstrate the necessity for stringent control of NF-kappa B. " ], "offsets": [ [ 0, 1389 ] ] } ]

[ { "id": "7590249_T1", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 87, 102 ] ], "normalized": [] }, { "id": "7590249_T2", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 233, 248 ] ], "normalized": [] }, { "id": "7590249_T3", "type": "Protein", "text": [ "I kappa B beta" ], "offsets": [ [ 253, 267 ] ], "normalized": [] }, { "id": "7590249_T4", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 297, 312 ] ], "normalized": [] }, { "id": "7590249_T5", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 683, 698 ] ], "normalized": [] }, { "id": "7590249_T6", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 707, 710 ] ], "normalized": [] }, { "id": "7590249_T7", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 821, 836 ] ], "normalized": [] }, { "id": "7590249_T8", "type": "Protein", "text": [ "I kappa B beta" ], "offsets": [ [ 982, 996 ] ], "normalized": [] }, { "id": "7590249_T9", "type": "Protein", "text": [ "I kappa b beta" ], "offsets": [ [ 1036, 1050 ] ], "normalized": [] }, { "id": "7590249_T10", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 1060, 1075 ] ], "normalized": [] }, { "id": "7590249_T11", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 1164, 1179 ] ], "normalized": [] } ]

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[ { "id": "9843840__text", "type": "abstract", "text": [ "Activation of human macrophages by mechanical ventilation in vitro. \nPositive-pressure mechanical ventilation supports gas exchange in patients with respiratory failure but is also responsible for significant lung injury. In this study, we have developed an in vitro model in which isolated lung cells can be submitted to a prolonged cyclic pressure-stretching strain resembling that of conventional mechanical ventilation. In this model, cells cultured on a Silastic membrane were elongated up to 7% of their initial diameter, corresponding to a 12% increase in cell surface. The lung macrophage was identified as the main cellular source for critical inflammatory mediators such as tumor necrosis factor-alpha, the chemokines interleukin (IL)-8 and -6, and matrix metalloproteinase-9 in this model system of mechanical ventilation. These mediators were measured in supernatants from ventilated alveolar macrophages, monocyte-derived macrophages, and promonocytic THP-1 cells. Nuclear factor-kappaB was found to be activated in ventilated macrophages. Synergistic proinflammatory effects of mechanical stress and molecules such as bacterial endotoxin were observed, suggesting that mechanical ventilation might be particularly deleterious in preinjured or infected lungs. Dexamethasone prevented IL-8 and tumor necrosis factor-alpha secretion in ventilated macrophages. Mechanical ventilation induced low levels of IL-8 secretion by alveolar type II-like cells. Other lung cell types such as endothelial cells, bronchial cells, and fibroblasts failed to produce IL-8 in response to a prolonged cyclic pressure-stretching load. This model is of particular value for exploring physical stress-induced signaling pathways, as well as for testing the effects of novel ventilatory strategies or adjunctive substances aimed at modulating cell activation induced by mechanical ventilation. " ], "offsets": [ [ 0, 1883 ] ] } ]

[ { "id": "9843840_T1", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 684, 711 ] ], "normalized": [] }, { "id": "9843840_T2", "type": "Protein", "text": [ "interleukin (IL)-8" ], "offsets": [ [ 728, 746 ] ], "normalized": [] }, { "id": "9843840_T3", "type": "Protein", "text": [ "-6" ], "offsets": [ [ 751, 753 ] ], "normalized": [] }, { "id": "9843840_T4", "type": "Protein", "text": [ "matrix metalloproteinase-9" ], "offsets": [ [ 759, 785 ] ], "normalized": [] }, { "id": "9843840_T5", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1297, 1301 ] ], "normalized": [] }, { "id": "9843840_T6", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 1306, 1333 ] ], "normalized": [] }, { "id": "9843840_T7", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1416, 1420 ] ], "normalized": [] }, { "id": "9843840_T8", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1563, 1567 ] ], "normalized": [] } ]

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[ { "id": "7623828__text", "type": "abstract", "text": [ "A functional T-cell receptor signaling pathway is required for p95vav activity. \nStimulation of the T-cell antigen receptor (TCR) induces activation of multiple tyrosine kinases, resulting in phosphorylation of numerous intracellular substrates. One substrate is p95vav, which is expressed exclusively in hematopoietic and trophoblast cells. It contains a number of structural motifs, including Src homology 2, Src homology 3, and pleckstrin homology domains and a putative guanine nucleotide exchange domain. The role of p95vav in TCR-mediated signaling processes is unclear. Here, we show that overexpression of p95vav alone in Jurkat T cells leads to activation of the nuclear factors, including NFAT, involved in interleukin-2 expression. Furthermore, p95vav synergizes with TCR stimulation in inducing NFAT- and interleukin-2-dependent transcription. In contrast, NFAT activation by a G-protein-coupled receptor is not modulated by p95vav overexpression, suggesting that the effect is specific to the TCR signaling pathways. Although removal of the first 67 amino acids of p95vav activates its transforming potential in NIH 3T3 cells, this region appears to be required for its function in T cells. We further demonstrate that the p95vav-induced NFAT activation is not mimicked by Ras activation, though its function is dependent upon Ras and Raf. Furthermore, the activating function of p95vav is blocked by FK506, suggesting that its activity also depends on calcineurin. To further dissect p95vav involvement in TCR signaling, we analyzed various Jurkat mutants deficient in TCR signaling function or TCR expression and showed that an intact TCR signaling pathway is required for p95vav to function. However, overexpression of p95vav does not appear to influence TCR-induced protein tyrosine phosphorylation or increases in cytoplasmic free calcium. Taken together, our data suggest that p95vav plays an important role at an yet unidentified proximal position in the TCR signaling cascade. " ], "offsets": [ [ 0, 1998 ] ] } ]

[ { "id": "7623828_T1", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 63, 69 ] ], "normalized": [] }, { "id": "7623828_T2", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 263, 269 ] ], "normalized": [] }, { "id": "7623828_T3", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 522, 528 ] ], "normalized": [] }, { "id": "7623828_T4", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 614, 620 ] ], "normalized": [] }, { "id": "7623828_T5", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 717, 730 ] ], "normalized": [] }, { "id": "7623828_T6", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 756, 762 ] ], "normalized": [] }, { "id": "7623828_T7", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 817, 830 ] ], "normalized": [] }, { "id": "7623828_T8", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 937, 943 ] ], "normalized": [] }, { "id": "7623828_T9", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 1078, 1084 ] ], "normalized": [] }, { "id": "7623828_T10", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 1236, 1242 ] ], "normalized": [] }, { "id": "7623828_T11", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 1393, 1399 ] ], "normalized": [] }, { "id": "7623828_T12", "type": "Protein", "text": [ "calcineurin" ], "offsets": [ [ 1466, 1477 ] ], "normalized": [] }, { "id": "7623828_T13", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 1498, 1504 ] ], "normalized": [] }, { "id": "7623828_T14", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 1688, 1694 ] ], "normalized": [] }, { "id": "7623828_T15", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 1735, 1741 ] ], "normalized": [] }, { "id": "7623828_T16", "type": "Protein", "text": [ "p95vav" ], "offsets": [ [ 1896, 1902 ] ], "normalized": [] } ]

[ { "id": "7623828_E1", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 50, 58 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7623828_T1" } ] }, { "id": "7623828_E2", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 280, 289 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7623828_T2" } ] }, { "id": "7623828_E3", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 596, 610 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7623828_E4" } ] }, { "id": "7623828_E4", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 596, 610 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7623828_T4" } ] }, { "id": "7623828_E5", "type": "Regulation", "trigger": { "text": [ "involved" ], "offsets": [ [ 705, 713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7623828_E6" } ] }, { "id": "7623828_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 731, 741 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7623828_T5" } ] }, { "id": "7623828_E7", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 944, 958 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7623828_E8" } ] }, { "id": "7623828_E8", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 944, 958 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7623828_T8" } ] }, { "id": "7623828_E9", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1717, 1731 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7623828_T15" } ] }, { "id": "7623828_E10", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1717, 1731 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7623828_T15" } ] } ]

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[ { "id": "7510689__text", "type": "abstract", "text": [ "Thrombin and thrombin receptor agonist peptide induce early events of T cell activation and synergize with TCR cross-linking for CD69 expression and interleukin 2 production. \nThrombin stimulation of the T leukemic cell line Jurkat induced a transient increase in [Ca2+]i. Proteolytic activity of the enzyme was required for this effect since diisopropyl fluorophosphate-thrombin failed to increase [Ca2+]i. Furthermore, hirudin and anti-thrombin III inhibited the thrombin-induced [Ca2+]i rise in Jurkat T cells. A synthetic thrombin receptor agonist peptide (TRP) of 7 residues (SFLLRNP) was found to be as effective as thrombin for [Ca2+]i mobilization, and both agonists induced Ca2+ release exclusively from internal stores. Thrombin stimulated tyrosine phosphorylation of several proteins of molecular mass 40, 42, 70, 120, and 130 kDa. There was a good correlation between thrombin-induced tyrosine phosphorylation of the latter three proteins and Ca2+ mobilization. Thrombin and TRP also caused translocation of protein kinase C from the cytosol to the plasma membrane. As a likely consequence of these events, thrombin activated the nuclear factor NF-kB. Several cell lines of hematopoietic origin including the leukemic T cell line HPB.ALL and the erythroleukemic cell line K562 were responsive to thrombin, whereas others such as THP1, a myelomonocytic cell line, and BL2, a Burkitt lymphoma were refractory to thrombin or TRP stimulation. The magnitude of the thrombin response in the different cell types paralleled the expression of the thrombin receptor mRNA. We found that activation of Jurkat T cells by a combination of phytohemagglutinin and phorbol 12-myristate 13-acetate led to a dramatic inhibition of thrombin receptor mRNA expression and to a concomitant loss of the thrombin response. Finally, we demonstrate that thrombin and TRP enhanced CD69 expression and interleukin 2 production induced by T cell receptor cross-linking in both Jurkat T cells and peripheral blood lymphocytes. These findings highlight the role of thrombin as a potential regulator of T lymphocyte activation. " ], "offsets": [ [ 0, 2108 ] ] } ]

[ { "id": "7510689_T1", "type": "Protein", "text": [ "Thrombin" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "7510689_T2", "type": "Protein", "text": [ "CD69" ], "offsets": [ [ 129, 133 ] ], "normalized": [] }, { "id": "7510689_T3", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 149, 162 ] ], "normalized": [] }, { "id": "7510689_T4", "type": "Protein", "text": [ "Thrombin" ], "offsets": [ [ 176, 184 ] ], "normalized": [] }, { "id": "7510689_T5", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 371, 379 ] ], "normalized": [] }, { "id": "7510689_T6", "type": "Protein", "text": [ "thrombin III" ], "offsets": [ [ 438, 450 ] ], "normalized": [] }, { "id": "7510689_T7", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 465, 473 ] ], "normalized": [] }, { "id": "7510689_T8", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 622, 630 ] ], "normalized": [] }, { "id": "7510689_T9", "type": "Protein", "text": [ "Thrombin" ], "offsets": [ [ 730, 738 ] ], "normalized": [] }, { "id": "7510689_T10", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 880, 888 ] ], "normalized": [] }, { "id": "7510689_T11", "type": "Protein", "text": [ "Thrombin" ], "offsets": [ [ 974, 982 ] ], "normalized": [] }, { "id": "7510689_T12", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1119, 1127 ] ], "normalized": [] }, { "id": "7510689_T13", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1308, 1316 ] ], "normalized": [] }, { "id": "7510689_T14", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1422, 1430 ] ], "normalized": [] }, { "id": "7510689_T15", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1472, 1480 ] ], "normalized": [] }, { "id": "7510689_T16", "type": "Protein", "text": [ "thrombin receptor" ], "offsets": [ [ 1551, 1568 ] ], "normalized": [] }, { "id": "7510689_T17", "type": "Protein", "text": [ "phytohemagglutinin" ], "offsets": [ [ 1638, 1656 ] ], "normalized": [] }, { "id": "7510689_T18", "type": "Protein", "text": [ "thrombin receptor" ], "offsets": [ [ 1725, 1742 ] ], "normalized": [] }, { "id": "7510689_T19", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1792, 1800 ] ], "normalized": [] }, { "id": "7510689_T20", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1840, 1848 ] ], "normalized": [] }, { "id": "7510689_T21", "type": "Protein", "text": [ "CD69" ], "offsets": [ [ 1866, 1870 ] ], "normalized": [] }, { "id": "7510689_T22", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 1886, 1899 ] ], "normalized": [] }, { "id": "7510689_T23", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 2046, 2054 ] ], "normalized": [] } ]

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[ { "id": "8816454__text", "type": "abstract", "text": [ "Cloning and characterization of the beta subunit of human proximal sequence element-binding transcription factor and its involvement in transcription of small nuclear RNA genes by RNA polymerases II and III. \nThe proximal sequence element (PSE)-binding transcription factor (PTF), which binds the PSE of both RNA polymerase II- and RNA polymerase III-transcribed mammalian small nuclear RNA (snRNA) genes, is essential for their transcription. We previously reported the purification of human PTF, a complex of four subunits, and the molecular cloning and characterization of PTF gamma and delta subunits. Here we describe the isolation and expression of a cDNA encoding PTF beta, as well as functional studies using anti-PTF beta antibodies. Native PTF beta, in either protein fractions or a PTF-Oct-1-DNA complex, can be recognized by polyclonal antibodies raised against recombinant PTF beta. Immunodepletion studies show that PTF beta is required for transcription of both classes of snRNA genes in vitro. In addition, immunoprecipitation analyses demonstrate that substantial and similar molar amounts of TATA-binding protein (TBP) and TFIIIB90 can weakly associate with PTF at low salt conditions, but this association is dramatically reduced at high salt concentrations. Along with our previous demonstration of both physical interactions between PTF gamma/PTF delta and TBP and the involvement of TFIIIB90 in the transcription of class III snRNA genes, these results are consistent with the notion that a TBP-containing complex related to TFIIIB is required for the transcription of class III snRNA genes, and acts through weak interaction with the four-subunit PTF. " ], "offsets": [ [ 0, 1675 ] ] } ]

[ { "id": "8816454_T1", "type": "Protein", "text": [ "small nuclear RNA" ], "offsets": [ [ 153, 170 ] ], "normalized": [] }, { "id": "8816454_T2", "type": "Protein", "text": [ "small nuclear RNA" ], "offsets": [ [ 373, 390 ] ], "normalized": [] }, { "id": "8816454_T3", "type": "Protein", "text": [ "snRNA" ], "offsets": [ [ 392, 397 ] ], "normalized": [] }, { "id": "8816454_T4", "type": "Protein", "text": [ "PTF gamma" ], "offsets": [ [ 576, 585 ] ], "normalized": [] }, { "id": "8816454_T5", "type": "Protein", "text": [ "delta subunits" ], "offsets": [ [ 590, 604 ] ], "normalized": [] }, { "id": "8816454_T6", "type": "Protein", "text": [ "PTF beta" ], "offsets": [ [ 671, 679 ] ], "normalized": [] }, { "id": "8816454_T7", "type": "Protein", "text": [ "PTF beta" ], "offsets": [ [ 722, 730 ] ], "normalized": [] }, { "id": "8816454_T8", "type": "Protein", "text": [ "PTF beta" ], "offsets": [ [ 750, 758 ] ], "normalized": [] }, { "id": "8816454_T9", "type": "Protein", "text": [ "PTF beta" ], "offsets": [ [ 886, 894 ] ], "normalized": [] }, { "id": "8816454_T10", "type": "Protein", "text": [ "PTF beta" ], "offsets": [ [ 930, 938 ] ], "normalized": [] }, { "id": "8816454_T11", "type": "Protein", "text": [ "snRNA" ], "offsets": [ [ 988, 993 ] ], "normalized": [] }, { "id": "8816454_T12", "type": "Protein", "text": [ "TATA-binding protein" ], "offsets": [ [ 1110, 1130 ] ], "normalized": [] }, { "id": "8816454_T13", "type": "Protein", "text": [ "TBP" ], "offsets": [ [ 1132, 1135 ] ], "normalized": [] }, { "id": "8816454_T14", "type": "Protein", "text": [ "TFIIIB90" ], "offsets": [ [ 1141, 1149 ] ], "normalized": [] }, { "id": "8816454_T15", "type": "Protein", "text": [ "PTF gamma" ], "offsets": [ [ 1354, 1363 ] ], "normalized": [] }, { "id": "8816454_T16", "type": "Protein", "text": [ "PTF delta" ], "offsets": [ [ 1364, 1373 ] ], "normalized": [] }, { "id": "8816454_T17", "type": "Protein", "text": [ "TBP" ], "offsets": [ [ 1378, 1381 ] ], "normalized": [] }, { "id": "8816454_T18", "type": "Protein", "text": [ "TFIIIB90" ], "offsets": [ [ 1405, 1413 ] ], "normalized": [] }, { "id": "8816454_T19", "type": "Protein", "text": [ "snRNA" ], "offsets": [ [ 1448, 1453 ] ], "normalized": [] }, { "id": "8816454_T20", "type": "Protein", "text": [ "TBP" ], "offsets": [ [ 1513, 1516 ] ], "normalized": [] }, { "id": "8816454_T21", "type": "Protein", "text": [ "snRNA" ], "offsets": [ [ 1601, 1606 ] ], "normalized": [] } ]

[ { "id": "8816454_E1", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 136, 149 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T1" } ] }, { "id": "8816454_E2", "type": "Positive_regulation", "trigger": { "text": [ "by" ], "offsets": [ [ 177, 179 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_E1" } ] }, { "id": "8816454_E3", "type": "Binding", "trigger": { "text": [ "binds" ], "offsets": [ [ 287, 292 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T3" } ] }, { "id": "8816454_E4", "type": "Transcription", "trigger": { "text": [ "transcribed" ], "offsets": [ [ 351, 362 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T3" } ] }, { "id": "8816454_E5", "type": "Positive_regulation", "trigger": { "text": [ "transcribed" ], "offsets": [ [ 351, 362 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_E4" } ] }, { "id": "8816454_E6", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 409, 418 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_E7" } ] }, { "id": "8816454_E7", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 429, 442 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T3" } ] }, { "id": "8816454_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 641, 651 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T6" } ] }, { "id": "8816454_E9", "type": "Binding", "trigger": { "text": [ "recognized" ], "offsets": [ [ 823, 833 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T8" } ] }, { "id": "8816454_E10", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 942, 950 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_E11" }, { "role": "Cause", "ref_id": "8816454_T10" } ] }, { "id": "8816454_E11", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 955, 968 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T11" } ] }, { "id": "8816454_E12", "type": "Binding", "trigger": { "text": [ "associate" ], "offsets": [ [ 1161, 1170 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T13" } ] }, { "id": "8816454_E13", "type": "Binding", "trigger": { "text": [ "associate" ], "offsets": [ [ 1161, 1170 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T14" } ] }, { "id": "8816454_E14", "type": "Binding", "trigger": { "text": [ "physical interactions" ], "offsets": [ [ 1324, 1345 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T15" }, { "role": "Theme", "ref_id": "8816454_T17" } ] }, { "id": "8816454_E15", "type": "Binding", "trigger": { "text": [ "physical interactions" ], "offsets": [ [ 1324, 1345 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T16" }, { "role": "Theme", "ref_id": "8816454_T17" } ] }, { "id": "8816454_E16", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1421, 1434 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T19" } ] }, { "id": "8816454_E17", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 1557, 1565 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_E18" } ] }, { "id": "8816454_E18", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1574, 1587 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T21" } ] }, { "id": "8816454_E19", "type": "Positive_regulation", "trigger": { "text": [ "acts" ], "offsets": [ [ 1618, 1622 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_E17" }, { "role": "Cause", "ref_id": "8816454_E21" } ] }, { "id": "8816454_E20", "type": "Positive_regulation", "trigger": { "text": [ "acts" ], "offsets": [ [ 1618, 1622 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_E17" } ] }, { "id": "8816454_E21", "type": "Binding", "trigger": { "text": [ "interaction" ], "offsets": [ [ 1636, 1647 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816454_T20" } ] } ]

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[ { "id": "9052839__text", "type": "abstract", "text": [ "TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95). \nA novel member of the tumor necrosis factor (TNF) receptor family, designated TRAMP, has been identified. The structural organization of the 393 amino acid long human TRAMP is most homologous to TNF receptor 1. TRAMP is abundantly expressed on thymocytes and lymphocytes. Its extracellular domain is composed of four cysteine-rich domains, and the cytoplasmic region contains a death domain known to signal apoptosis. Overexpression of TRAMP leads to two major responses, NF-kappaB activation and apoptosis. TRAMP-induced cell death is inhibited by an inhibitor of ICE-like proteases, but not by Bcl-2. In addition, TRAMP does not appear to interact with any of the known apoptosis-inducing ligands of the TNF family. " ], "offsets": [ [ 0, 843 ] ] } ]

[ { "id": "9052839_T1", "type": "Protein", "text": [ "TRAMP" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "9052839_T2", "type": "Protein", "text": [ "tumor necrosis factor receptor 1" ], "offsets": [ [ 70, 102 ] ], "normalized": [] }, { "id": "9052839_T3", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 107, 110 ] ], "normalized": [] }, { "id": "9052839_T4", "type": "Protein", "text": [ "Apo-1" ], "offsets": [ [ 111, 116 ] ], "normalized": [] }, { "id": "9052839_T5", "type": "Protein", "text": [ "CD95" ], "offsets": [ [ 117, 121 ] ], "normalized": [] }, { "id": "9052839_T6", "type": "Protein", "text": [ "TRAMP" ], "offsets": [ [ 203, 208 ] ], "normalized": [] }, { "id": "9052839_T7", "type": "Protein", "text": [ "TRAMP" ], "offsets": [ [ 292, 297 ] ], "normalized": [] }, { "id": "9052839_T8", "type": "Protein", "text": [ "TNF receptor 1" ], "offsets": [ [ 320, 334 ] ], "normalized": [] }, { "id": "9052839_T9", "type": "Protein", "text": [ "TRAMP" ], "offsets": [ [ 336, 341 ] ], "normalized": [] }, { "id": "9052839_T10", "type": "Protein", "text": [ "TRAMP" ], "offsets": [ [ 561, 566 ] ], "normalized": [] }, { "id": "9052839_T11", "type": "Protein", "text": [ "TRAMP" ], "offsets": [ [ 633, 638 ] ], "normalized": [] }, { "id": "9052839_T12", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 721, 726 ] ], "normalized": [] }, { "id": "9052839_T13", "type": "Protein", "text": [ "TRAMP" ], "offsets": [ [ 741, 746 ] ], "normalized": [] } ]

[ { "id": "9052839_E1", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 356, 365 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9052839_T9" } ] }, { "id": "9052839_E2", "type": "Positive_regulation", "trigger": { "text": [ "Overexpression" ], "offsets": [ [ 543, 557 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9052839_T10" } ] }, { "id": "9052839_E3", "type": "Binding", "trigger": { "text": [ "interact" ], "offsets": [ [ 766, 774 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9052839_T13" } ] } ]

[ { "id": "9052839_1", "entity_ids": [ "9052839_T4", "9052839_T5" ] } ]

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[ { "id": "10477683__text", "type": "abstract", "text": [ "c-Maf induces monocytic differentiation and apoptosis in bipotent myeloid progenitors. \nThe transcriptional mechanisms that drive colony-forming unit granulocyte-macrophage (CFU-GM) myeloid progenitors to differentiate into cells of either the granulocytic or monocytic lineage are not fully understood. We have shown that the c-Maf and c-Myb transcription factors physically interact in myeloid cells to form inhibitory complexes that hinder transactivation of c-Myb target genes through direct binding to Myb consensus sites. These complexes arise in a developmentally regulated pattern, peaking at the promyelocyte stage, or in cell model systems, appearing soon after the induction of monocytic differentiation. We wished to determine if this developmentally related interaction is a consequence of myeloid differentiation or an intrinsic differentiating stimulus. Because the elevated Myb:Maf status seen in differentiating cells can be recapitulated by overexpression of c-Maf in myeloid cell lines, we inducibly expressed the c-Maf cDNA in 2 bipotent human myeloid progenitor cells. Elevated levels of c-Maf protein led to marked increases in Myb:Maf complexes and the accumulation of monocyte/macrophage cells, followed by eventual programmed cell death. Analysis of targets that could mediate these phenotypic changes indicated that c-Maf likely plays a key role in myeloid cell development through dual mechanisms; inhibition of a select set of c-Myb regulated targets, such as Bcl-2 and CD13/APN, coupled with the activation of as yet undefined differentiation-promoting genes. " ], "offsets": [ [ 0, 1589 ] ] } ]

[ { "id": "10477683_T1", "type": "Protein", "text": [ "c-Maf" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "10477683_T2", "type": "Protein", "text": [ "c-Maf" ], "offsets": [ [ 327, 332 ] ], "normalized": [] }, { "id": "10477683_T3", "type": "Protein", "text": [ "c-Myb" ], "offsets": [ [ 337, 342 ] ], "normalized": [] }, { "id": "10477683_T4", "type": "Protein", "text": [ "c-Myb" ], "offsets": [ [ 462, 467 ] ], "normalized": [] }, { "id": "10477683_T5", "type": "Protein", "text": [ "c-Maf" ], "offsets": [ [ 977, 982 ] ], "normalized": [] }, { "id": "10477683_T6", "type": "Protein", "text": [ "c-Maf" ], "offsets": [ [ 1033, 1038 ] ], "normalized": [] }, { "id": "10477683_T7", "type": "Protein", "text": [ "c-Maf" ], "offsets": [ [ 1109, 1114 ] ], "normalized": [] }, { "id": "10477683_T8", "type": "Protein", "text": [ "c-Maf" ], "offsets": [ [ 1342, 1347 ] ], "normalized": [] }, { "id": "10477683_T9", "type": "Protein", "text": [ "c-Myb" ], "offsets": [ [ 1455, 1460 ] ], "normalized": [] }, { "id": "10477683_T10", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1488, 1493 ] ], "normalized": [] }, { "id": "10477683_T11", "type": "Protein", "text": [ "CD13" ], "offsets": [ [ 1498, 1502 ] ], "normalized": [] }, { "id": "10477683_T12", "type": "Protein", "text": [ "APN" ], "offsets": [ [ 1503, 1506 ] ], "normalized": [] } ]

[ { "id": "10477683_E1", "type": "Binding", "trigger": { "text": [ "physically interact" ], "offsets": [ [ 365, 384 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10477683_T2" }, { "role": "Theme", "ref_id": "10477683_T3" } ] }, { "id": "10477683_E2", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 959, 973 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10477683_E3" } ] }, { "id": "10477683_E3", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 959, 973 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10477683_T5" } ] }, { "id": "10477683_E4", "type": "Positive_regulation", "trigger": { "text": [ "Elevated levels" ], "offsets": [ [ 1090, 1105 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10477683_T7" } ] }, { "id": "10477683_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1425, 1435 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10477683_T11" }, { "role": "Cause", "ref_id": "10477683_T8" } ] }, { "id": "10477683_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 1425, 1435 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10477683_T10" }, { "role": "Cause", "ref_id": "10477683_T8" } ] }, { "id": "10477683_E7", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1461, 1470 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10477683_T11" }, { "role": "Cause", "ref_id": "10477683_T9" } ] }, { "id": "10477683_E8", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1461, 1470 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10477683_T10" }, { "role": "Cause", "ref_id": "10477683_T9" } ] } ]

[ { "id": "10477683_1", "entity_ids": [ "10477683_T11", "10477683_T12" ] } ]

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[ { "id": "8436816__text", "type": "abstract", "text": [ "Protease treatment of nuclear extracts distinguishes between class II MHC X1 box DNA-binding proteins in wild-type and class II-deficient B cells. \nThe X box region is critical for directing the expression of class II major histocompatibility complex genes in B lymphocytes. Although several class II promoter-specific DNA binding factors have been described, only the X box region factor, RFX, shows a genetic correlation with class II expression, being deficient in some B cell lines derived from patients with class II-deficient congenital immunodeficiency. To further evaluate the role of X box DNA-binding proteins in class II gene expression, the role of the X box region was examined in both class II-positive and -negative lymphoid cells. In addition to the wild-type B cell line Raji, two class II transcriptional mutant cell lines, SJO and RJ2.2.5, and Jurkat, a class II negative T cell line, were examined. In contrast to wild-type B cells, neither of the class II mutant cell lines could use the X box region to direct the expression of a transiently transfected reporter gene, indicating that the X box-dependent transcriptional pathway is defective in these cells. The binding activity of the X1 box DNA-binding protein RFX was examined and found to be present in wild-type B cells and the mutant RJ2.2.5 but was absent in SJO and Jurkat. However, other X1 box-specific activities were detected in all these cell lines. To determine whether these different X1 box activities represented distinct DNA binding proteins or multimeric forms of the same factor(s), protease treatment of the crude nuclear extracts followed by DNA-binding assays were carried out and demonstrated that B cell extracts contain at least two X1-specific factors. One of these cleaved products (band 1 pk) correlates with RFX activity. A similar comparison with protease-treated extracts prepared from Jurkat cells demonstrated the presence of the band 1pk activity despite an absence of the native RFX activity. In contrast, protease treatment and analysis of SJO extracts showed no detectable levels of the band 1pk activity. These results demonstrate that multiple X1 box-specific DNA-binding activities exist in all lymphoid cells, but the presence of an actively binding RFX species correlates with class II transcription. " ], "offsets": [ [ 0, 2316 ] ] } ]

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[ { "id": "2111447__text", "type": "abstract", "text": [ "Involvement of a second lymphoid-specific enhancer element in the regulation of immunoglobulin heavy-chain gene expression. \nTo determine whether enhancer elements in addition to the highly conserved octamer (OCTA)-nucleotide motif are important for lymphoid-specific expression of the immunoglobulin heavy-chain (IgH) gene, we have investigated the effect of mutating the binding site for a putative additional lymphoid-specific transcription factor, designated NF-microB, in the murine IgH enhancer. We demonstrate that the NF-microB-binding site plays a critical role in the IgH enhancer, because mutation of the microB DNA motif decreased transcriptional activity of the IgH enhancer in cells of the B-cell lineage but not in nonlymphoid cells. This effect was comparable to or even stronger than the effect of a mutation in the OCTA site. Moreover, combined mutation of both microB and OCTA sites further reduced enhancer activity in lymphoid cells. Interestingly, alteration of either the microB or E3 site in a 70-base-pair fragment of the IgH enhancer that lacks the binding site for OCTA abolished enhancer activity in lymphoid cells completely. Nevertheless, a multimer of the microB motif alone showed no enhancer activity. DNase footprinting analysis corroborated the functional data showing that a lymphoid-specific protein binds to the microB DNA motif. Our results suggest that the microB element is a new crucial element important for lymphoid-specific expression of the IgH gene but that interaction with another enhancer element is essential for its activity. " ], "offsets": [ [ 0, 1578 ] ] } ]

[ { "id": "2111447_T1", "type": "Protein", "text": [ "NF-microB" ], "offsets": [ [ 463, 472 ] ], "normalized": [] }, { "id": "2111447_T2", "type": "Protein", "text": [ "NF-microB" ], "offsets": [ [ 526, 535 ] ], "normalized": [] } ]

[ { "id": "2111447_E1", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 373, 380 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2111447_T1" } ] } ]

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[ { "id": "10426995__text", "type": "abstract", "text": [ "Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. \nThe generation of cell-mediated immunity against many infectious pathogens involves the production of interleukin-12 (IL-12), a key signal of the innate immune system. Yet, for many pathogens, the molecules that induce IL-12 production by macrophages and the mechanisms by which they do so remain undefined. Here it is shown that microbial lipoproteins are potent stimulators of IL-12 production by human macrophages, and that induction is mediated by Toll-like receptors (TLRs). Several lipoproteins stimulated TLR-dependent transcription of inducible nitric oxide synthase and the production of nitric oxide, a powerful microbicidal pathway. Activation of TLRs by microbial lipoproteins may initiate innate defense mechanisms against infectious pathogens. " ], "offsets": [ [ 0, 848 ] ] } ]

[ { "id": "10426995_T1", "type": "Protein", "text": [ "interleukin-12" ], "offsets": [ [ 192, 206 ] ], "normalized": [] }, { "id": "10426995_T2", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 208, 213 ] ], "normalized": [] }, { "id": "10426995_T3", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 309, 314 ] ], "normalized": [] }, { "id": "10426995_T4", "type": "Protein", "text": [ "IL-12" ], "offsets": [ [ 469, 474 ] ], "normalized": [] }, { "id": "10426995_T5", "type": "Protein", "text": [ "nitric oxide synthase" ], "offsets": [ [ 643, 664 ] ], "normalized": [] } ]

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[ { "id": "10426995_1", "entity_ids": [ "10426995_T1", "10426995_T2" ] } ]

[]

[ { "id": "8077662__text", "type": "abstract", "text": [ "Induction of IL-8 expression in T cells uses the CD28 costimulatory pathway. \nIL-8, a potent chemotactic factor for neutrophil granulocytes and lymphocytes, is a proinflammatory cytokine secreted by a variety of cell types, including T cells. Stimulation of the CD28 cell surface molecule delivers costimulatory signals essential for lymphokine production in activated T cells via a conserved sequence element found in the promoter of several lymphokine genes. Anti-CD28-stimulated T cells produced significant amounts of IL-8; additionally, costimulation with anti-CD3 and anti-CD28 Abs resulted in a synergistic induction of IL-8 secretion. Sequence homology, single nucleotide mutations, and anti-CD28 Ab stimulation studies established that the NF-kappa B-like sequence in the promoter of the IL-8 gene functioned as a CD28 response element. Furthermore, cyclosporin A, but not rapamycin, blocked the synergistic induction of IL-8 expression achieved with anti-CD3 and anti-CD28 costimulation. The involvement of a CD28 response element in the induction of IL-8 expression in activated T cells may provide new insights into the pathogenesis and persistence of immune disorders characterized by increased levels of IL-8, such as psoriasis and rheumatoid arthritis. " ], "offsets": [ [ 0, 1268 ] ] } ]

[ { "id": "8077662_T1", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 13, 17 ] ], "normalized": [] }, { "id": "8077662_T2", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 49, 53 ] ], "normalized": [] }, { "id": "8077662_T3", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 78, 82 ] ], "normalized": [] }, { "id": "8077662_T4", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 262, 266 ] ], "normalized": [] }, { "id": "8077662_T5", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 466, 470 ] ], "normalized": [] }, { "id": "8077662_T6", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 522, 526 ] ], "normalized": [] }, { "id": "8077662_T7", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 579, 583 ] ], "normalized": [] }, { "id": "8077662_T8", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 627, 631 ] ], "normalized": [] }, { "id": "8077662_T9", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 700, 704 ] ], "normalized": [] }, { "id": "8077662_T10", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 797, 801 ] ], "normalized": [] }, { "id": "8077662_T11", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 823, 827 ] ], "normalized": [] }, { "id": "8077662_T12", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 930, 934 ] ], "normalized": [] }, { "id": "8077662_T13", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 978, 982 ] ], "normalized": [] }, { "id": "8077662_T14", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1019, 1023 ] ], "normalized": [] }, { "id": "8077662_T15", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1061, 1065 ] ], "normalized": [] }, { "id": "8077662_T16", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1218, 1222 ] ], "normalized": [] }, { "id": "8077662_T26", "type": "Entity", "text": [ "NF-kappa B-like sequence" ], "offsets": [ [ 749, 773 ] ], "normalized": [] } ]

[ { "id": "8077662_E1", "type": "Positive_regulation", "trigger": { "text": [ "Induction" ], "offsets": [ [ 0, 9 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_E2" } ] }, { "id": "8077662_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 18, 28 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_T1" } ] }, { "id": "8077662_E3", "type": "Positive_regulation", "trigger": { "text": [ "uses" ], "offsets": [ [ 40, 44 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_E1" } ] }, { "id": "8077662_E4", "type": "Localization", "trigger": { "text": [ "secreted" ], "offsets": [ [ 187, 195 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_T3" } ] }, { "id": "8077662_E5", "type": "Positive_regulation", "trigger": { "text": [ "Stimulation" ], "offsets": [ [ 243, 254 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_T4" } ] }, { "id": "8077662_E6", "type": "Gene_expression", "trigger": { "text": [ "produced" ], "offsets": [ [ 490, 498 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_T6" } ] }, { "id": "8077662_E7", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 588, 596 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_E8" } ] }, { "id": "8077662_E8", "type": "Positive_regulation", "trigger": { "text": [ "synergistic induction" ], "offsets": [ [ 602, 623 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_E9" } ] }, { "id": "8077662_E9", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 632, 641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_T8" } ] }, { "id": "8077662_E10", "type": "Regulation", "trigger": { "text": [ "response" ], "offsets": [ [ 828, 836 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_T10" }, { "role": "Cause", "ref_id": "8077662_T11" }, { "role": "Site", "ref_id": "8077662_T26" } ] }, { "id": "8077662_E11", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 893, 900 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_E12" } ] }, { "id": "8077662_E12", "type": "Positive_regulation", "trigger": { "text": [ "synergistic induction" ], "offsets": [ [ 905, 926 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_E13" } ] }, { "id": "8077662_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 935, 945 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_T12" } ] }, { "id": "8077662_E14", "type": "Positive_regulation", "trigger": { "text": [ "involvement" ], "offsets": [ [ 1002, 1013 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_E15" } ] }, { "id": "8077662_E15", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1048, 1057 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_E16" } ] }, { "id": "8077662_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1066, 1076 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_T15" } ] }, { "id": "8077662_E17", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1198, 1207 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_E18" } ] }, { "id": "8077662_E18", "type": "Gene_expression", "trigger": { "text": [ "levels" ], "offsets": [ [ 1208, 1214 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8077662_T16" } ] } ]

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[ { "id": "1987353__text", "type": "abstract", "text": [ "The NF kappa B independent cis-acting sequences in HIV-1 LTR responsive to T-cell activation. \nThe rate of transcription initiation directed by the long terminal repeat (LTR) of HIV-1 increases in response to mitogenic stimuli of T cells. Here we show that the response of the HIV-1 LTR may be governed by two independent sequences located 5' to the site of transcription initiation sequences that bind either NFAT-1 or NF kappa B. The rate of LTR-directed gene expression increased in response to treatment with either a phorbol ester or tumor necrosis factor alpha if either the NFAT-1 or NF kappa B binding sites were deleted, but failed to respond to these mitogenic stimuli if both sequences were absent. The HIV-1 mutant virus containing both NF kappa B and NFAT-1 deletion was able to replicate although at a much decreased growth rate, while the deletion of NFAT-1 alone increased the viral growth rate in Jurkat cells. Neither deletion of NF kappa B nor deletion of NFAT-1 decreased activation of viral replication by phorbol ester. " ], "offsets": [ [ 0, 1042 ] ] } ]

[ { "id": "1987353_T1", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 410, 416 ] ], "normalized": [] }, { "id": "1987353_T2", "type": "Protein", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 539, 566 ] ], "normalized": [] }, { "id": "1987353_T3", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 581, 587 ] ], "normalized": [] }, { "id": "1987353_T4", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 764, 770 ] ], "normalized": [] }, { "id": "1987353_T5", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 866, 872 ] ], "normalized": [] }, { "id": "1987353_T6", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 975, 981 ] ], "normalized": [] } ]

[ { "id": "1987353_E1", "type": "Binding", "trigger": { "text": [ "bind" ], "offsets": [ [ 398, 402 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1987353_T1" } ] } ]

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[ { "id": "9748323__text", "type": "abstract", "text": [ "Activation of distinct transcription factors in neutrophils by bacterial LPS, interferon-gamma, and GM-CSF and the necessity to overcome the action of endogenous proteases. \nHuman neutrophils can be induced to actively transcribe a number of early-response genes, in particular those encoding cytokines, chemokines, and the high-affinity surface receptor for IgG, FcgammaRI. Although little is known to date about the regulation of gene transcription in neutrophils, several indications point to a role for distinct transcription factors, such as members of the NF-kappaB and STAT families. In this study, we investigated whether these transcription factors become activated under stimulatory conditions which are known to induce gene transcription in neutrophils. Unexpectedly, we found that conventional procedures employed to prepare cellular extracts cause the release of proteolytic activities that are normally stored in intracellular granules, resulting in the degradation of various NF-kappaB/Rel and STAT proteins. To circumvent this problem, we developed an alternative procedure which allowed us to show that in neutrophils, LPS and TNFalpha induce a NF-kappaB DNA-binding activity which essentially consists of p50/RelA dimers, and that IFNgamma promotes the binding of STAT1 homodimers to the IFNgamma response region of the FcgammaRI promoter. Moreover, we report that neutrophil stimulation with GM-CSF results in the formation of a STAT5-containing DNA-binding activity. Collectively, the current findings open new perspectives about mechanisms that are likely to regulate gene transcription in neutrophils. In addition, the procedure described herein could prove useful in other cell types that express high levels of endogenous proteases. " ], "offsets": [ [ 0, 1757 ] ] } ]

[ { "id": "9748323_T1", "type": "Protein", "text": [ "interferon-gamma" ], "offsets": [ [ 78, 94 ] ], "normalized": [] }, { "id": "9748323_T2", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 100, 106 ] ], "normalized": [] }, { "id": "9748323_T3", "type": "Protein", "text": [ "FcgammaRI" ], "offsets": [ [ 364, 373 ] ], "normalized": [] }, { "id": "9748323_T4", "type": "Protein", "text": [ "TNFalpha" ], "offsets": [ [ 1144, 1152 ] ], "normalized": [] }, { "id": "9748323_T5", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1223, 1226 ] ], "normalized": [] }, { "id": "9748323_T6", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 1227, 1231 ] ], "normalized": [] }, { "id": "9748323_T7", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1249, 1257 ] ], "normalized": [] }, { "id": "9748323_T8", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1282, 1287 ] ], "normalized": [] }, { "id": "9748323_T9", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1306, 1314 ] ], "normalized": [] }, { "id": "9748323_T10", "type": "Protein", "text": [ "FcgammaRI" ], "offsets": [ [ 1338, 1347 ] ], "normalized": [] }, { "id": "9748323_T11", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 1411, 1417 ] ], "normalized": [] } ]

[ { "id": "9748323_E1", "type": "Positive_regulation", "trigger": { "text": [ "Activation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9748323_T2" } ] }, { "id": "9748323_E2", "type": "Positive_regulation", "trigger": { "text": [ "Activation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9748323_T1" } ] }, { "id": "9748323_E3", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 199, 206 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9748323_E4" } ] }, { "id": "9748323_E4", "type": "Transcription", "trigger": { "text": [ "transcribe" ], "offsets": [ [ 219, 229 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9748323_T3" } ] }, { "id": "9748323_E5", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1176, 1183 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9748323_T5" } ] }, { "id": "9748323_E6", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1176, 1183 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9748323_T6" } ] }, { "id": "9748323_E7", "type": "Positive_regulation", "trigger": { "text": [ "promotes" ], "offsets": [ [ 1258, 1266 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9748323_E8" }, { "role": "Cause", "ref_id": "9748323_T7" } ] }, { "id": "9748323_E8", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1271, 1278 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9748323_T8" } ] } ]

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[ { "id": "7823943__text", "type": "abstract", "text": [ "Distinct roles of the molecular chaperone hsp90 in modulating dioxin receptor function via the basic helix-loop-helix and PAS domains. \nThe intracellular dioxin receptor mediates signal transduction by dioxin and functions as a ligand-activated transcription factor. It contains a basic helix-loop-helix (bHLH) motif contiguous with a Per-Arnt-Sim (PAS) homology region. In extracts from nonstimulated cells the receptor is recovered in an inducible cytoplasmic form associated with the 90-kDa heat shock protein (hsp90), a molecular chaperone. We have reconstituted ligand-dependent activation of the receptor to a DNA-binding form by using the dioxin receptor and its bHLH-PAS partner factor Arnt expressed by in vitro translation in reticulocyte lysate. Deletion of the PAS domain of the receptor resulted in constitutive dimerization with Arnt. In contrast, this receptor mutant showed low levels of xenobiotic response element-binding activity, indicating that the PAS domain may be important for DNA-binding affinity and/or specificity of the receptor. It was not possible to reconstitute dioxin receptor function with proteins expressed in wheat germ lysate. In line with these observations, reticulocyte lysate but not wheat germ lysate promoted the association of de novo synthesized dioxin receptor with hsp90. At least two distinct domains of the receptor mediated interaction with hsp90: the ligand-binding domain located within the PAS region and, surprisingly, the bHLH domain. Whereas ligand-binding activity correlated with association with hsp90, bHLH-hsp90 interaction appeared to be important for DNA-binding activity but not for dimerization of the receptor. Several distinct roles for hsp90 in modulating dioxin receptor function are therefore likely: correct folding of the ligand-binding domain, interference with Arnt heterodimerization, and folding of a DNA-binding conformation of the bHLH domain. Thus, the dioxin receptor system provides a complex and interesting model of the regulation of transcription factors by hsp90. " ], "offsets": [ [ 0, 2051 ] ] } ]

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[ { "id": "8816436__text", "type": "abstract", "text": [ "Cell-type-specific regulation of the human tumor necrosis factor alpha gene in B cells and T cells by NFATp and ATF-2/JUN. \nThe human tumor necrosis factor alpha (TNF-alpha) gene is one of the earliest genes transcribed after the stimulation of a B cell through its antigen receptor or via the CD-40 pathway. In both cases, induction of TNF-alpha gene transcription can be blocked by the immunosuppressants cyclosporin A and FK506, which suggested a role for the NFAT family of proteins in the regulation of the gene in B cells. Furthermore, in T cells, two molecules of NFATp bind to the TNF-alpha promoter element kappa 3 in association with ATF-2 and Jun proteins bound to an immediately adjacent cyclic AMP response element (CRE) site. Here, using the murine B-cell lymphoma cell line A20, we show that the TNF-alpha gene is regulated in a cell-type-specific manner. In A20 B cells, the TNF-alpha gene is not regulated by NFATp bound to the kappa 3 element. Instead, ATF-2 and Jun proteins bind to the composite kappa 3/CRE site and NFATp binds to a newly identified second NFAT site centered at -76 nucleotides relative to the TNF-alpha transcription start site. This new site plays a critical role in the calcium-mediated, cyclosporin A-sensitive induction of TNF-alpha in both A20 B cells and Ar-5 cells. Consistent with these results, quantitative DNase footprinting of the TNF-alpha promoter using increasing amounts of recombinant NFATp demonstrated that the -76 site binds to NFATp with a higher affinity than the kappa 3 site. Two other previously unrecognized NFATp-binding sites in the proximal TNF-alpha promoter were also identified by this analysis. Thus, through the differential use of the same promoter element, the composite kappa 3/CRE site, the TNF-alpha gene is regulated in a cell-type-specific manner in response to the same extracellular signal. " ], "offsets": [ [ 0, 1873 ] ] } ]

[ { "id": "8816436_T1", "type": "Protein", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 43, 70 ] ], "normalized": [] }, { "id": "8816436_T2", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 102, 107 ] ], "normalized": [] }, { "id": "8816436_T3", "type": "Protein", "text": [ "ATF-2" ], "offsets": [ [ 112, 117 ] ], "normalized": [] }, { "id": "8816436_T4", "type": "Protein", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 134, 161 ] ], "normalized": [] }, { "id": "8816436_T5", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 163, 172 ] ], "normalized": [] }, { "id": "8816436_T6", "type": "Protein", "text": [ "CD-40" ], "offsets": [ [ 294, 299 ] ], "normalized": [] }, { "id": "8816436_T7", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 337, 346 ] ], "normalized": [] }, { "id": "8816436_T8", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 571, 576 ] ], "normalized": [] }, { "id": "8816436_T9", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 589, 598 ] ], "normalized": [] }, { "id": "8816436_T10", "type": "Protein", "text": [ "ATF-2" ], "offsets": [ [ 644, 649 ] ], "normalized": [] }, { "id": "8816436_T11", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 811, 820 ] ], "normalized": [] }, { "id": "8816436_T12", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 891, 900 ] ], "normalized": [] }, { "id": "8816436_T13", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 926, 931 ] ], "normalized": [] }, { "id": "8816436_T14", "type": "Protein", "text": [ "ATF-2" ], "offsets": [ [ 971, 976 ] ], "normalized": [] }, { "id": "8816436_T15", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 1037, 1042 ] ], "normalized": [] }, { "id": "8816436_T16", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1132, 1141 ] ], "normalized": [] }, { "id": "8816436_T17", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1266, 1275 ] ], "normalized": [] }, { "id": "8816436_T18", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1382, 1391 ] ], "normalized": [] }, { "id": "8816436_T19", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 1441, 1446 ] ], "normalized": [] }, { "id": "8816436_T20", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 1487, 1492 ] ], "normalized": [] }, { "id": "8816436_T21", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 1573, 1578 ] ], "normalized": [] }, { "id": "8816436_T22", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1609, 1618 ] ], "normalized": [] }, { "id": "8816436_T23", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1768, 1777 ] ], "normalized": [] } ]

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[ { "id": "9720648__text", "type": "abstract", "text": [ "Nuclear factor-kappaB induction in CD45RO+ and CD45RA+ T cell subsets during aging. \nAn increase in the ratio of memory to naive T cells has been postulated to underlie immune hyporesponsiveness accompanying aging. Our analyses of the induction of nuclear factor-kappaB (NFkappaB) in activated memory (CD45RO+) and naive (CD45RA+) T cell subsets from young and elderly donors has demonstrated that, regardless of donor age, memory T cells are not significantly altered in their responsiveness to TNF-alpha-mediated induction of NFkappaB. Although treatment with TNF-alpha induced nuclear localization of NFkappaB in both memory and naive T cell subsets, irrespective of the age of the donor, the levels of induced NFkappaB were significantly lower in both subsets of T cells obtained from the elderly, when compared to those in young. Examination of IkappaB alpha regulation revealed that TNF-alpha-mediated degradation of IkappaB alpha in both memory and naive T cells from the elderly was severely impaired, thus contributing to the lowered induction of the observed NFkappaB. In addition, this age-related decrease in induction of nuclear NFkappaB correlated with decrease in intracellular IL-2 receptor expression and anti-CD3-induced proliferation of both memory and naive T cells subsets. Taken together, our results suggest that the age-related hyporesponsiveness cannot be attributed to a skewing of the T cell population towards a memory phenotype in the elderly. " ], "offsets": [ [ 0, 1473 ] ] } ]

[ { "id": "9720648_T1", "type": "Protein", "text": [ "CD45RO" ], "offsets": [ [ 35, 41 ] ], "normalized": [] }, { "id": "9720648_T2", "type": "Protein", "text": [ "CD45RA" ], "offsets": [ [ 47, 53 ] ], "normalized": [] }, { "id": "9720648_T3", "type": "Protein", "text": [ "CD45RO" ], "offsets": [ [ 302, 308 ] ], "normalized": [] }, { "id": "9720648_T4", "type": "Protein", "text": [ "CD45RA" ], "offsets": [ [ 322, 328 ] ], "normalized": [] }, { "id": "9720648_T5", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 496, 505 ] ], "normalized": [] }, { "id": "9720648_T6", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 562, 571 ] ], "normalized": [] }, { "id": "9720648_T7", "type": "Protein", "text": [ "IkappaB alpha" ], "offsets": [ [ 850, 863 ] ], "normalized": [] }, { "id": "9720648_T8", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 889, 898 ] ], "normalized": [] }, { "id": "9720648_T9", "type": "Protein", "text": [ "IkappaB alpha" ], "offsets": [ [ 923, 936 ] ], "normalized": [] } ]

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[ { "id": "7945272__text", "type": "abstract", "text": [ "Arrested development: understanding v-abl. \nThe protein tyrosine kinase activity of the v-abl oncogene has been demonstrated to subvert the normal second messenger systems used by lymphoid cells for growth and differentiation. Transformation of bone marrow with the Abelson murine leukemia virus results in the appearance of B cell lineage cells arrested at the pre-B cell stage. Recent reports have characterized these cells expressing high v-abl kinase activity as deficient in detectable NF-kappaB DNA binding activity and low level RAG gene expression. These observations suggest that v-abl may be inhibiting the differentiation of B cells by blocking these two crucial elements in the maturation pathway. " ], "offsets": [ [ 0, 710 ] ] } ]

[ { "id": "7945272_T1", "type": "Protein", "text": [ "v-abl" ], "offsets": [ [ 36, 41 ] ], "normalized": [] }, { "id": "7945272_T2", "type": "Protein", "text": [ "v-abl" ], "offsets": [ [ 88, 93 ] ], "normalized": [] }, { "id": "7945272_T3", "type": "Protein", "text": [ "v-abl" ], "offsets": [ [ 442, 447 ] ], "normalized": [] }, { "id": "7945272_T4", "type": "Protein", "text": [ "v-abl" ], "offsets": [ [ 589, 594 ] ], "normalized": [] } ]

[]

[]

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[ { "id": "2204723__text", "type": "abstract", "text": [ "Cell-specific differences in activation of NF-kappa B regulatory elements of human immunodeficiency virus and beta interferon promoters by tumor necrosis factor. \nThree aspects of the involvement of tumor necrosis factor in human immunodeficiency virus (HIV) pathogenesis were examined. Tumor necrosis factor alpha (TNF-alpha) mRNA production was analyzed by polymerase chain reaction amplification in monocytic U937 cells and in a chronically HIV infected U937 cell line (U9-IIIB). TNF-alpha RNA was undetectable in U937 cells, whereas a low constitutive level was detected in U9-IIIB cells. Paramyxovirus infection induced a 5- to 10-fold increase in the steady-state level of TNF-alpha RNA in U9-IIIB cells compared with U937 cells, suggesting that HIV-infected monocytic cells produced higher levels of TNF-alpha than did normal cells after a secondary virus infection. The effects of TNF-alpha on gene expression were examined by transient expression assays using reporter chloramphenicol acetyltransferase plasmids linked to regulatory elements from the HIV long terminal repeat (LTR) and the beta interferon promoter. In U937 and Jurkat T lymphoid cells, the inducibility of the different hybrid promoters by TNF-alpha or phorbol ester varied in a cell type- and promoter context-specific manner; the levels of gene activity of NF-kappa B-containing plasmids correlated directly with induction of NF-kappa B DNA-binding activity. Although the intact beta interferon promoter was only weakly stimulated by phorbol ester or TNF-alpha, multimers of the PRDII NF-kappa B-binding domain were inducible by both agents. TNF-alpha was able to increase expression of the HIV LTR in T cells, but in monocytic cells, TNF-alpha did not induce the HIV LTR above a constitutive level of activity. This level of NF-kappa B-independent activity appears to be sufficient for virus multiplication, since TNF-alpha treatment had no effect on the kinetics of de novo HIV type 1 (HIV-1) infection and viral RNA production in U937 cells. However, in Jurkat cells, TNF-alpha dramatically enhanced the spread of HIV-1 through the cell population and increased viral RNA synthesis, indicating that in T cells HIV-1 multiplication was stimulated by TNF-alpha treatment. " ], "offsets": [ [ 0, 2251 ] ] } ]

[ { "id": "2204723_T1", "type": "Protein", "text": [ "tumor necrosis factor" ], "offsets": [ [ 139, 160 ] ], "normalized": [] }, { "id": "2204723_T2", "type": "Protein", "text": [ "tumor necrosis factor" ], "offsets": [ [ 199, 220 ] ], "normalized": [] }, { "id": "2204723_T3", "type": "Protein", "text": [ "Tumor necrosis factor alpha" ], "offsets": [ [ 287, 314 ] ], "normalized": [] }, { "id": "2204723_T4", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 316, 325 ] ], "normalized": [] }, { "id": "2204723_T5", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 483, 492 ] ], "normalized": [] }, { "id": "2204723_T6", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 679, 688 ] ], "normalized": [] }, { "id": "2204723_T7", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 807, 816 ] ], "normalized": [] }, { "id": "2204723_T8", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 889, 898 ] ], "normalized": [] }, { "id": "2204723_T9", "type": "Protein", "text": [ "chloramphenicol acetyltransferase" ], "offsets": [ [ 978, 1011 ] ], "normalized": [] }, { "id": "2204723_T10", "type": "Protein", "text": [ "beta interferon" ], "offsets": [ [ 1099, 1114 ] ], "normalized": [] }, { "id": "2204723_T11", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1216, 1225 ] ], "normalized": [] }, { "id": "2204723_T12", "type": "Protein", "text": [ "beta interferon" ], "offsets": [ [ 1457, 1472 ] ], "normalized": [] }, { "id": "2204723_T13", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1529, 1538 ] ], "normalized": [] }, { "id": "2204723_T14", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1620, 1629 ] ], "normalized": [] }, { "id": "2204723_T15", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1713, 1722 ] ], "normalized": [] }, { "id": "2204723_T16", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1893, 1902 ] ], "normalized": [] }, { "id": "2204723_T17", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 2049, 2058 ] ], "normalized": [] }, { "id": "2204723_T18", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 2230, 2239 ] ], "normalized": [] }, { "id": "2204723_T26", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1473, 1481 ] ], "normalized": [] } ]

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[ { "id": "8947512__text", "type": "abstract", "text": [ "Sterol dependent LDL-receptor gene transcription in lymphocytes from normal and CML patients. \nSterol regulatory element (SRE) has been recognized to regulate various key genes coding for especially low density lipoprotein (LDL)-receptor, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and HMG-CoA synthase known to play a crucial role in the cholesterol feedback mechanism. The deranged cholesterol feedback mechanism has been widely recognised in initiation as well as progression of various types of cancers including chronic myeloid leukaemia (CML). Consequently, the present study was addressed to understand this phenomenon and revealed the existence of a unique 47 kDa protein factor having affinity for this SRE sequence in lymphocytes from normal subjects as well as its absence in lymphocytes from untreated CML patients. However, this factor appeared when the CML patients achieved complete haematological remission (CHR) through alpha-interferon therapy. Further, an inverse relationship was also observed between sterol modulated LDL-receptor gene transcription and the binding affinity of this 47 kDa factor to the SRE sequence. Based upon these results we propose that alpha-interferon through its receptor initiates phosphatidic acid dependent signalling which in turn regulates the affinity of 47 kDa sterol regulatory element binding factor as well as LDL-receptor gene transcription in lymphocytes from CML patients. " ], "offsets": [ [ 0, 1447 ] ] } ]

[ { "id": "8947512_T1", "type": "Protein", "text": [ "LDL-receptor" ], "offsets": [ [ 17, 29 ] ], "normalized": [] }, { "id": "8947512_T2", "type": "Protein", "text": [ "low density lipoprotein (LDL)-receptor" ], "offsets": [ [ 199, 237 ] ], "normalized": [] }, { "id": "8947512_T3", "type": "Protein", "text": [ "3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase" ], "offsets": [ [ 239, 296 ] ], "normalized": [] }, { "id": "8947512_T4", "type": "Protein", "text": [ "HMG-CoA synthase" ], "offsets": [ [ 301, 317 ] ], "normalized": [] }, { "id": "8947512_T5", "type": "Protein", "text": [ "alpha-interferon" ], "offsets": [ [ 952, 968 ] ], "normalized": [] }, { "id": "8947512_T6", "type": "Protein", "text": [ "LDL-receptor" ], "offsets": [ [ 1054, 1066 ] ], "normalized": [] }, { "id": "8947512_T7", "type": "Protein", "text": [ "alpha-interferon" ], "offsets": [ [ 1195, 1211 ] ], "normalized": [] }, { "id": "8947512_T8", "type": "Protein", "text": [ "LDL-receptor" ], "offsets": [ [ 1381, 1393 ] ], "normalized": [] } ]

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[ { "id": "2394747__text", "type": "abstract", "text": [ "Cell type specificity and activation requirements for NFAT-1 (nuclear factor of activated T-cells) transcriptional activity determined by a new method using transgenic mice to assay transcriptional activity of an individual nuclear factor. \nNuclear factor of activated T-cells (NFAT-1) is a transcription factor which is considered to be an important regulator in early T-cell activation. We have developed a system to monitor the transcriptional activity of NFAT-1 at the single cell level in whole animals. The system is based on the use of an oligomerized NFAT-1 binding motif that directs transcription of SV40 T-antigen in transgenic mice. This report represents the first demonstration that a multimerized short binding motif can function appropriately in transgenic mice. NFAT-1 activity had previously been thought to be confined to activated T-lymphocytes upon release of intracellular calcium. By targeting NFAT-1-dependent gene expression in transgenic mice we discovered new sites of NFAT-1 activity. Besides in T-lymphocytes NFAT-1 activity could also be induced in T-lymphocyte-depleted spleen cells and purified B-lymphocytes and requires agents that both release intracellular calcium and activate protein kinase C. A difference in the time course of appearance of NFAT-1 activity between T-lymphocytes and non-T-lymphocytes was revealed. Constitutive expression was observed in a small population of cells in the dermis and some mice have developed skin lesions. Interestingly, the tissue pattern of expression of the NFAT-1 activity resembles the expression pattern described for HIV-LTR/tat transgenic mice (Vogel, J., Hinrichs, S. H., Reynolds, R. K., Luciw, P. A., and Jay, G. (1988) Nature 335, 606-611). This similarity in expression and the fact that NFAT-1 has been shown to bind functional sequences in HIV-LTR suggest a role for NFAT-1 in dermal activation of the HIV-LTR. " ], "offsets": [ [ 0, 1900 ] ] } ]

[ { "id": "2394747_T1", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 54, 60 ] ], "normalized": [] }, { "id": "2394747_T2", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 278, 284 ] ], "normalized": [] }, { "id": "2394747_T3", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 459, 465 ] ], "normalized": [] }, { "id": "2394747_T4", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 559, 565 ] ], "normalized": [] }, { "id": "2394747_T5", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 779, 785 ] ], "normalized": [] }, { "id": "2394747_T6", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 917, 923 ] ], "normalized": [] }, { "id": "2394747_T7", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 996, 1002 ] ], "normalized": [] }, { "id": "2394747_T8", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 1038, 1044 ] ], "normalized": [] }, { "id": "2394747_T9", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 1281, 1287 ] ], "normalized": [] }, { "id": "2394747_T10", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 1535, 1541 ] ], "normalized": [] }, { "id": "2394747_T11", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 1775, 1781 ] ], "normalized": [] }, { "id": "2394747_T12", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 1856, 1862 ] ], "normalized": [] }, { "id": "2394747_T16", "type": "Entity", "text": [ "tissue" ], "offsets": [ [ 1499, 1505 ] ], "normalized": [] }, { "id": "2394747_T19", "type": "Entity", "text": [ "HIV-LTR/tat transgenic mice" ], "offsets": [ [ 1598, 1625 ] ], "normalized": [] } ]

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[ { "id": "9276471__text", "type": "abstract", "text": [ "Activation of transcription factor NF-kappa B by phagocytic stimuli in human neutrophils. \nPhagocytosis represents an important physiological trigger for the inducible expression of several genes in human neutrophils. Here, we report that a DNA-binding activity primarily consisting of the classical NF-kappa B heterodimer, p50/RelA, is induced in phagocytosing neutrophils. Under these conditions, NF-kappa B activation was found to be a rapid and transient response, reaching a maximum by 10-15 min, and returning to near-basal levels by 30 min. In neutrophils undergoing the phagocytosis of opsonized yeasts, the onset of NF-kappa B activation was paralleled by a decline in immunoreactive I kappa B-alpha protein levels, and the cellular I kappa B-alpha pool was replenished by 30 min, in agreement with our gel shift data. We conclude that NF-kappa B activation could constitute one of the mechanisms whereby the expression of kappa B-responsive genes is enhanced in phagocytosing neutrophils. To our knowledge, this represents the first demonstration that phagocytic stimuli can induce NF-kappa B activation in human neutrophils. " ], "offsets": [ [ 0, 1136 ] ] } ]

[ { "id": "9276471_T1", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 324, 327 ] ], "normalized": [] }, { "id": "9276471_T2", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 328, 332 ] ], "normalized": [] }, { "id": "9276471_T3", "type": "Protein", "text": [ "I kappa B-alpha" ], "offsets": [ [ 693, 708 ] ], "normalized": [] }, { "id": "9276471_T4", "type": "Protein", "text": [ "I kappa B-alpha" ], "offsets": [ [ 742, 757 ] ], "normalized": [] } ]

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[ { "id": "9442377__text", "type": "abstract", "text": [ "NF-kappa B/Rel family members regulating the ICAM-1 promoter in monocytic THP-1 cells. \nA kappa B-site was identified in the promoter of the intercellular adhesion molecule-1 (ICAM-1) gene, which is involved in regulation of ICAM-1 expression by tumor necrosis factor alpha (TNF-alpha) and glucocorticoids. We now report on the transcription factors which bind and transactivate this enhancer sequence. In vitro, the ICAM-1 kappa B site appeared to bind RelA and c-Rel homodimers as well as heterodimers with NF-kappa B1, but weakly NF-kappa B1 homodimers. In addition, both RelA and c-Rel, but not NF-kappa B1, were shown to transactivate an ICAM-1 kappa B-reporter construct. In monocytic THP-1 cells TNF-alpha induced two nuclear complexes which in vitro bound to the ICAM-1 kappa B site. Using antibodies in an electrophoretic mobility supershift assay, one of these complexes was shown to contain NF-kappa B1 and RelA, and to bind with higher affinity to the consensus kappa B site in the HIV long terminal repeat. The second complex contained RelA, and exhibited higher affinity towards the ICAM-1 kappa B than to the HIV kappa B site. The glucocorticoid receptor was shown to repress activity of both the RelA homodimer and the NF-kappa B1/RelA heterodimer. We argue that in vivo RelA homodimers are likely to play a dominant role in TNF-alpha-induced ICAM-1 transcription in monocytic cells. " ], "offsets": [ [ 0, 1400 ] ] } ]

[ { "id": "9442377_T1", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 45, 51 ] ], "normalized": [] }, { "id": "9442377_T2", "type": "Protein", "text": [ "intercellular adhesion molecule-1" ], "offsets": [ [ 141, 174 ] ], "normalized": [] }, { "id": "9442377_T3", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 176, 182 ] ], "normalized": [] }, { "id": "9442377_T4", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 225, 231 ] ], "normalized": [] }, { "id": "9442377_T5", "type": "Protein", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 246, 273 ] ], "normalized": [] }, { "id": "9442377_T6", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 275, 284 ] ], "normalized": [] }, { "id": "9442377_T7", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 417, 423 ] ], "normalized": [] }, { "id": "9442377_T8", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 454, 458 ] ], "normalized": [] }, { "id": "9442377_T9", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 463, 468 ] ], "normalized": [] }, { "id": "9442377_T10", "type": "Protein", "text": [ "NF-kappa B1" ], "offsets": [ [ 509, 520 ] ], "normalized": [] }, { "id": "9442377_T11", "type": "Protein", "text": [ "NF-kappa B1" ], "offsets": [ [ 533, 544 ] ], "normalized": [] }, { "id": "9442377_T12", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 575, 579 ] ], "normalized": [] }, { "id": "9442377_T13", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 584, 589 ] ], "normalized": [] }, { "id": "9442377_T14", "type": "Protein", "text": [ "NF-kappa B1" ], "offsets": [ [ 599, 610 ] ], "normalized": [] }, { "id": "9442377_T15", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 643, 649 ] ], "normalized": [] }, { "id": "9442377_T16", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 703, 712 ] ], "normalized": [] }, { "id": "9442377_T17", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 771, 777 ] ], "normalized": [] }, { "id": "9442377_T18", "type": "Protein", "text": [ "NF-kappa B1" ], "offsets": [ [ 902, 913 ] ], "normalized": [] }, { "id": "9442377_T19", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 918, 922 ] ], "normalized": [] }, { "id": "9442377_T20", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 1049, 1053 ] ], "normalized": [] }, { "id": "9442377_T21", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1097, 1103 ] ], "normalized": [] }, { "id": "9442377_T22", "type": "Protein", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 1146, 1169 ] ], "normalized": [] }, { "id": "9442377_T23", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 1212, 1216 ] ], "normalized": [] }, { "id": "9442377_T24", "type": "Protein", "text": [ "NF-kappa B1" ], "offsets": [ [ 1235, 1246 ] ], "normalized": [] }, { "id": "9442377_T25", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 1247, 1251 ] ], "normalized": [] }, { "id": "9442377_T26", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 1287, 1291 ] ], "normalized": [] }, { "id": "9442377_T27", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1341, 1350 ] ], "normalized": [] }, { "id": "9442377_T28", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1359, 1365 ] ], "normalized": [] }, { "id": "9442377_T30", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 52, 60 ] ], "normalized": [] }, { "id": "9442377_T31", "type": "Entity", "text": [ "kappa B-site" ], "offsets": [ [ 90, 102 ] ], "normalized": [] } ]

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[]

[ { "id": "9733716__text", "type": "abstract", "text": [ "Phosphatidylinositides bind to plasma membrane CD14 and can prevent monocyte activation by bacterial lipopolysaccharide. \nAlthough bacterial lipopolysaccharides (LPS) and several other microbial agonists can bind to mCD14 (membrane CD14), a cell-surface receptor found principally on monocytes and neutrophils, host-derived mCD14 ligands are poorly defined. We report here that phosphatidylinositol (PtdIns), phosphatidylinositol-4-phosphate, and other phosphatidylinositides can bind to mCD14. Phosphatidylserine (PS), another anionic glycerophospholipid, binds to mCD14 with lower apparent affinity than does PtdIns. LPS-binding protein, a lipid transfer protein found in serum, facilitates both PS- and PtdIns-mCD14 binding. PtdIns binding to mCD14 can be blocked by anti-CD14 monoclonal antibodies that inhibit LPS-mCD14 binding, and PtdIns can inhibit both LPS-mCD14 binding and LPS-induced responses in monocytes. Serum-equilibrated PtdIns also binds to mCD14-expressing cells, raising the possibility that endogenous PtdIns may modulate cellular responses to LPS and other mCD14 ligands in vivo. " ], "offsets": [ [ 0, 1103 ] ] } ]

[ { "id": "9733716_T1", "type": "Protein", "text": [ "CD14" ], "offsets": [ [ 47, 51 ] ], "normalized": [] }, { "id": "9733716_T2", "type": "Protein", "text": [ "mCD14" ], "offsets": [ [ 216, 221 ] ], "normalized": [] }, { "id": "9733716_T3", "type": "Protein", "text": [ "CD14" ], "offsets": [ [ 232, 236 ] ], "normalized": [] }, { "id": "9733716_T4", "type": "Protein", "text": [ "mCD14" ], "offsets": [ [ 324, 329 ] ], "normalized": [] }, { "id": "9733716_T5", "type": "Protein", "text": [ "mCD14" ], "offsets": [ [ 488, 493 ] ], "normalized": [] }, { "id": "9733716_T6", "type": "Protein", "text": [ "mCD14" ], "offsets": [ [ 566, 571 ] ], "normalized": [] }, { "id": "9733716_T7", "type": "Protein", "text": [ "mCD14" ], "offsets": [ [ 713, 718 ] ], "normalized": [] }, { "id": "9733716_T8", "type": "Protein", "text": [ "mCD14" ], "offsets": [ [ 746, 751 ] ], "normalized": [] }, { "id": "9733716_T9", "type": "Protein", "text": [ "CD14" ], "offsets": [ [ 775, 779 ] ], "normalized": [] }, { "id": "9733716_T10", "type": "Protein", "text": [ "mCD14" ], "offsets": [ [ 819, 824 ] ], "normalized": [] }, { "id": "9733716_T11", "type": "Protein", "text": [ "mCD14" ], "offsets": [ [ 866, 871 ] ], "normalized": [] }, { "id": "9733716_T12", "type": "Protein", "text": [ "mCD14" ], "offsets": [ [ 960, 965 ] ], "normalized": [] }, { "id": "9733716_T13", "type": "Protein", "text": [ "mCD14" ], "offsets": [ [ 1080, 1085 ] ], "normalized": [] } ]

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[ { "id": "9888865__text", "type": "abstract", "text": [ "Tissue factor expression of human monocytes is suppressed by lysophosphatidylcholine. \nThe expression of tissue factor (TF), the principal initiator of coagulation, is increased during inflammation and atherosclerosis. Both conditions are promoted by lysophosphatidylcholine (lysoPC). We observed in the present study that lysoPC (1 to 10 micromol/L) dose-dependently reduced TF activity in human monocytes, as elicited by lipopolysaccharide (LPS). Lysophosphatidylethanolamine (lysoPE) and other lysophospholipids did not affect LPS-induced TF activity of human monocytes. TF antigen expression as elicited by LPS was also lowered by lysoPC. Phospholipid analyses indicated a selective increase in the lysoPC content of the monocytes after preincubation with the lysophospholipid. LysoPC inhibited the TF activity of Mono Mac-6 cells to a similar extent as in the monocytes. LPS binding to plasma membrane receptors and internalization of LPS into monocytes were not affected by lysoPC. In contrast, LPS-mediated nuclear binding of nuclear factor-kappaB/Rel to a TF-specific kappaB site was inhibited by lysoPC. Induction of TF mRNA expression by LPS tended to be partially reduced by the lysophospholipid. Preincubation with lysoPC increased monocytic cAMP levels. Inhibition of adenylyl cyclase by pretreatment with 2'-deoxy-3'-adenosine monophosphate partially reversed the inhibition of TF activity promoted by lysoPC. In conclusion, lysoPC markedly decreases LPS-mediated TF expression of human monocytes, the effect probably being mediated by both transcriptional and posttranscriptional mechanisms. LysoPC may thus attenuate activation of coagulation during inflammation and atherosclerosis. " ], "offsets": [ [ 0, 1700 ] ] } ]

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[ { "id": "9278334__text", "type": "abstract", "text": [ "Human monocyte binding to fibronectin enhances IFN-gamma-induced early signaling events. \nLeukocyte integrins are fundamentally important in modulating adhesion to extracellular matrix components and to other cells. This integrin-mediated adhesion controls leukocyte arrest and extravasation during the onset of inflammatory responses. Moreover, integrin-ligand interactions trigger signaling pathways that may influence leukocyte phenotype and function at sites of inflammation. In the current studies, we evaluated the combinatorial effects of monocyte adhesion and IFN-gamma on intracellular signaling pathways. IFN-gamma triggers a well-defined signal transduction pathway, which although not directly stimulated by monocyte adherence to fibronectin or arginine-glycine-aspartate (RGD)-coated substrata, was enhanced significantly in these matrix-adherent cells. Compared with monocytes in suspension or adherent on plastic surfaces, monocytes adherent to fibronectin or RGD exhibited a greater than threefold increase in steady state levels of IFN-gamma-induced mRNA for the high affinity Fc gammaRI receptor. By electrophoretic mobility shift assays, this increase in mRNA was associated with a 5- to 10-fold increase in the STAT1-containing DNA-binding complex that binds to Fc gammaRI promoter elements. Furthermore, the tyrosine phosphorylation of STAT1 and the tyrosine kinases JAK1 and JAK2 was enhanced significantly in RGD-adherent monocytes compared with control cells. These results suggest a novel mechanism by which integrin-mediated cell adhesion can modulate the magnitude of cytokine-induced signal transduction pathways, thereby amplifying cellular events leading to monocyte activation and inflammation. " ], "offsets": [ [ 0, 1726 ] ] } ]

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[ { "id": "9209268__text", "type": "abstract", "text": [ "Activation of nuclear factor-kappa B by beta-amyloid peptides and interferon-gamma in murine microglia. \nAn increasing body of evidence suggests that amyloid-beta (A beta) peptides and microglia are crucially involved in the pathogenesis of Alzheimer's disease. In an effort to further elucidate the biological effects of A beta towards microglia, we investigated the ability of A beta peptides to activate nuclear factor (NF)-kappa B in the N9 murine microglial cell line. Co-stimulation of microglia with suboptimal concentrations of A beta(25-35) and 100 U/ml IFN gamma resulted in the detection of a specific NF-kappa B DNA-binding activity in nuclear extracts, as determined in gel mobility shift assays. This response required at least 120 min to be evident and supershift experiments revealed that the NF-kappa B complex contains both RelA and p50. Accordingly, immunoblot experiments showed that amongst NF-kappa B/Rel proteins, RelA and p50 are mobilized to the nucleus following microglial cell stimulation with A beta(25-35) plus IFN gamma. Higher concentrations of A beta(25-35) were effective by themselves in inducing NF-kappa B activation, both in the N9 microglial cell line and in rat primary microglia, as well as in human monocytes. For purposes of comparison, microglia were also stimulated with bacterial LPS, a known NF-kappa B inducer. As expected, LPS strongly induced the formation of two NF-kappa B DNA-binding activities, one of which was identified as RelA/p50. The LPS response was also more rapid, as it was already evident by 40 min and remained sustained for up to 3 h. Collectively, these findings indicate that NF-kappa B activation might constitute one of the mechanisms underlying the inducible expression of kappa B-dependent genes in microglia stimulated by A beta peptides and IFN gamma, or by LPS. " ], "offsets": [ [ 0, 1838 ] ] } ]

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[ { "id": "9075924__text", "type": "abstract", "text": [ "The T cell activation factor NF-ATc positively regulates HIV-1 replication and gene expression in T cells. \nClinical deterioration in human immunodeficiency virus type 1 (HIV-1) infection is associated with increased levels of viral replication and burden in the peripheral blood and lymphoid organs. T cell activation and ensuing cellular gene activation can be critical for HIV-1 replication. The hypothesis that the nuclear factor of activated T cells (NF-AT) may influence HIV-1 replication is therefore compelling given the tight correlation of HIV-1 transcriptional induction to T cell activation. We report that certain NF-AT(Rel) family members productively bind the kappaB regulatory elements, synergize with NF-kappaB and Tat in transcriptional activation of HIV-1, and enhance HIV-1 replication in T cells. These results link regulatory factors critical to T cell commitment directly to HIV-1 replication. " ], "offsets": [ [ 0, 917 ] ] } ]

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[ { "id": "2196387__text", "type": "abstract", "text": [ "Inducible nuclear factor binding to the kappa B elements of the human immunodeficiency virus enhancer in T cells can be blocked by cyclosporin A in a signal-dependent manner. \nCyclosporin A (CsA) is thought to exert its immunosuppressive effects by inhibiting the expression of a distinct set of lymphokine genes which are induced upon T-cell activation, among them the gene coding for interleukin-2. In addition, the activation of the human immunodeficiency virus (HIV) is partially suppressed. To better understand the molecular mechanisms underlying suppression by CsA, we have investigated the effects of this drug on transcription factors in T cells. Here we report that the formation of two distinct mitogen-inducible DNA-binding complexes, the kappa B complex within the HIV enhancer and the NFAT-1 complex within the interleukin-2 enhancer, is inhibited in the presence of CsA. The kappa B-binding activity with the HIV enhancer is inhibited only if it is activated via the mitogen phytohemagglutinin whereas phorbol myristate acetate-mediated activation is completely insensitive to the drug. This suggests a model in which functionally indistinguishable kappa B complexes can be activated via two separate pathways of signal transduction distinguishable by CsA. " ], "offsets": [ [ 0, 1272 ] ] } ]

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[ { "id": "10347175__text", "type": "abstract", "text": [ "SLP-76 and Vav function in separate, but overlapping pathways to augment interleukin-2 promoter activity. \nSLP-76 and Vav, two hematopoietic cell specific molecules, are critical for T cell development and activation. Following T cell antigen receptor stimulation, SLP-76 and Vav both undergo tyrosine phosphorylation and associate with each other via the SH2 domain of Vav and phosphorylated tyrosines of SLP-76. Furthermore, SLP-76 and Vav have a synergistic effect on interleukin (IL)-2 promoter activity in T cells. In this report, we show that two tyrosines, Tyr-113 and Tyr-128, of SLP-76 are required for its binding to Vav, both in vitro and in intact cells. Surprisingly, we find also that the interaction between SLP-76 and Vav is not required for their cooperation in augmenting IL-2 promoter activity, as the two molecules appear to function in different signaling pathways upstream of IL-2 gene expression. Overexpression of SLP-76 in the Jurkat T cell line potentiates the activities of both nuclear factor of activated T cells and AP-1 transcription factors. In contrast, overexpression of Vav leads to enhanced nuclear factor of activated T cells activity without affecting AP-1. Additionally, overexpression of Vav, but not SLP-76, augments CD28-induced IL-2 promoter activity. These findings suggest that the synergy between SLP-76 and Vav in regulating IL-2 gene expression reflects the cooperation between different signaling pathways. " ], "offsets": [ [ 0, 1456 ] ] } ]

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[ { "id": "7836389__text", "type": "abstract", "text": [ "Two distinct signalling pathways are involved in the control of the biphasic junB transcription induced by interleukin-6 in the B cell hybridoma 7TD1. \nWe have measured the level of junB mRNA in the B hybridoma cell line 7TD1, under interleukin-6 (IL-6) stimulation. IL-6 increases junB mRNA in a biphasic fashion. The first early-induced peak was transient and likely corresponds to the well documented typical junB mRNA, stimulated in response to numerous growth factors, including IL-6. At variance, the second peak which has never been reported previously, lasted several hours. As a consequence of its effect on junB mRNA, IL-6 stimulated, in a biphasic fashion, the nuclear accumulation of the JunB protein. In this study, we demonstrated that IL-6 regulation occurred exclusively at the transcriptional level and that the bimodal increase of junB mRNA and JunB protein can be accounted for by a biphasic stimulation of junB transcription. Furthermore, our data point to two major differences between the mechanism of control of the early and the late IL-6-induced junB transcription waves. First, cycloheximide strongly potentiated the transcription of the second wave, whereas it failed to affect the early-induced burst. Second, tyrphostin, a tyrosine kinase inhibitor, impaired the expression of the first but not the second junB mRNA peak. Conversely, genistein, another tyrosine kinase inhibitor, totally abolished the expression of the second peak of junB mRNA whereas it did not affect the expression of the first peak. Altogether these data indicate that, in 7TD1 cells, IL-6 controls junB transcription in a biphasic fashion by means of two separate transduction pathways. " ], "offsets": [ [ 0, 1689 ] ] } ]

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"Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 1417, 1426 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7836389_E21" } ] }, { "id": "7836389_E21", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 1431, 1441 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7836389_T20" } ] }, { "id": "7836389_E22", "type": "Regulation", "trigger": { "text": [ "affect" ], "offsets": [ [ 1493, 1499 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7836389_E21" } ] }, { "id": "7836389_E23", "type": "Regulation", "trigger": { "text": [ "controls" ], "offsets": [ [ 1591, 1599 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7836389_E24" }, { "role": "Cause", "ref_id": "7836389_T21" } ] }, { "id": "7836389_E24", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1605, 1618 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7836389_T22" } ] }, { "id": "7836389_E25", "type": "Positive_regulation", "trigger": 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[ { "id": "9852310__text", "type": "abstract", "text": [ "Human immunodeficiency virus type-1 transcription: role of the 5'-untranslated leader region (review). \nHuman immunodeficiency virus type-1 (HIV-1) transcription is dependent on the interaction of host-cell transcription factors with cis-regulatory DNA elements within the viral long terminal repeat (LTR). Much attention has focused on the series of sequence elements upstream of the transcriptional initiation site in the U3 region of the LTR including the Sp1 and NF-kappaB binding sites. Recent studies, however, demonstrate that the transcribed 5'-untranslated leader region (5'-UTR) also contains important transcriptional elements. These regulatory elements situated downstream of transcription interact with constitutive and inducible transcription factors, mediate transmission of cellular activation signals, and are important for efficient HIV-1 transcription and replication. The 5'-UTR contains binding sites for the transcription factors AP-1, NF-kappaB, NF-AT, IRF, and Sp1. Mutations in these binding sites can interfere with the viral response to cell activation signals, decrease LTR transcription, and inhibit viral replication. The 5'-UTR also interacts with a specific nucleosome that is rapidly displaced during transcriptional activation of the latent provirus. We propose that the inducible transcription factor binding sites in the 5'-UTR comprise a downstream enhancer domain that can function independent of, or in concert with, the LTR promoter to rapidly increase latent proviral transcription in response to cell activation signals. In this review, we describe the host-cell transcription factors that interact with the 5'-UTR and discuss their role in the transcriptional regulation of HIV-1 gene expression. " ], "offsets": [ [ 0, 1740 ] ] } ]

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[ { "id": "7919963__text", "type": "abstract", "text": [ "A low NM23.H1 gene expression identifying high malignancy human melanomas. \nThe NM23 gene has been proposed as a metastasis-suppressor gene, and its use has been suggested as prognostic factor. NM23 was identified in a system of murine melanoma cell lines, in which an inverse relationship was found between NM23 expression and metastatic ability. In a human malignant melanoma study NM23 expression was found to be significantly lower in metastases that developed less than 24 months after diagnosis of the primary tumours. The present paper studies the expression of the NM23.H1 gene in cell lines which derive from primary or metastatic human malignant melanomas in relation to staging, infiltration degree, lymphocytic infiltration, cell morphology, cell pigmentation, karyotype, and disease-free survival. The level of mRNA expression of the NM23 gene is significantly lower in cell lines that derive from more infiltrating primary melanomas than in cell lines obtained from less infiltrating tumours. Moreover, cell lines derived from tumours of patients with a disease-free survival of more than 24 months (24-58 months) express the NM23 gene at higher levels than cell lines obtained from melanomas of patients with a disease-free survival of less than 24 months (6-15 months). " ], "offsets": [ [ 0, 1286 ] ] } ]

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[ { "id": "8666783__text", "type": "abstract", "text": [ "Modulation of the expression of the IFN-gamma receptor beta-chain controls responsiveness to IFN-gamma in human peripheral blood T cells. \nIFN-gamma has potent antiproliferative and apoptotic effects in T cells that are important in determining T cell development and polarized differentiation. Therefore, any event that enables T cells to become less responsive to IFN- gamma may potentially alter immune responsiveness to Ag. In this work, we show that human peripheral blood T cells that are stimulated through the TCR and expanded with IL-2 are unresponsive to IFN-gamma, as determined by a lack of activation of jak kinases and the transcription factor, STAT1(alpha), a signal transducer and activator of transcription. This nonresponsiveness occurs because of a lack of expression of the beta- chain (accessory factor) of the IFN-gamma receptor, while at the same time maintaining IFN-gamma receptor alpha-chain expression. Expression of the beta-chain can be restored by secondary TCR ligation or PMA treatment. T cell blasts treated with PMA are now responsive to IFN-gamma. When freshly isolated, highly enriched (>98%) T cells are examined for IFN-gamma responsiveness; these cells can respond to IFN-gamma and express beta-chain. Therefore, as T cells progress from primary TCR activation through IL-2-dependent proliferation, followed by secondary TCR stimulation, their responsiveness to IFN-gamma varies, and this may affect their ability to participate in an ongoing immune response. " ], "offsets": [ [ 0, 1499 ] ] } ]

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[ { "id": "10191934__text", "type": "abstract", "text": [ "[Corticoids and allergy] \nInflammation is constantly observed in allergic reactions. Corticosteroids are most effective in preventing the late phase of allergic reaction. The action of glucocorticosteroids is mediated through glucocorticoid receptors present in the cellular cytoplasm. When activated, glucocorticoid receptors form a dimer and bind to DNA after migration into the nucleus. Interaction to DNA induces changes in the transcription rate, leading to either gene induction or gene repression. Glucocorticoid receptors are also able to interact with transcriptional factors such as AP-1 (activator protein-1) of NF-kappa B (nuclear factor-kappa B). Through these actions glucocorticosteroids are susceptible to modify functions of cells involved in the allergic inflammatory response. They are in particular able to inhibit most of the pro-inflammatory functions of the eosinophils. " ], "offsets": [ [ 0, 894 ] ] } ]

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[ { "id": "10318942__text", "type": "abstract", "text": [ "Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. \nThe role of the transcription factor NF-kappaB in the pathogenesis of rheumatoid arthritis has long been a subject of controversy. We used an adenoviral technique of blocking NF-kappaB through overexpression of the inhibitory subunit IkappaBalpha, which has the advantage that it can be used in the diseased tissue itself, with >90% of the synovial macrophages, fibroblasts, and T cells infected. We found that the spontaneous production of tumor necrosis factor alpha and other pro-inflammatory cytokines is NF-kappaB-dependent in rheumatoid synovial tissue, in contrast to the main anti-inflammatory mediators, like IL-10 and -11, and the IL-1 receptor antagonist. Of even more interest, IkappaBalpha overexpression inhibited the production of matrix metalloproteinases 1 and 3 while not affecting their tissue inhibitor. Blocking NF-kappaB in the rheumatoid joint thus has a very beneficial profile, reducing both the inflammatory response and the tissue destruction. The adenoviral technique described here has widespread applicability, allowing rapid testing of the effects of blocking a potential therapeutic target in either cultures of normal cells or in the diseased tissue itself. " ], "offsets": [ [ 0, 1378 ] ] } ]

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[]

[ { "id": "8038234__text", "type": "abstract", "text": [ "IL-4 down-regulates IL-2-, IL-3-, and GM-CSF-induced cytokine gene expression in peripheral blood monocytes. \nIL-4, a product of the T-helper 0 (Th0) and 2 (Th2) subset, was originally described as a B-cell stimulatory factor and has subsequently been found to suppress IL-1 alpha, IL-1 beta, IL-6, IL-8, and TNF-alpha gene expression in monocytes stimulated with LPS, and to upregulate IL-1 receptor antagonist (IL1-RA) gene expression. In this study we investigated the effect of IL-4 on the expression of cytokine genes in monocytes evoked by other T-helper cell cytokines: IL-2, IL-3, and GM-CSF. IL-4 down-regulated mRNA accumulation of the proinflammatory cytokines IL-1 beta, IL-8, and TNF-alpha in monocytes stimulated with IL-2, IL-3, and GM-CSF. IL-4 also suppressed the IL-2-induced IL-6 mRNA expression. Temporal analysis of the IL-4 down-regulatory effect on the IL-2-, IL-3-, or GM-CSF-induced proinflammatory cytokine gene expression in monocytes provided evidence that IL-4 acts predominantly on the post-transcriptional level. This was supported by the observation that the down-regulatory capacity of IL-4 appeared to be dependent on de novo protein synthesis. IL-4 did not exert significant influence on the induction of expression of IL-1-RA or various CSFs by IL-2, IL-3, and GM-CSF. (ABSTRACT TRUNCATED AT 250 WORDS) " ], "offsets": [ [ 0, 1339 ] ] } ]

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[ { "id": "8493578__text", "type": "abstract", "text": [ "Regulation of the Ets-related transcription factor Elf-1 by binding to the retinoblastoma protein. \nThe retinoblastoma gene product (Rb) is a nuclear phosphoprotein that regulates cell cycle progression. Elf-1 is a lymphoid-specific Ets transcription factor that regulates inducible gene expression during T cell activation. In this report, it is demonstrated that Elf-1 contains a sequence motif that is highly related to the Rb binding sites of several viral oncoproteins and binds to the pocket region of Rb both in vitro and in vivo. Elf-1 binds exclusively to the underphosphorylated form of Rb and fails to bind to Rb mutants derived from patients with retinoblastoma. Co-immunoprecipitation experiments demonstrated an association between Elf-1 and Rb in resting normal human T cells. After T cell activation, the phosphorylation of Rb results in the release of Elf-1, which is correlated temporally with the activation of Elf-1-mediated transcription. Overexpression of a phosphorylation-defective form of Rb inhibited Elf-1-dependent transcription during T cell activation. These results demonstrate that Rb interacts specifically with a lineage-restricted Ets transcription factor. This regulated interaction may be important for the coordination of lineage-specific effector functions such as lymphokine production with cell cycle progression in activated T cells. " ], "offsets": [ [ 0, 1376 ] ] } ]

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[ { "id": "8079992__text", "type": "abstract", "text": [ "The severe phenotype of females with tiny ring X chromosomes is associated with inability of these chromosomes to undergo X inactivation. \nMental retardation and a constellation of congenital malformations not usually associated with Turner syndrome are seen in some females with a mosaic 45,X/46,X,r(X) karyotype. Studies of these females show that the XIST locus on their tiny ring X chromosomes is either not present or not expressed. As XIST transcription is well correlated with inactivation of the X chromosome in female somatic cells and spermatogonia, nonexpression of the locus even when it is present suggests that these chromosomes are transcriptionally active. We examined the transcriptional activity of ring X chromosomes lacking XIST expression (XISTE-), from three females with severe phenotypes. The two tiny ring X chromosomes studied with an antibody specific for the acetylated isoforms of histone H4 marking transcribed chromatin domains were labeled at a level consistent with their being active. We also examined tow of the XISTE- ring chromosomes to determine whether genes that are normally silent on an inactive X are expressed from these chromosomes. Analyses of hybrid cells show that TIMP, ZXDA, and ZXDB loci on the proximal short arm, and AR and PHKA1 loci on the long arm, are well expressed from the tiny ring X chromosome lacking XIST DNA. Studies of the ring chromosome that has XIST DNA but does not transcribe it show that its AR allele is transcribed along with the one on the normal X allele. (ABSTRACT TRUNCATED AT 250 WORDS) " ], "offsets": [ [ 0, 1566 ] ] } ]

[ { "id": "8079992_T1", "type": "Protein", "text": [ "XIST" ], "offsets": [ [ 354, 358 ] ], "normalized": [] }, { "id": "8079992_T2", "type": "Protein", "text": [ "XIST" ], "offsets": [ [ 441, 445 ] ], "normalized": [] }, { "id": "8079992_T3", "type": "Protein", "text": [ "XIST" ], "offsets": [ [ 744, 748 ] ], "normalized": [] }, { "id": "8079992_T4", "type": "Protein", "text": [ "histone H4" ], "offsets": [ [ 910, 920 ] ], "normalized": [] }, { "id": "8079992_T5", "type": "Protein", "text": [ "ZXDA" ], "offsets": [ [ 1219, 1223 ] ], "normalized": [] }, { "id": "8079992_T6", "type": "Protein", "text": [ "ZXDB" ], "offsets": [ [ 1229, 1233 ] ], "normalized": [] }, { "id": "8079992_T7", "type": "Protein", "text": [ "PHKA1" ], "offsets": [ [ 1277, 1282 ] ], "normalized": [] }, { "id": "8079992_T8", "type": "Protein", "text": [ "XIST" ], "offsets": [ [ 1364, 1368 ] ], "normalized": [] }, { "id": "8079992_T9", "type": "Protein", "text": [ "XIST" ], "offsets": [ [ 1414, 1418 ] ], "normalized": [] } ]

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[ { "id": "9233623__text", "type": "abstract", "text": [ "RP1, a new member of the adenomatous polyposis coli-binding EB1-like gene family, is differentially expressed in activated T cells. \nCross-linking of the CD3 and CD28 molecules on T lymphocytes represents one of the most effective signals for T lymphocyte activation and triggering of their cytotoxic effector function. To identify genes that are expressed in T cells after stimulation, mRNA from T lymphocytes that had been activated by the simultaneous stimulation of the CD3 and CD28 trigger molecules was transcribed for a differential mRNA display analysis into cDNA and was compared with cDNA from CD28- or CD3-activated or resting lymphocytes. Differential expression was confirmed subsequently by Northern blot analysis. One of the cDNA fragments expressed specifically in CD3- and CD28-activated T cells was designated RP1. The predictive protein-coding region of RP1 had a significant homology to members of the recently found adenomatous polyposis coli (APC) protein-binding EB1 gene family, which codes for yet unknown protein(s). Bacterially expressed RP1 protein revealed specific binding to wild-type but not to mutated APC protein. The rapid up-regulation of RP1 mRNA in properly activated T cells suggests that this gene might belong to the immediate/early gene family, which controls the signal transduction cascade downstream of the TCR. As the expression level of the RP1 gene in activated T cells and a spectrum of tumor-derived cell lines correlates with the proliferative status of the cells, members of the EB1-like gene family may not only be involved in the tumorigenesis of colorectal cancers but may also play a role in the proliferative control of normal cells. " ], "offsets": [ [ 0, 1691 ] ] } ]

[ { "id": "9233623_T1", "type": "Protein", "text": [ "RP1" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "9233623_T2", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 162, 166 ] ], "normalized": [] }, { "id": "9233623_T3", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 482, 486 ] ], "normalized": [] }, { "id": "9233623_T4", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 604, 608 ] ], "normalized": [] }, { "id": "9233623_T5", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 790, 794 ] ], "normalized": [] }, { "id": "9233623_T6", "type": "Protein", "text": [ "RP1" ], "offsets": [ [ 873, 876 ] ], "normalized": [] }, { "id": "9233623_T7", "type": "Protein", "text": [ "adenomatous polyposis coli (APC) protein" ], "offsets": [ [ 937, 977 ] ], "normalized": [] }, { "id": "9233623_T8", "type": "Protein", "text": [ "EB1" ], "offsets": [ [ 986, 989 ] ], "normalized": [] }, { "id": "9233623_T9", "type": "Protein", "text": [ "RP1" ], "offsets": [ [ 1065, 1068 ] ], "normalized": [] }, { "id": "9233623_T10", "type": "Protein", "text": [ "APC" ], "offsets": [ [ 1135, 1138 ] ], "normalized": [] }, { "id": "9233623_T11", "type": "Protein", "text": [ "RP1" ], "offsets": [ [ 1175, 1178 ] ], "normalized": [] }, { "id": "9233623_T12", "type": "Protein", "text": [ "RP1" ], "offsets": [ [ 1388, 1391 ] ], "normalized": [] } ]

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[ { "id": "7859735__text", "type": "abstract", "text": [ "Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor. \nInduction of apoptosis in lymphocytes, which may account for the therapeutic effects of glucocorticoids in various diseases including leukemia, depends on the glucocorticoid receptor. However, the events leading from the activated receptor to cell lysis are not understood. A prevailing hypothesis postulates induction of so-called 'lysis genes' by the activated receptor. In this study, we show that an activation-deficient glucocorticoid receptor mutant is as effective as the wild-type receptor in repression of AP-1 activity, inhibition of interleukin-2 production, inhibition of c-myc expression and induction of apoptosis. Furthermore, we show that retinoic acid can also induce apoptosis in these cells through the retinoic acid receptor, whose repressive functions but not target site specificity, are similar to those of the glucocorticoid receptor. Therefore, the primary effect of the receptor in glucocorticoid-mediated apoptosis correlates with transcriptional repression rather than activation and could be mediated by interference with other transcription factors required for cell survival. " ], "offsets": [ [ 0, 1234 ] ] } ]

[ { "id": "7859735_T1", "type": "Protein", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 101, 124 ] ], "normalized": [] }, { "id": "7859735_T2", "type": "Protein", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 286, 309 ] ], "normalized": [] }, { "id": "7859735_T3", "type": "Protein", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 552, 575 ] ], "normalized": [] }, { "id": "7859735_T4", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 671, 684 ] ], "normalized": [] }, { "id": "7859735_T5", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 711, 716 ] ], "normalized": [] }, { "id": "7859735_T6", "type": "Protein", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 961, 984 ] ], "normalized": [] } ]

[ { "id": "7859735_E1", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 348, 357 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7859735_T2" } ] }, { "id": "7859735_E2", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 480, 489 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7859735_T2" } ] }, { "id": "7859735_E3", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 657, 667 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7859735_E4" }, { "role": "Cause", "ref_id": "7859735_T3" } ] }, { "id": "7859735_E4", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 685, 695 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7859735_T4" } ] }, { "id": "7859735_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 697, 707 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7859735_E6" }, { "role": "Cause", "ref_id": "7859735_T3" } ] }, { "id": "7859735_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 717, 727 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7859735_T5" } ] } ]

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[ { "id": "9808586__text", "type": "abstract", "text": [ "Interaction of sickle erythrocytes with endothelial cells in the presence of endothelial cell conditioned medium induces oxidant stress leading to transendothelial migration of monocytes. \nThe abnormal adherence of sickle red blood cells (SS RBC) to endothelial cells has been thought to contribute to vascular occlusion, a major cause of morbidity in sickle cell disease (SCD). We determined whether the interaction of SS RBC with cultured endothelial cells induced cellular oxidant stress that would culminate in expression of cell adhesion molecules (CAMs) involved in the adhesion and diapedesis of monocytes and the adherence of SS reticulocytes. We showed that the interaction of SS RBC at 2% concentration in the presence of multimers of von Willebrand factor (vWf), derived from endothelial cell-derived conditioned medium (E-CM) with cultured human umbilical vein endothelial cells (HUVEC), resulted in a fivefold increased formation of thiobarbituric acid-reactive substances (TBARS) and activation of the transcription factor NF-kB, both indicators of cellular oxidant stress. Normal RBC show none of these phenomena. The oxidant stress-induced signaling resulted in an increased surface expression of a subset of CAMs, ICAM-1, E-selectin, and VCAM-1 in HUVEC. The addition of oxygen radical scavenger enzymes (catalase, superoxide dismutase) and antioxidant (probucol) inhibited these events. Additionally, preincubation of HUVEC with a synthetic peptide Arg-Gly-Asp (RGD) that prevents vWf-mediated adhesion of SS RBC reduced the surface expression of VCAM-1 and NF-kB activation. Furthermore, SS RBC-induced oxidant stress resulted in a twofold increase in the transendothelial migration of both monocyte-like HL-60 cells and human peripheral blood monocytes, and approximately a sixfold increase in platelet-endothelial cell adhesion molecule-1 (PECAM-1) phosphorylation, each of which was blocked by protein kinase C inhibitor and antioxidants. These results suggest that the adherence/contact of SS RBC to endothelial cells in large vessel can generate enhanced oxidant stress leading to increased adhesion and diapedesis of monocytes, as well as heightened adherence of SS reticulocytes, indicating that injury/activation of endothelium can contribute to vaso-occlusion in SCD. " ], "offsets": [ [ 0, 2296 ] ] } ]

[ { "id": "9808586_T1", "type": "Protein", "text": [ "von Willebrand factor" ], "offsets": [ [ 745, 766 ] ], "normalized": [] }, { "id": "9808586_T2", "type": "Protein", "text": [ "vWf" ], "offsets": [ [ 768, 771 ] ], "normalized": [] }, { "id": "9808586_T3", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1231, 1237 ] ], "normalized": [] }, { "id": "9808586_T4", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 1239, 1249 ] ], "normalized": [] }, { "id": "9808586_T5", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1255, 1261 ] ], "normalized": [] }, { "id": "9808586_T6", "type": "Protein", "text": [ "catalase" ], "offsets": [ [ 1322, 1330 ] ], "normalized": [] }, { "id": "9808586_T7", "type": "Protein", "text": [ "superoxide dismutase" ], "offsets": [ [ 1332, 1352 ] ], "normalized": [] }, { "id": "9808586_T8", "type": "Protein", "text": [ "vWf" ], "offsets": [ [ 1499, 1502 ] ], "normalized": [] }, { "id": "9808586_T9", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1565, 1571 ] ], "normalized": [] }, { "id": "9808586_T10", "type": "Protein", "text": [ "platelet-endothelial cell adhesion molecule-1" ], "offsets": [ [ 1814, 1859 ] ], "normalized": [] }, { "id": "9808586_T11", "type": "Protein", "text": [ "PECAM-1" ], "offsets": [ [ 1861, 1868 ] ], "normalized": [] }, { "id": "9808586_T14", "type": "Entity", "text": [ "surface" ], "offsets": [ [ 1191, 1198 ] ], "normalized": [] } ]

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[ { "id": "9808586_1", "entity_ids": [ "9808586_T1", "9808586_T2" ] }, { "id": "9808586_2", "entity_ids": [ "9808586_T10", "9808586_T11" ] } ]

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[ { "id": "10194184__text", "type": "abstract", "text": [ "Activation of NF-kappaB in Mycobacterium tuberculosis- induced interleukin-2 receptor expression in mononuclear phagocytes. \nSoluble interleukin-2 receptor-alpha (IL-2Ralpha) has been reported to be increased in the sera of patients with advanced tuberculosis, and levels decline after therapy in accordance with improvement of radiologic findings. We investigated expression of the IL-2Ralpha in bronchoalveolar lavage (BAL) cells in active pulmonary tuberculosis, and evaluated the mechanism Mycobacterium tuberculosis induces in the IL-2Ralpha using the THP-1 mononuclear phagocyte cell line. We found IL-2Ralpha expression to be increased in BAL cells from involved sites of active pulmonary tuberculosis. Expression of the alpha-chain of IL-2Ralpha on peripheral blood monocytes (PBM) was induced by M. tuberculosis by flow cytometry evaluation. Northern analysis demonstrated increased IL-2Ralpha gene expression after stimulation with M. tuberculosis which was further induced by interferon-gamma (IFN-gamma). The IL-2Ralpha promoter containing the nuclear factor kappa B (NF-kappaB) site was transcriptionally induced by M. tuberculosis and this NF-kappaB site could confer inducibility to a heterologous herpes thymidine kinase (TK) promoter by M. tuberculosis. Electrophoretic mobility shift assays (EMSAs) revealed specific binding of nuclear protein to the NF-kappaB site upon induction with M. tuberculosis. Using antibodies against the p50 and p65 subunits of NF-kappaB in EMSAs, the involvement of both p50 and p65 proteins was further demonstrated. Functional expression of the IL-2Ralpha on mononuclear phagocytes in M. tuberculosis infection may play an important immunomodulatory role in the host response. " ], "offsets": [ [ 0, 1726 ] ] } ]

[ { "id": "10194184_T1", "type": "Protein", "text": [ "interleukin-2 receptor-alpha" ], "offsets": [ [ 133, 161 ] ], "normalized": [] }, { "id": "10194184_T2", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 163, 173 ] ], "normalized": [] }, { "id": "10194184_T3", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 383, 393 ] ], "normalized": [] }, { "id": "10194184_T4", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 536, 546 ] ], "normalized": [] }, { "id": "10194184_T5", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 605, 615 ] ], "normalized": [] }, { "id": "10194184_T6", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 743, 753 ] ], "normalized": [] }, { "id": "10194184_T7", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 892, 902 ] ], "normalized": [] }, { "id": "10194184_T8", "type": "Protein", "text": [ "interferon-gamma" ], "offsets": [ [ 987, 1003 ] ], "normalized": [] }, { "id": "10194184_T9", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1005, 1014 ] ], "normalized": [] }, { "id": "10194184_T10", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 1021, 1031 ] ], "normalized": [] }, { "id": "10194184_T11", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1450, 1453 ] ], "normalized": [] }, { "id": "10194184_T12", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1458, 1461 ] ], "normalized": [] }, { "id": "10194184_T13", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1518, 1521 ] ], "normalized": [] }, { "id": "10194184_T14", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1526, 1529 ] ], "normalized": [] }, { "id": "10194184_T15", "type": "Protein", "text": [ "IL-2Ralpha" ], "offsets": [ [ 1594, 1604 ] ], "normalized": [] }, { "id": "10194184_T27", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1032, 1040 ] ], "normalized": [] } ]

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[]

[ { "id": "8657101__text", "type": "abstract", "text": [ "A novel interferon regulatory factor family transcription factor, ICSAT/Pip/LSIRF, that negatively regulates the activity of interferon-regulated genes. \nWe have isolated a novel cDNA clone encoding interferon (IFN) consensus sequence-binding protein in adult T-cell leukemia cell line or activated T cells (ICSAT); this protein is the human homolog of the recently cloned Pip/LSIRF. ICSAT is structurally most closely related to the previously cloned ICSBP, a member of the IFN regulatory factor (IRF) family of proteins that binds to interferon consensus sequences (ICSs) found in many promoters of the IFN-regulated genes. Among T-cell lines investigated, ICSAT was abundantly expressed in human T-cell leukemia virus type 1 (HTLV-1)-infected T cells. When the HTLV-1 tax gene was expressed or phorbol myristake acetate-A23187 stimulation was used, ICSAT expression was induced in Jurkat cells which otherwise do not express ICSAT. When the binding of ICSAT to four different ICSs was tested, the relative differences in binding affinities for those ICSs were determined. To study the functional role of ICSAT, we performed cotransfection experiments with the human embryonal carcinoma cell line N-Tera2. ICSAT was demonstrated to possess repressive function over the gene activation induced by IFN stimulation or by IRF-1 cotransfection. Such repressive function is similar to that seen in IRF-2 or ICSBP. However, we have found that ICSAT has a different repressive effect from that of IRF-2 or ICSBP in some IFN-responsive reporter constructs. These results suggest that a novel mechanism of gene regulation by \"differential repression\" is used by multiple members of repressor proteins with different repressive effects on the IFN-responsive genes. " ], "offsets": [ [ 0, 1756 ] ] } ]

[ { "id": "8657101_T1", "type": "Protein", "text": [ "ICSAT" ], "offsets": [ [ 66, 71 ] ], "normalized": [] }, { "id": "8657101_T2", "type": "Protein", "text": [ "Pip" ], "offsets": [ [ 72, 75 ] ], "normalized": [] }, { "id": "8657101_T3", "type": "Protein", "text": [ "LSIRF" ], "offsets": [ [ 76, 81 ] ], "normalized": [] }, { "id": "8657101_T4", "type": "Protein", "text": [ "interferon (IFN) consensus sequence-binding protein in adult T-cell leukemia cell line or activated T cells" ], "offsets": [ [ 199, 306 ] ], "normalized": [] }, { "id": "8657101_T5", "type": "Protein", "text": [ "ICSAT" ], "offsets": [ [ 308, 313 ] ], "normalized": [] }, { "id": "8657101_T6", "type": "Protein", "text": [ "Pip" ], "offsets": [ [ 373, 376 ] ], "normalized": [] }, { "id": "8657101_T7", "type": "Protein", "text": [ "LSIRF" ], "offsets": [ [ 377, 382 ] ], "normalized": [] }, { "id": "8657101_T8", "type": "Protein", "text": [ "ICSAT" ], "offsets": [ [ 384, 389 ] ], "normalized": [] }, { "id": "8657101_T9", "type": "Protein", "text": [ "ICSBP" ], "offsets": [ [ 452, 457 ] ], "normalized": [] }, { "id": "8657101_T10", "type": "Protein", "text": [ "ICSAT" ], "offsets": [ [ 659, 664 ] ], "normalized": [] }, { "id": "8657101_T11", "type": "Protein", "text": [ "tax" ], "offsets": [ [ 771, 774 ] ], "normalized": [] }, { "id": "8657101_T12", "type": "Protein", "text": [ "ICSAT" ], "offsets": [ [ 852, 857 ] ], "normalized": [] }, { "id": "8657101_T13", "type": "Protein", "text": [ "ICSAT" ], "offsets": [ [ 928, 933 ] ], "normalized": [] }, { "id": "8657101_T14", "type": "Protein", "text": [ "ICSAT" ], "offsets": [ [ 955, 960 ] ], "normalized": [] }, { "id": "8657101_T15", "type": "Protein", "text": [ "ICSAT" ], "offsets": [ [ 1107, 1112 ] ], "normalized": [] }, { "id": "8657101_T16", "type": "Protein", "text": [ "ICSAT" ], "offsets": [ [ 1208, 1213 ] ], "normalized": [] }, { "id": "8657101_T17", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 1320, 1325 ] ], "normalized": [] }, { "id": "8657101_T18", "type": "Protein", "text": [ "IRF-2" ], "offsets": [ [ 1394, 1399 ] ], "normalized": [] }, { "id": "8657101_T19", "type": "Protein", "text": [ "ICSBP" ], "offsets": [ [ 1403, 1408 ] ], "normalized": [] }, { "id": "8657101_T20", "type": "Protein", "text": [ "ICSAT" ], "offsets": [ [ 1438, 1443 ] ], "normalized": [] }, { "id": "8657101_T21", "type": "Protein", "text": [ "IRF-2" ], "offsets": [ [ 1491, 1496 ] ], "normalized": [] }, { "id": "8657101_T22", "type": "Protein", "text": [ "ICSBP" ], "offsets": [ [ 1500, 1505 ] ], "normalized": [] } ]

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[ { "id": "9133417__text", "type": "abstract", "text": [ "Jak3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells. \nCD40 is a receptor that is critical for the survival, growth, differentiation, and isotype switching of B lymphocytes. Although CD40 lacks intrinsic tyrosine kinase activity, its ligation induces protein tyrosine phosphorylation, which is necessary for several CD40-mediated events. We show that engagement of CD40 induces tyrosine phosphorylation and activation of Jak3 as well as of STAT3. Jak3 is constitutively associated with CD40, and this interaction requires a proline-rich sequence in the membrane-proximal region of CD40. Deletion of this sequence abolishes the capacity of CD40 to induce expression of CD23, ICAM-1, and lymphotoxin-alpha genes in B cells. These results indicate that signaling through Jak3 is activated by CD40 and plays an important role in CD40-mediated functions. " ], "offsets": [ [ 0, 891 ] ] } ]

[ { "id": "9133417_T1", "type": "Protein", "text": [ "Jak3" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "9133417_T2", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 24, 28 ] ], "normalized": [] }, { "id": "9133417_T3", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 49, 53 ] ], "normalized": [] }, { "id": "9133417_T4", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 96, 100 ] ], "normalized": [] }, { "id": "9133417_T5", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 224, 228 ] ], "normalized": [] }, { "id": "9133417_T6", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 357, 361 ] ], "normalized": [] }, { "id": "9133417_T7", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 406, 410 ] ], "normalized": [] }, { "id": "9133417_T8", "type": "Protein", "text": [ "Jak3" ], "offsets": [ [ 462, 466 ] ], "normalized": [] }, { "id": "9133417_T9", "type": "Protein", "text": [ "STAT3" ], "offsets": [ [ 481, 486 ] ], "normalized": [] }, { "id": "9133417_T10", "type": "Protein", "text": [ "Jak3" ], "offsets": [ [ 488, 492 ] ], "normalized": [] }, { "id": "9133417_T11", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 527, 531 ] ], "normalized": [] }, { "id": "9133417_T12", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 622, 626 ] ], "normalized": [] }, { "id": "9133417_T13", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 680, 684 ] ], "normalized": [] }, { "id": "9133417_T14", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 709, 713 ] ], "normalized": [] }, { "id": "9133417_T15", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 715, 721 ] ], "normalized": [] }, { "id": "9133417_T16", "type": "Protein", "text": [ "lymphotoxin-alpha" ], "offsets": [ [ 727, 744 ] ], "normalized": [] }, { "id": "9133417_T17", "type": "Protein", "text": [ "Jak3" ], "offsets": [ [ 809, 813 ] ], "normalized": [] }, { "id": "9133417_T18", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 830, 834 ] ], "normalized": [] }, { "id": "9133417_T19", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 866, 870 ] ], "normalized": [] }, { "id": "9133417_T23", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 419, 427 ] ], "normalized": [] }, { "id": "9133417_T28", "type": "Entity", "text": [ "proline-rich sequence" ], "offsets": [ [ 565, 586 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "8543789__text", "type": "abstract", "text": [ "Polymorphic nucleotides within the human IL-4 promoter that mediate overexpression of the gene. \nAtopy, which predisposes individuals to develop asthma, severe systemic anaphylaxis, and atopic dermatitis, is usually associated with dramatically elevated total serum IgE levels and is thought to be controlled by a major susceptibility gene and multiple minor susceptibility genes. A recent sib-pair analysis revealed a tight linkage between markers on 5q31.1 and a major susceptibility gene controlling total serum IgE levels. Due to its location within this cluster and its biologic role in Ig class switching and Th2 cell differentiation, the IL-4 gene has emerged as one major candidate for the atopy gene. In one model, polymorphisms within IL-4 regulatory elements might result in overexpression of the gene, amplifying Th2 cell differentiation and class switching to IgE. In support of this model, we report that the human IL-4 promoter exists in multiple allelic forms that exhibit distinct transcriptional activities in IL-4-positive T cells. A particular allele has an unusually high transcriptional activity. A nucleotide substitution within a recently described OAP40 element located just upstream of an NF-AT site (P sequence) appears to be largely responsible for the increased promotor strength of this particular allelic form of the IL-4 promoter. In EMSAs, this substitution results in a markedly enhanced affinity for sequence-specific complexes exhibiting an AP-1 specificity. The identification of allelic nucleotides, which results in overexpression of the IL-4 gene, provides specific targets for a comprehensive screening of atopic and nonatopic individuals and may provide a clue for genetic predisposition for atopy. " ], "offsets": [ [ 0, 1741 ] ] } ]

[ { "id": "8543789_T1", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 41, 45 ] ], "normalized": [] }, { "id": "8543789_T2", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 645, 649 ] ], "normalized": [] }, { "id": "8543789_T3", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 745, 749 ] ], "normalized": [] }, { "id": "8543789_T4", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 929, 933 ] ], "normalized": [] }, { "id": "8543789_T5", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1028, 1032 ] ], "normalized": [] }, { "id": "8543789_T6", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1348, 1352 ] ], "normalized": [] }, { "id": "8543789_T7", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1577, 1581 ] ], "normalized": [] }, { "id": "8543789_T8", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 46, 54 ] ], "normalized": [] } ]

[ { "id": "8543789_E1", "type": "Positive_regulation", "trigger": { "text": [ "mediate" ], "offsets": [ [ 60, 67 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_E2" }, { "role": "Cause", "ref_id": "8543789_T1" }, { "role": "CSite", "ref_id": "8543789_T8" } ] }, { "id": "8543789_E2", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 68, 82 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_E3" } ] }, { "id": "8543789_E3", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 68, 82 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_T1" } ] }, { "id": "8543789_E4", "type": "Positive_regulation", "trigger": { "text": [ "result" ], "offsets": [ [ 776, 782 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_E6" } ] }, { "id": "8543789_E5", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 786, 800 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_T3" } ] }, { "id": "8543789_E6", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 786, 800 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_E5" } ] }, { "id": "8543789_E7", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 998, 1013 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_T4" } ] }, { "id": "8543789_E8", "type": "Gene_expression", "trigger": { "text": [ "positive" ], "offsets": [ [ 1033, 1041 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_T5" } ] }, { "id": "8543789_E9", "type": "Positive_regulation", "trigger": { "text": [ "high" ], "offsets": [ [ 1088, 1092 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_E10" } ] }, { "id": "8543789_E10", "type": "Transcription", "trigger": { "text": [ "transcriptional activity" ], "offsets": [ [ 1093, 1117 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_T4" } ] }, { "id": "8543789_E11", "type": "Positive_regulation", "trigger": { "text": [ "results" ], "offsets": [ [ 1544, 1551 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_E12" } ] }, { "id": "8543789_E12", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1555, 1569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_E13" } ] }, { "id": "8543789_E13", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 1555, 1569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8543789_T7" } ] } ]

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[ { "id": "7958618__text", "type": "abstract", "text": [ "Functions of glutathione and glutathione disulfide in immunology and immunopathology. \nEven a moderate increase in the cellular cysteine supply elevates the intracellular glutathione (GSH) and glutathione disulfide (GSSG) levels and potentiates immunological functions of lymphocytes in vitro. At low GSSG levels, T cells cannot optimally activate the immunologically important transcription factor NF kappa B, whereas high GSSG levels inhibit the DNA binding activity of NF kappa B. The effects of GSSG are antagonized by reduced thioredoxin (TRX). As the protein tyrosine kinase activities p56lck and p59fyn are activated in intact cells by hydrogen peroxide, they are likely targets for GSSG action. These redox-regulated enzymes trigger signal cascades for NF kappa B activation and transduce signals from the T cell antigen receptor, from CD4 and CD8 molecules, and from the IL-2 receptor beta-chain. The effector phase of cytotoxic T cell responses and IL-2-dependent functions are inhibited even by a partial depletion of the intracellular GSH pool. As signal transduction is facilitated by prooxidant conditions, we propose that the well-known immunological consequences of GSH depletion ultimately may be results of the accompanying GSSG deficiency. As HIV-infected patients and SIV-infected rhesus macaques have, on the average, significantly decreased plasma cyst(e)ine and intracellular GSH levels, we also hypothesize that AIDS may be the consequence of a GSSG deficiency as well. " ], "offsets": [ [ 0, 1494 ] ] } ]

[ { "id": "7958618_T1", "type": "Protein", "text": [ "thioredoxin" ], "offsets": [ [ 531, 542 ] ], "normalized": [] }, { "id": "7958618_T2", "type": "Protein", "text": [ "TRX" ], "offsets": [ [ 544, 547 ] ], "normalized": [] }, { "id": "7958618_T3", "type": "Protein", "text": [ "p56lck" ], "offsets": [ [ 592, 598 ] ], "normalized": [] }, { "id": "7958618_T4", "type": "Protein", "text": [ "p59fyn" ], "offsets": [ [ 603, 609 ] ], "normalized": [] }, { "id": "7958618_T5", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 844, 847 ] ], "normalized": [] }, { "id": "7958618_T6", "type": "Protein", "text": [ "IL-2 receptor beta-chain" ], "offsets": [ [ 880, 904 ] ], "normalized": [] }, { "id": "7958618_T7", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 959, 963 ] ], "normalized": [] } ]

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[ { "id": "7958618_1", "entity_ids": [ "7958618_T1", "7958618_T2" ] } ]

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[ { "id": "7622191__text", "type": "abstract", "text": [ "Thapsigargin induces IL-2 receptor alpha-chain in human peripheral and Jurkat T cells via a protein kinase C-independent mechanism. \nThapsigargin (TG), an inhibitor of Ca(2+)-ATPase, depletes intracellular Ca2+ stores and induces a sustained Ca2+ influx without altering phosphatidyl inositol levels. TG plus phorbol myristate acetate (PMA) but not TG alone induced IL-2 in Jurkat T cells, suggesting that TG had no effect on protein kinase C (PKC). However, TG induced increases in IL-2R alpha protein as well as IL-2R alpha mRNA in Jurkat T cells in a dose-dependent manner. A similar increase in IL-2R alpha by TG was also observed in human peripheral T cells. Further, like PMA, TG markedly induced NF kappa B in Jurkat T cells. However, TG and PMA exhibited a synergistic action on IL-2R alpha expression, suggesting that TG and PMA induce IL-2R alpha through distinct pathways. PMA- but not TG-induced IL-2R alpha is inhibited by the PKC inhibitor H7, whereas TG- but not PMA-induced IL-2R alpha was inhibited by cholera toxin, forskolin and 1,9-dideoxy forskolin. In toto, these results suggest that TG induces IL-2R alpha in human T cells through a PKC-independent pathway. " ], "offsets": [ [ 0, 1182 ] ] } ]

[ { "id": "7622191_T1", "type": "Protein", "text": [ "IL-2 receptor alpha-chain" ], "offsets": [ [ 21, 46 ] ], "normalized": [] }, { "id": "7622191_T2", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 366, 370 ] ], "normalized": [] }, { "id": "7622191_T3", "type": "Protein", "text": [ "IL-2R alpha" ], "offsets": [ [ 483, 494 ] ], "normalized": [] }, { "id": "7622191_T4", "type": "Protein", "text": [ "IL-2R alpha" ], "offsets": [ [ 514, 525 ] ], "normalized": [] }, { "id": "7622191_T5", "type": "Protein", "text": [ "IL-2R alpha" ], "offsets": [ [ 599, 610 ] ], "normalized": [] }, { "id": "7622191_T6", "type": "Protein", "text": [ "IL-2R alpha" ], "offsets": [ [ 787, 798 ] ], "normalized": [] }, { "id": "7622191_T7", "type": "Protein", "text": [ "IL-2R alpha" ], "offsets": [ [ 845, 856 ] ], "normalized": [] }, { "id": "7622191_T8", "type": "Protein", "text": [ "IL-2R alpha" ], "offsets": [ [ 908, 919 ] ], "normalized": [] }, { "id": "7622191_T9", "type": "Protein", "text": [ "IL-2R alpha" ], "offsets": [ [ 990, 1001 ] ], "normalized": [] }, { "id": "7622191_T10", "type": "Protein", "text": [ "IL-2R alpha" ], "offsets": [ [ 1118, 1129 ] ], "normalized": [] }, { "id": "7622191_T12", "type": "Entity", "text": [ "protein kinase C-independent mechanism" ], "offsets": [ [ 92, 130 ] ], "normalized": [] } ]

[ { "id": "7622191_E1", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 13, 20 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_T1" }, { "role": "Cause", "ref_id": "7622191_E2" } ] }, { "id": "7622191_E2", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 13, 20 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_T1" }, { "role": "Site", "ref_id": "7622191_T12" } ] }, { "id": "7622191_E3", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 358, 365 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_T2" } ] }, { "id": "7622191_E4", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 470, 479 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_T3" } ] }, { "id": "7622191_E5", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 470, 479 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_T4" } ] }, { "id": "7622191_E6", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 587, 595 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_T5" } ] }, { "id": "7622191_E7", "type": "Regulation", "trigger": { "text": [ "synergistic action" ], "offsets": [ [ 765, 783 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_E8" } ] }, { "id": "7622191_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 799, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_T6" } ] }, { "id": "7622191_E9", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 838, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_T7" } ] }, { "id": "7622191_E10", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 900, 907 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_T8" } ] }, { "id": "7622191_E11", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 923, 932 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_E10" } ] }, { "id": "7622191_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 982, 989 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_T9" } ] }, { "id": "7622191_E13", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1006, 1015 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_E12" } ] }, { "id": "7622191_E14", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 1110, 1117 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7622191_T10" } ] } ]

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[ { "id": "9277478__text", "type": "abstract", "text": [ "alpha-Tocopheryl succinate inhibits monocytic cell adhesion to endothelial cells by suppressing NF-kappa B mobilization. \nThe adherence of monocytes to activated endothelium is an early event in atherogenesis. Because antioxidants have been considered to be of antiatherosclerotic potential, we investigated the effects of alpha-tocopherol (TCP) and its acetate and succinate esters on monocyte adhesion to cytokine-stimulated human umbilical vein endothelial cells (HUVEC). Endothelial cells were treated with TCP, alpha-tocopherol acetate (TCP acetate), or alpha-tocopheryl succinate (TCP succinate) before stimulation with tumor necrosis factor-alpha (TNF-alpha; 10 U/ml, 6 h) or interleukin-1 beta (IL-1 beta; 10 U/ml, 6 h). Cytokine-stimulated cell surface expression of vascular cell adhesion molecule-1 (VCAM-1, CD106) and E-selectin (ELAM-1, CD62E), but not of intercellular adhesion molecule-1 (ICAM-1, CD54), was time- and dose-dependently inhibited by TCP succinate but not by TCP or TCP acetate. TCP succinate (200 microM, 24 h) reduced TNF-induced VCAM-1 and E-selectin expression from a specific mean fluorescence intensity of 151 +/- 28 to 12 +/- 4 channels and from 225 +/- 38 to 79 +/- 21 channels, respectively. Succinate alone had no effect. Decreased adhesion molecule expression was associated with a reduction of monocytic cell adhesion. TCP succinate (20 microM, 72 h), but not TCP (200 microM, 72 h), reduced U-937 cell adhesion to TNF-alpha-stimulated (10 U/ml, 6 h) HUVEC by 30% (P < 0.025) and to IL-1 beta-stimulated HUVEC by 56% (P < 0.010). Electrophoretic mobility-shift assays of HUVEC nuclear proteins revealed a decrease in TNF-alpha-stimulated nuclear factor-kappa B (NF-kappa B) activation after pretreatment of HUVEC with TCP succinate but not with TCP, TCP acetate, or succinate alone. In conclusion, we demonstrate that the vitamin E derivative TCP succinate prevents monocytic cell adhesion to cytokine-stimulated endothelial cells by inhibiting the activation of NF-kappa B, further emphasizing the antiatherosclerotic potential of lipid soluble antioxidants. " ], "offsets": [ [ 0, 2101 ] ] } ]

[ { "id": "9277478_T1", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 626, 653 ] ], "normalized": [] }, { "id": "9277478_T2", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 655, 664 ] ], "normalized": [] }, { "id": "9277478_T3", "type": "Protein", "text": [ "interleukin-1 beta" ], "offsets": [ [ 683, 701 ] ], "normalized": [] }, { "id": "9277478_T4", "type": "Protein", "text": [ "IL-1 beta" ], "offsets": [ [ 703, 712 ] ], "normalized": [] }, { "id": "9277478_T5", "type": "Protein", "text": [ "vascular cell adhesion molecule-1" ], "offsets": [ [ 776, 809 ] ], "normalized": [] }, { "id": "9277478_T6", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 811, 817 ] ], "normalized": [] }, { "id": "9277478_T7", "type": "Protein", "text": [ "CD106" ], "offsets": [ [ 819, 824 ] ], "normalized": [] }, { "id": "9277478_T8", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 830, 840 ] ], "normalized": [] }, { "id": "9277478_T9", "type": "Protein", "text": [ "ELAM-1" ], "offsets": [ [ 842, 848 ] ], "normalized": [] }, { "id": "9277478_T10", "type": "Protein", "text": [ "CD62E" ], "offsets": [ [ 850, 855 ] ], "normalized": [] }, { "id": "9277478_T11", "type": "Protein", "text": [ "intercellular adhesion molecule-1" ], "offsets": [ [ 869, 902 ] ], "normalized": [] }, { "id": "9277478_T12", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 904, 910 ] ], "normalized": [] }, { "id": "9277478_T13", "type": "Protein", "text": [ "CD54" ], "offsets": [ [ 912, 916 ] ], "normalized": [] }, { "id": "9277478_T14", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1061, 1067 ] ], "normalized": [] }, { "id": "9277478_T15", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 1072, 1082 ] ], "normalized": [] }, { "id": "9277478_T16", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1456, 1465 ] ], "normalized": [] }, { "id": "9277478_T17", "type": "Protein", "text": [ "IL-1 beta" ], "offsets": [ [ 1524, 1533 ] ], "normalized": [] }, { "id": "9277478_T18", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1658, 1667 ] ], "normalized": [] } ]

[ { "id": "9277478_E1", "type": "Positive_regulation", "trigger": { "text": [ "stimulated" ], "offsets": [ [ 738, 748 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E3" } ] }, { "id": "9277478_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 762, 772 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_T9" } ] }, { "id": "9277478_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 762, 772 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_T6" } ] }, { "id": "9277478_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 762, 772 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_T12" } ] }, { "id": "9277478_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 950, 959 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E2" } ] }, { "id": "9277478_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 950, 959 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E3" } ] }, { "id": "9277478_E7", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 950, 959 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E4" } ] }, { "id": "9277478_E8", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1041, 1048 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E10" } ] }, { "id": "9277478_E9", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1041, 1048 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E11" } ] }, { "id": "9277478_E10", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1053, 1060 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E12" } ] }, { "id": "9277478_E11", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1053, 1060 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E13" } ] }, { "id": "9277478_E12", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1083, 1093 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_T14" } ] }, { "id": "9277478_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1083, 1093 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_T15" } ] }, { "id": "9277478_E14", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1253, 1259 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E13" } ] }, { "id": "9277478_E15", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1253, 1259 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E12" } ] }, { "id": "9277478_E16", "type": "Negative_regulation", "trigger": { "text": [ "Decreased" ], "offsets": [ [ 1261, 1270 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E13" } ] }, { "id": "9277478_E17", "type": "Negative_regulation", "trigger": { "text": [ "Decreased" ], "offsets": [ [ 1261, 1270 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9277478_E12" } ] } ]

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[]

[ { "id": "8555489__text", "type": "abstract", "text": [ "The promoter and 5' flanking sequences controlling human B29 gene expression. \nThe product of the B-cell-specific B29 gene (B29, Ig beta, CD79b) is essential for Ig-mediated B-cell activation via the B-cell antigen receptor complex (BCR) on human and murine B lymphocytes. To better understand the regulation of this pivotal gene, we have analyzed the human genomic DNA sequence upstream of the B29 ATG start codon for transcriptional control activity. The human B29 gene lacks either a TATA or a CAAT box and transcription is initiated at multiple sites. The minimal promoter of the human B29 gene is contained within a 193-bp region 5' of these multiple start sites. This minimal promoter exhibits B-cell-specific activity and contains SP1, ETS, OCT, and IKAROS/LYF-1 transcription factor motifs. All these motifs are strikingly conserved in sequence and placement relative to the previously characterized murine B29 promoter. Additional upstream gene segments dramatically affected B29 minimal promoter activity. A newly identified motif called the B29 conserved sequence (BCS), found upstream of both human and murine B29 promoters, appears to stimulate B29 transcription through a novel mechanism. A single BCS had little effect either on the minimal B29 promoter or on a heterologous promoter. Instead, the BCS stimulated transcription by counteracting 5' negative regulatory DNA sequences that block the activity of the B29 minimal promoter in its absence. These findings indicate that B29 gene expression is controlled by the complex interplay of positive and negative regulatory elements. " ], "offsets": [ [ 0, 1598 ] ] } ]

[ { "id": "8555489_T1", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 57, 60 ] ], "normalized": [] }, { "id": "8555489_T2", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 114, 117 ] ], "normalized": [] }, { "id": "8555489_T3", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 124, 127 ] ], "normalized": [] }, { "id": "8555489_T4", "type": "Protein", "text": [ "Ig beta" ], "offsets": [ [ 129, 136 ] ], "normalized": [] }, { "id": "8555489_T5", "type": "Protein", "text": [ "CD79b" ], "offsets": [ [ 138, 143 ] ], "normalized": [] }, { "id": "8555489_T6", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 395, 398 ] ], "normalized": [] }, { "id": "8555489_T7", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 463, 466 ] ], "normalized": [] }, { "id": "8555489_T8", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 590, 593 ] ], "normalized": [] }, { "id": "8555489_T9", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 915, 918 ] ], "normalized": [] }, { "id": "8555489_T10", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 985, 988 ] ], "normalized": [] }, { "id": "8555489_T11", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 1052, 1055 ] ], "normalized": [] }, { "id": "8555489_T12", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 1122, 1125 ] ], "normalized": [] }, { "id": "8555489_T13", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 1158, 1161 ] ], "normalized": [] }, { "id": "8555489_T14", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 1256, 1259 ] ], "normalized": [] }, { "id": "8555489_T15", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 1427, 1430 ] ], "normalized": [] }, { "id": "8555489_T16", "type": "Protein", "text": [ "B29" ], "offsets": [ [ 1493, 1496 ] ], "normalized": [] }, { "id": "8555489_T22", "type": "Entity", "text": [ "minimal promoter" ], "offsets": [ [ 989, 1005 ] ], "normalized": [] }, { "id": "8555489_T26", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1260, 1268 ] ], "normalized": [] }, { "id": "8555489_T29", "type": "Entity", "text": [ "minimal promoter" ], "offsets": [ [ 1431, 1447 ] ], "normalized": [] } ]

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[ { "id": "9852211__text", "type": "abstract", "text": [ "The control of lytic replication of Epstein-Barr virus in B lymphocytes (Review). \nUncontrolled replication of a virus, which is harmful to the host is also disadvantageous to the virus. Most viruses cannot compete with the various immune mechanisms and become eliminated in the course of infection. Therefore, only the time between infection and eradication remains for these viruses to proliferate. A few viruses, like the Herpesviruses or the papillomaviruses, however, have developed a sophisticated strategy for persisting lifelong, usually asymptomatically in the host, hiding from the immune system and producing infectious progeny at the same time. This strategy depends on a separation of latency and the lytic replication, either by time due to differentiation-dependent mechanisms or by spatial separation as the result of different host cell types. Both are true for the Epstein-Barr virus (EBV). B cells and epithelial cells have a pivotal role in the life cycle of the virus. The former can become latently infected and are thought to be the virus reservoir in vivo, whereas the latter were shown to be permissive for lytic replication. However, replication of EBV in vivo is controlled primarily by host immune mechanisms selecting for cells that are not permissive for viral replication as the result of a particular set of transcription factors. These factors control the activity of the regulatory immediate-early genes and, in addition, lytic and latent cycle regulatory genes negatively interfere with each other and thus link cellular and viral gene regulatory mechanisms. Disturbance of both the immune surveillance as well as viral gene regulation may result in EBV-associated disease. " ], "offsets": [ [ 0, 1709 ] ] } ]

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[ { "id": "9388475__text", "type": "abstract", "text": [ "Molecular cloning and functional characterization of murine cDNA encoding transcription factor NFATc. \nTranscription factors of the NFAT (nuclear factor of activated T cells) family play important roles in immune and inflammatory responses by regulating the expression of genes encoding cytokines and immunoregulatory proteins. Here we describe cloning and characterization of full-length cDNA encoding murine (m) NFATc which predicts that the protein has all the conserved structural motifs of NFAT family members, including the rel homology domain, the NFAT homology domain and the nuclear translocation signals. mNFATc complexed with AP-1 bound specifically to the murine IL-2 NFAT recognition sequence and activated transcription from the co-transfected IL-2 promoter in COS-7 cells. Northern blot analysis showed that the cDNA probe hybridized with a 4.5 kb transcript which is highly inducible in murine T cells. By Northern and in situ hybridization, mNFATc transcript was detected from the early stage of development. In the mouse embryo, mNFATc transcript was strongly expressed in thymus, lung and submandibular gland and weakly in skeletal muscle and heart suggesting that mNFATc may have a role both in embryogenesis and in mature T cells. " ], "offsets": [ [ 0, 1252 ] ] } ]

[ { "id": "9388475_T1", "type": "Protein", "text": [ "NFATc" ], "offsets": [ [ 95, 100 ] ], "normalized": [] }, { "id": "9388475_T2", "type": "Protein", "text": [ "murine (m) NFATc" ], "offsets": [ [ 403, 419 ] ], "normalized": [] }, { "id": "9388475_T3", "type": "Protein", "text": [ "mNFATc" ], "offsets": [ [ 615, 621 ] ], "normalized": [] }, { "id": "9388475_T4", "type": "Protein", "text": [ "AP-1" ], "offsets": [ [ 637, 641 ] ], "normalized": [] }, { "id": "9388475_T5", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 675, 679 ] ], "normalized": [] }, { "id": "9388475_T6", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 758, 762 ] ], "normalized": [] }, { "id": "9388475_T7", "type": "Protein", "text": [ "mNFATc" ], "offsets": [ [ 958, 964 ] ], "normalized": [] }, { "id": "9388475_T8", "type": "Protein", "text": [ "mNFATc" ], "offsets": [ [ 1047, 1053 ] ], "normalized": [] }, { "id": "9388475_T9", "type": "Protein", "text": [ "mNFATc" ], "offsets": [ [ 1184, 1190 ] ], "normalized": [] } ]

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[ { "id": "2065663__text", "type": "abstract", "text": [ "Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. \nHydrogen peroxide and oxygen radicals are agents commonly produced during inflammatory processes. In this study, we show that micromolar concentrations of H2O2 can induce the expression and replication of HIV-1 in a human T cell line. The effect is mediated by the NF-kappa B transcription factor which is potently and rapidly activated by an H2O2 treatment of cells from its inactive cytoplasmic form. N-acetyl-L-cysteine (NAC), a well characterized antioxidant which counteracts the effects of reactive oxygen intermediates (ROI) in living cells, prevented the activation of NF-kappa B by H2O2. NAC and other thiol compounds also blocked the activation of NF-kappa B by cycloheximide, double-stranded RNA, calcium ionophore, TNF-alpha, active phorbol ester, interleukin-1, lipopolysaccharide and lectin. This suggests that diverse agents thought to activate NF-kappa B by distinct intracellular pathways might all act through a common mechanism involving the synthesis of ROI. ROI appear to serve as messengers mediating directly or indirectly the release of the inhibitory subunit I kappa B from NF-kappa B. " ], "offsets": [ [ 0, 1247 ] ] } ]

[ { "id": "2065663_T1", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 863, 872 ] ], "normalized": [] } ]

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[ { "id": "10075645__text", "type": "abstract", "text": [ "Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. \nBacterial lipopolysaccharide (LPS)-mediated immune responses, including activation of monocytes, macrophages, and endothelial cells, play an important role in the pathogenesis of Gram-negative bacteria-induced sepsis syndrome. Activation of NF-kappaB is thought to be required for cytokine release from LPS-responsive cells, a critical step for endotoxic effects. Here we investigated the role and involvement of interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) signal transducer molecules in LPS signaling in human dermal microvessel endothelial cells (HDMEC) and THP-1 monocytic cells. LPS stimulation of HDMEC and THP-1 cells initiated an IL-1 receptor-like NF-kappaB signaling cascade. In transient cotransfection experiments, dominant negative mutants of the IL-1 signaling pathway, including MyD88, IRAK, IRAK2, and TRAF6 inhibited both IL-1- and LPS-induced NF-kappaB-luciferase activity. LPS-induced NF-kappaB activation was not inhibited by a dominant negative mutant of TRAF2 that is involved in TNF signaling. LPS-induced activation of NF-kappaB-responsive reporter gene was not inhibited by IL-1 receptor antagonist. TLR2 and TLR4 were expressed on the cell surface of HDMEC and THP-1 cells. These findings suggest that a signal transduction molecule in the LPS receptor complex may belong to the IL-1 receptor/toll-like receptor (TLR) super family, and the LPS signaling cascade uses an analogous molecular framework for signaling as IL-1 in mononuclear phagocytes and endothelial cells. " ], "offsets": [ [ 0, 1686 ] ] } ]

[ { "id": "10075645_T1", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 636, 645 ] ], "normalized": [] }, { "id": "10075645_T2", "type": "Protein", "text": [ "MyD88" ], "offsets": [ [ 983, 988 ] ], "normalized": [] }, { "id": "10075645_T3", "type": "Protein", "text": [ "IRAK" ], "offsets": [ [ 990, 994 ] ], "normalized": [] }, { "id": "10075645_T4", "type": "Protein", "text": [ "IRAK2" ], "offsets": [ [ 996, 1001 ] ], "normalized": [] }, { "id": "10075645_T5", "type": "Protein", "text": [ "TRAF6" ], "offsets": [ [ 1007, 1012 ] ], "normalized": [] }, { "id": "10075645_T6", "type": "Protein", "text": [ "TRAF2" ], "offsets": [ [ 1165, 1170 ] ], "normalized": [] }, { "id": "10075645_T7", "type": "Protein", "text": [ "TLR2" ], "offsets": [ [ 1314, 1318 ] ], "normalized": [] }, { "id": "10075645_T8", "type": "Protein", "text": [ "TLR4" ], "offsets": [ [ 1323, 1327 ] ], "normalized": [] } ]

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[ { "id": "9261181__text", "type": "abstract", "text": [ "Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. \nInterleukin-5 (IL-5), which is produced by CD4(+) T helper 2 (Th2) cells, but not by Th1 cells, plays a key role in the development of eosinophilia in asthma. Despite increasing evidence that the outcome of many diseases is determined by the ratio of the two subsets of CD4(+) T helper cells, Th1 and Th2, the molecular basis for Th1- and Th2- specific gene expression remains to be elucidated. We previously established a critical role for the transcription factor GATA-3 in IL-5 promoter activation in EL-4 cells, which express both Th1- and Th2-type cytokines. Our studies reported here demonstrate that GATA-3 is critical for expression of the IL-5 gene in bona fide Th2 cells. Whereas mutations in the GATA-3 site abolished antigen- or cAMP- stimulated IL-5 promoter activation in Th2 cells, ectopic expression of GATA-3 in Th1 cells or in a non-lymphoid, non-IL-5-producing cell line activated the IL-5 promoter. During the differentiation of naive CD4(+) T cells isolated from T cell receptor transgenic mice, GATA-3 gene expression was up-regulated in developing Th2 cells, but was down-regulated in Th1 cells, and antigen- or cAMP-activated Th2 cells (but not Th1 cells) expressed the GATA-3 protein. Thus, GATA-3 may play an important role in the balance between Th1 and Th2 subsets in immune responses. Inhibition of GATA-3 activity has therapeutic potential in the treatment of asthma and other hypereosinophilic diseases. " ], "offsets": [ [ 0, 1584 ] ] } ]

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[ { "id": "9312094__text", "type": "abstract", "text": [ "The DNA binding domain of the A-MYB transcription factor is responsible for its B cell-specific activity and binds to a B cell 110-kDa nuclear protein. \nExpression studies as well as the use of transgenic animals have demonstrated that the A-MYB transcription factor plays central and specific role in the regulation of mature B cell proliferation and/or differentiation. Furthermore, it is highly expressed in Burkitt's lymphoma cells and may participate in the pathogenesis of this disease. We have therefore investigated the transcriptional activity of A-MYB and its regulation in several human lymphoid cell lines using co-transfection assays and show that A-MYB is transcriptionally active in all the B cell lines studied, but not in T cells. In particular the best responder cell line was the Burkitt's cell line Namalwa. The activity of A-MYB in B and not T cells was observed when either an artificial construct or the c-MYC promoter was used as a reporter. Furthermore, the functional domains responsible for DNA binding, transactivation, and negative regulation, previously characterized in a fibroblast context, were found to have similar activity in B cells. The region of A-MYB responsible for the B cell specific activity was defined to be the N-terminal 218 amino acids containing the DNA binding domain. Finally, a 110-kDa protein has been identified in the nuclei of all the B, but not T, cell lines that specifically binds to this A-MYB N-terminal domain. We hypothesize that this 110-kDa protein may be a functionally important B cell-specific co-activator of A-MYB. " ], "offsets": [ [ 0, 1586 ] ] } ]

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[]

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[ { "id": "9440542__text", "type": "abstract", "text": [ "A thiol antioxidant regulates IgE isotype switching by inhibiting activation of nuclear factor-kappaB. \nThe binding site for nuclear factor-kappaB (NF-kappaB) is present at the promoter region of the germline Cepsilon gene, but there is little information on whether this factor is involved in regulating IgE synthesis by human B cells. Accordingly, we studied the role of NF-kappaB in germline Cepsilon transcription by using two human Burkitt's lymphoma B cell lines, DND39 and DG75. In both cell lines, n-acetyl-L-cysteine (NAC), a potent thiol antioxidant, inhibited the triggering of the nuclear expression of NF-kappaB by IL-4 and by anti-CD40 monoclonal antibody. Although IL-4 activated signal transducers and activators of transcription (STAT) 6 in addition to NF-kappaB, NAC treatment or the transfection of decoy oligodeoxynucleotides for NF-kappaB or STAT6 only partly blocked IL-4-induced germline Cepsilon transcription. However, these two decoy oligodeoxynucleotides together almost completely abrogated IL-4-induced germline Cepsilon transcription. Of note, CD40-mediated enhancement of IL-4-driven germline Cepsilon transcription was markedly decreased by NAC or by a decoy oligodeoxynucleotide for NF-kappaB. The effect of NAC was also examined on deletional switch recombination underlying the isotype switch to IgE. NAC inhibited the generation of Smu/Sepsilon switch fragments in normal human B cells costimulated with IL-4 and anti-CD40 monoclonal antibody. It also abolished IL-4-induced upregulation of CD40 but promoted upregulation of CD23. These results suggest that coordination of NF-kappaB and STAT6 may be required for induction of germline Cepsilon transcription by IL-4, and that CD40-mediated NF-kappaB activation may be important in regulating both enhancement of germline Cepsilon transcription and class switching to IgE. " ], "offsets": [ [ 0, 1859 ] ] } ]

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[ { "id": "10383940__text", "type": "abstract", "text": [ "STAT1 activation during monocyte to macrophage maturation: role of adhesion molecules. \nHuman monocytes isolated from peripheral blood of healthy donors show a time-dependent differentiation into macrophages upon in vitro cultivation, closely mimicking their in vivo migration and maturation into extravascular tissues. The mediator(s) of this maturation process has not been yet defined. We investigated the involvement of signal transducers and activators of transcription (STAT) factors in this phenomenon and reported the specific, time-dependent, activation of STAT1 protein starting at day 0/1 of cultivation and maximally expressed at day 5. STAT1 activity was evident on the STAT binding sequences (SBE) present in the promoters of genes which are up-regulated during monocyte to macrophage maturation such as FcgammaRI and ICAM-1, and in the promoter of the transcription factor IFN regulatory factor-1. Moreover, the effect of cell adhesion to fibronectin or laminin was studied to investigate mechanisms involved in STAT1 activation. Compared with monocytes adherent on plastic surfaces, freshly isolated cells allowed to adhere either to fibronectin- or laminin-coated flasks exhibited an increased STAT1 binding activity both in control and in IFN-gamma-treated cells. The molecular events leading to enhanced STAT1 activation and cytokine responsiveness concerned both Y701 and S727 STAT1 phosphorylation. Exogenous addition of transforming growth factor-beta, which exerts an inhibitory effect on some monocytic differentiation markers, inhibited macrophage maturation, integrin expression and STAT1 binding activity. Taken together these results indicate that STAT1 plays a pivotal role in the differentiation/maturation process of monocytes as an early transcription factor initially activated by adherence and then able to modulate the expression of functional genes, such as ICAM-1 and FcgammaRI. " ], "offsets": [ [ 0, 1916 ] ] } ]

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[ { "id": "1502202__text", "type": "abstract", "text": [ "NF-kappa B-dependent induction of the NF-kappa B p50 subunit gene promoter underlies self-perpetuation of human immunodeficiency virus transcription in monocytic cells. \nThe molecular mechanisms underlying the sustained nuclear translocation of NF-kappa B observed in U937 monocytic cells chronically infected with human immunodeficiency virus (HIV) were studied. The activity of the promoter regulating the synthesis of the p105 precursor of the NF-kappa B p50 subunit was enhanced in these cells. Deletions in this promoter indicated that this upregulation was mediated through the NF-kappa B- but not the AP-1-binding motif, by bona fide p50/p65 heterodimers. Analysis of cytosolic extracts indicated that NF-kappa B levels were increased in HIV-infected cells. In contrast to the transient NF-kappa B activation induced by phorbol ester, the permanent NF-kappa B translocation induced by HIV infection was not dependent on PKC isoenzymes alpha and beta as shown by the use of a specific inhibitor (GF 109203X). These observations indicate that during chronic HIV infection of U937 cells, continuous NF-kappa B (p50/p65) translocation results in p105 promoter upregulation with subsequent cytosolic NF-kappa B accumulation, ready for further translocation. This HIV-mediated mechanism results in a self-perpetuating loop of NF-kappa B production. " ], "offsets": [ [ 0, 1350 ] ] } ]

[ { "id": "1502202_T1", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 49, 52 ] ], "normalized": [] }, { "id": "1502202_T2", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 425, 429 ] ], "normalized": [] }, { "id": "1502202_T3", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 458, 461 ] ], "normalized": [] }, { "id": "1502202_T4", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 641, 644 ] ], "normalized": [] }, { "id": "1502202_T5", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 645, 648 ] ], "normalized": [] }, { "id": "1502202_T6", "type": "Protein", "text": [ "PKC isoenzymes alpha" ], "offsets": [ [ 927, 947 ] ], "normalized": [] }, { "id": "1502202_T7", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 952, 956 ] ], "normalized": [] }, { "id": "1502202_T8", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1115, 1118 ] ], "normalized": [] }, { "id": "1502202_T9", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1119, 1122 ] ], "normalized": [] }, { "id": "1502202_T10", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 1149, 1153 ] ], "normalized": [] }, { "id": "1502202_T12", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 66, 74 ] ], "normalized": [] }, { "id": "1502202_T23", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1154, 1162 ] ], "normalized": [] } ]

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[ { "id": "10229815__text", "type": "abstract", "text": [ "CTLA-4-Mediated inhibition of early events of T cell proliferation. \nCTLA-4 engagement by mAbs inhibits, while CD28 enhances, IL-2 production and proliferation upon T cell activation. Here, we have analyzed the mechanisms involved in CTLA-4-mediated inhibition of T cell activation of naive CD4+ T cells using Ab cross-linking. CTLA-4 ligation inhibited CD3/CD28-induced IL-2 mRNA accumulation by inhibiting IL-2 transcription, which appears to be mediated in part through decreasing NF-AT accumulation in the nuclei. However, CTLA-4 ligation did not appear to affect the CD28-mediated stabilization of IL-2 mRNA. Further, CTLA-4 engagement inhibited progression through the cell cycle by inhibiting the production of cyclin D3, cyclin-dependent kinase (cdk)4, and cdk6 when the T cells were stimulated with anti-CD3/CD28 and with anti-CD3 alone. These results indicate that CTLA-4 signaling inhibits events early in T cell activation both at IL-2 transcription and at the level of IL-2-independent events of the cell cycle, and does not simply oppose CD28-mediated costimulation. " ], "offsets": [ [ 0, 1081 ] ] } ]

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"10229815_E16" } ] }, { "id": "10229815_E20", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 704, 714 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10229815_T17" } ] }, { "id": "10229815_E21", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 704, 714 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10229815_T15" } ] }, { "id": "10229815_E22", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 704, 714 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10229815_T16" } ] }, { "id": "10229815_E23", "type": "Positive_regulation", "trigger": { "text": [ "when" ], "offsets": [ [ 770, 774 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10229815_E22" } ] }, { "id": "10229815_E24", "type": "Positive_regulation", "trigger": { "text": [ "when" ], "offsets": [ [ 770, 774 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10229815_E21" } ] }, { "id": "10229815_E25", "type": 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[ { "id": "2258623__text", "type": "abstract", "text": [ "Differences in transcriptional enhancers of HIV-1 and HIV-2. Response to T cell activation signals. \nT cell activation results in high levels of HIV replication and is thought to be one mechanism leading to the conversion from latent to active viral infection. In HIV-1, the sequences that respond to these signaling events are found in the long terminal repeat (LTR) and comprise the transcriptional enhancer, which contains two conserved binding sites for the nuclear factor kappa B (NF kappa B). The corresponding region in the second AIDS retrovirus, HIV-2, contains a conserved and a divergent NF kappa B binding site. We demonstrate that the HIV-1 LTR responds better than the HIV-2 LTR to T cell activation signals. These qualitative differences in the response to T cell activation are reproduced not only when HIV-1 or HIV-2 enhancers are placed upstream of a heterologous promoter but also when these enhancers are switched between their respective LTR. In electrophoretic mobility shift assays, NF kappa B binds to both conserved sites in the HIV-1 transcriptional enhancer and only to the single conserved site in the HIV-2 transcriptional enhancer. Instead of NF kappa B, the activator protein 3 binds to the divergent site in HIV-2. In conclusion, HIV-1 and HIV-2 are differentially regulated by T cell activation signals, and this difference may account for the longer period of viral latency observed with HIV-2 than with HIV-1 infection. " ], "offsets": [ [ 0, 1455 ] ] } ]

[ { "id": "2258623_T1", "type": "Protein", "text": [ "activator protein 3" ], "offsets": [ [ 1189, 1208 ] ], "normalized": [] } ]

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[ { "id": "8627768__text", "type": "abstract", "text": [ "Permanent occupancy of the human immunodeficiency virus type 1 enhancer by NF-kappa B is needed for persistent viral replication in monocytes. \nThis work aimed to ascertain the role of kappaB-responsive elements of the human immunodeficiency virus type 1 (HIV-1) enhancer not only in early initiation but also in long-term maintenance of proviral transcription in cells of the monocytic lineage. For this purpose, we used three main approaches. The first was to abruptly terminate tumor necrosis factor-induced NF-kappaB binding to the enhancer sequences in U1 monocytic cells, using a short pulse of exogenous tumor necrosis factor. This resulted in concomitant decrease in nuclear NF-kappaB DNA-binding activity and endogenous long terminal repeat transcriptional activity. The second was to suppress the permanent NF-kappaB translocation induced by HIV-1 replication itself in chronically infected U937 cells, using a specific proteasome inhibitor (Z-LLL-H). As early as 2 h after addition of the inhibitor to the culture medium, there was an inhibition of both constitutive activation of NF-kappaB and HIV-1 genome expression. The third approach was to monitor the replication competence in U937 cells of an infectious HIV-1 provirus carrying point mutations in the kappaB-responsive elements of both long terminal repeats. Compared with its wild-type counterpart, this mutated provirus showed a profoundly decreased, Z-LLL-H-insensitive transcriptional and replicative activity in U937 monocytes. Together, our results indicate that occupancy of the viral enhancer by NF-kappaB (p50/p65) heterodimers is required for ongoing transcription of integrated HIV provirus in monocytes, even in cells chronically infected and permanently producing functional HIV Tat protein. Thus, the ability of HIV-1 replication to activate NF-kappaB is crucial to the intense self-perpetuated viral transcription observed in cells of the monocytic lineage. " ], "offsets": [ [ 0, 1942 ] ] } ]

[ { "id": "8627768_T1", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1584, 1587 ] ], "normalized": [] }, { "id": "8627768_T2", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1588, 1591 ] ], "normalized": [] }, { "id": "8627768_T3", "type": "Protein", "text": [ "Tat" ], "offsets": [ [ 1761, 1764 ] ], "normalized": [] } ]

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[ { "id": "1847170__text", "type": "abstract", "text": [ "Platelet-activating factor induces phospholipid turnover, calcium flux, arachidonic acid liberation, eicosanoid generation, and oncogene expression in a human B cell line. \nPlatelet-activating factor is a potent mediator of the inflammatory response. Studies of the actions of platelet-activating factor have centered mainly around neutrophils, monocytes, and platelets. In this report we begin to uncover the influence of platelet-activating factor on B lymphocytes. Employing the EBV-transformed human B cell line SKW6.4, we demonstrate that platelet-activating factor significantly alters membrane phospholipid metabolism indicated by the incorporation of 32P into phosphatidylcholine, phosphatidylinositol, and phosphatidic acid but not significantly into phosphatidylethanolamine at concentrations ranging from 10(-9) to 10(-6) M. The inactive precursor, lyso-platelet-activating factor, at a concentration as high as 10(-7) M had no effect on any of the membrane phospholipids. We also show that platelet-activating factor from 10(-12) to 10(-6) M induced rapid and significant elevation in intracellular calcium levels, whereas lyso-platelet-activating factor was again ineffective. We further demonstrate the impact of platelet-activating factor binding to B cells by measuring platelet-activating factor induced arachidonic acid release and 5-hydroxyeicosatetraenoic acid production. Moreover, platelet-activating factor was capable of inducing transcription of the nuclear proto-oncogenes c-fos and c-jun. Finally we explored the possible role of 5-hydroxyeicosatetraenoic acid as a regulator of arachidonic acid liberation demonstrating that endogenous 5-lipoxygenase activity modulates platelet-activating factor induced arachidonic acid release perhaps acting at the level of phospholipase A2. In summary, platelet-activating factor is shown here to have a direct and profound effect on a pure B cell line. " ], "offsets": [ [ 0, 1920 ] ] } ]

[ { "id": "1847170_T1", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 1499, 1504 ] ], "normalized": [] }, { "id": "1847170_T2", "type": "Protein", "text": [ "c-jun" ], "offsets": [ [ 1509, 1514 ] ], "normalized": [] }, { "id": "1847170_T3", "type": "Protein", "text": [ "5-lipoxygenase" ], "offsets": [ [ 1664, 1678 ] ], "normalized": [] }, { "id": "1847170_T4", "type": "Protein", "text": [ "phospholipase A2" ], "offsets": [ [ 1789, 1805 ] ], "normalized": [] } ]

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[ { "id": "10432288__text", "type": "abstract", "text": [ "Bcl-2-mediated drug resistance: inhibition of apoptosis by blocking nuclear factor of activated T lymphocytes (NFAT)-induced Fas ligand transcription. \nBcl-2 inhibits apoptosis induced by a variety of stimuli, including chemotherapy drugs and glucocorticoids. It is generally accepted that Bcl-2 exerts its antiapoptotic effects mainly by dimerizing with proapoptotic members of the Bcl-2 family such as Bax and Bad. However, the mechanism of the antiapoptotic effects is unclear. Paclitaxel and other drugs that disturb microtubule dynamics kill cells in a Fas/Fas ligand (FasL)-dependent manner; antibody to FasL inhibits paclitaxel-induced apoptosis. We have found that Bcl-2 overexpression leads to the prevention of chemotherapy (paclitaxel)-induced expression of FasL and blocks paclitaxel-induced apoptosis. The mechanism of this effect is that Bcl-2 prevents the nuclear translocation of NFAT (nuclear factor of activated T lymphocytes, a transcription factor activated by microtubule damage) by binding and sequestering calcineurin, a calcium-dependent phosphatase that must dephosphorylate NFAT to move to the nucleus. Without NFAT nuclear translocation, the FasL gene is not transcribed. Thus, it appears that paclitaxel and other drugs that disturb microtubule function kill cells at least in part through the induction of FasL. Furthermore, Bcl-2 antagonizes drug-induced apoptosis by inhibiting calcineurin activation, blocking NFAT nuclear translocation, and preventing FasL expression. The effects of Bcl-2 can be overcome, at least partially, through phosphorylation of Bcl-2. Phosphorylated Bcl-2 cannot bind calcineurin, and NFAT activation, FasL expression, and apoptosis can occur after Bcl-2 phosphorylation. " ], "offsets": [ [ 0, 1731 ] ] } ]

[ { "id": "10432288_T1", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "10432288_T2", "type": "Protein", "text": [ "Fas ligand" ], "offsets": [ [ 125, 135 ] ], "normalized": [] }, { "id": "10432288_T3", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 152, 157 ] ], "normalized": [] }, { "id": "10432288_T4", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 290, 295 ] ], "normalized": [] }, { "id": "10432288_T5", "type": "Protein", "text": [ "Bax" ], "offsets": [ [ 404, 407 ] ], "normalized": [] }, { "id": "10432288_T6", "type": "Protein", "text": [ "Bad" ], "offsets": [ [ 412, 415 ] ], "normalized": [] }, { "id": "10432288_T7", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 558, 561 ] ], "normalized": [] }, { "id": "10432288_T8", "type": "Protein", "text": [ "Fas ligand" ], "offsets": [ [ 562, 572 ] ], "normalized": [] }, { "id": "10432288_T9", "type": "Protein", "text": [ "FasL" ], "offsets": [ [ 574, 578 ] ], "normalized": [] }, { "id": "10432288_T10", "type": "Protein", "text": [ "FasL" ], "offsets": [ [ 610, 614 ] ], "normalized": [] }, { "id": "10432288_T11", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 673, 678 ] ], "normalized": [] }, { "id": "10432288_T12", "type": "Protein", "text": [ "FasL" ], "offsets": [ [ 769, 773 ] ], "normalized": [] }, { "id": "10432288_T13", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 852, 857 ] ], "normalized": [] }, { "id": "10432288_T14", "type": "Protein", "text": [ "FasL" ], "offsets": [ [ 1169, 1173 ] ], "normalized": [] }, { "id": "10432288_T15", "type": "Protein", "text": [ "FasL" ], "offsets": [ [ 1335, 1339 ] ], "normalized": [] }, { "id": "10432288_T16", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1354, 1359 ] ], "normalized": [] }, { "id": "10432288_T17", "type": "Protein", "text": [ "FasL" ], "offsets": [ [ 1485, 1489 ] ], "normalized": [] }, { "id": "10432288_T18", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1517, 1522 ] ], "normalized": [] }, { "id": "10432288_T19", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1587, 1592 ] ], "normalized": [] }, { "id": "10432288_T20", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1609, 1614 ] ], "normalized": [] }, { "id": "10432288_T21", "type": "Protein", "text": [ "calcineurin" ], "offsets": [ [ 1627, 1638 ] ], "normalized": [] }, { "id": "10432288_T22", "type": "Protein", "text": [ "FasL" ], "offsets": [ [ 1661, 1665 ] ], "normalized": [] }, { "id": "10432288_T23", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1708, 1713 ] ], "normalized": [] } ]

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[ { "id": "10432288_1", "entity_ids": [ "10432288_T8", "10432288_T9" ] } ]

[]

[ { "id": "10202034__text", "type": "abstract", "text": [ "Extracellular-regulated kinase 1/2, Jun N-terminal kinase, and c-Jun are involved in NF-kappa B-dependent IL-6 expression in human monocytes. \nIn the present study we investigated the possible involvement of the mitogen-activated protein kinase family members extracellular-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) in mediating IL-6 gene expression in human monocytes, in particular their role in enhancing NF-kappa B activity. Freshly isolated monocytes treated with the protein phosphatase inhibitor okadaic acid secreted high levels of IL-6 protein, which coincided with enhanced binding activity of NF-kappa B as well as with phosphorylation and activation of the ERK1/2 and JNK proteins. The ERK pathway-specific inhibitor PD98059 inhibited IL-6 secretion from monocytes. Transient overexpression of inactive mutants of either Raf-1 or JNK1 showed that both pathways were involved in kappa B-dependent IL-6 promoter activity. By using PD98059, we demonstrated that the Raf1/MEK1/ERK1/2 pathway did not affect the DNA binding of NF-kappa B but, rather, acted at the level of transcriptional activity of NF-kappa B. Interestingly, it was shown that NF-kappa B-mediated gene transcription, both in the context of the IL-6 promoter as well as on its own, was dependent on both serine kinase activity and interaction with c-Jun protein. We conclude that okadaic acid-induced IL-6 gene expression is at least partly mediated through the ERK1/2 and JNK pathway-dependent activation of NF-kappa B transcriptional capacity. Our results suggest that the JNK pathway may regulate NF-kappa B-mediated gene transcription through its phosphorylation and activation of c-Jun. " ], "offsets": [ [ 0, 1689 ] ] } ]

[ { "id": "10202034_T1", "type": "Protein", "text": [ "Extracellular-regulated kinase 1" ], "offsets": [ [ 0, 32 ] ], "normalized": [] }, { "id": "10202034_T2", "type": "Protein", "text": [ "2" ], "offsets": [ [ 33, 34 ] ], "normalized": [] }, { "id": "10202034_T3", "type": "Protein", "text": [ "Jun N-terminal kinase" ], "offsets": [ [ 36, 57 ] ], "normalized": [] }, { "id": "10202034_T4", "type": "Protein", "text": [ "c-Jun" ], "offsets": [ [ 63, 68 ] ], "normalized": [] }, { "id": "10202034_T5", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 106, 110 ] ], "normalized": [] }, { "id": "10202034_T6", "type": "Protein", "text": [ "extracellular-regulated kinase 1" ], "offsets": [ [ 260, 292 ] ], "normalized": [] }, { "id": "10202034_T7", "type": "Protein", "text": [ "2" ], "offsets": [ [ 293, 294 ] ], "normalized": [] }, { "id": "10202034_T8", "type": "Protein", "text": [ "ERK1" ], "offsets": [ [ 296, 300 ] ], "normalized": [] }, { "id": "10202034_T9", "type": "Protein", "text": [ "2" ], "offsets": [ [ 301, 302 ] ], "normalized": [] }, { "id": "10202034_T10", "type": "Protein", "text": [ "c-Jun N-terminal kinase" ], "offsets": [ [ 308, 331 ] ], "normalized": [] }, { "id": "10202034_T11", "type": "Protein", "text": [ "JNK" ], "offsets": [ [ 333, 336 ] ], "normalized": [] }, { "id": "10202034_T12", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 351, 355 ] ], "normalized": [] }, { "id": "10202034_T13", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 562, 566 ] ], "normalized": [] }, { "id": "10202034_T14", "type": "Protein", "text": [ "JNK" ], "offsets": [ [ 702, 705 ] ], "normalized": [] }, { "id": "10202034_T15", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 769, 773 ] ], "normalized": [] }, { "id": "10202034_T16", "type": "Protein", "text": [ "Raf-1" ], "offsets": [ [ 855, 860 ] ], "normalized": [] }, { "id": "10202034_T17", "type": "Protein", "text": [ "JNK1" ], "offsets": [ [ 864, 868 ] ], "normalized": [] }, { "id": "10202034_T18", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 930, 934 ] ], "normalized": [] }, { "id": "10202034_T19", "type": "Protein", "text": [ "Raf1" ], "offsets": [ [ 997, 1001 ] ], "normalized": [] }, { "id": "10202034_T20", "type": "Protein", "text": [ "MEK1" ], "offsets": [ [ 1002, 1006 ] ], "normalized": [] }, { "id": "10202034_T21", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 1242, 1246 ] ], "normalized": [] }, { "id": "10202034_T22", "type": "Protein", "text": [ "c-Jun" ], "offsets": [ [ 1345, 1350 ] ], "normalized": [] }, { "id": "10202034_T23", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 1398, 1402 ] ], "normalized": [] }, { "id": "10202034_T24", "type": "Protein", "text": [ "JNK" ], "offsets": [ [ 1572, 1575 ] ], "normalized": [] }, { "id": "10202034_T25", "type": "Protein", "text": [ "c-Jun" ], "offsets": [ [ 1682, 1687 ] ], "normalized": [] }, { "id": "10202034_T37", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 935, 943 ] ], "normalized": [] } ]

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[ { "id": "10202034_1", "entity_ids": [ "10202034_T10", "10202034_T11" ] } ]

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[ { "id": "8839844__text", "type": "abstract", "text": [ "E3, a hematopoietic-specific transcript directly regulated by the retinoic acid receptor alpha. \nRetinoic acid (RA)-induced maturation mediated by the retinoic acid receptor alpha (RAR alpha) has been implicated in myeloid development. We have used differential hybridization analysis of a cDNA library constructed from the murine RA-inducible MPRO promyelocyte cell line to identify immediate-early genes induced by RA during granulocytic differentiation. E3, one of nine sequences identified, was upregulated in an immediate-early manner, with transcript levels peaking after 60 minutes exposure to RA. E3 transcripts were RA-inducible in HL60 cells, but not in an RA-resistant subclone, HL60R, that harbors a mutated RAR alpha gene. However, when HL60R cells were transduced with a functional copy of the RAR alpha gene, RA induced a 10-fold increase in E3 mRNA levels. E3 transcripts are present in the myeloid, B-lymphoid, and erythroid lineages, absent in nonhematopoietic cells, and encode a highly hydrophobic, potentially phosphorylated polypeptide of unknown function with significant homology to a putative protein expressed in myeloid cells. The murine E3 promoter harbors a single bipartite retinoic acid response element which in transient transfection assays conferred RA sensitivity. These results indicate that E3 is a hematopoietic-specific gene that is an immediate target for the activated RAR alpha during myelopoiesis. " ], "offsets": [ [ 0, 1441 ] ] } ]

[ { "id": "8839844_T1", "type": "Protein", "text": [ "E3" ], "offsets": [ [ 0, 2 ] ], "normalized": [] }, { "id": "8839844_T2", "type": "Protein", "text": [ "retinoic acid receptor alpha" ], "offsets": [ [ 66, 94 ] ], "normalized": [] }, { "id": "8839844_T3", "type": "Protein", "text": [ "retinoic acid receptor alpha" ], "offsets": [ [ 151, 179 ] ], "normalized": [] }, { "id": "8839844_T4", "type": "Protein", "text": [ "RAR alpha" ], "offsets": [ [ 181, 190 ] ], "normalized": [] }, { "id": "8839844_T5", "type": "Protein", "text": [ "E3" ], "offsets": [ [ 457, 459 ] ], "normalized": [] }, { "id": "8839844_T6", "type": "Protein", "text": [ "E3" ], "offsets": [ [ 605, 607 ] ], "normalized": [] }, { "id": "8839844_T7", "type": "Protein", "text": [ "RAR alpha" ], "offsets": [ [ 720, 729 ] ], "normalized": [] }, { "id": "8839844_T8", "type": "Protein", "text": [ "RAR alpha" ], "offsets": [ [ 808, 817 ] ], "normalized": [] }, { "id": "8839844_T9", "type": "Protein", "text": [ "E3" ], "offsets": [ [ 857, 859 ] ], "normalized": [] }, { "id": "8839844_T10", "type": "Protein", "text": [ "E3" ], "offsets": [ [ 873, 875 ] ], "normalized": [] }, { "id": "8839844_T11", "type": "Protein", "text": [ "E3" ], "offsets": [ [ 1165, 1167 ] ], "normalized": [] }, { "id": "8839844_T12", "type": "Protein", "text": [ "E3" ], "offsets": [ [ 1328, 1330 ] ], "normalized": [] }, { "id": "8839844_T13", "type": "Protein", "text": [ "RAR alpha" ], "offsets": [ [ 1410, 1419 ] ], "normalized": [] }, { "id": "8839844_T25", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1168, 1176 ] ], "normalized": [] } ]

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[ { "id": "8839844_1", "entity_ids": [ "8839844_T3", "8839844_T4" ] } ]

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[ { "id": "10329625__text", "type": "abstract", "text": [ "Disruption of alpha beta but not of gamma delta T cell development by overexpression of the helix-loop-helix protein Id3 in committed T cell progenitors. \nEnforced expression of Id3, which has the capacity to inhibit many basic helix-loop-helix (bHLH) transcription factors, in human CD34(+) hematopoietic progenitor cells that have not undergone T cell receptor (TCR) gene rearrangements inhibits development of the transduced cells into TCRalpha beta and gamma delta cells in a fetal thymic organ culture (FTOC). Here we document that overexpression of Id3, in progenitors that have initiated TCR gene rearrangements (pre-T cells), inhibits development into TCRalpha beta but not into TCRgamma delta T cells. Furthermore, Id3 impedes expression of recombination activating genes and downregulates pre-Talpha mRNA. These observations suggest possible mechanisms by which Id3 overexpression can differentially affect development of pre-T cells into TCRalpha beta and gamma delta cells. We also observed that cell surface CD4(-)CD8(-)CD3(-) cells with rearranged TCR genes developed from Id3-transduced but not from control-transduced pre-T cells in an FTOC. These cells had properties of both natural killer (NK) and pre-T cells. These findings suggest that bHLH factors are required to control T cell development after the T/NK developmental checkpoint. " ], "offsets": [ [ 0, 1355 ] ] } ]

[ { "id": "10329625_T1", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 117, 120 ] ], "normalized": [] }, { "id": "10329625_T2", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 178, 181 ] ], "normalized": [] }, { "id": "10329625_T3", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 284, 288 ] ], "normalized": [] }, { "id": "10329625_T4", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 555, 558 ] ], "normalized": [] }, { "id": "10329625_T5", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 724, 727 ] ], "normalized": [] }, { "id": "10329625_T6", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 872, 875 ] ], "normalized": [] }, { "id": "10329625_T7", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1021, 1024 ] ], "normalized": [] }, { "id": "10329625_T8", "type": "Protein", "text": [ "Id3" ], "offsets": [ [ 1087, 1090 ] ], "normalized": [] } ]

[ { "id": "10329625_E1", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 70, 84 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329625_E2" } ] }, { "id": "10329625_E2", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 70, 84 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329625_T1" } ] }, { "id": "10329625_E3", "type": "Positive_regulation", "trigger": { "text": [ "Enforced" ], "offsets": [ [ 155, 163 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329625_E4" } ] }, { "id": "10329625_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 164, 174 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329625_T2" } ] }, { "id": "10329625_E5", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 537, 551 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329625_T4" } ] }, { "id": "10329625_E6", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 876, 890 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329625_T6" } ] }, { "id": "10329625_E7", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 876, 890 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329625_E6" } ] } ]

[]

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[ { "id": "10437913__text", "type": "abstract", "text": [ "Retinoblastoma protein expression leads to reduced Oct-1 DNA binding activity and enhances interleukin-8 expression. \nTumor cell lines with a defective retinoblastoma gene are unable to transcribe the HLA class II genes in response to IFN-gamma treatment, and reconstitution of functional Rb rescues IFN-gamma-induced class II gene expression. However, the molecular mechanism of Rb rescue of the class II genes is unknown. We have examined the effect of Rb expression on the activation of the promoter for HLA-DRA, the prototype class II gene. Oct-1, a POU domain transcription factor, was identified as a repressor of HLA-DRA promoter activity in the Rb-defective cells. Rb expression led to phosphorylation of Oct-1, thus relieving its repressive effect. Oct-1 has also been shown to repress interleukin 8 promoter activity. Consistent with reduced levels of Oct-1 DNA binding activity in the Rb-transformed cell lines, interleukin 8 expression is higher in these cell lines. " ], "offsets": [ [ 0, 979 ] ] } ]

[ { "id": "10437913_T1", "type": "Protein", "text": [ "Retinoblastoma" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "10437913_T2", "type": "Protein", "text": [ "Oct-1" ], "offsets": [ [ 51, 56 ] ], "normalized": [] }, { "id": "10437913_T3", "type": "Protein", "text": [ "interleukin-8" ], "offsets": [ [ 91, 104 ] ], "normalized": [] }, { "id": "10437913_T4", "type": "Protein", "text": [ "retinoblastoma" ], "offsets": [ [ 152, 166 ] ], "normalized": [] }, { "id": "10437913_T5", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 235, 244 ] ], "normalized": [] }, { "id": "10437913_T6", "type": "Protein", "text": [ "Rb" ], "offsets": [ [ 289, 291 ] ], "normalized": [] }, { "id": "10437913_T7", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 300, 309 ] ], "normalized": [] }, { "id": "10437913_T8", "type": "Protein", "text": [ "Rb" ], "offsets": [ [ 380, 382 ] ], "normalized": [] }, { "id": "10437913_T9", "type": "Protein", "text": [ "Rb" ], "offsets": [ [ 455, 457 ] ], "normalized": [] }, { "id": "10437913_T10", "type": "Protein", "text": [ "Oct-1" ], "offsets": [ [ 545, 550 ] ], "normalized": [] }, { "id": "10437913_T11", "type": "Protein", "text": [ "Rb" ], "offsets": [ [ 653, 655 ] ], "normalized": [] }, { "id": "10437913_T12", "type": "Protein", "text": [ "Rb" ], "offsets": [ [ 673, 675 ] ], "normalized": [] }, { "id": "10437913_T13", "type": "Protein", "text": [ "Oct-1" ], "offsets": [ [ 713, 718 ] ], "normalized": [] }, { "id": "10437913_T14", "type": "Protein", "text": [ "Oct-1" ], "offsets": [ [ 758, 763 ] ], "normalized": [] }, { "id": "10437913_T15", "type": "Protein", "text": [ "interleukin 8" ], "offsets": [ [ 795, 808 ] ], "normalized": [] }, { "id": "10437913_T16", "type": "Protein", "text": [ "Oct-1" ], "offsets": [ [ 862, 867 ] ], "normalized": [] }, { "id": "10437913_T17", "type": "Protein", "text": [ "Rb" ], "offsets": [ [ 896, 898 ] ], "normalized": [] }, { "id": "10437913_T18", "type": "Protein", "text": [ "interleukin 8" ], "offsets": [ [ 923, 936 ] ], "normalized": [] }, { "id": "10437913_T31", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 809, 817 ] ], "normalized": [] } ]

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[ { "id": "7578980__text", "type": "abstract", "text": [ "IFN-gamma priming of monocytes enhances LPS-induced TNF production by augmenting both transcription and MRNA stability. \nThe induction of cytokine expression in monocytes/macrophages by bacterial endotoxin or lipopolysaccharide is a critical, highly regulated host defence response. The augmentation of LPS responses by interferon gamma (IFN-gamma), referred to as priming, is well established. However, the mechanism(s) by which priming occurs is poorly defined. Using tumour necrosis factor (TNF) induction as a model, experiments were designed to analyse in detail the priming effect on the LPS response in human monocytes. Priming by IFN-gamma was primarily manifested at the level of TNF mRNA accumulation. IFN-gamma pre-treatment affected the magnitude rather than the sensitivity of the LPS response. Priming occurred after several hours of treatment, and the primed state was induced by either IFN-gamma or GM-CSF, but not M-CSF. Primed monocytes transcribed TNF mRNA at a higher rate than freshly isolated monocytes upon activation with LPS. The increased transcriptional rate correlated with a marked increase in nuclear factor-kappa B activity in these cells as determined by electrophoretic mobility shift assay using a consensus NF-kappa B oligonucleotide. An additional significant finding was than TNF mRNA induced in primed cells was much more stable than in unprimed cells (T1/2 increased 6-8-fold). Consistent with the increased mRNA stability, the duration of mRNA accumulation was longer following LPS stimulation in primed monocytes, in addition to being of greater magnitude. Finally, primed and unprimed cells possessed a differential sensitivity to the kinase inhibitor H-89. H-89 substantially suppressed LPS-induced TNF mRNA accumulation in unprimed cells, but had no effect on primed monocytes following LPS stimulation. (ABSTRACT TRUNCATED AT 250 WORDS) " ], "offsets": [ [ 0, 1882 ] ] } ]

[ { "id": "7578980_T1", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "7578980_T2", "type": "Protein", "text": [ "interferon gamma" ], "offsets": [ [ 320, 336 ] ], "normalized": [] }, { "id": "7578980_T3", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 338, 347 ] ], "normalized": [] }, { "id": "7578980_T4", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 638, 647 ] ], "normalized": [] }, { "id": "7578980_T5", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 712, 721 ] ], "normalized": [] }, { "id": "7578980_T6", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 902, 911 ] ], "normalized": [] }, { "id": "7578980_T7", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 915, 921 ] ], "normalized": [] }, { "id": "7578980_T8", "type": "Protein", "text": [ "M-CSF" ], "offsets": [ [ 931, 936 ] ], "normalized": [] } ]

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[ { "id": "7578980_1", "entity_ids": [ "7578980_T2", "7578980_T3" ] } ]

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[ { "id": "2116990__text", "type": "abstract", "text": [ "Tandem AP-1-binding sites within the human beta-globin dominant control region function as an inducible enhancer in erythroid cells. \nA powerful enhancer has been mapped to an 18-bp DNA segment located 11 kb 5' to the human epsilon-globin gene within the dominant control or locus-activating region. This enhancer is inducible in K562 human erythroleukemia cells, increasing linked gamma-globin promoter/luciferase gene expression to 170-fold over an enhancerless construct. The enhancer consists of tandem AP-1-binding sites, phased 10 bp apart, which are both required for full activity. DNA-protein binding assays with nuclear extracts from induced cells demonstrate a high molecular weight complex on the enhancer. The formation of this complex also requires both AP-1 sites and correlates with maximal enhancer activity. Induction of the enhancer may have a role in the increase in globin gene transcription that characterizes erythroid maturation. Enhancer activity appears to be mediated by the binding of a complex of proteins from the jun and fos families to tandem AP-1 consensus sequences. " ], "offsets": [ [ 0, 1101 ] ] } ]

[ { "id": "2116990_T1", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 43, 54 ] ], "normalized": [] }, { "id": "2116990_T2", "type": "Protein", "text": [ "epsilon-globin" ], "offsets": [ [ 224, 238 ] ], "normalized": [] }, { "id": "2116990_T3", "type": "Protein", "text": [ "gamma-globin" ], "offsets": [ [ 382, 394 ] ], "normalized": [] }, { "id": "2116990_T4", "type": "Protein", "text": [ "luciferase" ], "offsets": [ [ 404, 414 ] ], "normalized": [] } ]

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[ { "id": "7706710__text", "type": "abstract", "text": [ "Functional characterization of novel IL-2 transcriptional inhibitors. \nIL-2-mediated T cell proliferation is a critical early event in the inflammatory process. Formation of the NFAT-1 transcriptional complex on the IL-2 promoter is essential for IL-2 transcription. Using a cell line that is stably transfected with a trimer of the NFAT-1 regulatory element linked to a lac-Z reporter gene, we screened for inhibitors of NFAT-1-mediated beta-galactosidase activity. WIN 61058 and WIN 53071 were identified as microM inhibitors. These compounds also inhibited beta-galactosidase mRNA levels. Similar inhibition of NFAT-1-mediated gene expression was observed in a second cell line, which is stably transfected with NFAT-1 regulatory elements linked to the reporter gene for sCD8. At 10 microM, both compounds inhibited IL-2 mRNA and protein levels in the NFAT-1-linked lac-Z transfectants, and in human lymphocytes. Both compounds inhibited the mixed lymphocyte reaction, and this inhibition was reversed by exogenous IL-2. WIN 53071 inhibited IL-2 production induced in the calcium-dependent PMA and ionomycin pathway. Conversely, calcium-independent anti-CD28 Ab and PMA-induced IL-2 production was resistant. Both compounds altered the NFAT-1 transcriptional complex, causing its retarded mobility on gels. By these functional criteria, we believe we have identified two structurally distinct, novel inhibitors of NFAT-1-mediated transcription. " ], "offsets": [ [ 0, 1448 ] ] } ]

[ { "id": "7706710_T1", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 37, 41 ] ], "normalized": [] }, { "id": "7706710_T2", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 71, 75 ] ], "normalized": [] }, { "id": "7706710_T3", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 178, 184 ] ], "normalized": [] }, { "id": "7706710_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 216, 220 ] ], "normalized": [] }, { "id": "7706710_T5", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 247, 251 ] ], "normalized": [] }, { "id": "7706710_T6", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 333, 339 ] ], "normalized": [] }, { "id": "7706710_T7", "type": "Protein", "text": [ "lac-Z" ], "offsets": [ [ 371, 376 ] ], "normalized": [] }, { "id": "7706710_T8", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 422, 428 ] ], "normalized": [] }, { "id": "7706710_T9", "type": "Protein", "text": [ "beta-galactosidase" ], "offsets": [ [ 438, 456 ] ], "normalized": [] }, { "id": "7706710_T10", "type": "Protein", "text": [ "beta-galactosidase" ], "offsets": [ [ 560, 578 ] ], "normalized": [] }, { "id": "7706710_T11", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 614, 620 ] ], "normalized": [] }, { "id": "7706710_T12", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 715, 721 ] ], "normalized": [] }, { "id": "7706710_T13", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 819, 823 ] ], "normalized": [] }, { "id": "7706710_T14", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 855, 861 ] ], "normalized": [] }, { "id": "7706710_T15", "type": "Protein", "text": [ "lac-Z" ], "offsets": [ [ 869, 874 ] ], "normalized": [] }, { "id": "7706710_T16", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1018, 1022 ] ], "normalized": [] }, { "id": "7706710_T17", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1044, 1048 ] ], "normalized": [] }, { "id": "7706710_T18", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1181, 1185 ] ], "normalized": [] }, { "id": "7706710_T19", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 1239, 1245 ] ], "normalized": [] }, { "id": "7706710_T20", "type": "Protein", "text": [ "NFAT-1" ], "offsets": [ [ 1417, 1423 ] ], "normalized": [] }, { "id": "7706710_T23", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 221, 229 ] ], "normalized": [] } ]

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[ { "id": "8088776__text", "type": "abstract", "text": [ "Structure and expression of the human GATA3 gene. \nGATA3, a member of the GATA family that is abundantly expressed in the T-lymphocyte lineage, is thought to participate in T-cell receptor gene activation through binding to enhancers. To understand GATA3 gene regulation, we cloned the human gene and the 5' end of the mouse GATA3 gene. We show that the human GATA3 gene contains six exons distributed over 17 kb of DNA. The two human GATA3 zinc fingers are encoded by two separate exons highly conserved with those of GATA1, but no other structural homologies between these two genes can be found. The human and mouse GATA3 transcription units start at a major initiation site. The promoter sequence analysis of these two genes revealed that they are embedded within a CpG island and share structural features often found in the promoters of housekeeping genes. Finally, we show that a DNA fragment containing the human GATA3 transcription unit, 3 kb upstream from the initiation site and 4 kb downstream from the polyadenylation site, displays T-cell specificity. " ], "offsets": [ [ 0, 1066 ] ] } ]

[ { "id": "8088776_T1", "type": "Protein", "text": [ "GATA3" ], "offsets": [ [ 38, 43 ] ], "normalized": [] }, { "id": "8088776_T2", "type": "Protein", "text": [ "GATA3" ], "offsets": [ [ 51, 56 ] ], "normalized": [] }, { "id": "8088776_T3", "type": "Protein", "text": [ "GATA3" ], "offsets": [ [ 249, 254 ] ], "normalized": [] }, { "id": "8088776_T4", "type": "Protein", "text": [ "GATA3" ], "offsets": [ [ 325, 330 ] ], "normalized": [] }, { "id": "8088776_T5", "type": "Protein", "text": [ "GATA3" ], "offsets": [ [ 360, 365 ] ], "normalized": [] }, { "id": "8088776_T6", "type": "Protein", "text": [ "GATA3" ], "offsets": [ [ 435, 440 ] ], "normalized": [] }, { "id": "8088776_T7", "type": "Protein", "text": [ "GATA1" ], "offsets": [ [ 519, 524 ] ], "normalized": [] }, { "id": "8088776_T8", "type": "Protein", "text": [ "GATA3" ], "offsets": [ [ 619, 624 ] ], "normalized": [] }, { "id": "8088776_T9", "type": "Protein", "text": [ "GATA3" ], "offsets": [ [ 921, 926 ] ], "normalized": [] } ]

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[ { "id": "8137243__text", "type": "abstract", "text": [ "Hypoxia causes the activation of nuclear factor kappa B through the phosphorylation of I kappa B alpha on tyrosine residues. \nThe response of mammalian cells to stress is controlled by transcriptional regulatory proteins such as nuclear factor kappa B (NF-kappa B) to induce a wide variety of early response genes. In this report, we show that exposure of cells to hypoxia (0.02% O2) results in I kappa B alpha degradation, increased NF-kappa B DNA binding activity, and transactivation of a reporter gene construct containing two NF-kappa B DNA binding sites. Pretreatment of cells with protein tyrosine kinase inhibitors and the dominant negative allele of c-Raf-1 (Raf 301) inhibited I kappa B alpha degradation, NF-kappa B binding, and transactivation of kappa B reporter constructs by hypoxia. To demonstrate a direct link between changes in the phosphorylation pattern of I kappa B alpha with NF-kappa B activation, we immunoprecipitated I kappa B alpha after varying times of hypoxic exposure and found that its tyrosine phosphorylation status increased during hypoxic exposure. Inhibition of the transfer of tyrosine phosphoryl groups onto I kappa B alpha prevented I kappa B alpha degradation and NF-kappa B binding. In comparison to other activators of NF-kappa B such as phorbol myristate acetate or tumor necrosis factor, we did not detect changes in the tyrosine phosphorylation status of I kappa B alpha following treatment with either of these agents. These results suggest that tyrosine phosphorylation of I kappa B alpha during hypoxia is an important proximal step which precedes its dissociation and degradation from NF-kappa B. " ], "offsets": [ [ 0, 1648 ] ] } ]

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[ { "id": "1972889__text", "type": "abstract", "text": [ "Stimulation of the human immunodeficiency virus type 2 (HIV-2) gene expression by the cytomegalovirus and HIV-2 transactivator gene. \nHuman immunodeficiency virus (HIV) often causes latent infection. Transactivation by some DNA viruses has been implicated in inducing HIV-1 replication and pathogenesis. The transactivator (IE-2) gene of the human cytomegalovirus (CMV) can enhance HIV-2 as well as HIV-1 gene expression in vitro. This inducer can act in concert with the HIV-2 tat gene and T-cell activation in enhancing gene expression in human CD4+ lymphocytes. While the HIV-2 and HIV-1 tat genes and T-cell activators apparently employ independent modes of action, the CMV transactivator in combination with the HIV-2 tat or T-cell activators may employ a gene activation pathway with some common and some distinct components. Both HIV-2 and CMV transactivators enhance HIV-2 gene expression by transcriptional activation involving transcript initiation as well as elongation, with CMV transactivator affecting elongation more than the initiation. A significant proportion of transcripts appear to terminate prematurely in the absence of transactivators. Deletion mutation analysis of the HIV-2 long terminal repeat (LTR) suggests that the element that responds to CMV transactivation in human CD4+ lymphocytes is either a diffuse one or located downstream of the HIV-2 enhancer element. " ], "offsets": [ [ 0, 1393 ] ] } ]

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[ { "id": "2088505__text", "type": "abstract", "text": [ "A novel T-cell trans-activator that recognizes a phorbol ester-inducible element of the interleukin-2 promoter. \nThe interleukin 2 (IL-2) gene promoter is recognized by several cell-type-specific and ubiquitous transcriptional regulators that integrate information transmitted by various signaling systems leading to IL-2 production and T-cell activation. Using a combination of transfection, protein-DNA binding, and in vitro transcription methods, we have discovered the novel T-cell-specific transcriptional activator TCF-1 (for T-Cell Factor-1), which recognizes a T-cell-specific response element (TCE) located within the IL-2 promoter. Although the TCE is similar in sequence to a consensus NF kappa B site, several criteria indicate that TCF-1 is distinct from NF kappa B. However, like NF kappa B, TCF-1 activity is induced by phorbol esters and other T-cell activators. " ], "offsets": [ [ 0, 879 ] ] } ]

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