Datasets:

bigbio

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bionlp_shared_task_2009

like 2

[ { "id": "7629157__text", "type": "abstract", "text": [ "Activation of NF-kappa B by phosphatase inhibitors involves the phosphorylation of I kappa B alpha at phosphatase 2A-sensitive sites. \nActivation of NF-kappa B by various cellular stimuli involves the phosphorylation and subsequent degradation of its inhibitor, I kappa B alpha, although the underlying mechanism remains unclear. In the present study, the role of serine/threonine phosphatases in the regulation of I kappa B alpha phosphorylation was investigated. Our studies demonstrate that incubation of human T cells with low concentrations (approximately 1-5 nM) of calyculin A or okadaic acid, potent inhibitors of protein phosphatase type 1 (PP-1) and type 2A (PP-2A), induces the phosphorylation of I kappa B alpha even in the absence of any cellular stimulus. This action of the phosphatase inhibitors, which is associated with the activation of the RelA.p50 NF-kappa B heterodimer, is not affected by agents that block the induction of I kappa B alpha phosphorylation by tumor necrosis factor alpha (TNF-alpha). Furthermore, the phosphorylated I kappa B alpha from calyculin A-treated cells, but not that from TNF-alpha-stimulated cells, is sensitive to PP-2A in vitro, suggesting the existence of fundamental differences in the phosphorylation of I kappa B alpha induced by the two different NF-kappa B inducers. However, induction of I kappa B alpha phosphorylation by both TNF-alpha and the phosphatase inhibitors is associated with the subsequent degradation of I kappa B alpha. We further demonstrate that TNF-alpha- and calyculin A-induced I kappa B alpha degradation exhibits similar but not identical sensitivities to a proteasome inhibitor. Together, these results suggest that phosphorylation of I kappa B alpha, mediated through both the TNF-alpha-inducible and the PP-2A-opposing kinases, may serve to target I kappa B alpha for proteasome-mediated degradation. " ], "offsets": [ [ 0, 1885 ] ] } ]

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"Theme", "ref_id": "7629157_E6" } ] }, { "id": "7629157_E12", "type": "Negative_regulation", "trigger": { "text": [ "block" ], "offsets": [ [ 924, 929 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_E13" } ] }, { "id": "7629157_E13", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 934, 943 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_E14" }, { "role": "Cause", "ref_id": "7629157_T9" } ] }, { "id": "7629157_E14", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 963, 978 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_T7" } ] }, { "id": "7629157_E15", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylated" ], "offsets": [ [ 1040, 1054 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_T10" } ] }, { "id": "7629157_E16", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1240, 1255 ] ] }, "arguments": [ { "role": "Theme", 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] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_T13" } ] }, { "id": "7629157_E22", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1462, 1473 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_T15" } ] }, { "id": "7629157_E23", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1549, 1556 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_E25" } ] }, { "id": "7629157_E24", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1549, 1556 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_E25" }, { "role": "Cause", "ref_id": "7629157_T16" } ] }, { "id": "7629157_E25", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1573, 1584 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_T17" } ] }, { "id": "7629157_E26", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1698, 1713 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_T18" } ] }, { "id": "7629157_E27", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1734, 1742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_E26" } ] }, { "id": "7629157_E28", "type": "Regulation", "trigger": { "text": [ "serve to target" ], "offsets": [ [ 1816, 1831 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_E30" } ] }, { "id": "7629157_E29", "type": "Regulation", "trigger": { "text": [ "serve to target" ], "offsets": [ [ 1816, 1831 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_E30" }, { "role": "Cause", "ref_id": "7629157_E27" } ] }, { "id": "7629157_E30", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1863, 1871 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_E31" } ] }, { "id": "7629157_E31", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1872, 1883 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7629157_T20" } ] } ]

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[ { "id": "10440930__text", "type": "abstract", "text": [ "Suppression of TNFalpha-mediated NFkappaB activity by myricetin and other flavonoids through downregulating the activity of IKK in ECV304 cells. \nFlavonoids are a group of naturally-occurring phenolic compounds in the plant kingdom, and many flavonoids are found with vascular protective properties. Nevertheless how the protective response is exerted by flavonoids is not well characterized. In view of the nuclear factor-kappaB (NFkappaB) may play a central role in the initiation of atherosclerosis, prevention of the activation of NFkappaB represents an important role in protecting vascular injury. In this study, the effects of flavonoids on NFkappaB/inhibitor-kappaB (IkappaB) system in ECV304 cells activated with tumor necrosis factor-alpha (TNFalpha) were examined. We investigated the inhibitory action of six flavonoids on IkappaB kinase (IKK) activity, an enzyme recently found to phosphorylate critical serine residues of IkappaB for degradation. Of six flavonoids tested, myricetin was found to strongly inhibit IKK kinase activity, and prevent the degradation of IkappaBalpha and IkappaBbeta in activated endothelial cells. Furthermore, myricetin was also found to inhibit NFkappaB activity correlated with suppression of monocyte adhesion to ECV304 cells. Therefore we conclude that flavonoids may be of therapeutic value for vascular disease through down regulation of NFkappaB/IkappaB system. Copyright 1999 Wiley-Liss, Inc. " ], "offsets": [ [ 0, 1444 ] ] } ]

[ { "id": "10440930_T1", "type": "Protein", "text": [ "TNFalpha" ], "offsets": [ [ 15, 23 ] ], "normalized": [] }, { "id": "10440930_T2", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 722, 749 ] ], "normalized": [] }, { "id": "10440930_T3", "type": "Protein", "text": [ "TNFalpha" ], "offsets": [ [ 751, 759 ] ], "normalized": [] }, { "id": "10440930_T4", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 1079, 1091 ] ], "normalized": [] }, { "id": "10440930_T5", "type": "Protein", "text": [ "IkappaBbeta" ], "offsets": [ [ 1096, 1107 ] ], "normalized": [] } ]

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[ { "id": "10202178__text", "type": "abstract", "text": [ "Differential induction of interferon (IFN)-inducible protein 10 following differentiation of a monocyte, macrophage cell lineage is related to the changes of nuclear proteins bound to IFN stimulus response element and kappaB sites. \nWe examined chemokine gene expression following the differentiation of a monocyte, macrophage cell lineage. The human monoblastic cell line, U937 was differentiated to macrophages by the treatment with either phorbol 12-myristate 13-acetate (PMA), retinoic acid (RA), or vitamin D3 (VitD3). The gene expression of interferon (IFN)-inducible protein 10 (IP-10) (a CXC chemokine) was markedly augmented by the IFNgamma treatment in PMA- or RA-differentiated U937 cells, but only marginally in undifferentiated or VitD3-treated cells. In contrast, another inducible gene expression of monocyte chemotactic protein-1 (a CC chemokine) and the activation of the transcriptional factor (FcRFgamma) bound to the gamma response region were similarly or less abundantly induced by IFNgamma treatment in PMA- or RA-differentiated U937 cells, indicating that increased IP-10 mRNA induction was not due to the augmented ability of the cells to respond to the presence of IFNgamma. Increased expression of IFNgamma-induced IP-10 mRNA following the differentiation of U937 cells was mediated largely by augmented transcriptional activity of the gene and was related to differentiation-dependent changes of the proteins bound to IFN stimulus response element (ISRE) and kB sites, suggesting that these nuclear proteins may determine the IP-10 mRNA inducibility by IFNgamma. " ], "offsets": [ [ 0, 1591 ] ] } ]

[ { "id": "10202178_T1", "type": "Protein", "text": [ "interferon (IFN)-inducible protein 10" ], "offsets": [ [ 26, 63 ] ], "normalized": [] }, { "id": "10202178_T2", "type": "Protein", "text": [ "interferon (IFN)-inducible protein 10" ], "offsets": [ [ 547, 584 ] ], "normalized": [] }, { "id": "10202178_T3", "type": "Protein", "text": [ "IP-10" ], "offsets": [ [ 586, 591 ] ], "normalized": [] }, { "id": "10202178_T4", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 641, 649 ] ], "normalized": [] }, { "id": "10202178_T5", "type": "Protein", "text": [ "monocyte chemotactic protein-1" ], "offsets": [ [ 815, 845 ] ], "normalized": [] }, { "id": "10202178_T6", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1004, 1012 ] ], "normalized": [] }, { "id": "10202178_T7", "type": "Protein", "text": [ "IP-10" ], "offsets": [ [ 1090, 1095 ] ], "normalized": [] }, { "id": "10202178_T8", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1191, 1199 ] ], "normalized": [] }, { "id": "10202178_T9", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1225, 1233 ] ], "normalized": [] }, { "id": "10202178_T10", "type": "Protein", "text": [ "IP-10" ], "offsets": [ [ 1242, 1247 ] ], "normalized": [] }, { "id": "10202178_T11", "type": "Protein", "text": [ "IP-10" ], "offsets": [ [ 1554, 1559 ] ], "normalized": [] }, { "id": "10202178_T12", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1581, 1589 ] ], "normalized": [] } ]

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[]

[ { "id": "1545132__text", "type": "abstract", "text": [ "Human T cell activation through the activation-inducer molecule/CD69 enhances the activity of transcription factor AP-1. \nThe induction of the AP-1 transcription factor has been ascribed to the early events leading to T cell differentiation and activation. We have studied the regulation of AP-1 activity in human peripheral blood T lymphocytes stimulated through the activation inducer molecule (AIM)/CD69 activation pathway. Phorbol esters are required to induce AIM/CD69 cell-surface expression as well as for triggering the proliferation of T cells in conjunction with anti-AIM mAb. Mobility shift assays showed that addition of anti-AIM mAb to PMA-treated T lymphocytes markedly enhanced the binding activity of AP-1 to its cognate sequence, the phorbol ester response element. In contrast, anti-AIM mAb did not induce any change in the binding activity of NF-kappa B, a transcription factor whose activity is also regulated by protein kinase C. The increase in AP-1-binding activity was accompanied by the marked stimulation of the transcription of c-fos but not that of c-jun. Blockade of the DNA-binding complexes with an anti-Fos mAb demonstrated a direct participation of c-Fos in the AP-1 complexes induced by anti-AIM mAb. Most of the AP-1 activity could be eliminated when the anti-AIM mAb was added to the culture medium in the presence of cycloheximide, suggesting that de novo protein synthesis is crucial for the induction of AP-1-binding activity. These data provide the evidence that activation of human peripheral blood T cells through the AIM activation pathway regulate the activity of AP-1. Therefore, this pathway appears as a crucial step in the initiation of early T cell activation events. " ], "offsets": [ [ 0, 1717 ] ] } ]

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[ { "id": "1777483__text", "type": "abstract", "text": [ "Activity of the kappa B enhancer of the interleukin-2 receptor alpha chain in somatic cell hybrids is accompanied by the nuclear localization of NF-kappa B. \nThe two nuclear proteins NF-kappa B (consisting of subunits p50 and p65) and the DNA-binding subunit of NF-kappa B (p50) by itself, also called KBF1, are constitutively expressed and localized in the nucleus of the human T-cell line IARC 301.5. In order to define the roles of these two factors, which bind to the same kappa B enhancers, in transcription activation we have prepared somatic cell hybrids between IARC 301.5 and a murine myeloma. Most hybrids express both KBF1 and NF-kappa B in their nuclei, but one hybrid expresses only KBF1. The kappa B enhancer of the gene encoding the interleukin-2 (IL-2) receptor alpha chain (IL-2R alpha) is functional only in the hybrids expressing nuclear NF-kappa B. These findings show that nuclear NF-kappa B is necessary to activate the kappa B enhancer, while KBF1 by itself is not sufficient. We propose that KBF1 is a competitive inhibitor of NF-kappa B and discuss how these factors may be involved in the transient expression of IL-2 and IL-2R alpha genes during the immune response. " ], "offsets": [ [ 0, 1194 ] ] } ]

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[ { "id": "8298127__text", "type": "abstract", "text": [ "Retinoic acid downmodulates erythroid differentiation and GATA1 expression in purified adult-progenitor culture. \nAll-trans retinoic acid (RA) is an important morphogen in vertebrate development, a normal constituent in human adult blood and is also involved in the control of cell growth and differentiation in acute promyelocytic leukemia. We have examined the effects of RA on normal hematopoiesis by using early hematopoietic progenitor cells (HPC) stringently purified from adult peripheral blood. In clonogenetic fetal calf serum-supplemented (FCS+) or -nonsupplemented (FCS-) culture treated with saturating levels of interleukin-3 (IL-3) granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Ep) (combined with c-kit ligand in FCS(-)-culture conditions), RA induces a dramatic dose-dependent shift from erythroid to granulomonocytic colony formation, the latter colonies being essentially represented by granulocytic clones. This shift is apparently not caused by a recruitment phenomenon, because in FCS+ culture, the total number of colonies is not significantly modified by RA addition. In FCS- liquid-suspension culture supplemented with saturating Ep level and low-dose IL-3/GM-CSF, adult HPC undergo unilineage erythropoietic differentiation: Here again, treatment with high-dose RA induces a shift from the erythroid to granulocytic differentiation pathway. Studies on RA time-response or pulse treatment in semisolid or liquid culture show that early RA addition is most effective, thus indicating that early but not late HPC are sensitive to its action. We then analyzed the expression of the master GATA1 gene, which encodes a finger transcription factor required for normal erythroid development; addition of RA to HPC stimulated into unilineage erythropoietic differentiation in liquid culture caused a virtually complete inhibition of GATA1 mRNA induction. These results indicate that RA directly inhibits the erythroid differentiation program at the level of early adult HPC, and may lead to a shift from the erythroid to granulocytic differentiation pathway. This phenomenon is correlated with inhibition of GATA1 induction in the early stages of erythropoietic differentiation. " ], "offsets": [ [ 0, 2226 ] ] } ]

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[ { "id": "9952372__text", "type": "abstract", "text": [ "Lactobacilli and vaginal host defense: activation of the human immunodeficiency virus type 1 long terminal repeat, cytokine production, and NF-kappaB. \nLactobacilli, a component of the normal vaginal flora, can activate the human immunodeficiency virus (HIV)-1 long terminal repeat (LTR) in the Jurkat T lymphocyte and THP-1 macrophage cell lines. Activation of the LTR in Jurkat cells was strongly enhanced by vanadate and inhibited by catalase, implicating H2O2. In contrast, activation in THP-1 cells occurred in the absence of vanadate and was unaffected by catalase. The active material partitioned into the phenol layer on hot aqueous phenol extraction. Lactobacilli also increased tumor necrosis factor-alphaand interleukin-1betaproduction and activated NF-kappaB in THP-1 cells and increased tumor necrosis factor-alphaproduction by human monocytes. Human vaginal fluid specimens had comparable properties, which correlated with their bacterial content. These findings suggest the presence in vaginal fluid of agent(s) derived from indigenous bacteria that can activate the HIV-1 LTR, cytokine production, and NF-kappaB in cells of macrophage lineage, with possible influence on vaginal physiology and host defense. " ], "offsets": [ [ 0, 1224 ] ] } ]

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[ { "id": "9187264__text", "type": "abstract", "text": [ "Histamine modulates the expression of c-fos through cyclic AMP production via the H2 receptor in the human promonocytic cell line U937. \nWe examined the effects of histamine and its agonists on the expression of the c-fos and c-myc proto-oncogenes at the transcriptional and translational levels in the human promonocytic U937 cell line. Histamine transiently increased cAMP and c-fos expression through H2 receptors. Dibutyryl cAMP also increased c-fos mRNA and protein, and levels remained elevated even after 12 hr of treatment. Dose-dependence studies using histamine and dimaprit showed that the EC50 values for cAMP production and c-fos increase were similar, suggesting that cAMP might be involved in c-fos induction via H2 receptors. Furthermore, studies carried out using H7, a protein kinase A/protein kinase C inhibitor, blocked c-fos induction, whereas no effect was observed with bisindolylmaleimide, a specific protein kinase C inhibitor. No modification of c-myc expression could be detected on treatment with histamine or its analogues. Nevertheless, dibutyryl cAMP induced a down-regulation of the levels of this proto-oncogene. In addition, dibutyryl cAMP inhibited cell growth in a dose-dependent manner, whereas histamine failed to affect proliferation and differentiation of U937 cells. Cells pretreated with dimaprit showed a decrease in the cAMP response to subsequent addition of H2 agonists, whereas the cAMP response to prostaglandin E2 remained unaltered. This homologous mechanism of H2 receptor desensitization was time dependent. These results indicate that histamine activates several mechanisms involved in the induction of differentiation, such as cAMP and c-fos production, but fails to promote differentiation of U937 cells, apparently due to the rapid desensitization of H2 receptors. " ], "offsets": [ [ 0, 1821 ] ] } ]

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[ { "id": "9707608__text", "type": "abstract", "text": [ "Epstein-Barr virus-transforming protein latent infection membrane protein 1 activates transcription factor NF-kappaB through a pathway that includes the NF-kappaB-inducing kinase and the IkappaB kinases IKKalpha and IKKbeta. \nThe Epstein-Barr virus oncoprotein latent infection membrane protein 1 (LMP1) is a constitutively aggregated pseudo-tumor necrosis factor receptor (TNFR) that activates transcription factor NF-kappaB through two sites in its C-terminal cytoplasmic domain. One site is similar to activated TNFRII in associating with TNFR-associated factors TRAF1 and TRAF2, and the second site is similar to TNFRI in associating with the TNFRI death domain interacting protein TRADD. TNFRI has been recently shown to activate NF-kappaB through association with TRADD, RIP, and TRAF2; activation of the NF-kappaB-inducing kinase (NIK); activation of the IkappaB alpha kinases (IKKalpha and IKKbeta); and phosphorylation of IkappaB alpha. IkappaB alpha phosphorylation on Ser-32 and Ser-36 is followed by its degradation and NF-kappaB activation. In this report, we show that NF-kappaB activation by LMP1 or by each of its effector sites is mediated by a pathway that includes NIK, IKKalpha, and IKKbeta. Dominant negative mutants of NIK, IKKalpha, or IKKbeta substantially inhibited NF-kappaB activation by LMP1 or by each of its effector sites. " ], "offsets": [ [ 0, 1354 ] ] } ]

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[]

[ { "id": "9632764__text", "type": "abstract", "text": [ "Coactivation by OCA-B: definition of critical regions and synergism with general cofactors. \nMolecular dissection of the B-cell-specific transcription coactivator OCA-B has revealed distinct regions important, respectively, for recruitment to immunoglobulin promoters through interaction with octamer-bound Oct-1 and for subsequent coactivator function. Further analysis of general coactivator requirements showed that selective removal of PC4 from the essential USA fraction severely impairs Oct-1 and OCA-B function in a cell-free system reconstituted with partially purified factors. Full activity can be restored by the combined action of recombinant PC4 and the PC4-depleted USA fraction, thus suggesting a joint requirement for PC4 and another, USA-derived component(s) for optimal function of Oct-1/OCA-B in the reconstituted system. Indeed, USA-derived PC2 was found to act synergistically with PC4 in reproducing the function of intact USA in the assay system. Consistent with the requirement for PC4 in the reconstituted system, OCA-B was found to interact directly with PC4. Surprisingly, however, removal of PC4 from the unfractionated nuclear extract has no detrimental effect on OCA-B/Oct-1-dependent transcription. These results lead to a general model for the synergistic function of activation domains in Oct-1 and OCA-B (mediated by the combined action of the multiple USA components) and, further, suggest a functional redundancy in general coactivators. " ], "offsets": [ [ 0, 1474 ] ] } ]

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[ { "id": "2302185__text", "type": "abstract", "text": [ "Characterization of the human immunodeficiency virus type 1 enhancer-binding proteins from the human T-cell line Jurkat. \nThe transcription of the human immunodeficiency virus type 1 (HIV-1) is under the control of cellular proteins that bind to the viral long terminal repeat (LTR). Among the protein-binding regions of the HIV-1 LTR is the transcription-enhancer region. We show that at least one inducible, C1, and one constitutive, C2, protein can bind to the HIV enhancer in Jurkat cells. The two proteins differ in their surface charge, since they are separable by anion-exchange chromatography. Bivalent cations such as Mg2+ and Zn2+ differentially affect their binding to oligonucleotides which contain the HIV-enhancer domain. Both C1 and C2 proteins also bind to a similar sequence found in the interleukin-2-receptor alpha-subunit enhancer. The inducible C1 protein was partially purified by three chromatographic steps and characterized by u.v. cross-linking as a 47 kDa protein. " ], "offsets": [ [ 0, 992 ] ] } ]

[ { "id": "2302185_T1", "type": "Protein", "text": [ "C1" ], "offsets": [ [ 410, 412 ] ], "normalized": [] }, { "id": "2302185_T2", "type": "Protein", "text": [ "C2" ], "offsets": [ [ 436, 438 ] ], "normalized": [] }, { "id": "2302185_T3", "type": "Protein", "text": [ "C1" ], "offsets": [ [ 741, 743 ] ], "normalized": [] }, { "id": "2302185_T4", "type": "Protein", "text": [ "C2" ], "offsets": [ [ 748, 750 ] ], "normalized": [] }, { "id": "2302185_T5", "type": "Protein", "text": [ "interleukin-2-receptor alpha-subunit" ], "offsets": [ [ 805, 841 ] ], "normalized": [] }, { "id": "2302185_T6", "type": "Protein", "text": [ "C1" ], "offsets": [ [ 866, 868 ] ], "normalized": [] }, { "id": "2302185_T11", "type": "Entity", "text": [ "enhancer" ], "offsets": [ [ 842, 850 ] ], "normalized": [] } ]

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[ { "id": "10087993__text", "type": "abstract", "text": [ "Identification of upstream regulatory elements that repress expression of adult beta-like globin genes in a primitive erythroid environment. \nOur investigations have focused on localizing cis-elements responsible for the down regulation of the adult beta-like globin genes (delta and beta) in immature, or primitive erythroid tissues. We studied their activity after transfection into K562 cells, an erythroleukemia cell line with an embryonic-fetal phenotype. Analyzed DNA sequences included delta and beta 5' flanking regions extending from approximately -500 to +50bp (promoter regions), truncated delta and beta 5' flanking regions extending from approximately -250 to +50 bp, and chimeric promoter constructions, which consisted of a distal delta or beta fragment fused to a proximal beta or delta sequence. In CAT reporter constructions no appreciable level of CAT activity was supported by the beta globin promoter, and only low level activity by the delta promoter. Truncation of the beta globin promoter led to a 2-3 fold increase in promoter activity. In contrast, deletion of the upstream portion of the delta promoter led to a 10 fold decrease in expression. Coupling of the upstream beta globin sequence from approximately -500 to -250 bp to the truncated delta promoter fragment led to complete extinction of transcription activity, consistent with a negative regulatory effect of the beta globin gene upstream element(s). Fusion of the upstream portion of the delta promoter to the truncated beta globin promoter yielded a modest increase in promoter strength relative to the truncated beta gene promoter, indicating the presence of a positive transcriptional element(s) in the upstream delta globin regulatory region. Site-directed mutagenesis of binding sites for the repressor proteins BP1 and BP2 in the upstream portion of the beta globin gene flanking region led to a 4-6 fold increase in promoter activity. DNase I footprinting of the upstream delta-globin region revealed protected sequences corresponding to consensus binding sites for GATA-1 and BP2. These results confirm that sequences in the upstream promoter region of the adult beta globin gene contribute to its factor-mediated suppression early in development and then may modulate its expression at a later stage. " ], "offsets": [ [ 0, 2297 ] ] } ]

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[ { "id": "8872606__text", "type": "abstract", "text": [ "Soluble factors secreted by activated T-lymphocytes modulate the transcription of the immunosuppressive cytokine TGF-beta 2 in glial cells. \nCoordination of the immune response to injury or disease in the brain is postulated to involve bi-directional discourse between the immune system and the central nervous system. This cross communication involves soluble mediators, including various growth factors, cytokines, and neuropeptides. In this report, we demonstrate that the supernatant from activated T-lymphocytes is able to induce the transcription of a potent cytokine, TGF-beta 2 in glial cells. The activating stimulus invokes signaling mechanisms distinct from known kinase or protease pathways. Activation of TGF-beta 2 transcription correlates with the loss of binding activity for an 80 kDA glial labile repressor protein, GLRP, to a responsive region within the TFG-beta 2 promoter. Although GLRP shares some characteristics with the inducible transcription factor AP-1, it appears to be distinct from known AP-1 family members. These data along with previous observations demonstrating the potent immunosuppressive activity of TGF-beta 2, support a model for a feedback mechanism between the activated T-lymphocytes and astrocytes via TGF-beta 2 to regulate the immune response. " ], "offsets": [ [ 0, 1292 ] ] } ]

[ { "id": "8872606_T1", "type": "Protein", "text": [ "TGF-beta 2" ], "offsets": [ [ 113, 123 ] ], "normalized": [] }, { "id": "8872606_T2", "type": "Protein", "text": [ "TGF-beta 2" ], "offsets": [ [ 575, 585 ] ], "normalized": [] }, { "id": "8872606_T3", "type": "Protein", "text": [ "TGF-beta 2" ], "offsets": [ [ 718, 728 ] ], "normalized": [] }, { "id": "8872606_T4", "type": "Protein", "text": [ "GLRP" ], "offsets": [ [ 834, 838 ] ], "normalized": [] }, { "id": "8872606_T5", "type": "Protein", "text": [ "TFG-beta 2" ], "offsets": [ [ 874, 884 ] ], "normalized": [] }, { "id": "8872606_T6", "type": "Protein", "text": [ "GLRP" ], "offsets": [ [ 904, 908 ] ], "normalized": [] }, { "id": "8872606_T7", "type": "Protein", "text": [ "TGF-beta 2" ], "offsets": [ [ 1140, 1150 ] ], "normalized": [] }, { "id": "8872606_T8", "type": "Protein", "text": [ "TGF-beta 2" ], "offsets": [ [ 1248, 1258 ] ], "normalized": [] }, { "id": "8872606_T17", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 885, 893 ] ], "normalized": [] } ]

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[ { "id": "9390691__text", "type": "abstract", "text": [ "Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. \nCell cycle progression initiated by interleukin-2 (IL-2) in T cells is critical for lymphoproliferation and an immune response. Phosphatidyl inositol 3-kinase (PI3K) is activated by IL-2. However, nuclear targets for PI3K are not known. Here we identify the cell cycle regulator E2F as an IL-2 target in T lymphocytes and PI3K as the critical signaling pathway. We eliminate both Stat5 and Raf/MEK pathways from E2F regulation. Protein kinase B (PKB) is activated by IL-2 via PI3K. The expression of an active PKB is sufficient to induce E2F activity. Inhibition of PI3K inhibits phosphorylation of Rb, induction of cyclin D3, and degradation of p27kip1. These results establish a crucial PI3K/PKB-mediated link between the IL-2 teceptor and the cell cycle machinery. " ], "offsets": [ [ 0, 867 ] ] } ]

[ { "id": "9390691_T1", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 42, 55 ] ], "normalized": [] }, { "id": "9390691_T2", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 135, 148 ] ], "normalized": [] }, { "id": "9390691_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 150, 154 ] ], "normalized": [] }, { "id": "9390691_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 281, 285 ] ], "normalized": [] }, { "id": "9390691_T5", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 388, 392 ] ], "normalized": [] }, { "id": "9390691_T6", "type": "Protein", "text": [ "Stat5" ], "offsets": [ [ 479, 484 ] ], "normalized": [] }, { "id": "9390691_T7", "type": "Protein", "text": [ "Protein kinase B" ], "offsets": [ [ 527, 543 ] ], "normalized": [] }, { "id": "9390691_T8", "type": "Protein", "text": [ "PKB" ], "offsets": [ [ 545, 548 ] ], "normalized": [] }, { "id": "9390691_T9", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 566, 570 ] ], "normalized": [] }, { "id": "9390691_T10", "type": "Protein", "text": [ "PKB" ], "offsets": [ [ 609, 612 ] ], "normalized": [] }, { "id": "9390691_T11", "type": "Protein", "text": [ "Rb" ], "offsets": [ [ 698, 700 ] ], "normalized": [] }, { "id": "9390691_T12", "type": "Protein", "text": [ "p27kip1" ], "offsets": [ [ 745, 752 ] ], "normalized": [] }, { "id": "9390691_T13", "type": "Protein", "text": [ "PKB" ], "offsets": [ [ 793, 796 ] ], "normalized": [] }, { "id": "9390691_T14", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 823, 827 ] ], "normalized": [] }, { "id": "9390691_T16", "type": "Entity", "text": [ "PI3K" ], "offsets": [ [ 575, 579 ] ], "normalized": [] } ]

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[ { "id": "9065737__text", "type": "abstract", "text": [ "Activation of the transcription factor NF-kappaB in lipopolysaccharide-stimulated U937 cells. \nDuring the course of serious bacterial infections, lipopolysaccharide (LPS) interacts with monocyte/macrophage receptors, resulting in the generation of inflammatory cytokines. Transcription factor NF-kappaB is crucial in activating the transcription of genes encoding proinflammatory cytokines. In this paper, we demonstrate that the activation of NF-kappaB by LPS in a promonocytic cell line (U937) followed a rather slow kinetics, depending on the rate of IkappaB-alpha inhibitor hydrolysis. No degradation of p105 and p100 inhibitors was observed under these conditions. The transduction pathway leading to NF-kappaB activation in U937 cells involved the intracellular generation of reactive oxygen species (ROS), as demonstrated by the concomitant inhibitory effects of antioxidants on NF-kappaB activation and the emission of a fluorescent probe reacting intracellularly with hydrogen peroxide. This ROS pathway was also characterized by the use of other inhibitors. This finding indicates that phospholipase A2 and 5-lipoxygenase are also involved. However, the NF-kappaB activation pathway involving the acidic sphingomyelinase of the endolysosomial membrane did not seem to participate in the LPS-induced NF-kappaB activation in U937 cells. " ], "offsets": [ [ 0, 1345 ] ] } ]

[ { "id": "9065737_T1", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 554, 567 ] ], "normalized": [] }, { "id": "9065737_T2", "type": "Protein", "text": [ "5-lipoxygenase" ], "offsets": [ [ 1117, 1131 ] ], "normalized": [] }, { "id": "9065737_T3", "type": "Protein", "text": [ "acidic sphingomyelinase" ], "offsets": [ [ 1207, 1230 ] ], "normalized": [] } ]

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[ { "id": "9813178__text", "type": "abstract", "text": [ "Tobacco smoke induces coordinate activation of HSF and inhibition of NFkappaB in human monocytes: effects on TNFalpha release. \nTobacco smoke (TS) exposure is a major risk factor for human disease, and macrophages of healthy smokers have a depressed capacity to release cytokines, including tumor necrosis factor (TNF)alpha. TS induces the synthesis of heat shock (HS)/stress proteins (HSP), and, in particular, of Hsp70. We determined whether Hsp70 induction by TS was mediated by the activation of the HS transcription factor, HSF. HSF activation has been shown to inhibit NFkappaB. Thus, we also determined the effects of TS on NFkappaB. U937 cells and human peripheral blood monocytes were exposed to TS, binding activities of the respective transcription factors were analyzed, and Hsp70 expression and TNFalpha release were determined in parallel. TS activated HSF, which was associated with Hsp70 overexpression and inhibition of NFkappaB binding activity and TNFalpha release. The altered cytokine profile observed in smokers may relate to an HSF/Hsp70-mediated inhibition of NFkappaB activity. Copyright 1998 Academic Press. " ], "offsets": [ [ 0, 1134 ] ] } ]

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[ { "id": "9199898__text", "type": "abstract", "text": [ "S-allyl cysteine inhibits activation of nuclear factor kappa B in human T cells. \nReactive oxygen species are involved in signal transduction pathways leading to nuclear factor kappa B (NF-kappa B) activation which has been implicated in the regulation of gene transcription. We recently reported that a garlic compound, S-allyl cysteine (SAC), protects bovine pulmonary artery endothelial cells from oxidant injury induced by hydrogen peroxide (H2O2). In this study we determined the effects of SAC on NF-kappa B activation in human T lymphocytes (Jurkat cells) induced by tumor necrosis factor alpha (TNF- alpha) and H2O2. Activated NF-kappa B in nuclear extracts was measured by an electrophoretic mobility shift assay using 32P-labeled probe. SAC consistently exhibited a dose-dependent inhibition of NF-kappa B activation induced by both TNF-alpha and H2O2. Supershift with specific antibodies to NF-kappa B subunits confirmed that the inducible retarded bands observed in the EMSA and p65-p50 heterodimer of the NF-kappa B/Rel protein. Our data suggest that SAC may act via antioxidant mechanisms to block NF-kappa B activation in Jurkat cells. " ], "offsets": [ [ 0, 1151 ] ] } ]

[ { "id": "9199898_T1", "type": "Protein", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 574, 601 ] ], "normalized": [] }, { "id": "9199898_T2", "type": "Protein", "text": [ "TNF- alpha" ], "offsets": [ [ 603, 613 ] ], "normalized": [] }, { "id": "9199898_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 843, 852 ] ], "normalized": [] }, { "id": "9199898_T4", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 991, 994 ] ], "normalized": [] }, { "id": "9199898_T5", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 995, 998 ] ], "normalized": [] } ]

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[ { "id": "9887050__text", "type": "abstract", "text": [ "Differential monocyte adhesion and adhesion molecule expression in venous and arterial endothelial cells. \nWe compared U-937 cell adhesion and adhesion molecule expression in human umbilical venous (HUVECs) and arterial (HUAECs) endothelial cells exposed to tumor necrosis factor (TNF), interleukin-1, and lipopolysaccharide (LPS). TNF and LPS stimulated vascular cell adhesion molecule (VCAM)-1 surface expression and adhesion of U-937 monocyte-like cells to HUVECs but not to HUAECs. Antibody studies demonstrated that in HUVECs at least 75% of the adhesion response is VCAM-1 mediated. Interleukin-1 stimulated U-937 cell adhesion to and VCAM-1 surface expression in both HUVECs and HUAECs. Pyrrolidinedithiocarbamate and the proteasome inhibitor MG-132 blocked TNF- and LPS-stimulated U-937 cell adhesion to HUVECs. These agents also significantly decreased TNF- and LPS-stimulated increases in HUVEC surface VCAM-1. TNF increased VCAM-1 protein and mRNA in HUVECs that was blocked by pyrrolidinedithiocarbamate. However, neither TNF or LPS stimulated VCAM-1 expression in HUAECs. TNF stimulated expression of both intercellular adhesion molecule-1 and E-selectin in HUVECs, but in HUAECs, only intercellular adhesion molecule-1 was increased. Electrophoretic mobility shift assays demonstrated no difference in the pattern of TNF-stimulated nuclear factor-kappaB activation between HUVECs and HUAECs. These studies demonstrate a novel and striking insensitivity of arterial endothelium to the effects of TNF and LPS and indicate a dissociation between the ability of HUAECs to upregulate nuclear factor-kappaB and VCAM-1. " ], "offsets": [ [ 0, 1627 ] ] } ]

[ { "id": "9887050_T1", "type": "Protein", "text": [ "vascular cell adhesion molecule (VCAM)-1" ], "offsets": [ [ 355, 395 ] ], "normalized": [] }, { "id": "9887050_T2", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 572, 578 ] ], "normalized": [] }, { "id": "9887050_T3", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 641, 647 ] ], "normalized": [] }, { "id": "9887050_T4", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 913, 919 ] ], "normalized": [] }, { "id": "9887050_T5", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 935, 941 ] ], "normalized": [] }, { "id": "9887050_T6", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1056, 1062 ] ], "normalized": [] }, { "id": "9887050_T7", "type": "Protein", "text": [ "intercellular adhesion molecule-1" ], "offsets": [ [ 1119, 1152 ] ], "normalized": [] }, { "id": "9887050_T8", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 1157, 1167 ] ], "normalized": [] }, { "id": "9887050_T9", "type": "Protein", "text": [ "intercellular adhesion molecule-1" ], "offsets": [ [ 1199, 1232 ] ], "normalized": [] }, { "id": "9887050_T10", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1619, 1625 ] ], "normalized": [] } ]

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[ { "id": "8747083__text", "type": "abstract", "text": [ "Transcription specific differences visualized by fluorescence in situ hybridization pattern on interphase nuclei of different cell types. \nApplication of a \"formamide free\" and thus \"material preserving\" in situ hybridization technique using the cDNA of the myf3 gene revealed the following results: Human rhabdomyosarcoma cells, characterized by a high expression of myf3 show intensive hybridization signals in their interphase. RNase treatment prior to hybridization considerably reduces the size of this signals. In comparison, isolated nuclei of human lymphocytes in which no need for the expression of this gene exists, show barely hybridization signals. Correspondingly, RNase treatment had no effect on hybridization pattern at all. In conclusion an increased transcription efficiency of a cell type specific gene is accompanied by a higher hybridization accessibility in the corresponding cell nuclei. " ], "offsets": [ [ 0, 911 ] ] } ]

[ { "id": "8747083_T1", "type": "Protein", "text": [ "myf3" ], "offsets": [ [ 258, 262 ] ], "normalized": [] }, { "id": "8747083_T2", "type": "Protein", "text": [ "myf3" ], "offsets": [ [ 368, 372 ] ], "normalized": [] } ]

[ { "id": "8747083_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 354, 364 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8747083_T2" } ] }, { "id": "8747083_E2", "type": "Positive_regulation", "trigger": { "text": [ "intensive" ], "offsets": [ [ 378, 387 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8747083_E3" } ] }, { "id": "8747083_E3", "type": "Gene_expression", "trigger": { "text": [ "hybridization signals" ], "offsets": [ [ 388, 409 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8747083_T2" } ] }, { "id": "8747083_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 594, 604 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8747083_T2" } ] } ]

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[ { "id": "10070274__text", "type": "abstract", "text": [ "Nuclear factor-kappa B activity in T cells from patients with rheumatic diseases: a preliminary report. \nOBJECTIVE: The NF-kappa B/Rel family of transcription factors regulates the expression of many genes involved in the immune or inflammatory response at the transcriptional level. The aim of this study was to determine whether distinctive patterns of NF-kappa B activation are seen in different forms of joint disease. METHODS: The DNA binding activity of these nucleoproteins was examined in purified synovial and peripheral T cells from patients with various chronic rheumatic diseases (12: four with rheumatoid arthritis; five with spondyloarthropathies; and three with osteoarthritis). RESULTS: Electrophoretic mobility shift assays disclosed two specific complexes bound to a NF-kappa B specific 32P-labelled oligonucleotide in nucleoproteins extracted from purified T cells isolated from synovial fluid and peripheral blood of patients with rheumatoid arthritis. The complexes consisted of p50/p50 homodimers and p50/p65 heterodimers. Increased NF-kappa B binding to DNA in synovial T cells was observed relative to peripheral T cells. In non-rheumatoid arthritis, binding of NF-kappa B in synovial T cells was exclusively mediated by p50/p50 homodimers. CONCLUSION: Overall, the results suggest that NF-kappa B may play a central part in the activation of infiltrating T cells in chronic rheumatoid arthritis. The activation of this nuclear factor is qualitatively different in rheumatoid synovial T cells to that in other forms of non-rheumatoid arthritis (for example, osteoarthritis, spondyloarthropathies). " ], "offsets": [ [ 0, 1622 ] ] } ]

[ { "id": "10070274_T1", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1000, 1003 ] ], "normalized": [] }, { "id": "10070274_T2", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1004, 1007 ] ], "normalized": [] }, { "id": "10070274_T3", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1023, 1026 ] ], "normalized": [] }, { "id": "10070274_T4", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1027, 1030 ] ], "normalized": [] }, { "id": "10070274_T5", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1245, 1248 ] ], "normalized": [] }, { "id": "10070274_T6", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1249, 1252 ] ], "normalized": [] } ]

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[ { "id": "10070274_1", "entity_ids": [ "10070274_T5", "10070274_T6" ] }, { "id": "10070274_2", "entity_ids": [ "10070274_T1", "10070274_T2" ] } ]

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[ { "id": "2123553__text", "type": "abstract", "text": [ "Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. \nProliferation and immunologic function of T lymphocytes are initiated by signals from the antigen receptor that are inhibited by the immunosuppressant FK506 but not by its structural analog, rapamycin. On the other hand, interleukin 2 (IL-2)-induced signals are blocked by rapamycin but not by FK506. Remarkably, these two drugs inhibit each other's actions, raising the possibility that both act by means of a common immunophilin (immunosuppressant binding protein). We find that the dissociation constant of rapamycin to the FK506 binding protein FKBP (Kd = 0.2 nM) is close to the dissociation constant of FK506 to FKBP (Kd = 0.4 nM) and to their effective biologic inhibitory concentrations. However, an excess of rapamycin is needed to revert FK506-mediated inhibition of IL-2 production, apoptosis, and transcriptional activation of NF-AT, a T-cell-specific transcription factor necessary for IL-2 gene activation. Similarly, an excess of FK506 is needed to revert rapamycin-mediated inhibition of IL-2-induced proliferation. The drug concentrations required for antagonism may be explained by the relative affinity of the drugs to, and by the abundance of, the immunophilin FKBP. FKBP has been shown to catalyze the interconversion of the cis- and trans-rotamers of the peptidyl-prolyl amide bond of peptide substrates; here we show that rapamycin, like FK506, is a potent inhibitor of the rotamase activity of FKBP (Ki = 0.2 nM). Neither FKBP binding nor inhibition of rotamase activity of FKBP alone is sufficient to explain the biologic actions of these drugs. Rather, these findings suggest that immunophilin bound to FK506 interferes with antigen receptor-induced signals, while rapamycin bound to the immunophilin interferes with IL-2-induced signals. " ], "offsets": [ [ 0, 1914 ] ] } ]

[ { "id": "2123553_T1", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 370, 383 ] ], "normalized": [] }, { "id": "2123553_T2", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 385, 389 ] ], "normalized": [] }, { "id": "2123553_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 926, 930 ] ], "normalized": [] }, { "id": "2123553_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1048, 1052 ] ], "normalized": [] }, { "id": "2123553_T5", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1153, 1157 ] ], "normalized": [] }, { "id": "2123553_T6", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1892, 1896 ] ], "normalized": [] } ]

[ { "id": "2123553_E1", "type": "Negative_regulation", "trigger": { "text": [ "needed to revert" ], "offsets": [ [ 880, 896 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2123553_E2" } ] }, { "id": "2123553_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 912, 922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2123553_E3" } ] }, { "id": "2123553_E3", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 931, 941 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2123553_T3" } ] }, { "id": "2123553_E4", "type": "Positive_regulation", "trigger": { "text": [ "necessary" ], "offsets": [ [ 1034, 1043 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2123553_E5" } ] }, { "id": "2123553_E5", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 1058, 1068 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2123553_T4" } ] } ]

[ { "id": "2123553_1", "entity_ids": [ "2123553_T1", "2123553_T2" ] } ]

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[ { "id": "10426996__text", "type": "abstract", "text": [ "Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. \nApoptosis is implicated in the generation and resolution of inflammation in response to bacterial pathogens. All bacterial pathogens produce lipoproteins (BLPs), which trigger the innate immune response. BLPs were found to induce apoptosis in THP-1 monocytic cells through human Toll-like receptor-2 (hTLR2). BLPs also initiated apoptosis in an epithelial cell line transfected with hTLR2. In addition, BLPs stimulated nuclear factor-kappaB, a transcriptional activator of multiple host defense genes, and activated the respiratory burst through hTLR2. Thus, hTLR2 is a molecular link between microbial products, apoptosis, and host defense mechanisms. " ], "offsets": [ [ 0, 740 ] ] } ]

[ { "id": "10426996_T1", "type": "Protein", "text": [ "toll-like receptor-2" ], "offsets": [ [ 64, 84 ] ], "normalized": [] }, { "id": "10426996_T2", "type": "Protein", "text": [ "human Toll-like receptor-2" ], "offsets": [ [ 360, 386 ] ], "normalized": [] }, { "id": "10426996_T3", "type": "Protein", "text": [ "hTLR2" ], "offsets": [ [ 388, 393 ] ], "normalized": [] }, { "id": "10426996_T4", "type": "Protein", "text": [ "hTLR2" ], "offsets": [ [ 470, 475 ] ], "normalized": [] }, { "id": "10426996_T5", "type": "Protein", "text": [ "hTLR2" ], "offsets": [ [ 633, 638 ] ], "normalized": [] }, { "id": "10426996_T6", "type": "Protein", "text": [ "hTLR2" ], "offsets": [ [ 646, 651 ] ], "normalized": [] } ]

[ { "id": "10426996_E1", "type": "Positive_regulation", "trigger": { "text": [ "transfected" ], "offsets": [ [ 453, 464 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10426996_E2" } ] }, { "id": "10426996_E2", "type": "Gene_expression", "trigger": { "text": [ "transfected" ], "offsets": [ [ 453, 464 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10426996_T4" } ] } ]

[ { "id": "10426996_1", "entity_ids": [ "10426996_T2", "10426996_T3" ] } ]

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[ { "id": "8757316__text", "type": "abstract", "text": [ "Alpha 4 beta 1 (CD49d/CD29) integrin costimulation of human T cells enhances transcription factor and cytokine induction in the absence of altered sensitivity to anti-CD3 stimulation. \nThe integrin alpha 4 beta 1 can provide a costimulus to induce IL-2 secretion and IL-2R expression leading to enhanced proliferation of purified, peripheral blood T cells. Similar to expression of IL-2, we demonstrated that recombinant vascular-cell adhesion molecule-1, when co-immobilized with anti-CD3 mAb, significantly enhanced the induction of transcription factors NF-AT, AP-1, and NF-kappa B as determined by electromobility shift assays. alpha 4 beta 1 ligation alone had no effect on transcription factor binding. The requirements for induction of transcription factors reflected the requirements for the secretion of multiple cytokines, including IL-2, TNF-alpha, IFN-gamma, and granulocyte macrophage-CSF. In contrast to freshly isolated T cells, in vitro-cultured T cells did not require costimulation for cytokine secretion in response to anti-CD3 alone. Comparison of the dose response to anti-CD3 stimulation demonstrated that half-maximal induction of IL-2 was achieved using the same dose of anti-CD3 for both freshly isolated and cultured T cells. Furthermore, the dose of OKT3 required to achieve half-maximal activation was the same using PMA or different concentrations of alpha 4 beta 1 ligands. Therefore, costimulation by alpha 4 beta 1 ligands was not due to stabilization of the interaction of the cells with its substrate. We conclude, rather, that alpha 4 beta 1 in freshly isolated T cells delivers a distinct signal that synergizes early with signals initiated by TCR/CD3 ligation to induce DNA binding of multiple transcription factors required for cytokine gene induction. " ], "offsets": [ [ 0, 1791 ] ] } ]

[ { "id": "8757316_T1", "type": "Protein", "text": [ "Alpha 4 beta 1 (CD49d/CD29) integrin" ], "offsets": [ [ 0, 36 ] ], "normalized": [] }, { "id": "8757316_T2", "type": "Protein", "text": [ "integrin alpha 4 beta 1" ], "offsets": [ [ 189, 212 ] ], "normalized": [] }, { "id": "8757316_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 248, 252 ] ], "normalized": [] }, { "id": "8757316_T4", "type": "Protein", "text": [ "IL-2R" ], "offsets": [ [ 267, 272 ] ], "normalized": [] }, { "id": "8757316_T5", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 382, 386 ] ], "normalized": [] }, { "id": "8757316_T6", "type": "Protein", "text": [ "vascular-cell adhesion molecule-1" ], "offsets": [ [ 421, 454 ] ], "normalized": [] }, { "id": "8757316_T7", "type": "Protein", "text": [ "alpha 4 beta 1" ], "offsets": [ [ 632, 646 ] ], "normalized": [] }, { "id": "8757316_T8", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 843, 847 ] ], "normalized": [] }, { "id": "8757316_T9", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 849, 858 ] ], "normalized": [] }, { "id": "8757316_T10", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 860, 869 ] ], "normalized": [] }, { "id": "8757316_T11", "type": "Protein", "text": [ "granulocyte macrophage-CSF" ], "offsets": [ [ 875, 901 ] ], "normalized": [] }, { "id": "8757316_T12", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1154, 1158 ] ], "normalized": [] }, { "id": "8757316_T13", "type": "Protein", "text": [ "alpha 4 beta 1" ], "offsets": [ [ 1380, 1394 ] ], "normalized": [] }, { "id": "8757316_T14", "type": "Protein", "text": [ "alpha 4 beta 1" ], "offsets": [ [ 1432, 1446 ] ], "normalized": [] }, { "id": "8757316_T15", "type": "Protein", "text": [ "alpha 4 beta 1" ], "offsets": [ [ 1562, 1576 ] ], "normalized": [] } ]

[ { "id": "8757316_E1", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 241, 247 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8757316_E3" }, { "role": "Cause", "ref_id": "8757316_T2" } ] }, { "id": "8757316_E2", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 241, 247 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8757316_E4" }, { "role": "Cause", "ref_id": "8757316_T2" } ] }, { "id": "8757316_E3", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 253, 262 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8757316_T3" } ] }, { "id": "8757316_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 273, 283 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8757316_T4" } ] }, { "id": "8757316_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 368, 378 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8757316_T5" } ] }, { "id": "8757316_E6", "type": "Binding", "trigger": { "text": [ "ligation" ], "offsets": [ [ 647, 655 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8757316_T7" } ] }, { "id": "8757316_E7", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 800, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8757316_T11" } ] }, { "id": "8757316_E8", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 800, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8757316_T10" } ] }, { "id": "8757316_E9", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 800, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8757316_T8" } ] }, { "id": "8757316_E10", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 800, 809 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8757316_T9" } ] }, { "id": "8757316_E11", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1141, 1150 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8757316_T12" } ] } ]

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[ { "id": "9384661__text", "type": "abstract", "text": [ "Expression of c-fos correlates with IFN-alpha responsiveness in Philadelphia chromosome positive chronic myelogenous leukemia. \nThis study evaluates (i) constitutive levels of oncogene and p53 transcripts in chronic phase CML patients and (ii) their modulations subsequent to in vivo therapy with rIFN-alpha 2c. Peripheral blood mononuclear cells (pbmc) and bone marrow cells of 26 patients were examined for c-fos, c-myc, p53 and the hybrid bcr/abl mRNA levels. Results indicated that (i) constitutive c-fos transcript levels are significantly higher in patients subsequently responding to IFN-alpha therapy (p < 0.01) and positively correlated with the proportion of lymphocytes (r = 0.6895, p < 0.01) and negatively with the proportion of immature cells (r = -0.568, p < 0.01) contained in the pbmc preparations tested, (ii) constitutive mRNA levels of the hybrid bcr/abl, c-myc and p53 are positively correlated with each other, but failed to relate to disease parameters, and (iii) acute and chronic in vivo exposure to IFN-alpha is accompanied by upregulation of c-fos and downregulation of c-myc mRNA levels in responder patients. " ], "offsets": [ [ 0, 1138 ] ] } ]

[ { "id": "9384661_T1", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 14, 19 ] ], "normalized": [] }, { "id": "9384661_T2", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 189, 192 ] ], "normalized": [] }, { "id": "9384661_T3", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 409, 414 ] ], "normalized": [] }, { "id": "9384661_T4", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 416, 421 ] ], "normalized": [] }, { "id": "9384661_T5", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 423, 426 ] ], "normalized": [] }, { "id": "9384661_T6", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 876, 881 ] ], "normalized": [] }, { "id": "9384661_T7", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 886, 889 ] ], "normalized": [] }, { "id": "9384661_T8", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 1069, 1074 ] ], "normalized": [] }, { "id": "9384661_T9", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 1097, 1102 ] ], "normalized": [] } ]

[ { "id": "9384661_E1", "type": "Gene_expression", "trigger": { "text": [ "Expression" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9384661_T1" } ] }, { "id": "9384661_E2", "type": "Transcription", "trigger": { "text": [ "levels" ], "offsets": [ [ 166, 172 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9384661_T2" } ] }, { "id": "9384661_E3", "type": "Transcription", "trigger": { "text": [ "levels" ], "offsets": [ [ 455, 461 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9384661_T5" } ] }, { "id": "9384661_E4", "type": "Transcription", "trigger": { "text": [ "levels" ], "offsets": [ [ 455, 461 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9384661_T4" } ] }, { "id": "9384661_E5", "type": "Transcription", "trigger": { "text": [ "levels" ], "offsets": [ [ 455, 461 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9384661_T3" } ] }, { "id": "9384661_E6", "type": "Positive_regulation", "trigger": { "text": [ "accompanied by upregulation" ], "offsets": [ [ 1038, 1065 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9384661_T8" } ] }, { "id": "9384661_E7", "type": "Negative_regulation", "trigger": { "text": [ "downregulation" ], "offsets": [ [ 1079, 1093 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9384661_T9" } ] } ]

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[ { "id": "10329958__text", "type": "abstract", "text": [ "Regulation of low shear flow-induced HAEC VCAM-1 expression and monocyte adhesion. \nWe recently reported that prolonged exposure of human aortic endothelial cells (HAEC) to low shear stress flow patterns is associated with a sustained increase in the activated form of the transcriptional regulator nuclear factor-kappaB (NF-kappaB). Here we investigate the hypothesis that low shear-induced activation of NF-kappaB is responsible for enhanced expression of vascular cell adhesion molecule (VCAM-1) resulting in augmented endothelial cell-monocyte (EC-Mn) adhesion and that this activation is dependent on intracellular oxidant activity. Before exposure to low shear (2 dyn/cm2) for 6 h, HAEC were preincubated with or without the antioxidants pyrrolidine dithiocarbamate (PDTC) or N-acetyl-L-cysteine (NAC). PDTC strongly inhibited low shear-induced activation of NF-kappaB, expression of VCAM-1, and EC-Mn adhesion. Paradoxically, NAC exerted a positive effect on low shear-induced VCAM-1 expression and EC-Mn adhesion and only slightly downregulated NF-kappaB activation. However, cytokine-induced NF-kappaB activation and VCAM-1 expression are blocked by both PDTC and NAC. These data suggest that NF-kappaB plays a key role in low shear-induced VCAM-1 expression and that pathways mediating low shear- and cytokine-induced EC-Mn adhesion may be differentially regulated. " ], "offsets": [ [ 0, 1376 ] ] } ]

[ { "id": "10329958_T1", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 42, 48 ] ], "normalized": [] }, { "id": "10329958_T2", "type": "Protein", "text": [ "vascular cell adhesion molecule" ], "offsets": [ [ 458, 489 ] ], "normalized": [] }, { "id": "10329958_T3", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 491, 497 ] ], "normalized": [] }, { "id": "10329958_T4", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 890, 896 ] ], "normalized": [] }, { "id": "10329958_T5", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 984, 990 ] ], "normalized": [] }, { "id": "10329958_T6", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1126, 1132 ] ], "normalized": [] }, { "id": "10329958_T7", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1250, 1256 ] ], "normalized": [] } ]

[ { "id": "10329958_E1", "type": "Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 0, 10 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_E2" } ] }, { "id": "10329958_E2", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 29, 36 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_E3" } ] }, { "id": "10329958_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 49, 59 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_T1" } ] }, { "id": "10329958_E4", "type": "Positive_regulation", "trigger": { "text": [ "responsible for enhanced" ], "offsets": [ [ 419, 443 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_E5" } ] }, { "id": "10329958_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 444, 454 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_T3" } ] }, { "id": "10329958_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 823, 832 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_E7" } ] }, { "id": "10329958_E7", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 843, 850 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_E8" } ] }, { "id": "10329958_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 876, 886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_T4" } ] }, { "id": "10329958_E9", "type": "Positive_regulation", "trigger": { "text": [ "exerted a positive effect" ], "offsets": [ [ 937, 962 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_E10" } ] }, { "id": "10329958_E10", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 976, 983 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_E11" } ] }, { "id": "10329958_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 991, 1001 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_T5" } ] }, { "id": "10329958_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1093, 1100 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_E13" } ] }, { "id": "10329958_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1133, 1143 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_T6" } ] }, { "id": "10329958_E14", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1148, 1155 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_E12" } ] }, { "id": "10329958_E15", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1242, 1249 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_E16" } ] }, { "id": "10329958_E16", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1257, 1267 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10329958_T7" } ] } ]

[ { "id": "10329958_1", "entity_ids": [ "10329958_T2", "10329958_T3" ] } ]

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[ { "id": "10064064__text", "type": "abstract", "text": [ "AML and Ets proteins regulate the I alpha1 germ-line promoter. \nThe immunoglobulin heavy chain (IgH) class switch recombination of B lymphocytes preferentially targets unrearranged IgH genes that have already been rendered transcriptionally active. Transcription of the germ-line IgH genes is controlled by intervening (I) regions upstream of their switch regions. The I alpha1 promoter activates transcription of the human germ-line C alpha1 gene for IgA1 and mediates the transforming growth factor (TGF)-beta1 responsiveness of this locus. Here we show that the I alpha1 promoter contains several binding sites for the AML/PEBP2/CBF family of transcription factors and that AML and Ets proteins are major regulators of the basal and TGF-beta-inducible promoter activity. Our data constitute a starting point for studies to elucidate the molecular mechanism by which TGF-beta regulates IgA production. " ], "offsets": [ [ 0, 904 ] ] } ]

[ { "id": "10064064_T1", "type": "Protein", "text": [ "transforming growth factor (TGF)-beta1" ], "offsets": [ [ 474, 512 ] ], "normalized": [] } ]

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[]

[ { "id": "10228008__text", "type": "abstract", "text": [ "The evolutionarily conserved sequence upstream of the human Ig heavy chain S gamma 3 region is an inducible promoter: synergistic activation by CD40 ligand and IL-4 via cooperative NF-kappa B and STAT-6 binding sites. \nGermline C gamma gene transcription is a crucial event in the process that leads to switch DNA recombination to IgG, but its regulation in the human is poorly understood. We took advantage of our monoclonal model of germinal center B cell differentiation, IgM+ IgD+ CL-01 cells, to define the role of the I gamma 3 evolutionarily conserved sequence (ECS) in the germline transcriptional activation of the human C gamma 3 gene. The I gamma 3 ECS lies upstream of the major I gamma 3 transcription initiation site and displays more than 90% identity with the corresponding human I gamma 1, I gamma 2, and I gamma 4 regions. Reporter luciferase gene vectors containing the human gamma 3 ECS were used to transfect CL-01 cells, which have been shown to undergo Smu-->S gamma 3 DNA recombination, upon engagement of CD40 by CD40 ligand (CD40L) and exposure to IL-4. In these transfected CL-01 cells, CD40:CD40L engagement and exposure to IL-4 synergistically induced gamma 3 ECS-dependent luciferase reporter gene activation. Targeted mutational analysis demonstrated that a tandem NF-kappa B/Rel binding motif is critical for the gamma 3 ECS responsiveness to both CD40L and IL-4, while a STAT-6-binding site is additionally required for IL-4 inducibility. Electrophoretic mobility shift assays showed that p50/p65/c-Rel and STAT-6 are effectively induced by CD40L and IL-4, respectively, and bind to specific DNA motifs within the ECS. These partially overlapping CD40L and IL-4 responsive elements are functionally cooperative as the disruption of one of them prevents synergistic promoter activation. Thus, the gamma 3 ECS is an inducible promoter containing cis elements that critically mediate CD40L and IL-4-triggered transcriptional activation of the human C gamma 3 gene. " ], "offsets": [ [ 0, 1995 ] ] } ]

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[ { "id": "8164666__text", "type": "abstract", "text": [ "Positive regulators of the lineage-specific transcription factor GATA-1 in differentiating erythroid cells. \nThe zinc finger transcription factor GATA-1 is a major regulator of gene expression in erythroid, megakaryocyte, and mast cell lineages. GATA-1 binds to WGATAR consensus motifs in the regulatory regions of virtually all erythroid cell-specific genes. Analyses with cultured cells and cell-free systems have provided strong evidence that GATA-1 is involved in control of globin gene expression during erythroid differentiation. Targeted mutagenesis of the GATA-1 gene in embryonic stem cells has demonstrated its requirement in normal erythroid development. Efficient rescue of the defect requires an intact GATA element in the distal promoter, suggesting autoregulatory control of GATA-1 transcription. To examine whether GATA-1 expression involves additional regulatory factors or is maintained entirely by an autoregulatory loop, we have used a transient heterokaryon system to test the ability of erythroid factors to activate the GATA-1 gene in nonerythroid nuclei. We show here that proerythroblasts and mature erythroid cells contain a diffusible activity (TAG) capable of transcriptional activation of GATA-1 and that this activity decreases during the terminal differentiation of erythroid cells. Nuclei from GATA-1- mutant embryonic stem cells can still be reprogrammed to express their globin genes in erythroid heterokaryons, indicating that de novo induction of GATA-1 is not required for globin gene activation following cell fusion. " ], "offsets": [ [ 0, 1556 ] ] } ]

[ { "id": "8164666_T1", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 65, 71 ] ], "normalized": [] }, { "id": "8164666_T2", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 146, 152 ] ], "normalized": [] }, { "id": "8164666_T3", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 246, 252 ] ], "normalized": [] }, { "id": "8164666_T4", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 446, 452 ] ], "normalized": [] }, { "id": "8164666_T5", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 564, 570 ] ], "normalized": [] }, { "id": "8164666_T6", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 790, 796 ] ], "normalized": [] }, { "id": "8164666_T7", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 831, 837 ] ], "normalized": [] }, { "id": "8164666_T8", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1043, 1049 ] ], "normalized": [] }, { "id": "8164666_T9", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1218, 1224 ] ], "normalized": [] }, { "id": "8164666_T10", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1326, 1332 ] ], "normalized": [] }, { "id": "8164666_T11", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1483, 1489 ] ], "normalized": [] } ]

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[ { "id": "10102791__text", "type": "abstract", "text": [ "PGG-glucan, a soluble beta-(1,3)-glucan, enhances the oxidative burst response, microbicidal activity, and activates an NF-kappa B-like factor in human PMN: evidence for a glycosphingolipid beta-(1,3)-glucan receptor. \nPGG-Glucan, a soluble beta-(1,6)-branched beta-(1,3)-linked glucose homopolymer derived from the cell wall of the yeast Saccharomyces cerevisiae, is an immunomodulator which enhances leukocyte anti-infective activity and enhances myeloid and megakaryocyte progenitor proliferation. Incubation of human whole blood with PGG-Glucan significantly enhanced the oxidative burst response of subsequently isolated blood leukocytes to both soluble and particulate activators in a dose-dependent manner, and increased leukocyte microbicidal activity. No evidence for inflammatory cytokine production was obtained under these conditions. Electrophoretic mobility shift assays demonstrated that PGG-Glucan induced the activation of an NF-kappaB-like nuclear transcription factor in purified human neutrophils. The binding of 3H-PGG-Glucan to human leukocyte membranes was specific, concentration-dependent, saturable, and high affinity (Kd approximately 6 nM). A monoclonal antibody specific to the glycosphingolipid lactosylceramide was able to inhibit activation of the NF-kappaB-like factor by PGG-Glucan, and ligand binding data, including polysaccharide specificity, suggested that the PGG-Glucan binding moiety was lactosylceramide. These results indicate that PGG-Glucan enhances neutrophil anti-microbial functions and that interaction between this beta-glucan and human neutrophils is mediated by the glycosphingolipid lactosylceramide present at the cell surface. " ], "offsets": [ [ 0, 1682 ] ] } ]

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[ { "id": "9633826__text", "type": "abstract", "text": [ "Limited proteolysis for assaying ligand binding affinities of nuclear receptors. \nThe binding of natural or synthetic ligands to nuclear receptors is the triggering event leading to gene transcription activation or repression. Ligand binding to the ligand binding domain of these receptors induces conformational changes that are evidenced by an increased resistance of this domain to proteases. In vitro labeled receptors were incubated with various synthetic or natural agonists or antagonists and submitted to trypsin digestion. Proteolysis products were separated by SDS-PAGE and quantified. The amount of trypsin-resistant fragments was proportional to receptor occupancy by the ligand, and allowed the determination of dissociation constants (kDa). Using the wild-type or mutated human retinoic acid receptor alpha as a model, kDa values determined by classical competition binding assays using tritiated ligands are in agreement with those measured by the proteolytic assay. This method was successfully extended to human retinoic X receptor alpha, glucocorticoid receptor, and progesterone receptor, thus providing a basis for a new, faster assay to determine simultaneously the affinity and conformation of receptors when bound to a given ligand. " ], "offsets": [ [ 0, 1256 ] ] } ]

[ { "id": "9633826_T1", "type": "Protein", "text": [ "retinoic acid receptor alpha" ], "offsets": [ [ 792, 820 ] ], "normalized": [] }, { "id": "9633826_T2", "type": "Protein", "text": [ "retinoic X receptor alpha" ], "offsets": [ [ 1029, 1054 ] ], "normalized": [] }, { "id": "9633826_T3", "type": "Protein", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 1056, 1079 ] ], "normalized": [] } ]

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[ { "id": "9243748__text", "type": "abstract", "text": [ "Induction of nuclear factor kappa B/Rel nuclear activity in human peripheral blood T lymphocytes by anti-HLA class I monoclonal antibodies. \nMonoclonal antibodies against either monomorphic or polymorphic determinants of class I antigen induced in PBMC and highly purified T lymphocytes the nuclear activity of NF-kappa B/Rel complexes. These included both p50/p50 and p50/p65 dimers, recognized by specific antibodies in EMSA. The induced complexes were detectable in extracts of cells incubated with anti-class I monoclonal antibody (mAb) for 1.5 h; the induction was maximal at 5 h, persistent at 16 h and no longer observed at 40 h. The mAb failed to induce NF-kappa B/Rel nuclear activity in cells incubated in the presence of 3,4-dichloroisocoumarin, an inhibitor of I kappa B-alpha degradation. Together, these results suggest that class I triggering can induce the activity of NF-kappa B/Rel nuclear activity in peripheral blood T lymphocytes, thereby modulating the expression of genes regulated by these transcription factors. " ], "offsets": [ [ 0, 1037 ] ] } ]

[ { "id": "9243748_T1", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 357, 360 ] ], "normalized": [] }, { "id": "9243748_T2", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 361, 364 ] ], "normalized": [] }, { "id": "9243748_T3", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 369, 372 ] ], "normalized": [] }, { "id": "9243748_T4", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 373, 376 ] ], "normalized": [] }, { "id": "9243748_T5", "type": "Protein", "text": [ "I kappa B-alpha" ], "offsets": [ [ 773, 788 ] ], "normalized": [] } ]

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[ { "id": "8163658__text", "type": "abstract", "text": [ "Hypoxic induction of interleukin-8 gene expression in human endothelial cells. \nBecause leukocyte-mediated tissue damage is an important component of the pathologic picture in ischemia/reperfusion, we have sought mechanisms by which PMNs are directed into hypoxic tissue. Incubation of human endothelial cells (ECs) in hypoxia, PO2 approximately 14-18 Torr, led to time-dependent release of IL-8 antigen into the conditioned medium; this was accompanied by increased chemotactic activity for PMNs, blocked by antibody to IL-8. Production of IL-8 by hypoxic ECs occurred concomitantly with both increased levels of IL-8 mRNA, based on polymerase chain reaction analysis, and increased IL-8 transcription, based on nuclear run-on assays. Northern analysis of mRNA from hypoxic ECs also demonstrated increased levels of mRNA for macrophage chemotactic protein-1, another member of the chemokine superfamily of proinflammatory cytokines. IL-8 gene induction was associated with the presence of increased binding activity in nuclear extracts from hypoxic ECs for the NF-kB site. Studies with human umbilical vein segments exposed to hypoxia also demonstrated increased elaboration of IL-8 antigen compared with normoxic controls. In mice exposed to hypoxia (PO2 approximately 30-40 Torr), there was increased pulmonary leukostasis, as evidenced by increased myeloperoxidase activity in tissue homogenates. In parallel, increased levels of transcripts for IP-10, a murine homologue in the chemokine family related to IL-8, were observed in hypoxic lung tissue. Taken together, these data suggest that hypoxia constitutes a stimulus for leukocyte chemotaxis and tissue leukostasis. " ], "offsets": [ [ 0, 1675 ] ] } ]

[ { "id": "8163658_T1", "type": "Protein", "text": [ "interleukin-8" ], "offsets": [ [ 21, 34 ] ], "normalized": [] }, { "id": "8163658_T2", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 391, 395 ] ], "normalized": [] }, { "id": "8163658_T3", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 521, 525 ] ], "normalized": [] }, { "id": "8163658_T4", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 541, 545 ] ], "normalized": [] }, { "id": "8163658_T5", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 614, 618 ] ], "normalized": [] }, { "id": "8163658_T6", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 684, 688 ] ], "normalized": [] }, { "id": "8163658_T7", "type": "Protein", "text": [ "macrophage chemotactic protein-1" ], "offsets": [ [ 826, 858 ] ], "normalized": [] }, { "id": "8163658_T8", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 934, 938 ] ], "normalized": [] }, { "id": "8163658_T9", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1179, 1183 ] ], "normalized": [] }, { "id": "8163658_T10", "type": "Protein", "text": [ "myeloperoxidase" ], "offsets": [ [ 1353, 1368 ] ], "normalized": [] }, { "id": "8163658_T11", "type": "Protein", "text": [ "IP-10" ], "offsets": [ [ 1450, 1455 ] ], "normalized": [] }, { "id": "8163658_T12", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1511, 1515 ] ], "normalized": [] } ]

[ { "id": "8163658_E1", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 8, 17 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_E2" } ] }, { "id": "8163658_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 40, 50 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_T1" } ] }, { "id": "8163658_E3", "type": "Positive_regulation", "trigger": { "text": [ "led" ], "offsets": [ [ 358, 361 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_E4" } ] }, { "id": "8163658_E4", "type": "Localization", "trigger": { "text": [ "release" ], "offsets": [ [ 380, 387 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_T2" } ] }, { "id": "8163658_E5", "type": "Positive_regulation", "trigger": { "text": [ "Production" ], "offsets": [ [ 527, 537 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_T4" } ] }, { "id": "8163658_E6", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 594, 603 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_T5" } ] }, { "id": "8163658_E7", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 674, 683 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_E8" } ] }, { "id": "8163658_E8", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 689, 702 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_T6" } ] }, { "id": "8163658_E9", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 797, 806 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_T7" } ] }, { "id": "8163658_E10", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 944, 953 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_T8" } ] }, { "id": "8163658_E11", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1154, 1163 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_T9" } ] }, { "id": "8163658_E12", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1414, 1423 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8163658_T11" } ] } ]

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[ { "id": "8319574__text", "type": "abstract", "text": [ "Differential autoregulation of glucocorticoid receptor expression in human T- and B-cell lines. \nRegulation of glucocorticoid receptor (GR) expression by its cognate ligand was examined in the glucocorticoid-sensitive human leukemic T-cell line 6TG1.1 and in the human B-cell line IM-9. In contrast to the decrease in GR mRNA seen in IM-9 cells after treatment with 1 microM dexamethasone for 16-18 h, treatment of 6TG1.1 cells resulted in an 8-fold increase in GR mRNA, as determined by Northern blot and RNase protection analysis, with a corresponding 3- to 4-fold increase in GR protein. Half-maximal induction of GR mRNA and protein in 6TG1.1 cells was observed between 10-100 nM dexamethasone, and inclusion of 1 microM RU 38486 completely blocked the effects of 100 nM dexamethasone, demonstrating that positive autoregulation of GR expression in 6TG1.1 cells is a receptor-mediated response. Positive autoregulation of GR expression was also observed in glucocorticoid-resistant CEM-C1 cells, which contain functional GR, but whose growth is unaffected by glucocorticoids. Thus, positive autoregulation is neither a consequence nor the sole cause of growth arrest. The degree of negative autoregulation in IM-9 cells and positive autoregulation in 6TG1.1 cells was unaffected by inhibition of protein synthesis with cycloheximide. Measurement of GR mRNA turnover in 6TG1.1 cells treated with actinomycin-D revealed a half-life of 2.5 h, which was unaffected by dexamethasone treatment. A similar half-life was determined in IM-9 cells and was also unaffected by steroid treatment. These results are consistent with the interpretation that glucocorticoid-mediated autoregulation of GR expression is a tissue-specific primary transcriptional response. " ], "offsets": [ [ 0, 1757 ] ] } ]

[ { "id": "8319574_T1", "type": "Protein", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 31, 54 ] ], "normalized": [] }, { "id": "8319574_T2", "type": "Protein", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 111, 134 ] ], "normalized": [] }, { "id": "8319574_T3", "type": "Protein", "text": [ "GR" ], "offsets": [ [ 136, 138 ] ], "normalized": [] }, { "id": "8319574_T4", "type": "Protein", "text": [ "GR" ], "offsets": [ [ 318, 320 ] ], "normalized": [] }, { "id": "8319574_T5", "type": "Protein", "text": [ "GR" ], "offsets": [ [ 462, 464 ] ], "normalized": [] }, { "id": "8319574_T6", "type": "Protein", "text": [ "GR" ], "offsets": [ [ 579, 581 ] ], "normalized": [] }, { "id": "8319574_T7", "type": "Protein", "text": [ "GR" ], "offsets": [ [ 617, 619 ] ], "normalized": [] }, { "id": "8319574_T8", "type": "Protein", "text": [ "GR" ], "offsets": [ [ 836, 838 ] ], "normalized": [] }, { "id": "8319574_T9", "type": "Protein", "text": [ "GR" ], "offsets": [ [ 926, 928 ] ], "normalized": [] }, { "id": "8319574_T10", "type": "Protein", "text": [ "GR" ], "offsets": [ [ 1025, 1027 ] ], "normalized": [] }, { "id": "8319574_T11", "type": "Protein", "text": [ "GR" ], "offsets": [ [ 1353, 1355 ] ], "normalized": [] }, { "id": "8319574_T12", "type": "Protein", "text": [ "GR" ], "offsets": [ [ 1688, 1690 ] ], "normalized": [] } ]

[ { "id": "8319574_E1", "type": "Regulation", "trigger": { "text": [ "autoregulation" ], "offsets": [ [ 13, 27 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_E2" } ] }, { "id": "8319574_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 55, 65 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_T1" } ] }, { "id": "8319574_E3", "type": "Regulation", "trigger": { "text": [ "Regulation" ], "offsets": [ [ 97, 107 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_E4" } ] }, { "id": "8319574_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 140, 150 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_T3" } ] }, { "id": "8319574_E5", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 306, 314 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_T4" } ] }, { "id": "8319574_E6", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 450, 458 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_T5" } ] }, { "id": "8319574_E7", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 567, 575 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_T6" } ] }, { "id": "8319574_E8", "type": "Transcription", "trigger": { "text": [ "induction" ], "offsets": [ [ 604, 613 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_T7" } ] }, { "id": "8319574_E9", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 745, 752 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_E8" } ] }, { "id": "8319574_E10", "type": "Positive_regulation", "trigger": { "text": [ "positive autoregulation" ], "offsets": [ [ 809, 832 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_E11" }, { "role": "Cause", "ref_id": "8319574_T8" } ] }, { "id": "8319574_E11", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 839, 849 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_T8" } ] }, { "id": "8319574_E12", "type": "Regulation", "trigger": { "text": [ "Positive autoregulation" ], "offsets": [ [ 899, 922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_E13" } ] }, { "id": "8319574_E13", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 929, 939 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_T9" } ] }, { "id": "8319574_E14", "type": "Positive_regulation", "trigger": { "text": [ "consequence" ], "offsets": [ [ 1123, 1134 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_E12" } ] }, { "id": "8319574_E15", "type": "Negative_regulation", "trigger": { "text": [ "negative autoregulation" ], "offsets": [ [ 1186, 1209 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_E13" } ] }, { "id": "8319574_E16", "type": "Positive_regulation", "trigger": { "text": [ "positive autoregulation" ], "offsets": [ [ 1228, 1251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_E13" } ] }, { "id": "8319574_E17", "type": "Regulation", "trigger": { "text": [ "unaffected" ], "offsets": [ [ 1272, 1282 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_E15" } ] }, { "id": "8319574_E18", "type": "Regulation", "trigger": { "text": [ "unaffected" ], "offsets": [ [ 1272, 1282 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_E16" } ] }, { "id": "8319574_E19", "type": "Regulation", "trigger": { "text": [ "unaffected" ], "offsets": [ [ 1454, 1464 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_T11" } ] }, { "id": "8319574_E20", "type": "Regulation", "trigger": { "text": [ "unaffected" ], "offsets": [ [ 1555, 1565 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_T11" } ] }, { "id": "8319574_E21", "type": "Regulation", "trigger": { "text": [ "autoregulation" ], "offsets": [ [ 1670, 1684 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_E22" } ] }, { "id": "8319574_E22", "type": "Transcription", "trigger": { "text": [ "transcriptional" ], "offsets": [ [ 1731, 1746 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8319574_T12" } ] } ]

[ { "id": "8319574_1", "entity_ids": [ "8319574_T2", "8319574_T3" ] } ]

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[ { "id": "9032403__text", "type": "abstract", "text": [ "Identification of nucleotide sequences that regulate transcription of the MCF13 murine leukemia virus long terminal repeat in activated T cells. \nThe region downstream of the enhancer (DEN) of the long terminal repeat of the mink cell focus-forming murine leukemia virus is important for viral pathogenicity. Another important activity of DEN is its control of transcription in activated T cells, and we have determined that an NF-kappaB site is critical for this activity. " ], "offsets": [ [ 0, 474 ] ] } ]

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[ { "id": "8645086__text", "type": "abstract", "text": [ "Heat shock induces HIV-1 replication in chronically infected promyelocyte cell line OM10.1. \nA long period of clinical latency before development of symptoms is characteristic of human immunodeficiency virus type 1 (HIV-1) infection. OM10.1, a promyelocyte cell line latently infected with HIV-1, has been developed as a model for studying the mechanism of viral latency and the activation of virus expression. We found that this latently infected cell line with heat shock at 42 degrees C for 2 h resulted in a high level of HIV-1 production without addition of any cytokines. The mechanism of activation was analyzed by using anti-TNF-alpha antibody and various inhibitors. Although the TNF-alpha level in culture supernatants was below the sensitivity of an ELISA assay system, addition of anti-TNF-alpha antibody in culture medium could partially suppress the heat shock induced HIV-1 production. Staurosporine (PKC inhibitor), pentoxifylline (NF-kappa B inhibitor), and Ro5-3335 (HIV-1 Tat inhibitor) also inhibited significantly the heat shock induced virus activation. In particular, staurosporine achieved approximately 90% inhibition of the HIV-1 antigen expression in heat shock-treated OM10.1 at a non-toxic concentration. Although the mechanism of HIV-1 activation with heat shock has not been fully elucidated yet, it is presumed PKC plays an important role in HIV-1 activation. Thus, the present observations will provide a further insight into the pathogenesis of HIV-1 infections. " ], "offsets": [ [ 0, 1497 ] ] } ]

[ { "id": "8645086_T1", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 633, 642 ] ], "normalized": [] }, { "id": "8645086_T2", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 689, 698 ] ], "normalized": [] }, { "id": "8645086_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 798, 807 ] ], "normalized": [] }, { "id": "8645086_T4", "type": "Protein", "text": [ "Tat" ], "offsets": [ [ 991, 994 ] ], "normalized": [] } ]

[ { "id": "8645086_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibitor" ], "offsets": [ [ 995, 1004 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8645086_T4" } ] } ]

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[ { "id": "7915519__text", "type": "abstract", "text": [ "Signals transduced through the CD4 molecule on T lymphocytes activate NF-kappa B. \nWe have demonstrated that native envelope glycoproteins of HIV-1, gp160 can induce activation of the transcription factor, NF-kappa B. The stimulatory effects of gp160 are mediated through the CD4 molecule, since pretreatment with soluble CD4 abrogates its activity. The gp160-induced NF-kappa B complex consists of p65, p50 and c-rel proteins. The stimulatory effect of gp160 on NF-kappa B activation is protein synthesis independent, is dependent upon protein tyrosine phosphorylation, and abrogated by inhibitors of protein kinase C. The gp160-mediated activation of NF-kappa B in CD4 positive T cells may be involved in biological effects, e.g., enhanced HIV replication, hypergammaglobulinemia, increased cytokine secretion, hypercellularity in bone marrow and apoptosis. " ], "offsets": [ [ 0, 860 ] ] } ]

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[ { "id": "7915519_E1", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 360, 367 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7915519_E2" }, { "role": "Cause", "ref_id": "7915519_T6" } ] }, { "id": "7915519_E2", "type": "Binding", "trigger": { "text": [ "complex" ], "offsets": [ [ 379, 386 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7915519_T7" }, { "role": "Theme", "ref_id": "7915519_T8" }, { "role": "Theme", "ref_id": "7915519_T9" } ] } ]

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[ { "id": "7629508__text", "type": "abstract", "text": [ "Functional roles of the transcription factor Oct-2A and the high mobility group protein I/Y in HLA-DRA gene expression. \nThe class II major histocompatibility complex gene HLA-DRA is expressed in B cells, activated T lymphocytes, and in antigen-presenting cells. In addition, HLA-DRA gene expression is inducible in a variety of cell types by interferon-gamma (IFN-gamma). Here we show that the lymphoid-specific transcription factor Oct-2A plays a critical role in HLA-DRA gene expression in class II-positive B cell lines, and that the high mobility group protein (HMG) I/Y binds to multiple sites within the DRA promoter, including the Oct-2A binding site. Coexpression of HMG I/Y and Oct-2 in cell lines lacking Oct-2 results in high levels of HLA-DRA gene expression, and in vitro DNA-binding studies reveal that HMG I/Y stimulates Oct-2A binding to the HLA-DRA promoter. Thus, Oct-2A and HMG I/Y may synergize to activate HLA-DRA expression in B cells. By contrast, Oct-2A is not involved in the IFN-gamma induction of the HLA-DRA gene in HeLa cells, but antisense HMG I/Y dramatically decreases the level of induction. We conclude that distinct sets of transcription factors are involved in the two modes of HLA-DRA expression, and that HMG I/Y may be important for B cell-specific expression, and is essential for IFN-gamma induction. " ], "offsets": [ [ 0, 1343 ] ] } ]

[ { "id": "7629508_T1", "type": "Protein", "text": [ "Oct-2A" ], "offsets": [ [ 45, 51 ] ], "normalized": [] }, { "id": "7629508_T2", "type": "Protein", "text": [ "I/Y" ], "offsets": [ [ 88, 91 ] ], "normalized": [] }, { "id": "7629508_T3", "type": "Protein", "text": [ "interferon-gamma" ], "offsets": [ [ 343, 359 ] ], "normalized": [] }, { "id": "7629508_T4", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 361, 370 ] ], "normalized": [] }, { "id": "7629508_T5", "type": "Protein", "text": [ "Oct-2A" ], "offsets": [ [ 434, 440 ] ], "normalized": [] }, { "id": "7629508_T6", "type": "Protein", "text": [ "I/Y" ], "offsets": [ [ 572, 575 ] ], "normalized": [] }, { "id": "7629508_T7", "type": "Protein", "text": [ "Oct-2A" ], "offsets": [ [ 639, 645 ] ], "normalized": [] }, { "id": "7629508_T8", "type": "Protein", "text": [ "I/Y" ], "offsets": [ [ 680, 683 ] ], "normalized": [] }, { "id": "7629508_T9", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 688, 693 ] ], "normalized": [] }, { "id": "7629508_T10", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 716, 721 ] ], "normalized": [] }, { "id": "7629508_T11", "type": "Protein", "text": [ "I/Y" ], "offsets": [ [ 822, 825 ] ], "normalized": [] }, { "id": "7629508_T12", "type": "Protein", "text": [ "Oct-2A" ], "offsets": [ [ 837, 843 ] ], "normalized": [] }, { "id": "7629508_T13", "type": "Protein", "text": [ "Oct-2A" ], "offsets": [ [ 883, 889 ] ], "normalized": [] }, { "id": "7629508_T14", "type": "Protein", "text": [ "I/Y" ], "offsets": [ [ 898, 901 ] ], "normalized": [] }, { "id": "7629508_T15", "type": "Protein", "text": [ "Oct-2A" ], "offsets": [ [ 972, 978 ] ], "normalized": [] }, { "id": "7629508_T16", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1002, 1011 ] ], "normalized": [] }, { "id": "7629508_T17", "type": "Protein", "text": [ "I/Y" ], "offsets": [ [ 1075, 1078 ] ], "normalized": [] }, { "id": "7629508_T18", "type": "Protein", "text": [ "I/Y" ], "offsets": [ [ 1248, 1251 ] ], "normalized": [] }, { "id": "7629508_T19", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1322, 1331 ] ], "normalized": [] } ]

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[ { "id": "7629508_1", "entity_ids": [ "7629508_T3", "7629508_T4" ] } ]

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[ { "id": "10206480__text", "type": "abstract", "text": [ "Amelioration of rat cerulein pancreatitis by guamerin-derived peptide, a novel elastase inhibitor. \nIncreased activity of various proteases is observed in both human and experimental pancreatitis; however, the information on the effects of specific protease inhibitors on the disease is limited. In this study we show that a novel elastase inhibitor, guamerin-derived synthetic peptide (GDSP), improves the parameters of cerulein-induced acute pancreatitis in the rat. The effects of GDSP on pancreatic weight, serum amylase and lipase, morphologic changes in the pancreas, neutrophil infiltration, and nuclear factor KB (NF-KB) activation were measured in rats infused with supramaximal dose of cerulein (5 (g/kg/h) for 6 h. The effects of GDSP were also measured on superoxide formation by activated human neutrophils. The effects of GDSP were compared with those of another elastase inhibitor, elastatinal. GDSP significantly inhibited edema formation, neutrophil infiltration, acinar cell damage, and plasma lipase and amylase increases caused by cerulein. GDSP also completely inhibited superoxide formation in the human neutrophils stimulated by N-formyl-methionine-leucine-phenyl-alanine (fMLP) or 12-O-tetradecanoylphorbol-13-acetate (TPA). Elastatinal had some of the same effects as GDSP but was less potent and effective. These results demonstrate a beneficial effect of GDSP, a novel specific elastase inhibitor, on the development of rat cerulein pancreatitis. " ], "offsets": [ [ 0, 1474 ] ] } ]

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[ { "id": "10228026__text", "type": "abstract", "text": [ "Thrombin-induced p65 homodimer binding to downstream NF-kappa B site of the promoter mediates endothelial ICAM-1 expression and neutrophil adhesion. \nWe investigated the mechanisms by which proinflammatory mediator, thrombin, released during intravascular coagulation and tissue injury, induces ICAM-1 (CD54) expression in endothelial cells. Stimulation of HUVEC with thrombin resulted in dose- and time-dependent increases in ICAM-1 mRNA and cell surface expression and in ICAM-1-dependent endothelial adhesivity toward polymorphonuclear leukocytes. Transient transfection of endothelial cells with ICAM-1 promoter luciferase reporter gene (ICAM-1LUC) constructs indicated that deletion of upstream NF-kappa B site (-533 bases from translation start site) had no effect on thrombin responsiveness, whereas mutation/deletion of downstream NF-kappa B site (-223 bases from the translation start site) prevented the activation of ICAM-1 promoter, indicating that the downstream NF-kappa B site is critical for thrombin inducibility. NF-kappa B-directed luciferase activity increased approximately 3-fold when cells transfected with the plasmid pNF-kappa BLUC containing five copies of consensus NF-kappa B site linked to a minimal adenovirus E1B promoter-luciferase gene were exposed to thrombin, indicating that activation of NF-kappa B was essential for thrombin response. Gel supershift assays demonstrated that thrombin induced binding of NF-kappa Bp65 (Rel A) to downstream NF-kappa B site of the ICAM-1 promoter. Thrombin receptor activation peptide, a 14-amino-acid peptide representing the new NH2 terminus of proteolytically activated receptor-1, mimicked thrombin's action in inducing ICAM-1 expression. These data indicate that thrombin activates endothelial ICAM-1 expression and polymorphonuclear leukocyte adhesion by NF-kappa Bp65 binding to the downstream NF-kappa B site of ICAM-1 promoter after proteolytically activated receptor-1 activation. " ], "offsets": [ [ 0, 1960 ] ] } ]

[ { "id": "10228026_T1", "type": "Protein", "text": [ "Thrombin" ], "offsets": [ [ 0, 8 ] ], "normalized": [] }, { "id": "10228026_T2", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 17, 20 ] ], "normalized": [] }, { "id": "10228026_T3", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 106, 112 ] ], "normalized": [] }, { "id": "10228026_T4", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 216, 224 ] ], "normalized": [] }, { "id": "10228026_T5", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 295, 301 ] ], "normalized": [] }, { "id": "10228026_T6", "type": "Protein", "text": [ "CD54" ], "offsets": [ [ 303, 307 ] ], "normalized": [] }, { "id": "10228026_T7", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 368, 376 ] ], "normalized": [] }, { "id": "10228026_T8", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 427, 433 ] ], "normalized": [] }, { "id": "10228026_T9", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 474, 480 ] ], "normalized": [] }, { "id": "10228026_T10", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 600, 606 ] ], "normalized": [] }, { "id": "10228026_T11", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 774, 782 ] ], "normalized": [] }, { "id": "10228026_T12", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 928, 934 ] ], "normalized": [] }, { "id": "10228026_T13", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1008, 1016 ] ], "normalized": [] }, { "id": "10228026_T14", "type": "Protein", "text": [ "E1B" ], "offsets": [ [ 1240, 1243 ] ], "normalized": [] }, { "id": "10228026_T15", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1285, 1293 ] ], "normalized": [] }, { "id": "10228026_T16", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1354, 1362 ] ], "normalized": [] }, { "id": "10228026_T17", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1413, 1421 ] ], "normalized": [] }, { "id": "10228026_T18", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1451, 1454 ] ], "normalized": [] }, { "id": "10228026_T19", "type": "Protein", "text": [ "Rel A" ], "offsets": [ [ 1456, 1461 ] ], "normalized": [] }, { "id": "10228026_T20", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1500, 1506 ] ], "normalized": [] }, { "id": "10228026_T21", "type": "Protein", "text": [ "Thrombin receptor" ], "offsets": [ [ 1517, 1534 ] ], "normalized": [] }, { "id": "10228026_T22", "type": "Protein", "text": [ "proteolytically activated receptor-1" ], "offsets": [ [ 1616, 1652 ] ], "normalized": [] }, { "id": "10228026_T23", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1663, 1671 ] ], "normalized": [] }, { "id": "10228026_T24", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1693, 1699 ] ], "normalized": [] }, { "id": "10228026_T25", "type": "Protein", "text": [ "thrombin" ], "offsets": [ [ 1737, 1745 ] ], "normalized": [] }, { "id": "10228026_T26", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1768, 1774 ] ], "normalized": [] }, { "id": "10228026_T27", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1840, 1843 ] ], "normalized": [] }, { "id": "10228026_T28", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1889, 1895 ] ], "normalized": [] }, { "id": "10228026_T29", "type": "Protein", "text": [ "proteolytically activated receptor-1" ], "offsets": [ [ 1911, 1947 ] ], "normalized": [] }, { "id": "10228026_T41", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 935, 943 ] ], "normalized": [] }, { "id": "10228026_T44", "type": "Entity", "text": [ "downstream NF-kappa B site" ], "offsets": [ [ 1466, 1492 ] ], "normalized": [] }, { "id": "10228026_T50", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1896, 1904 ] ], "normalized": [] } ]

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[ { "id": "10228026_1", "entity_ids": [ "10228026_T5", "10228026_T6" ] }, { "id": "10228026_2", "entity_ids": [ "10228026_T18", "10228026_T19" ] } ]

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[ { "id": "10430922__text", "type": "abstract", "text": [ "Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. \ncDNA microarrays and a clustering algorithm were used to identify patterns of gene expression in human mammary epithelial cells growing in culture and in primary human breast tumors. Clusters of coexpressed genes identified through manipulations of mammary epithelial cells in vitro also showed consistent patterns of variation in expression among breast tumor samples. By using immunohistochemistry with antibodies against proteins encoded by a particular gene in a cluster, the identity of the cell type within the tumor specimen that contributed the observed gene expression pattern could be determined. Clusters of genes with coherent expression patterns in cultured cells and in the breast tumors samples could be related to specific features of biological variation among the samples. Two such clusters were found to have patterns that correlated with variation in cell proliferation rates and with activation of the IFN-regulated signal transduction pathway, respectively. Clusters of genes expressed by stromal cells and lymphocytes in the breast tumors also were identified in this analysis. These results support the feasibility and usefulness of this systematic approach to studying variation in gene expression patterns in human cancers as a means to dissect and classify solid tumors. " ], "offsets": [ [ 0, 1390 ] ] } ]

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[ { "id": "7541794__text", "type": "abstract", "text": [ "Integrin-mediated tyrosine phosphorylation and cytokine message induction in monocytic cells. A possible signaling role for the Syk tyrosine kinase. \nActivation of cytoplasmic tyrosine kinases is an important aspect of signal transduction mediated by integrins. In the human monocytic cell line THP-1, either integrin-dependent cell adhesion to fibronectin or ligation of beta 1 integrins with antibodies causes a rapid and intense tyrosine phosphorylation of two sets of proteins of about 65-75 and 120-125 kDa. In addition, integrin ligation leads to nuclear translocation of the p50 and p65 subunits of the NF-kappa B transcription factor, to activation of a reporter gene driven by a promoter containing NF-kappa B sites, and to increased levels of mRNAs for immediate-early genes, including the cytokine interleukin (IL)-1 beta. The tyrosine kinase inhibitors genistein and herbimycin A block both integrin-mediated tyrosine phosphorylation and increases in IL-1 beta message levels, indicating a causal relationship between the two events. The components tyrosine phosphorylated subsequent to cell adhesion include paxillin, pp125FAK, and the SH2 domain containing tyrosine kinase Syk. In contrast, integrin ligation with antibodies induces tyrosine phosphorylation of Syk but not of FAK or paxillin. In adhering cells, pre-treatment with cytochalasin D suppresses tyrosine phosphorylation of FAK and paxillin but not of Syk, while IL-1 beta message induction is unaffected. These observations indicate that the Syk tyrosine kinase may be an important component of an integrin signaling pathway in monocytic cells, leading to activation of NF-kappa B and to increased levels of cytokine messages. " ], "offsets": [ [ 0, 1703 ] ] } ]

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"7541794_T8" }, { "role": "Site", "ref_id": "7541794_T28" } ] }, { "id": "7541794_E21", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1256, 1271 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7541794_T10" }, { "role": "Site", "ref_id": "7541794_T28" } ] }, { "id": "7541794_E22", "type": "Negative_regulation", "trigger": { "text": [ "suppresses" ], "offsets": [ [ 1360, 1370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7541794_E27" } ] }, { "id": "7541794_E23", "type": "Negative_regulation", "trigger": { "text": [ "suppresses" ], "offsets": [ [ 1360, 1370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7541794_E25" } ] }, { "id": "7541794_E24", "type": "Negative_regulation", "trigger": { "text": [ "suppresses" ], "offsets": [ [ 1360, 1370 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7541794_E26" } ] }, { "id": "7541794_E25", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1380, 1395 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7541794_T12" }, { "role": "Site", "ref_id": "7541794_T31" } ] }, { "id": "7541794_E26", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1380, 1395 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7541794_T8" }, { "role": "Site", "ref_id": "7541794_T31" } ] }, { "id": "7541794_E27", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1380, 1395 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7541794_T13" }, { "role": "Site", "ref_id": "7541794_T31" } ] }, { "id": "7541794_E28", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1456, 1465 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7541794_T14" } ] }, { "id": "7541794_E29", "type": "Regulation", "trigger": { "text": [ "unaffected" ], "offsets": [ [ 1469, 1479 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7541794_E28" } ] } ]

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[ { "id": "8933518__text", "type": "abstract", "text": [ "Tissue and cell-type specific expression of the tuberous sclerosis gene, TSC2, in human tissues. \nTSC2 is a gene on chromosome 16p13.3 associated with the autosomal dominant neurocutaneous disorder, tuberous sclerosis complex (TSC). By using a partial nucleotide sequence from the cloned TSC2 and polymerase chain reaction methodology, we constructed a digoxigenin-labeled complementary DNA probe to examine TSC2 gene expression in autopsy- or biopsy-derived human tissues by in situ hybridization. TSC2 messenger RNA was widely expressed in various cell types throughout the body, including epithelia, lymphocytes, and cells with endocrine functions, e.g., adrenal cortex and anterior pituitary. It was prominently and selectively (within the central nervous system) expressed in pyramidal cells of the cerebral cortex and other motor neurons, e.g., in spinal cord and brainstem nuclei. Visceral TSC2 expression was comparable in autopsy tissues from patients with and without TSC; TSC2 messenger RNA expression was most prominent in cells with a rapid mitotic rate and turnover, e.g., epithelia and lymphocytes, with central nervous system pyramidal cells and other neurons being an obvious exception, and/or in cells with important secretory/transport functions. This widespread expression of the TSC2 gene supports the view that it encodes a protein vital to cell growth and metabolism or one that functions as a tumor/growth suppressor. " ], "offsets": [ [ 0, 1442 ] ] } ]

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[ { "id": "1505523__text", "type": "abstract", "text": [ "TAR-independent transactivation by Tat in cells derived from the CNS: a novel mechanism of HIV-1 gene regulation. \nThe Tat protein of human immunodeficiency virus type 1 (HIV-1) is essential for productive infection and is a potential target for antiviral therapy. Tat, a potent activator of HIV-1 gene expression, serves to greatly increase the rate of transcription directed by the viral promoter. This induction, which seems to be an important component in the progression of acquired immune deficiency syndrome (AIDS), may be due to increased transcriptional initiation, increased transcriptional elongation, or a combination of these processes. Much attention has been focused on the interaction of Tat with a specific RNA target termed TAR (transactivation responsive) which is present in the leader sequence of all HIV-1 mRNAs. This interaction is believed to be an important component of the mechanism of transactivation. In this report we demonstrate that in certain CNS-derived cells Tat is capable of activating HIV-1 through a TAR-independent pathway. A Tat-responsive element is found upstream within the viral promoter that in glial-derived cell lines allows transactivation in the absence of TAR. Deletion mapping and hybrid promoter constructs demonstrate that the newly identified Tat-responsive element corresponds to a sequence within the viral long terminal repeat (LTR) previously identified as the HIV-1 enhancer, or NF-kappa B domain. DNA band-shift analysis reveals NF-kappa B binding activity in glial cells that differs from that present in T lymphoid cells. Further, we observe that TAR-deleted mutants of HIV-1 demonstrate normal late gene expression in glial cells as evidenced by syncytia formation and production of viral p24 antigen. (ABSTRACT TRUNCATED AT 250 WORDS) " ], "offsets": [ [ 0, 1800 ] ] } ]

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[ { "id": "9398404__text", "type": "abstract", "text": [ "IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral blood T lymphoblasts. \nDespite differences in T cell responses induced by interleukin (IL)-2 and IL-7, both cytokines modulate T cell functions by activation of signal transducers and activators of transcription (STAT) proteins. We examined the contribution of the two isoforms of STAT5, STAT5A and STAT5B, to IL-2- and IL-7-induced activation of human peripheral blood T lymphoblasts. Both cytokines induced assembly of STAT5A and STAT5B containing complexes capable of binding to the interferon-gamma activation sequence (GAS), and these complexes rapidly translocated (within 1 min) into the nucleus of IL-2- or IL-7-treated cells. The kinetics of this translocation were delayed in IL-7-treated as compared to IL-2-treated cells. IL-2 and IL-7 were equivalent in their ability to induce tyrosine phosphorylation of STAT5A and STAT5B and to facilitate binding of these STATs to an immobilized GAS element. Both IL-2 and IL-7 induced substantial amounts of STAT5A/STAT5B heterodimerization. Moreover, we observed constitutive association of STAT3 with each STAT5 isomer. These data suggest that IL-2 and IL-7 induce assembly of STAT heterodimers in a similar manner and that subsequent cellular responses may be driven by induction of similar sets of genes. " ], "offsets": [ [ 0, 1338 ] ] } ]

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{ "role": "Cause", "ref_id": "9398404_T16" } ] }, { "id": "9398404_E19", "type": "Positive_regulation", "trigger": { "text": [ "facilitate" ], "offsets": [ [ 922, 932 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9398404_E21" }, { "role": "Cause", "ref_id": "9398404_T16" } ] }, { "id": "9398404_E20", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 933, 940 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9398404_T17" } ] }, { "id": "9398404_E21", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 933, 940 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9398404_T18" } ] }, { "id": "9398404_E22", "type": "Binding", "trigger": { "text": [ "heterodimerization" ], "offsets": [ [ 1051, 1069 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9398404_T21" }, { "role": "Theme", "ref_id": "9398404_T22" } ] }, { "id": "9398404_E23", "type": "Binding", "trigger": { "text": [ "association" ], "offsets": [ [ 1106, 1117 ] ] }, "arguments": [ { 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[ { "id": "8758898__text", "type": "abstract", "text": [ "C/EBP activators are required for HIV-1 replication and proviral induction in monocytic cell lines. \nPrevious work has shown that C/EBP sites and C/EBP transcriptional activators are necessary for HIV-1 LTR activity in monocytes/macrophages. We have investigated the role that C/EBP proteins play in induction and replication of HIV-1. Ectopic expression of the dominant negative C/EBP protein LIP inhibited HIV-1 mRNA and virus production in activated U1 cells, demonstrating that C/EBP proteins are required for provirus induction. U1 lines overexpressing C/EBP activator NF-IL-6 produced more viral mRNA and virus particles following cellular activation than control lines, demonstrating that C/EBP proteins are limiting for virus transcription. HIV-1 harboring mutations within two C/EBP sites were crippled in their ability to replicate in U937 promonocytic cells, indicating that these sites are required for replication. These data identify C/EBP proteins as regulators of HIV-1 expression in monocytes/macrophages. " ], "offsets": [ [ 0, 1023 ] ] } ]

[ { "id": "8758898_T1", "type": "Protein", "text": [ "NF-IL-6" ], "offsets": [ [ 574, 581 ] ], "normalized": [] } ]

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[ { "id": "8628274__text", "type": "abstract", "text": [ "Inactivation of IkappaBbeta by the tax protein of human T-cell leukemia virus type 1: a potential mechanism for constitutive induction of NF-kappaB. \nIn resting T lymphocytes, the transcription factor NF-kappaB is sequestered in the cytoplasm via interactions with members of the I kappa B family of inhibitors, including IkappaBalpha and IkappaBbeta. During normal T-cell activation, IkappaBalpha is rapidly phosphorylated, ubiquitinated, and degraded by the 26S proteasome, thus permitting the release of functional NF-kappaB. In contrast to its transient pattern of nuclear induction during an immune response, NF-kappaB is constitutively activated in cells expressing the Tax transforming protein of human T-cell leukemia virus type I (HTLV-1). Recent studies indicate that HTLV-1 Tax targets IkappaBalpha to the ubiquitin-proteasome pathway. However, it remains unclear how this viral protein induces a persistent rather than transient NF-kappaB response. In this report, we provide evidence that in addition to acting on IkappaBalpha, Tax stimulates the turnover Of IkappaBbeta via a related targeting mechanism. Like IkappaBalpha, Tax-mediated breakdown of IkappaBbeta in transfected T lymphocytes is blocked either by cell-permeable proteasome inhibitors or by mutation Of IkappaBbeta at two serine residues present within its N-terminal region. Despite the dual specificity of HTLV-1 Tax for IkappaBalpha and IkappaBbeta at the protein level, Tax selectively stimulates NF-kappaB-directed transcription of the IkappaBalpha gene. Consequently, IkappaBbeta protein expression is chronically downregulated in HTLV-1-infected T lymphocytes. These findings with IkappaBbeta provide a potential mechanism for the constitutive activation of NF-kappaB in Tax-expressing cells. " ], "offsets": [ [ 0, 1778 ] ] } ]

[ { "id": "8628274_T1", "type": "Protein", "text": [ "IkappaBbeta" ], "offsets": [ [ 16, 27 ] ], "normalized": [] }, { "id": "8628274_T2", "type": "Protein", "text": [ "tax" ], "offsets": [ [ 35, 38 ] ], "normalized": [] }, { "id": "8628274_T3", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 322, 334 ] ], "normalized": [] }, { "id": "8628274_T4", "type": "Protein", "text": [ "IkappaBbeta" ], "offsets": [ [ 339, 350 ] ], "normalized": [] }, { "id": "8628274_T5", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 385, 397 ] ], "normalized": [] }, { "id": "8628274_T6", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 676, 679 ] ], "normalized": [] }, { "id": "8628274_T7", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 785, 788 ] ], "normalized": [] }, { "id": "8628274_T8", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 797, 809 ] ], "normalized": [] }, { "id": "8628274_T9", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 1027, 1039 ] ], "normalized": [] }, { "id": "8628274_T10", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 1041, 1044 ] ], "normalized": [] }, { "id": "8628274_T11", "type": "Protein", "text": [ "IkappaBbeta" ], "offsets": [ [ 1072, 1083 ] ], "normalized": [] }, { "id": "8628274_T12", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 1124, 1136 ] ], "normalized": [] }, { "id": "8628274_T13", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 1138, 1141 ] ], "normalized": [] }, { "id": "8628274_T14", "type": "Protein", "text": [ "IkappaBbeta" ], "offsets": [ [ 1164, 1175 ] ], "normalized": [] }, { "id": "8628274_T15", "type": "Protein", "text": [ "IkappaBbeta" ], "offsets": [ [ 1281, 1292 ] ], "normalized": [] }, { "id": "8628274_T16", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 1393, 1396 ] ], "normalized": [] }, { "id": "8628274_T17", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 1401, 1413 ] ], "normalized": [] }, { "id": "8628274_T18", "type": "Protein", "text": [ "IkappaBbeta" ], "offsets": [ [ 1418, 1429 ] ], "normalized": [] }, { "id": "8628274_T19", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 1452, 1455 ] ], "normalized": [] }, { "id": "8628274_T20", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 1519, 1531 ] ], "normalized": [] }, { "id": "8628274_T21", "type": "Protein", "text": [ "IkappaBbeta" ], "offsets": [ [ 1552, 1563 ] ], "normalized": [] }, { "id": "8628274_T22", "type": "Protein", "text": [ "IkappaBbeta" ], "offsets": [ [ 1666, 1677 ] ], "normalized": [] }, { "id": "8628274_T23", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 1756, 1759 ] ], "normalized": [] } ]

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[ { "id": "9616159__text", "type": "abstract", "text": [ "Inhibition of nuclear factor kappaB activation attenuates apoptosis resistance in lymphoid cells. \nDeath-inducing ligands (DILs) such as tumor necrosis factor alpha (TNFalpha) or the cytotoxic drug doxorubicin have been shown to activate a nuclear factor kappaB (NFkappaB)-dependent program that may rescue cells from apoptosis induction. We demonstrate here that TRAIL (TNF-related apoptosis-inducing ligand), a recently identified DIL, also activates NFkappaB in lymphoid cell lines in a kinetic similar to TNFalpha. NFkappaB activity is independent from FADD, caspases, and apoptosis induction. To study the influence of NFkappaB activity on apoptosis mediated by TRAIL, CD95, TNFalpha, or doxorubicin, NFkappaB activation was inhibited using the proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal or transient overexpression of mutant IkappaBalpha. Sensitivity for induction of apoptosis was markedly increased by these treatments in apoptosis sensitive cell lines. Moreover, both in cell lines and in primary leukemia cells that are resistant towards induction of apoptosis by DILs and doxorubicin, antagonization of NFkappaB activity partially restored apoptosis sensitivity. These data suggest that inhibition of NFkappaB activation may provide a molecular approach to increase apoptosis sensitivity in anticancer treatment. " ], "offsets": [ [ 0, 1347 ] ] } ]

[ { "id": "9616159_T1", "type": "Protein", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 137, 164 ] ], "normalized": [] }, { "id": "9616159_T2", "type": "Protein", "text": [ "TNFalpha" ], "offsets": [ [ 166, 174 ] ], "normalized": [] }, { "id": "9616159_T3", "type": "Protein", "text": [ "TRAIL" ], "offsets": [ [ 364, 369 ] ], "normalized": [] }, { "id": "9616159_T4", "type": "Protein", "text": [ "TNF-related apoptosis-inducing ligand" ], "offsets": [ [ 371, 408 ] ], "normalized": [] }, { "id": "9616159_T5", "type": "Protein", "text": [ "TNFalpha" ], "offsets": [ [ 509, 517 ] ], "normalized": [] }, { "id": "9616159_T6", "type": "Protein", "text": [ "FADD" ], "offsets": [ [ 557, 561 ] ], "normalized": [] }, { "id": "9616159_T7", "type": "Protein", "text": [ "TRAIL" ], "offsets": [ [ 667, 672 ] ], "normalized": [] }, { "id": "9616159_T8", "type": "Protein", "text": [ "CD95" ], "offsets": [ [ 674, 678 ] ], "normalized": [] }, { "id": "9616159_T9", "type": "Protein", "text": [ "TNFalpha" ], "offsets": [ [ 680, 688 ] ], "normalized": [] }, { "id": "9616159_T10", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 854, 866 ] ], "normalized": [] } ]

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[ { "id": "9616159_1", "entity_ids": [ "9616159_T1", "9616159_T2" ] }, { "id": "9616159_2", "entity_ids": [ "9616159_T3", "9616159_T4" ] } ]

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[ { "id": "1527859__text", "type": "abstract", "text": [ "Human immunodeficiency virus type 1 Nef protein inhibits NF-kappa B induction in human T cells. \nHuman immunodeficiency virus type 1 (HIV-1) can establish a persistent and latent infection in CD4+ T lymphocytes (W.C.Greene, N.Engl.J. Med.324:308-317, 1991; S.M.Schnittman, M.C.Psallidopoulos, H.C. Lane, L.Thompson, M.Baseler, F.Massari, C.H.Fox, N.P.Salzman, and A.S.Fauci, Science 245:305-308, 1989). Production of HIV-1 from latently infected cells requires host cell activation by T-cell mitogens (T.Folks, D.M.Powell, M.M.Lightfoote, S.Benn, M.A. Martin, and A.S.Fauci, Science 231:600-602, 1986; D.Zagury, J. Bernard, R.Leonard, R.Cheynier, M.Feldman, P.S.Sarin, and R.C. Gallo, Science 231:850-853, 1986). This activation is mediated by the host transcription factor NF-kappa B [G.Nabel and D.Baltimore, Nature (London) 326:711-717, 1987]. We report here that the HIV-1-encoded Nef protein inhibits the induction of NF-kappa B DNA-binding activity by T- cell mitogens. However, Nef does not affect the DNA-binding activity of other transcription factors implicated in HIV-1 regulation, including SP-1, USF, URS, and NF-AT. Additionally, Nef inhibits the induction of HIV-1- and interleukin 2-directed gene expression, and the effect on HIV-1 transcription depends on an intact NF-kappa B-binding site. These results indicate that defective recruitment of NF-kappa B may underlie Nef's negative transcriptional effects on the HIV-1 and interleukin 2 promoters. Further evidence suggests that Nef inhibits NF-kappa B induction by interfering with a signal derived from the T-cell receptor complex. " ], "offsets": [ [ 0, 1603 ] ] } ]

[ { "id": "1527859_T1", "type": "Protein", "text": [ "Nef" ], "offsets": [ [ 36, 39 ] ], "normalized": [] }, { "id": "1527859_T2", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 192, 195 ] ], "normalized": [] }, { "id": "1527859_T3", "type": "Protein", "text": [ "Nef" ], "offsets": [ [ 885, 888 ] ], "normalized": [] }, { "id": "1527859_T4", "type": "Protein", "text": [ "Nef" ], "offsets": [ [ 985, 988 ] ], "normalized": [] }, { "id": "1527859_T5", "type": "Protein", "text": [ "SP-1" ], "offsets": [ [ 1103, 1107 ] ], "normalized": [] }, { "id": "1527859_T6", "type": "Protein", "text": [ "Nef" ], "offsets": [ [ 1144, 1147 ] ], "normalized": [] }, { "id": "1527859_T7", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 1185, 1198 ] ], "normalized": [] }, { "id": "1527859_T8", "type": "Protein", "text": [ "Nef" ], "offsets": [ [ 1386, 1389 ] ], "normalized": [] }, { "id": "1527859_T9", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 1442, 1455 ] ], "normalized": [] }, { "id": "1527859_T10", "type": "Protein", "text": [ "Nef" ], "offsets": [ [ 1498, 1501 ] ], "normalized": [] }, { "id": "1527859_T15", "type": "Entity", "text": [ "promoters" ], "offsets": [ [ 1456, 1465 ] ], "normalized": [] } ]

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[ { "id": "2026605__text", "type": "abstract", "text": [ "Tissue-specific expression of the platelet GPIIb gene. \nOne of the major objectives in the study of thrombogenesis is to determine the mechanisms by which a hematopoietic progenitor is activated and committed to the megakaryocytic lineage. Recent development of primary cultures of human megakaryocytes and the molecular cloning of genes that are specific to this lineage offer the possibility of getting some insights into the genetic mechanisms that control megakaryocytopoiesis. One gene of interest is the glycoprotein IIb (GPIIb) gene; GPIIb, the alpha subunit of the platelet cytoadhesin GPIIb-IIIa, is produced in megakaryocytes at an early stage of the differentiation, whereas the other subunit of this complex, GPIIIa, is expressed in other cells. For these reasons, the 5'-flanking region of the GPIIb gene was used to identify the regions that interact with DNA-binding nuclear factors. A fragment extending from -643 to +33 is capable of controlling the tissue-specific expression of the CAT gene in transfection experiments. Within this region, we have identified several sequences that are implicated in DNA protein interactions as shown in DNAse I footprints and gel mobility shift assays. One region, centered at -54, is similar to a nuclear factor E1-binding site, and a region located at position -233 contains a CCAAT motif. Two domains centered at positions -345 and -540, respectively, bind proteins that are present in megakaryocytic cells and nonrelated cells as well. Finally, two other domains, located at positions -460 and -510, interact with proteins that are only present in megakaryocytic cells. In addition, deletion of the region containing these two domains results in a significant decrease of the promoter activity. It is very likely that these domains bind megakaryocyte-specific nuclear proteins acting as positive transcription factors. " ], "offsets": [ [ 0, 1876 ] ] } ]

[ { "id": "2026605_T1", "type": "Protein", "text": [ "GPIIb" ], "offsets": [ [ 43, 48 ] ], "normalized": [] }, { "id": "2026605_T2", "type": "Protein", "text": [ "glycoprotein IIb" ], "offsets": [ [ 510, 526 ] ], "normalized": [] }, { "id": "2026605_T3", "type": "Protein", "text": [ "GPIIb" ], "offsets": [ [ 528, 533 ] ], "normalized": [] }, { "id": "2026605_T4", "type": "Protein", "text": [ "GPIIb" ], "offsets": [ [ 541, 546 ] ], "normalized": [] }, { "id": "2026605_T5", "type": "Protein", "text": [ "GPIIIa" ], "offsets": [ [ 721, 727 ] ], "normalized": [] }, { "id": "2026605_T6", "type": "Protein", "text": [ "GPIIb" ], "offsets": [ [ 807, 812 ] ], "normalized": [] }, { "id": "2026605_T7", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 1001, 1004 ] ], "normalized": [] }, { "id": "2026605_T8", "type": "Protein", "text": [ "nuclear factor E1" ], "offsets": [ [ 1251, 1268 ] ], "normalized": [] }, { "id": "2026605_T12", "type": "Entity", "text": [ "5'-flanking region" ], "offsets": [ [ 781, 799 ] ], "normalized": [] } ]

[ { "id": "2026605_E1", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 16, 26 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2026605_T1" } ] }, { "id": "2026605_E2", "type": "Gene_expression", "trigger": { "text": [ "produced" ], "offsets": [ [ 609, 617 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2026605_T4" } ] }, { "id": "2026605_E3", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 732, 741 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2026605_T5" } ] }, { "id": "2026605_E4", "type": "Binding", "trigger": { "text": [ "interact" ], "offsets": [ [ 856, 864 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2026605_T6" }, { "role": "Site", "ref_id": "2026605_T12" } ] }, { "id": "2026605_E5", "type": "Regulation", "trigger": { "text": [ "capable of controlling" ], "offsets": [ [ 940, 962 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2026605_E6" } ] }, { "id": "2026605_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 983, 993 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2026605_T7" } ] } ]

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[ { "id": "9130512__text", "type": "abstract", "text": [ "Retinoic acid-induced modulation of IL-2 mRNA production and IL-2 receptor expression on T cells. \nBACKGROUND: Retinoic acid (RA) has important immune-modulating effects on both T and B cell function. Our laboratory has shown that RA can enhance in vitro polyclonal B cell immunoglobulin (Ig) response. Investigating cytokines known to affect B cell differentiation, we have recently shown that IL-6 production is augmented by RA. In the present study we have examined the immune modulating effects of RA on IL-2 mRNA, another important cytokine for B cell immunoglobulin production, the expression of IL-2 receptors on T cells, and the RA nuclear receptors. METHODS: Purified T cells were obtained from adenoidal tissues, and incubated with RA (10(-7) M) or DMSO solvent/media control for 0, 6-8, and 24 h. Total mRNA was extracted from T cells, and using RT-PCR, changes in the production of IL-2 and RA receptors (RAR)-alpha,beta,gamma mRNA were determined. The effects of RA on IL-2-alpha receptor expression was determined by flow cytometry on T cells. CONCLUSION: These studies suggest that RA can augment IL-2 mRNA production by T cells with a possible paracrine effect on IL-2R-alpha expression. These changes appear to be mediated by RAR-alpha. Thus, IL-2 may be another important cytokine modulated by RA in the immune response. " ], "offsets": [ [ 0, 1339 ] ] } ]

[ { "id": "9130512_T1", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 36, 40 ] ], "normalized": [] }, { "id": "9130512_T2", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 61, 65 ] ], "normalized": [] }, { "id": "9130512_T3", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 395, 399 ] ], "normalized": [] }, { "id": "9130512_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 508, 512 ] ], "normalized": [] }, { "id": "9130512_T5", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 602, 606 ] ], "normalized": [] }, { "id": "9130512_T6", "type": "Protein", "text": [ "RA receptors (RAR)-alpha" ], "offsets": [ [ 903, 927 ] ], "normalized": [] }, { "id": "9130512_T7", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 928, 932 ] ], "normalized": [] }, { "id": "9130512_T8", "type": "Protein", "text": [ "gamma" ], "offsets": [ [ 933, 938 ] ], "normalized": [] }, { "id": "9130512_T9", "type": "Protein", "text": [ "IL-2-alpha receptor" ], "offsets": [ [ 982, 1001 ] ], "normalized": [] }, { "id": "9130512_T10", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1112, 1116 ] ], "normalized": [] }, { "id": "9130512_T11", "type": "Protein", "text": [ "IL-2R-alpha" ], "offsets": [ [ 1180, 1191 ] ], "normalized": [] }, { "id": "9130512_T12", "type": "Protein", "text": [ "RAR-alpha" ], "offsets": [ [ 1243, 1252 ] ], "normalized": [] }, { "id": "9130512_T13", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1260, 1264 ] ], "normalized": [] } ]

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[ { "id": "8960365__text", "type": "abstract", "text": [ "A novel immunosuppressive factor in bovine colostrum blocks activation of the interleukin 2 gene enhancer at the NFAT site. \nA factor in bovine colostrum (colostrum inhibitory factor, CIF) inhibits interleukin 2 (IL2) production in activated T helper cells by blocking the accumulation of IL2 mRNA. To determine whether CIF blocks at the level of IL2 transcription, we introduced reporter plasmids into the human T leukemia cell line Jurkat by transient transfection. These contained the luciferase gene under the control of either the human IL2 upstream enhancer region (segments -326 to +45) or three repeats of the NFAT element contained within it (segments -255 to -285). Expression of luciferase in these cells was induced by phorbol myristate acetate plus a calcium ionophore. CIF inhibited induction of either construct as did cyclosporine, which is known to block activation of the NFAT element. CIF failed to inhibit several other enhancer elements. The NFAT-controlled luciferase gene system distinguishes CIF from other T cell inhibitory activities present in colostrum, in particular, TGF beta 1 and TGF beta 2 and the glucocorticoids. Stably transfected Jurkat cells behaved similarly to the transiently transfected ones with respect to inhibition by CIF and cyclosporine. The NFAT-luc assay is a useful technique for the rapid, sensitive measurement of CIF or other immunosuppressants with a similar mode of action. " ], "offsets": [ [ 0, 1430 ] ] } ]

[ { "id": "8960365_T1", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 78, 91 ] ], "normalized": [] }, { "id": "8960365_T2", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 198, 211 ] ], "normalized": [] }, { "id": "8960365_T3", "type": "Protein", "text": [ "IL2" ], "offsets": [ [ 213, 216 ] ], "normalized": [] }, { "id": "8960365_T4", "type": "Protein", "text": [ "IL2" ], "offsets": [ [ 289, 292 ] ], "normalized": [] }, { "id": "8960365_T5", "type": "Protein", "text": [ "IL2" ], "offsets": [ [ 347, 350 ] ], "normalized": [] }, { "id": "8960365_T6", "type": "Protein", "text": [ "IL2" ], "offsets": [ [ 542, 545 ] ], "normalized": [] }, { "id": "8960365_T7", "type": "Protein", "text": [ "TGF beta 1" ], "offsets": [ [ 1097, 1107 ] ], "normalized": [] }, { "id": "8960365_T8", "type": "Protein", "text": [ "TGF beta 2" ], "offsets": [ [ 1112, 1122 ] ], "normalized": [] }, { "id": "8960365_T11", "type": "Entity", "text": [ "enhancer" ], "offsets": [ [ 97, 105 ] ], "normalized": [] } ]

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[ { "id": "10209036__text", "type": "abstract", "text": [ "SHP2-interacting transmembrane adaptor protein (SIT), a novel disulfide-linked dimer regulating human T cell activation. \nT lymphocytes express several low molecular weight transmembrane adaptor proteins that recruit src homology (SH)2 domain-containing intracellular molecules to the cell membrane via tyrosine-based signaling motifs. We describe here a novel molecule of this group termed SIT (SHP2 interacting transmembrane adaptor protein). SIT is a disulfide-linked homodimeric glycoprotein that is expressed in lymphocytes. After tyrosine phosphorylation by src and possibly syk protein tyrosine kinases SIT recruits the SH2 domain-containing tyrosine phosphatase SHP2 via an immunoreceptor tyrosine-based inhibition motif. Overexpression of SIT in Jurkat cells downmodulates T cell receptor- and phytohemagglutinin-mediated activation of the nuclear factor of activated T cells (NF-AT) by interfering with signaling processes that are probably located upstream of activation of phospholipase C. However, binding of SHP2 to SIT is not required for inhibition of NF-AT induction, suggesting that SIT not only regulates NF-AT activity but also controls NF-AT unrelated pathways of T cell activation involving SHP2. " ], "offsets": [ [ 0, 1219 ] ] } ]

[ { "id": "10209036_T1", "type": "Protein", "text": [ "SHP2-interacting transmembrane adaptor protein" ], "offsets": [ [ 0, 46 ] ], "normalized": [] }, { "id": "10209036_T2", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 48, 51 ] ], "normalized": [] }, { "id": "10209036_T3", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 391, 394 ] ], "normalized": [] }, { "id": "10209036_T4", "type": "Protein", "text": [ "SHP2 interacting transmembrane adaptor protein" ], "offsets": [ [ 396, 442 ] ], "normalized": [] }, { "id": "10209036_T5", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 445, 448 ] ], "normalized": [] }, { "id": "10209036_T6", "type": "Protein", "text": [ "src" ], "offsets": [ [ 564, 567 ] ], "normalized": [] }, { "id": "10209036_T7", "type": "Protein", "text": [ "syk" ], "offsets": [ [ 581, 584 ] ], "normalized": [] }, { "id": "10209036_T8", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 610, 613 ] ], "normalized": [] }, { "id": "10209036_T9", "type": "Protein", "text": [ "SHP2" ], "offsets": [ [ 670, 674 ] ], "normalized": [] }, { "id": "10209036_T10", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 748, 751 ] ], "normalized": [] }, { "id": "10209036_T11", "type": "Protein", "text": [ "phytohemagglutinin" ], "offsets": [ [ 803, 821 ] ], "normalized": [] }, { "id": "10209036_T12", "type": "Protein", "text": [ "SHP2" ], "offsets": [ [ 1022, 1026 ] ], "normalized": [] }, { "id": "10209036_T13", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 1030, 1033 ] ], "normalized": [] }, { "id": "10209036_T14", "type": "Protein", "text": [ "SIT" ], "offsets": [ [ 1101, 1104 ] ], "normalized": [] }, { "id": "10209036_T15", "type": "Protein", "text": [ "SHP2" ], "offsets": [ [ 1213, 1217 ] ], "normalized": [] }, { "id": "10209036_T17", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 536, 544 ] ], "normalized": [] } ]

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[ { "id": "10209036_1", "entity_ids": [ "10209036_T1", "10209036_T2" ] }, { "id": "10209036_2", "entity_ids": [ "10209036_T3", "10209036_T4" ] } ]

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[ { "id": "2127692__text", "type": "abstract", "text": [ "Transcriptional down-regulation of c-myc expression by protein synthesis-dependent and -independent pathways in a human T lymphoblastic tumor cell line. \nWe show that in the human T lymphoblastic tumor cell line Molt4 c-myc mRNA and protein expression is down-regulated after exposure to dimethyl sulfoxide, to phorbol myristate acetate, or to the calcium ionophore A23187, which raises the intracellular calcium concentration. A block to RNA elongation is largely responsible for decreased c-myc transcription. Although negative regulation by dimethyl sulfoxide takes place even when protein synthesis is inhibited by cycloheximide, the phorbol myristate acetate effect is blocked to some extent only by cycloheximide. The calcium ionophore-induced c-myc suppression, however, strictly requires de novo protein synthesis. Therefore, two different negative regulatory pathways are involved in c-myc regulation: one which is independent and one which depends on de novo protein synthesis. The latter one appears to be mediated by a rapidly calcium-dependent induced gene product. " ], "offsets": [ [ 0, 1079 ] ] } ]

[ { "id": "2127692_T1", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 35, 40 ] ], "normalized": [] }, { "id": "2127692_T2", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 218, 223 ] ], "normalized": [] }, { "id": "2127692_T3", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 491, 496 ] ], "normalized": [] }, { "id": "2127692_T4", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 750, 755 ] ], "normalized": [] }, { "id": "2127692_T5", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 893, 898 ] ], "normalized": [] } ]

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[ { "id": "9716600__text", "type": "abstract", "text": [ "Retinoic acid inhibits CD40 + interleukin-4-mediated IgE production in vitro. \nTo elucidate the role of retinoic acid (RA) in anti-CD40 + interleukin-4 (IL-4)-mediated B-cell activation, the effect of 10(-12) to 10(-6) mol/L RA was studied in anti-CD40 (1 microgram/mL) + IL-4 (5 ng/mL)-mediated proliferation and Ig synthesis by human peripheral blood mononuclear cells (PBMC) and B cells in healthy donors. Anti-CD40 + IL-4-mediated proliferation of PBMC and B cells was inhibited by RA in a dose-dependent manner, with maximal inhibition of 62% +/- 5% in PBMC and 55% +/- 4.4% in B cells by all-trans RA, and 58% +/- 6.7% and 51% +/- 4.7%, respectively by 13-cis RA. IgE synthesis was even more markedly inhibited by RA starting at concentrations of >10(-14) mol/L for B cells and >10(-10) mol/L for PBMC. Maximal inhibition of IgE production for B cells was at 10(-8) mol/L for all-trans RA (94% +/- 1.8%) and 96% +/- 3.2% for 13-cis RA. Low concentrations of RA inhibiting IgE synthesis (10(-10) mol/L) affected neither B-cell proliferation nor the production of IgA, IgG, and IgM. Elucidation of the mechanism involved in this inhibition of IgE production shows that epsilon germline transcription is decreased by RA, whereas production of interferon-gamma (IFN-gamma) was not enhanced in the presence of RA. To differentiate whether the RA effect was mediated by RA receptors alpha, beta, and gamma, the expression of the retinoic acid receptors (RAR) was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). The data show that unstimulated human peripheral B cells express mRNA of the RA receptor alpha, beta, and gamma. Using retinoids with different receptor binding specificity (CD336, CD437, CD2019, CD367), dose-dependent inhibition of IgE synthesis was shown by all four derivates, but was most marked by an RA binding the alpha receptor with high specificity. Taken together, this study shows that RA inhibits IgE production of anti-CD40 + IL-4-stimulated B cells in vitro. Copyright 1998 by The American Society of Hematology. " ], "offsets": [ [ 0, 2060 ] ] } ]

[ { "id": "9716600_T1", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 23, 27 ] ], "normalized": [] }, { "id": "9716600_T2", "type": "Protein", "text": [ "interleukin-4" ], "offsets": [ [ 30, 43 ] ], "normalized": [] }, { "id": "9716600_T3", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 131, 135 ] ], "normalized": [] }, { "id": "9716600_T4", "type": "Protein", "text": [ "interleukin-4" ], "offsets": [ [ 138, 151 ] ], "normalized": [] }, { "id": "9716600_T5", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 153, 157 ] ], "normalized": [] }, { "id": "9716600_T6", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 248, 252 ] ], "normalized": [] }, { "id": "9716600_T7", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 272, 276 ] ], "normalized": [] }, { "id": "9716600_T8", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 414, 418 ] ], "normalized": [] }, { "id": "9716600_T9", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 421, 425 ] ], "normalized": [] }, { "id": "9716600_T10", "type": "Protein", "text": [ "interferon-gamma" ], "offsets": [ [ 1246, 1262 ] ], "normalized": [] }, { "id": "9716600_T11", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1264, 1273 ] ], "normalized": [] }, { "id": "9716600_T12", "type": "Protein", "text": [ "RA receptors alpha" ], "offsets": [ [ 1370, 1388 ] ], "normalized": [] }, { "id": "9716600_T13", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 1390, 1394 ] ], "normalized": [] }, { "id": "9716600_T14", "type": "Protein", "text": [ "gamma" ], "offsets": [ [ 1400, 1405 ] ], "normalized": [] }, { "id": "9716600_T15", "type": "Protein", "text": [ "RA receptor alpha" ], "offsets": [ [ 1610, 1627 ] ], "normalized": [] }, { "id": "9716600_T16", "type": "Protein", "text": [ "beta" ], "offsets": [ [ 1629, 1633 ] ], "normalized": [] }, { "id": "9716600_T17", "type": "Protein", "text": [ "gamma" ], "offsets": [ [ 1639, 1644 ] ], "normalized": [] }, { "id": "9716600_T18", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 1965, 1969 ] ], "normalized": [] }, { "id": "9716600_T19", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1972, 1976 ] ], "normalized": [] } ]

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[ { "id": "1419905__text", "type": "abstract", "text": [ "Activation of NF-kappa B by interleukin 2 in human blood monocytes. \nWe report here that interleukin 2 (IL-2) acts on human blood monocytes by enhancing binding activity of the transcription factor NF-kappa B to its consensus sequence in the 5' regulatory enhancer region of the IL-2 receptor alpha chain (p55). Similarly, IL-2 activates NF-kappa B in the human monocytic cell line U 937, but not in resting human T-cells. This effect is detectable within 15 min and peaks 1 h after exposure to IL-2. Enhanced NF-kappa B binding activity is followed by functional activation in that inducibility of the IL-2 receptor alpha chain is mediated by enhanced NF-kappa B binding and that a heterologous promoter containing the NF-kappa B consensus sequence (-291 to -245) of the IL-2 receptor alpha chain gene is activated. In addition, IL-2 is capable of increasing transcript levels of the p50 gene coding for the p50 subunit of the NF-kappa B transcription factor, whereas mRNA levels of the p65 NF-kappa B gene remained unchanged. " ], "offsets": [ [ 0, 1028 ] ] } ]

[ { "id": "1419905_T1", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 28, 41 ] ], "normalized": [] }, { "id": "1419905_T2", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 89, 102 ] ], "normalized": [] }, { "id": "1419905_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 104, 108 ] ], "normalized": [] }, { "id": "1419905_T4", "type": "Protein", "text": [ "IL-2 receptor alpha chain" ], "offsets": [ [ 279, 304 ] ], "normalized": [] }, { "id": "1419905_T5", "type": "Protein", "text": [ "p55" ], "offsets": [ [ 306, 309 ] ], "normalized": [] }, { "id": "1419905_T6", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 323, 327 ] ], "normalized": [] }, { "id": "1419905_T7", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 495, 499 ] ], "normalized": [] }, { "id": "1419905_T8", "type": "Protein", "text": [ "IL-2 receptor alpha chain" ], "offsets": [ [ 603, 628 ] ], "normalized": [] }, { "id": "1419905_T9", "type": "Protein", "text": [ "IL-2 receptor alpha chain" ], "offsets": [ [ 772, 797 ] ], "normalized": [] }, { "id": "1419905_T10", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 830, 834 ] ], "normalized": [] }, { "id": "1419905_T11", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 885, 888 ] ], "normalized": [] }, { "id": "1419905_T12", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 909, 912 ] ], "normalized": [] }, { "id": "1419905_T13", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 988, 991 ] ], "normalized": [] } ]

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[ { "id": "1851743__text", "type": "abstract", "text": [ "Inhibition of protein phosphatases by okadaic acid induces AP1 in human T cells. \nTo examine the role of protein phosphatases in T cell activation, Jurkat cells were treated with okadaic acid, an inhibitor of type 1 and 2A phosphatases, and nuclear extracts were examined for the presence of AP1 as a measure of early T cell activation. Okadaic acid was found to be a potent inducer of AP1. In contrast to phorbol esters such as phorbol myristate acetate (PMA), the induction of AP1 by okadaic acid occurs predominantly by transcriptional activation of the jun and fos family of proto-oncogenes. Surprisingly, while the addition of phytohemagglutinin further enhanced the induction of AP1, the addition of PMA inhibited it. Okadaic acid treatment was found to dramatically increase mRNA transcripts of the jun family of proto-oncogenes including c-jun, junD, and junB and to a lesser extent the fos family including c-fos and fra-1. By comparison, PMA is a very inefficient inducer of the jun gene family in Jurkat cells. Similar to its effect on the induction of AP1 by okadaic acid, PMA inhibits the induction of c-jun mRNA by okadaic acid. Transfection of c-jun promoter constructs confirmed the marked difference between PMA and okadaic acid in inducing c-jun transcription. The induction of AP1 by okadaic acid suggests that protein phosphatases 1 and 2A (PP1 and PP2A) may be involved in T cell activation as important negative regulators of the transcription factor AP1. " ], "offsets": [ [ 0, 1478 ] ] } ]

[ { "id": "1851743_T1", "type": "Protein", "text": [ "phytohemagglutinin" ], "offsets": [ [ 632, 650 ] ], "normalized": [] }, { "id": "1851743_T2", "type": "Protein", "text": [ "c-jun" ], "offsets": [ [ 846, 851 ] ], "normalized": [] }, { "id": "1851743_T3", "type": "Protein", "text": [ "junD" ], "offsets": [ [ 853, 857 ] ], "normalized": [] }, { "id": "1851743_T4", "type": "Protein", "text": [ "junB" ], "offsets": [ [ 863, 867 ] ], "normalized": [] }, { "id": "1851743_T5", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 916, 921 ] ], "normalized": [] }, { "id": "1851743_T6", "type": "Protein", "text": [ "fra-1" ], "offsets": [ [ 926, 931 ] ], "normalized": [] }, { "id": "1851743_T7", "type": "Protein", "text": [ "c-jun" ], "offsets": [ [ 1115, 1120 ] ], "normalized": [] }, { "id": "1851743_T8", "type": "Protein", "text": [ "c-jun" ], "offsets": [ [ 1159, 1164 ] ], "normalized": [] }, { "id": "1851743_T9", "type": "Protein", "text": [ "c-jun" ], "offsets": [ [ 1258, 1263 ] ], "normalized": [] }, { "id": "1851743_T10", "type": "Protein", "text": [ "protein phosphatases 1" ], "offsets": [ [ 1330, 1352 ] ], "normalized": [] }, { "id": "1851743_T11", "type": "Protein", "text": [ "2A" ], "offsets": [ [ 1357, 1359 ] ], "normalized": [] } ]

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[ { "id": "7730624__text", "type": "abstract", "text": [ "Activation of transcription by binding of NF-E1 (YY1) to a newly identified element in the first exon of the human DR alpha gene. \nA previously unrecognized element, located downstream of the start site of transcription in the first exon of the DR alpha gene, has been defined that enhances promoter activity up to eightfold in a position-dependent manner. Mutations in this DNA-binding site abolished binding of a nuclear factor in human B cell nuclear extract and decreased the activity of the DR alpha promoter to a basal level. Significant sequence homology of this element was found in the DNA of the DR beta, DP alpha and -beta, and DQ alpha genes, always located downstream of the transcriptional start site. The nuclear factor binds to the DR alpha and DP alpha element but not to the element in the DQ alpha gene. It was identified as NF-E1 (YY1). This protein, previously identified by its binding to the Ig kappa 3' enhancer and the Ig heavy chain mu E1 site, thus also appears to be quite important in the regulation of MHC class II gene expression. " ], "offsets": [ [ 0, 1062 ] ] } ]

[ { "id": "7730624_T1", "type": "Protein", "text": [ "NF-E1" ], "offsets": [ [ 42, 47 ] ], "normalized": [] }, { "id": "7730624_T2", "type": "Protein", "text": [ "YY1" ], "offsets": [ [ 49, 52 ] ], "normalized": [] }, { "id": "7730624_T3", "type": "Protein", "text": [ "DR alpha" ], "offsets": [ [ 115, 123 ] ], "normalized": [] }, { "id": "7730624_T4", "type": "Protein", "text": [ "DR alpha" ], "offsets": [ [ 245, 253 ] ], "normalized": [] }, { "id": "7730624_T5", "type": "Protein", "text": [ "DR alpha" ], "offsets": [ [ 496, 504 ] ], "normalized": [] }, { "id": "7730624_T6", "type": "Protein", "text": [ "DR beta" ], "offsets": [ [ 606, 613 ] ], "normalized": [] }, { "id": "7730624_T7", "type": "Protein", "text": [ "DQ alpha" ], "offsets": [ [ 639, 647 ] ], "normalized": [] }, { "id": "7730624_T8", "type": "Protein", "text": [ "DR alpha" ], "offsets": [ [ 748, 756 ] ], "normalized": [] }, { "id": "7730624_T9", "type": "Protein", "text": [ "DP alpha" ], "offsets": [ [ 761, 769 ] ], "normalized": [] }, { "id": "7730624_T10", "type": "Protein", "text": [ "DQ alpha" ], "offsets": [ [ 808, 816 ] ], "normalized": [] }, { "id": "7730624_T11", "type": "Protein", "text": [ "NF-E1" ], "offsets": [ [ 844, 849 ] ], "normalized": [] }, { "id": "7730624_T12", "type": "Protein", "text": [ "YY1" ], "offsets": [ [ 851, 854 ] ], "normalized": [] }, { "id": "7730624_T15", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 505, 513 ] ], "normalized": [] }, { "id": "7730624_T17", "type": "Entity", "text": [ "element" ], "offsets": [ [ 793, 800 ] ], "normalized": [] } ]

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[ { "id": "9348104__text", "type": "abstract", "text": [ "Helenalin, an anti-inflammatory sesquiterpene lactone from Arnica, selectively inhibits transcription factor NF-kappaB [see comments] \nAlcoholic extracts prepared form Arnicae flos, the collective name for flowerheads from Arnica montana and A. chamissonis ssp. foliosa, are used therapeutically as anti-inflammatory remedies. The active ingredients mediating the pharmacological effect are mainly sesquiterpene lactones, such as helenalin, 11alpha,13-dihydrohelenalin, chamissonolid and their ester derivatives. While these compounds affect various cellular processes, current data do not fully explain how sesquiterpene lactones exert their anti-inflammatory effect. We show here that helenalin, and, to a much lesser degree, 11alpha,13-dihydrohelenalin and chamissonolid, inhibit activation of transcription factor NF-kappaB. This difference in efficacy, which correlates with the compounds' anti-inflammatory potency in vivo, may be explained by differences in structure and conformation. NF-kappaB, which resides in an inactive, cytoplasmic complex in unstimulated cells, is activated by phosphorylation and degradation of its inhibitory subunit, IkappaB. Helenalin inhibits NF-kappaB activation in response to four different stimuli in T-cells, B-cells and epithelial cells and abrogates kappaB-driven gene expression. This inhibition is selective, as the activity of four other transcription factors, Oct-1, TBP, Sp1 and STAT 5 was not affected. We show that inhibition is not due to a direct modification of the active NF-kappaB heterodimer. Rather, helenalin modifies the NF-kappaB/IkappaB complex, preventing the release of IkappaB. These data suggest a molecular mechanism for the anti-inflammatory effect of sesquiterpene lactones, which differs from that of other nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin and acetyl salicylic acid. " ], "offsets": [ [ 0, 1864 ] ] } ]

[ { "id": "9348104_T1", "type": "Protein", "text": [ "Oct-1" ], "offsets": [ [ 1408, 1413 ] ], "normalized": [] }, { "id": "9348104_T2", "type": "Protein", "text": [ "TBP" ], "offsets": [ [ 1415, 1418 ] ], "normalized": [] }, { "id": "9348104_T3", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1420, 1423 ] ], "normalized": [] } ]

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[ { "id": "8039243__text", "type": "abstract", "text": [ "Long-term inositol phosphate release, but not tyrosine kinase activity, correlates with IL-2 secretion and NF-AT induction in anti-CD3-activated peripheral human T lymphocytes. \nThe cascade of events within the first few minutes of T cell stimulation has been well characterized. Although many second messengers have been shown to be necessary and sufficient for T cell activation in a number of model systems, the rate-limiting step in peripheral T cells has not been demonstrated. To model effective versus ineffective CD3-mediated stimulation in peripheral T cells, we used two anti-CD3 mAbs that differ in their ability to stimulate purified T cells: OKT3, which causes early second messenger generation but is unable to activate T cells without a second signal, and 64.1, which stimulates T cell proliferation on its own. We found that tyrosine kinase activity was similar for both mAbs over a period of hours. However, the inositol phosphate response was stronger for 64.1 than for OKT3. To tie these events to gene activation, we measured NF-kappa B and NF-AT activity in the nucleus after anti-CD3 stimulation. Both stimuli induced the appearance of the NF-kappa B components (c-Rel, p65 (RelA), and p50 (NF-kappa B1)) and NF-kappa B DNA binding activity in the nucleus. However, only 64.1 induced NF-AT in the nucleus, correlating with its ability to activate T cells. Thus, NF-AT induction and IL-2 secretion were correlated with the levels of inositol phosphate release but not with gross levels of tyrosine kinase activity induced late following the response. On the other hand, NF-kappa B induction and IL-2 receptor expression occurred even with the smaller second messenger response generated by OKT3. " ], "offsets": [ [ 0, 1717 ] ] } ]

[ { "id": "8039243_T1", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 88, 92 ] ], "normalized": [] }, { "id": "8039243_T2", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 1185, 1190 ] ], "normalized": [] }, { "id": "8039243_T3", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1192, 1195 ] ], "normalized": [] }, { "id": "8039243_T4", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 1197, 1201 ] ], "normalized": [] }, { "id": "8039243_T5", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1208, 1211 ] ], "normalized": [] }, { "id": "8039243_T6", "type": "Protein", "text": [ "NF-kappa B1" ], "offsets": [ [ 1213, 1224 ] ], "normalized": [] }, { "id": "8039243_T7", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1404, 1408 ] ], "normalized": [] }, { "id": "8039243_T12", "type": "Entity", "text": [ "nucleus" ], "offsets": [ [ 1270, 1277 ] ], "normalized": [] } ]

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[ { "id": "8634413__text", "type": "abstract", "text": [ "STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients. \nA signal transduction pathway activated by many cytokines has recently been elaborated. The JAK kinases and the signal transducers and activators of transcription (STAT) factors have been found to be essential components. In this report, we describe the presence of constitutively activated STAT factors in peripheral blood cells from patients with acute leukemia. We used oligonucleotide probes from the beta-casein and IRF-1 gene promoters and the ISRE probe to detect STAT proteins in nuclear extracts from acute leukemia cells in bandshift assays. Specific DNA protein complex formation was observed with the probes from the beta-casein and IRF-1 gene promoters, but not with the ISRE oligonucleotide probe, when cell extracts from acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were investigated. We used nonradioactive oligonucleotides as competitors to show the specificity of the complex formation. Specific antibodies directed against the individual STAT proteins were used in supershift experiments. STAT5- and STAT1-related factors were detected in ALL and STAT1-, STAT3-, and STAT5-related proteins were present in nuclear cell extracts from AML. Since the cells were not treated with cytokines before the nuclear proteins were extracted, we conclude that these factors are constitutively activated in vivo. It is likely that the constitutive activation of STAT proteins is a part of the events of leukemogenesis. " ], "offsets": [ [ 0, 1568 ] ] } ]

[ { "id": "8634413_T1", "type": "Protein", "text": [ "beta-casein" ], "offsets": [ [ 526, 537 ] ], "normalized": [] }, { "id": "8634413_T2", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 542, 547 ] ], "normalized": [] }, { "id": "8634413_T3", "type": "Protein", "text": [ "beta-casein" ], "offsets": [ [ 750, 761 ] ], "normalized": [] }, { "id": "8634413_T4", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 766, 771 ] ], "normalized": [] }, { "id": "8634413_T5", "type": "Protein", "text": [ "STAT5" ], "offsets": [ [ 1152, 1157 ] ], "normalized": [] }, { "id": "8634413_T6", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1163, 1168 ] ], "normalized": [] }, { "id": "8634413_T7", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1210, 1215 ] ], "normalized": [] }, { "id": "8634413_T8", "type": "Protein", "text": [ "STAT3" ], "offsets": [ [ 1218, 1223 ] ], "normalized": [] }, { "id": "8634413_T9", "type": "Protein", "text": [ "STAT5" ], "offsets": [ [ 1230, 1235 ] ], "normalized": [] }, { "id": "8634413_T11", "type": "Entity", "text": [ "promoters" ], "offsets": [ [ 777, 786 ] ], "normalized": [] } ]

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[ { "id": "10233947__text", "type": "abstract", "text": [ "Immortalization of CD4(+) and CD8(+) T lymphocytes by human T-cell leukemia virus type 1 Tax mutants expressed in a functional molecular clone. \nThe human T-cell leukemia virus type 1 (HTLV-1) transcriptional trans-activator Tax has been demonstrated to have transforming activity in multiple cell culture and transgenic-mouse models. In addition to activating transcription from the viral long terminal repeat (LTR) through the cyclic AMP response element binding protein/activating transcription factor (CREB/ATF) family of transcription factors, Tax activates the expression of multiple cellular promoters through the NF-kappaB pathway of transcriptional activation. The Tax mutants M22 and M47 have previously been demonstrated to selectively abrogate the ability of Tax to activate transcription through the NF-kappaB or CREB/ATF pathway, respectively. These mutations were introduced in the tax gene of the ACH functional molecular clone of HTLV-1, and virus produced from the mutant ACH clones was examined for the ability to replicate and immortalize primary human lymphocytes. While virus derived from the clone containing the M47 mutation retained the ability to immortalize T lymphocytes, the M22 mutant lost the ability to immortalize infected cells. These results indicate that activation of the CREB/ATF pathway by Tax is dispensable for the immortalization of T cells by HTLV-1, whereas activation of the NF-kappaB pathway may be critical. " ], "offsets": [ [ 0, 1455 ] ] } ]

[ { "id": "10233947_T1", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 19, 22 ] ], "normalized": [] }, { "id": "10233947_T2", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 89, 92 ] ], "normalized": [] }, { "id": "10233947_T3", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 225, 228 ] ], "normalized": [] }, { "id": "10233947_T4", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 549, 552 ] ], "normalized": [] }, { "id": "10233947_T5", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 674, 677 ] ], "normalized": [] }, { "id": "10233947_T6", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 771, 774 ] ], "normalized": [] }, { "id": "10233947_T7", "type": "Protein", "text": [ "tax" ], "offsets": [ [ 897, 900 ] ], "normalized": [] }, { "id": "10233947_T8", "type": "Protein", "text": [ "Tax" ], "offsets": [ [ 1329, 1332 ] ], "normalized": [] } ]

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[ { "id": "8631821__text", "type": "abstract", "text": [ "Structural and functional characterization of the human CD36 gene promoter: identification of a proximal PEBP2/CBF site. \nCD36 is a cell surface glycoprotein composed of a single polypeptide chain, which interacts with thrombospondin, collagens type I and IV, oxidized low density lipoprotein, fatty acids, anionic phospholipids, and erythrocytes parasitized with Plasmodium falciparum. Its expression is restricted to a few cell types, including monocyte/macrophages. In these cells, CD36 is involved in phagocytosis of apoptotic cells, and foam cell formation by uptake of oxidized low density lipoprotein. To study the molecular mechanisms that control the transcription of the CD36 gene in monocytic cells we have isolated and analyzed the CD36 promoter. Transient expression experiments of 5'-deletion fragments of the CD36 promoter coupled to luciferase demonstrated that as few as 158 base pairs upstream from the transcription initiation site were sufficient to direct the monocyte-specific transcription of the reporter gene. Within the above region, the fragment spanning nucleotides -158 to -90 was required for optimal transcription in monocytic cells. Biochemical analysis of the region -158/-90 revealed a binding site for transcription factors of the polyomavirus enhancer-binding protein 2/core-binding factor (PEBP2/CBF) family at position -103. Disruption of the PEBP2/CBF site markedly diminished the role of the PEBP2/CBF factors in the constitutive transcription of the CD36 gene. The involvement of members of the PEBP2/CBF family in chromosome translocations associated with acute myeloid leukemia, and in the transcriptional regulation of the myeloid-specific genes encoding for myeloperoxidase, elastase, and the colony-stimulating factor receptor, highlights the relevance of the regulation of the CD36 gene promoter in monocytic cells by members of the PEBP2/CBF family. " ], "offsets": [ [ 0, 1898 ] ] } ]

[ { "id": "8631821_T1", "type": "Protein", "text": [ "CD36" ], "offsets": [ [ 56, 60 ] ], "normalized": [] }, { "id": "8631821_T2", "type": "Protein", "text": [ "CD36" ], "offsets": [ [ 122, 126 ] ], "normalized": [] }, { "id": "8631821_T3", "type": "Protein", "text": [ "CD36" ], "offsets": [ [ 485, 489 ] ], "normalized": [] }, { "id": "8631821_T4", "type": "Protein", "text": [ "CD36" ], "offsets": [ [ 681, 685 ] ], "normalized": [] }, { "id": "8631821_T5", "type": "Protein", "text": [ "CD36" ], "offsets": [ [ 744, 748 ] ], "normalized": [] }, { "id": "8631821_T6", "type": "Protein", "text": [ "CD36" ], "offsets": [ [ 824, 828 ] ], "normalized": [] }, { "id": "8631821_T7", "type": "Protein", "text": [ "CD36" ], "offsets": [ [ 1491, 1495 ] ], "normalized": [] }, { "id": "8631821_T8", "type": "Protein", "text": [ "myeloperoxidase" ], "offsets": [ [ 1703, 1718 ] ], "normalized": [] }, { "id": "8631821_T9", "type": "Protein", "text": [ "CD36" ], "offsets": [ [ 1824, 1828 ] ], "normalized": [] }, { "id": "8631821_T19", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1834, 1842 ] ], "normalized": [] } ]

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[ { "id": "8663060__text", "type": "abstract", "text": [ "Tissue-specific activity of the gammac chain gene promoter depends upon an Ets binding site and is regulated by GA-binding protein. \nThe gammac chain is a subunit of multiple cytokine receptors (interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15), the expression of which is restricted to hematopoietic lineages. A defect in gammac leads to the X-linked severe combined immunodeficiency characterized by a block in T cell differentiation. In order to better characterize the human gammac promoter and define the minimal tissue-specific promoter region, progressive 5'-deletion constructs of a segment extending 1053 base pairs upstream of the major transcription start site were generated and tested for promoter activity in various hematopoietic and nonhematopoietic cell types. The -1053/+34 construct allowed promoter activity only in cells of hematopoietic origin, and tissue specificity was conserved in all other constructs tested. The region downstream of -90 appeared critical for basal promoter activity. It contains two potential Ets binding sites conserved in the murine gammac promoter gene, one of which was found essential for functional promoter activity as determined by mutational analysis. The functional Ets binding site was found to bind Ets family proteins, principally GA-binding protein and Elf-1 and could be transactivated by GABPalpha and -beta synergistically. These results indicate that, as already reported for the IL2Rbeta promoter, GA-binding protein is an essential component of gammac basal promoter activity. Although GABP expression is not restricted to the hematopoietic lineage, its interaction with other specific factors may contribute to the tissue-specific expression of the gammac gene. " ], "offsets": [ [ 0, 1727 ] ] } ]

[ { "id": "8663060_T1", "type": "Protein", "text": [ "gammac" ], "offsets": [ [ 137, 143 ] ], "normalized": [] }, { "id": "8663060_T2", "type": "Protein", "text": [ "interleukin (IL)-2" ], "offsets": [ [ 195, 213 ] ], "normalized": [] }, { "id": "8663060_T3", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 215, 219 ] ], "normalized": [] }, { "id": "8663060_T4", "type": "Protein", "text": [ "IL-7" ], "offsets": [ [ 221, 225 ] ], "normalized": [] }, { "id": "8663060_T5", "type": "Protein", "text": [ "IL-9" ], "offsets": [ [ 227, 231 ] ], "normalized": [] }, { "id": "8663060_T6", "type": "Protein", "text": [ "IL-15" ], "offsets": [ [ 237, 242 ] ], "normalized": [] }, { "id": "8663060_T7", "type": "Protein", "text": [ "gammac" ], "offsets": [ [ 322, 328 ] ], "normalized": [] }, { "id": "8663060_T8", "type": "Protein", "text": [ "gammac" ], "offsets": [ [ 478, 484 ] ], "normalized": [] }, { "id": "8663060_T9", "type": "Protein", "text": [ "gammac" ], "offsets": [ [ 1079, 1085 ] ], "normalized": [] }, { "id": "8663060_T10", "type": "Protein", "text": [ "Elf-1" ], "offsets": [ [ 1311, 1316 ] ], "normalized": [] }, { "id": "8663060_T11", "type": "Protein", "text": [ "IL2Rbeta" ], "offsets": [ [ 1442, 1450 ] ], "normalized": [] }, { "id": "8663060_T12", "type": "Protein", "text": [ "gammac" ], "offsets": [ [ 1509, 1515 ] ], "normalized": [] }, { "id": "8663060_T13", "type": "Protein", "text": [ "GABP" ], "offsets": [ [ 1550, 1554 ] ], "normalized": [] }, { "id": "8663060_T14", "type": "Protein", "text": [ "gammac" ], "offsets": [ [ 1714, 1720 ] ], "normalized": [] } ]

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[ { "id": "9783909__text", "type": "abstract", "text": [ "Differential RNA display identifies novel genes associated with decreased vitamin D receptor expression. \nTo characterize further the function of the intracellular vitamin D receptor (VDR), we have developed stable transfectant variants of a vitamin D-responsive cell line (U937) which express either decreased or increased numbers of VDR. In this study we have analyzed changes in gene expression associated with this variable VDR expression. Initial experiments indicated that a 50% decrease in VDR levels was associated with a 2-fold increase in cell proliferation and a similar rise in c-myc mRNA expression. Further studies were carried out using differential RNA display (DD). Sequence analysis of DD products revealed two cDNAs with identity to known gene products: the catalytic sub-unit of DNA-protein kinase (DNA-PK(CS)), and the peroxisomal enzyme 17beta-hydroxysteroid dehydrogenase type IV (17beta-HSD IV). Northern analysis confirmed that expression of both mRNAs was reduced in cells with decreased numbers of VDR. Down-regulation of 17beta-HSD IV mRNA expression was associated with enhanced estradiol inactivation by U937 cells, suggesting a link between estrogenic pathways and cell proliferation. Further Northern analyses indicated that there was no significant change in 17beta-HSD IV or DNA-PK(CS) mRNA levels following treatment with 1,25(OH)2D3, although expression of both genes varied with changes in cell proliferation. These data suggest that, in addition to its established role as a hormone-dependent trans-activator, VDR may influence gene expression by ligand-independent mechanisms. " ], "offsets": [ [ 0, 1616 ] ] } ]

[ { "id": "9783909_T1", "type": "Protein", "text": [ "vitamin D receptor" ], "offsets": [ [ 74, 92 ] ], "normalized": [] }, { "id": "9783909_T2", "type": "Protein", "text": [ "vitamin D receptor" ], "offsets": [ [ 164, 182 ] ], "normalized": [] }, { "id": "9783909_T3", "type": "Protein", "text": [ "VDR" ], "offsets": [ [ 184, 187 ] ], "normalized": [] }, { "id": "9783909_T4", "type": "Protein", "text": [ "VDR" ], "offsets": [ [ 335, 338 ] ], "normalized": [] }, { "id": "9783909_T5", "type": "Protein", "text": [ "VDR" ], "offsets": [ [ 428, 431 ] ], "normalized": [] }, { "id": "9783909_T6", "type": "Protein", "text": [ "VDR" ], "offsets": [ [ 497, 500 ] ], "normalized": [] }, { "id": "9783909_T7", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 590, 595 ] ], "normalized": [] }, { "id": "9783909_T8", "type": "Protein", "text": [ "DNA-PK(CS)" ], "offsets": [ [ 819, 829 ] ], "normalized": [] }, { "id": "9783909_T9", "type": "Protein", "text": [ "17beta-hydroxysteroid dehydrogenase type IV" ], "offsets": [ [ 859, 902 ] ], "normalized": [] }, { "id": "9783909_T10", "type": "Protein", "text": [ "17beta-HSD IV" ], "offsets": [ [ 904, 917 ] ], "normalized": [] }, { "id": "9783909_T11", "type": "Protein", "text": [ "VDR" ], "offsets": [ [ 1025, 1028 ] ], "normalized": [] }, { "id": "9783909_T12", "type": "Protein", "text": [ "17beta-HSD IV" ], "offsets": [ [ 1049, 1062 ] ], "normalized": [] }, { "id": "9783909_T13", "type": "Protein", "text": [ "17beta-HSD IV" ], "offsets": [ [ 1292, 1305 ] ], "normalized": [] }, { "id": "9783909_T14", "type": "Protein", "text": [ "DNA-PK(CS)" ], "offsets": [ [ 1309, 1319 ] ], "normalized": [] }, { "id": "9783909_T15", "type": "Protein", "text": [ "VDR" ], "offsets": [ [ 1548, 1551 ] ], "normalized": [] } ]

[ { "id": "9783909_E1", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 64, 73 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_E2" } ] }, { "id": "9783909_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 93, 103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T1" } ] }, { "id": "9783909_E3", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 286, 293 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T4" } ] }, { "id": "9783909_E4", "type": "Positive_regulation", "trigger": { "text": [ "increased numbers" ], "offsets": [ [ 314, 331 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_E3" } ] }, { "id": "9783909_E5", "type": "Negative_regulation", "trigger": { "text": [ "numbers" ], "offsets": [ [ 324, 331 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_E3" } ] }, { "id": "9783909_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 432, 442 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T5" } ] }, { "id": "9783909_E7", "type": "Negative_regulation", "trigger": { "text": [ "decrease" ], "offsets": [ [ 485, 493 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T6" } ] }, { "id": "9783909_E8", "type": "Positive_regulation", "trigger": { "text": [ "rise" ], "offsets": [ [ 582, 586 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_E9" } ] }, { "id": "9783909_E9", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 601, 611 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T7" } ] }, { "id": "9783909_E10", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 953, 963 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T8" } ] }, { "id": "9783909_E11", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 953, 963 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T10" } ] }, { "id": "9783909_E12", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 982, 989 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_E11" }, { "role": "Cause", "ref_id": "9783909_E14" } ] }, { "id": "9783909_E13", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 982, 989 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_E10" }, { "role": "Cause", "ref_id": "9783909_E14" } ] }, { "id": "9783909_E14", "type": "Negative_regulation", "trigger": { "text": [ "decreased numbers" ], "offsets": [ [ 1004, 1021 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T11" } ] }, { "id": "9783909_E15", "type": "Negative_regulation", "trigger": { "text": [ "Down-regulation" ], "offsets": [ [ 1030, 1045 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_E16" } ] }, { "id": "9783909_E16", "type": "Transcription", "trigger": { "text": [ "expression" ], "offsets": [ [ 1068, 1078 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T12" } ] }, { "id": "9783909_E17", "type": "Regulation", "trigger": { "text": [ "change" ], "offsets": [ [ 1282, 1288 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T14" } ] }, { "id": "9783909_E18", "type": "Regulation", "trigger": { "text": [ "change" ], "offsets": [ [ 1282, 1288 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T13" } ] }, { "id": "9783909_E19", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1379, 1389 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T13" } ] }, { "id": "9783909_E20", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1379, 1389 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9783909_T14" } ] } ]

[ { "id": "9783909_1", "entity_ids": [ "9783909_T9", "9783909_T10" ] }, { "id": "9783909_2", "entity_ids": [ "9783909_T2", "9783909_T3" ] } ]

[]

[ { "id": "7926759__text", "type": "abstract", "text": [ "An active v-abl protein tyrosine kinase blocks immunoglobulin light-chain gene rearrangement. \nLymphoid cells transformed by Abelson murine leukemia virus have provided one of the classic models for study of early B-cell development and immunoglobulin rearrangement. Most of these cells have rearranged their heavy-chain locus but not their light chain genes, suggesting that an active v-abl protein interferes with this differentiation step. To test this hypothesis, light-chain gene structure was examined in pre-B cells transformed by temperature-sensitive mutants of the Abelson virus and in derivatives that survive at the nonpermissive temperature because they express a human BCL-2 gene. Our studies reveal that inactivation of the v-abl protein tyrosine kinase triggers high-frequency rearrangement of kappa and lambda light-chain genes. These events are accompanied by marked increases in the expression of RAG-1 and RAG-2 RNAs. These increases occur in the absence of protein synthesis but are dependent on inactivation of the v-abl protein tyrosine kinase. As documented in the accompanying paper (Klug et al., this issue), an active v-abl protein also suppresses the activity of NF-kappa B/rel and expression controlled by the kappa intron enhancer. Together these data demonstrate that the v-abl protein specifically interferes with light-chain gene rearrangement by suppressing at least two pathways essential for this stage of B-cell differentiation and suggest that tyrosine phosphorylation is important in regulating RAG gene expression. " ], "offsets": [ [ 0, 1555 ] ] } ]

[ { "id": "7926759_T1", "type": "Protein", "text": [ "v-abl" ], "offsets": [ [ 10, 15 ] ], "normalized": [] }, { "id": "7926759_T2", "type": "Protein", "text": [ "v-abl" ], "offsets": [ [ 386, 391 ] ], "normalized": [] }, { "id": "7926759_T3", "type": "Protein", "text": [ "BCL-2" ], "offsets": [ [ 683, 688 ] ], "normalized": [] }, { "id": "7926759_T4", "type": "Protein", "text": [ "v-abl" ], "offsets": [ [ 739, 744 ] ], "normalized": [] }, { "id": "7926759_T5", "type": "Protein", "text": [ "kappa" ], "offsets": [ [ 810, 815 ] ], "normalized": [] }, { "id": "7926759_T6", "type": "Protein", "text": [ "lambda light-chain" ], "offsets": [ [ 820, 838 ] ], "normalized": [] }, { "id": "7926759_T7", "type": "Protein", "text": [ "RAG-1" ], "offsets": [ [ 916, 921 ] ], "normalized": [] }, { "id": "7926759_T8", "type": "Protein", "text": [ "RAG-2" ], "offsets": [ [ 926, 931 ] ], "normalized": [] }, { "id": "7926759_T9", "type": "Protein", "text": [ "v-abl" ], "offsets": [ [ 1037, 1042 ] ], "normalized": [] }, { "id": "7926759_T10", "type": "Protein", "text": [ "v-abl" ], "offsets": [ [ 1145, 1150 ] ], "normalized": [] }, { "id": "7926759_T11", "type": "Protein", "text": [ "v-abl" ], "offsets": [ [ 1303, 1308 ] ], "normalized": [] } ]

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[ { "id": "10438913__text", "type": "abstract", "text": [ "IL-2-independent activation and proliferation in human T cells induced by CD28. \nAlthough the role of CD28 in T cell costimulation is firmly established, the mechanisms by which it exerts its costimulatory actions are less clear. In many circumstances it is difficult to distinguish the effects of CD28 from subsequent actions of cytokines, such as IL-2, on T cell proliferation. Here, we report a model of CD28 costimulation using PMA plus the natural ligand CD80 that resulted in very limited stimulation of IL-2, as evidenced by both cytokine production and IL-2 promoter stimulation. Promoter assays revealed CD28-dependent effects on both NF-kappaB and AP-1, but not on NF-AT or the intact IL-2 promoter. In addition, T cell proliferation was completely resistant to the actions of the immunosuppressant cyclosporin A (CsA). Moreover T cell proliferation was unaffected by the addition of blocking Abs to both IL-2 and the IL-2 receptor, demonstrating that this form of costimulation by CD28 was independent of IL-2. We also investigated the effects of stimulating T cell blasts with CD80 alone and found that there was a limited requirement for IL-2 in this system. We conclude that CD28 costimulation can cause substantial T cell proliferation in the absence of IL-2, which is driven by a soluble factor independent of NF-AT transactivation. " ], "offsets": [ [ 0, 1349 ] ] } ]

[ { "id": "10438913_T1", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "10438913_T2", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 74, 78 ] ], "normalized": [] }, { "id": "10438913_T3", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 102, 106 ] ], "normalized": [] }, { "id": "10438913_T4", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 298, 302 ] ], "normalized": [] }, { "id": "10438913_T5", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 349, 353 ] ], "normalized": [] }, { "id": "10438913_T6", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 407, 411 ] ], "normalized": [] }, { "id": "10438913_T7", "type": "Protein", "text": [ "CD80" ], "offsets": [ [ 460, 464 ] ], "normalized": [] }, { "id": "10438913_T8", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 510, 514 ] ], "normalized": [] }, { "id": "10438913_T9", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 561, 565 ] ], "normalized": [] }, { "id": "10438913_T10", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 613, 617 ] ], "normalized": [] }, { "id": "10438913_T11", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 695, 699 ] ], "normalized": [] }, { "id": "10438913_T12", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 915, 919 ] ], "normalized": [] }, { "id": "10438913_T13", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 992, 996 ] ], "normalized": [] }, { "id": "10438913_T14", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1016, 1020 ] ], "normalized": [] }, { "id": "10438913_T15", "type": "Protein", "text": [ "CD80" ], "offsets": [ [ 1089, 1093 ] ], "normalized": [] }, { "id": "10438913_T16", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1151, 1155 ] ], "normalized": [] }, { "id": "10438913_T17", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1189, 1193 ] ], "normalized": [] }, { "id": "10438913_T18", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1269, 1273 ] ], "normalized": [] }, { "id": "10438913_T22", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 566, 574 ] ], "normalized": [] }, { "id": "10438913_T25", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 700, 708 ] ], "normalized": [] } ]

[ { "id": "10438913_E1", "type": "Negative_regulation", "trigger": { "text": [ "resulted in very limited" ], "offsets": [ [ 470, 494 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10438913_E3" } ] }, { "id": "10438913_E2", "type": "Positive_regulation", "trigger": { "text": [ "resulted" ], "offsets": [ [ 470, 478 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10438913_E4" } ] }, { "id": "10438913_E3", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 495, 506 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10438913_T8" } ] }, { "id": "10438913_E4", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 575, 586 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10438913_T9" }, { "role": "Site", "ref_id": "10438913_T22" } ] }, { "id": "10438913_E5", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 628, 635 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10438913_T11" }, { "role": "Cause", "ref_id": "10438913_T10" }, { "role": "Site", "ref_id": "10438913_T25" } ] }, { "id": "10438913_E6", "type": "Negative_regulation", "trigger": { "text": [ "blocking" ], "offsets": [ [ 894, 902 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10438913_T12" } ] } ]

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[ { "id": "9307271__text", "type": "abstract", "text": [ "Activation of a novel gene in 3q21 and identification of intergenic fusion transcripts with ecotropic viral insertion site I in leukemia. \nWe have identified a novel gene, GR6, located within the leukemia breakpoint region of 3q21, that is normally expressed in early fetal development but not in adult peripheral blood. GR6 is activated in the UCSD-AML1 cell line and in a leukemic sample, both of which carry a t(3;3)(q21;q26). In UCSD-AML1, we have also identified fusion transcripts between the ecotropic viral insertion site I (EVI1) gene in 3q26 and GR6 and between EVI1 and Ribophorin I that maps 30 kb telomeric to GR6 in 3q21. All fusions splice the 5' ends of the 3q21 genes into exon 2 of the EVI1 gene, an event that is similar to the normal intergenic splicing of MDS1-EVI1 and to those previously documented in leukemias with t(3;21) and t(3;12), in which acute myelogenous leukemia 1-EVI1 fusions and ETV6-EVI1 fusions, respectively, occur. The Ribophorin I-EVI1 fusion in particular may be a common occurrence in t(3;3). " ], "offsets": [ [ 0, 1037 ] ] } ]

[ { "id": "9307271_T1", "type": "Protein", "text": [ "GR6" ], "offsets": [ [ 172, 175 ] ], "normalized": [] }, { "id": "9307271_T2", "type": "Protein", "text": [ "GR6" ], "offsets": [ [ 321, 324 ] ], "normalized": [] }, { "id": "9307271_T3", "type": "Protein", "text": [ "ecotropic viral insertion site I" ], "offsets": [ [ 499, 531 ] ], "normalized": [] }, { "id": "9307271_T4", "type": "Protein", "text": [ "EVI1" ], "offsets": [ [ 533, 537 ] ], "normalized": [] }, { "id": "9307271_T5", "type": "Protein", "text": [ "GR6" ], "offsets": [ [ 556, 559 ] ], "normalized": [] }, { "id": "9307271_T6", "type": "Protein", "text": [ "EVI1" ], "offsets": [ [ 572, 576 ] ], "normalized": [] }, { "id": "9307271_T7", "type": "Protein", "text": [ "Ribophorin I" ], "offsets": [ [ 581, 593 ] ], "normalized": [] }, { "id": "9307271_T8", "type": "Protein", "text": [ "GR6" ], "offsets": [ [ 623, 626 ] ], "normalized": [] }, { "id": "9307271_T9", "type": "Protein", "text": [ "EVI1" ], "offsets": [ [ 704, 708 ] ], "normalized": [] }, { "id": "9307271_T10", "type": "Protein", "text": [ "MDS1" ], "offsets": [ [ 777, 781 ] ], "normalized": [] }, { "id": "9307271_T11", "type": "Protein", "text": [ "EVI1" ], "offsets": [ [ 782, 786 ] ], "normalized": [] }, { "id": "9307271_T12", "type": "Protein", "text": [ "acute myelogenous leukemia 1" ], "offsets": [ [ 870, 898 ] ], "normalized": [] }, { "id": "9307271_T13", "type": "Protein", "text": [ "EVI1" ], "offsets": [ [ 899, 903 ] ], "normalized": [] }, { "id": "9307271_T14", "type": "Protein", "text": [ "ETV6" ], "offsets": [ [ 916, 920 ] ], "normalized": [] }, { "id": "9307271_T15", "type": "Protein", "text": [ "EVI1" ], "offsets": [ [ 921, 925 ] ], "normalized": [] }, { "id": "9307271_T16", "type": "Protein", "text": [ "Ribophorin I" ], "offsets": [ [ 960, 972 ] ], "normalized": [] }, { "id": "9307271_T17", "type": "Protein", "text": [ "EVI1" ], "offsets": [ [ 973, 977 ] ], "normalized": [] } ]

[ { "id": "9307271_E1", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 249, 258 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9307271_T1" } ] }, { "id": "9307271_E2", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 328, 337 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9307271_T2" } ] } ]

[ { "id": "9307271_1", "entity_ids": [ "9307271_T3", "9307271_T4" ] } ]

[]

[ { "id": "7673240__text", "type": "abstract", "text": [ "A regulatory element in the human interleukin 2 gene promoter is a binding site for the zinc finger proteins Sp1 and EGR-1. \nActivation of the interleukin 2 (IL-2) gene after antigen recognition is a critical event for T cell proliferation and effector function. Prior studies have identified several transcription factors that contribute to the activity of the IL-2 promoter in stimulated T lymphocytes. Here we describe a novel regulatory element within the IL-2 promoter located immediately upstream of the nuclear factor of activated T cell (NFAT) domain. This region (termed the zinc finger protein binding region (ZIP)) serves as binding site for two differently regulated zinc finger proteins: the constitutively expressed transcription factor Sp1 and the inducible early growth response protein EGR-1. In unstimulated cells which do not secrete IL-2, only Sp1 binds to this region, while in stimulated IL-2 secreting cells the inducible EGR-1 protein recognizes this element. In Jurkat T cells, the ZIP site serves as an activator for IL-2 gene expression, and a combination of ZIP and NFAT binding sites is required for maximal IL-2 promoter activity. These results suggest a critical role of the ZIP site for IL-2 promoter activity. " ], "offsets": [ [ 0, 1243 ] ] } ]

[ { "id": "7673240_T1", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 34, 47 ] ], "normalized": [] }, { "id": "7673240_T2", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 109, 112 ] ], "normalized": [] }, { "id": "7673240_T3", "type": "Protein", "text": [ "EGR-1" ], "offsets": [ [ 117, 122 ] ], "normalized": [] }, { "id": "7673240_T4", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 143, 156 ] ], "normalized": [] }, { "id": "7673240_T5", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 158, 162 ] ], "normalized": [] }, { "id": "7673240_T6", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 362, 366 ] ], "normalized": [] }, { "id": "7673240_T7", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 460, 464 ] ], "normalized": [] }, { "id": "7673240_T8", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 751, 754 ] ], "normalized": [] }, { "id": "7673240_T9", "type": "Protein", "text": [ "EGR-1" ], "offsets": [ [ 803, 808 ] ], "normalized": [] }, { "id": "7673240_T10", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 853, 857 ] ], "normalized": [] }, { "id": "7673240_T11", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 864, 867 ] ], "normalized": [] }, { "id": "7673240_T12", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 910, 914 ] ], "normalized": [] }, { "id": "7673240_T13", "type": "Protein", "text": [ "EGR-1" ], "offsets": [ [ 945, 950 ] ], "normalized": [] }, { "id": "7673240_T14", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1043, 1047 ] ], "normalized": [] }, { "id": "7673240_T15", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1137, 1141 ] ], "normalized": [] }, { "id": "7673240_T16", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1219, 1223 ] ], "normalized": [] }, { "id": "7673240_T17", "type": "Entity", "text": [ "regulatory element" ], "offsets": [ [ 2, 20 ] ], "normalized": [] }, { "id": "7673240_T21", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 367, 375 ] ], "normalized": [] }, { "id": "7673240_T33", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1142, 1150 ] ], "normalized": [] }, { "id": "7673240_T35", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1224, 1232 ] ], "normalized": [] } ]

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[ { "id": "1958222__text", "type": "abstract", "text": [ "Constitutive activation of NF-kB in human thymocytes. \nNF-kB is a eukaryotic transcription regulatory factor. In T cells and T cell lines, NF-kB is bound to a cytoplasmic proteic inhibitor, the IkB. Treatment of T cells with mitogens (phorbol esters) or cytokines (TNF alpha) induces NF-kB nuclear translocation and the subsequent expression of NF-kB dependent T cell genes. Here we examined the activation of NF-kB in human T cell thymic progenitors. We report differences in (Ca2+)i requirement for NF-kB activation in thymocytes as compared to mature T cells. Furthermore, our results indicated that thymocytes have a constitutively active form of NF-kB, suggesting that they are activated in vivo. " ], "offsets": [ [ 0, 702 ] ] } ]

[ { "id": "1958222_T1", "type": "Protein", "text": [ "TNF alpha" ], "offsets": [ [ 265, 274 ] ], "normalized": [] } ]

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[ { "id": "1931834__text", "type": "abstract", "text": [ "Synergism between two distinct elements of the HTLV-I enhancer during activation by the trans-activator of HTLV-I. \nWe have conducted functional studies of the enhancer elements of human T-cell leukemia virus type I (HTLV-I) using the human T-cell lines Jurkat and MOLT 4, which are negative for HTLV-I, and MT-2 and TL-Mor, which carry the proviral genome of HTLV-I. Two distinct elements have been implicated in function of the HTLV-I enhancer. One is the 21-base-pair (bp) core element that is responsible for trans-activation by the HTLV-I trans-activator p40tax and that has the ability to bind to cyclic-AMP responsive element binding factor (CREB)-like factor(s). The other is a region interposed between the 21-bp elements. In this study we demonstrate that a subfragment (C26) in the region between the 21-bp elements is involved in trans-activation by p40tax, possibly through binding to an NF-kappa B-like nuclear factor or factors. Formation of the protein-DNA complex with the C26 subfragment was positively affected by p40tax. The C26 element conferred partial responsiveness to p40tax when linked to one copy of the 21-bp element that, by itself, showed little activation in response to p40tax. However, the C26 element alone, even when repeated, could not be activated by p40tax, unlike other NF-kappa B-binding elements. In contrast, the C26 element itself was profoundly activated upon stimulation with 12-O-tetradecanoylphorbol-13-acetate. These findings therefore suggest that the HTLV-I enhancer contains multiple functional elements, including binding sites for at least CREB- and NF-kappa B-like factors, which synergistically cooperate in activation of the HTLV-I enhancer in response to p40tax. Our results also demonstrate that TPA-dependent activation of the HTLV-I enhancer may be mediated through the C26 element. " ], "offsets": [ [ 0, 1843 ] ] } ]

[ { "id": "1931834_T1", "type": "Protein", "text": [ "p40tax" ], "offsets": [ [ 560, 566 ] ], "normalized": [] }, { "id": "1931834_T2", "type": "Protein", "text": [ "cyclic-AMP responsive element binding factor" ], "offsets": [ [ 603, 647 ] ], "normalized": [] }, { "id": "1931834_T3", "type": "Protein", "text": [ "CREB" ], "offsets": [ [ 649, 653 ] ], "normalized": [] }, { "id": "1931834_T4", "type": "Protein", "text": [ "p40tax" ], "offsets": [ [ 862, 868 ] ], "normalized": [] }, { "id": "1931834_T5", "type": "Protein", "text": [ "p40tax" ], "offsets": [ [ 1033, 1039 ] ], "normalized": [] }, { "id": "1931834_T6", "type": "Protein", "text": [ "p40tax" ], "offsets": [ [ 1093, 1099 ] ], "normalized": [] }, { "id": "1931834_T7", "type": "Protein", "text": [ "p40tax" ], "offsets": [ [ 1202, 1208 ] ], "normalized": [] }, { "id": "1931834_T8", "type": "Protein", "text": [ "p40tax" ], "offsets": [ [ 1288, 1294 ] ], "normalized": [] }, { "id": "1931834_T9", "type": "Protein", "text": [ "CREB" ], "offsets": [ [ 1593, 1597 ] ], "normalized": [] }, { "id": "1931834_T10", "type": "Protein", "text": [ "p40tax" ], "offsets": [ [ 1712, 1718 ] ], "normalized": [] } ]

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[ { "id": "1946405__text", "type": "abstract", "text": [ "Isolation of a candidate repressor/activator, NF-E1 (YY-1, delta), that binds to the immunoglobulin kappa 3' enhancer and the immunoglobulin heavy-chain mu E1 site. \nWe have determined that the developmental control of immunoglobulin kappa 3' enhancer (kappa E3') activity is the result of the combined influence of positive- and negative-acting elements. We show that a central core in the kappa E3' enhancer is active at the pre-B-cell stage but is repressed by flanking negative-acting elements. The negative-acting sequences repress enhancer activity in a position- and orientation-independent manner at the pre-B-cell stage. We have isolated a human cDNA clone encoding a zinc finger protein (NF-E1) that binds to the negative-acting segment of the kappa E3' enhancer. This protein also binds to the immunoglobulin heavy-chain enhancer mu E1 site. NF-E1 is encoded by the same gene as the YY-1 protein, which binds to the adeno-associated virus P5 promoter. NF-E1 is also the human homologue of the mouse delta protein, which binds to ribosomal protein gene promoters. The predicted amino acid sequence of this protein contains features characteristic of transcriptional activators as well as transcriptional repressors. Cotransfection studies with this cDNA indicate that it can repress basal promoter activity. The apparent dual function of this protein is discussed. " ], "offsets": [ [ 0, 1375 ] ] } ]

[ { "id": "1946405_T1", "type": "Protein", "text": [ "NF-E1" ], "offsets": [ [ 46, 51 ] ], "normalized": [] }, { "id": "1946405_T2", "type": "Protein", "text": [ "YY-1" ], "offsets": [ [ 53, 57 ] ], "normalized": [] }, { "id": "1946405_T3", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 59, 64 ] ], "normalized": [] }, { "id": "1946405_T4", "type": "Protein", "text": [ "NF-E1" ], "offsets": [ [ 698, 703 ] ], "normalized": [] }, { "id": "1946405_T5", "type": "Protein", "text": [ "NF-E1" ], "offsets": [ [ 853, 858 ] ], "normalized": [] }, { "id": "1946405_T6", "type": "Protein", "text": [ "YY-1" ], "offsets": [ [ 894, 898 ] ], "normalized": [] }, { "id": "1946405_T7", "type": "Protein", "text": [ "NF-E1" ], "offsets": [ [ 963, 968 ] ], "normalized": [] }, { "id": "1946405_T8", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 1010, 1015 ] ], "normalized": [] } ]

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[ { "id": "7720085__text", "type": "abstract", "text": [ "Induction of transcription factors in human T lymphocytes by aspirin-like drugs. \nAspirin-like drugs (ALD) induce calcium mobilization, an essential component of T cell activation, but do not induce the biosynthesis of IL-2. To understand the extent to which ALD may mimic mitogenic stimulation, we studied cytoplasmic and nuclear signaling steps in ALD-treated T cells. We found that ALD induce a transient activation of protein kinase (PKC) but have no effect (in comparison to anti-CD3 antibodies) on protein tyrosine phosphorylation nor on PCL gamma 1 tyrosine phosphorylation. ALD-induced calcium mobilization and PKC activation are independent of tyrosine protein kinase activity as shown by the lack of effect of herbimycin, a tyrosine-protein kinase-specific inhibitor. Although we detected no IL-2 mRNA in ALD-treated cells, the nuclei of these cells contain proteins capable of binding to three regulatory sequences in the IL-2 promoter region: NFAT, NF kappa B, and AP-1. These binding activities are expressed only in activated T cells. The expression of AP-1 depended on calcium mobilization and PKC activation. These data suggest that ALD cause transient but significant changes in T cell transmembrane signaling, although some events induced by stimulation with anti-CD3 antibodies are not induced by ALD. The signal is transmitted to the nucleus and induces DNA-binding activity by several transcription factors. However, the ALD stimulus is not capable of causing complete T cell activation. " ], "offsets": [ [ 0, 1509 ] ] } ]

[ { "id": "7720085_T1", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 219, 223 ] ], "normalized": [] }, { "id": "7720085_T2", "type": "Protein", "text": [ "PCL gamma 1" ], "offsets": [ [ 544, 555 ] ], "normalized": [] }, { "id": "7720085_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 802, 806 ] ], "normalized": [] }, { "id": "7720085_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 933, 937 ] ], "normalized": [] }, { "id": "7720085_T8", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 556, 564 ] ], "normalized": [] }, { "id": "7720085_T12", "type": "Entity", "text": [ "promoter region" ], "offsets": [ [ 938, 953 ] ], "normalized": [] } ]

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[]

[ { "id": "10068671__text", "type": "abstract", "text": [ "Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells. \nInterferon-alpha (IFN-alpha) is a pleiotropic cytokine that has antiviral, antiproliferative, and immunoregulatory functions. There is increasing evidence that IFN-alpha has an important role in T-cell biology. We have analyzed the expression of IL-2Ralpha, c-myc, and pim-1 genes in anti-CD3-activated human T lymphocytes. The induction of these genes is associated with interleukin-2 (IL-2)-induced T-cell proliferation. Treatment of T lymphocytes with IFN-alpha, IL-2, IL-12, and IL-15 upregulated IL-2Ralpha, c-myc, and pim-1 gene expression. IFN-alpha also sensitized T cells to IL-2-induced proliferation, further suggesting that IFN-alpha may be involved in the regulation of T-cell mitogenesis. When we analyzed the nature of STAT proteins capable of binding to IL-2Ralpha, pim-1, and IRF-1 GAS elements after cytokine stimulation, we observed IFN-alpha-induced binding of STAT1, STAT3, and STAT4, but not STAT5 to all of these elements. Yet, IFN-alpha was able to activate binding of STAT5 to the high-affinity IFP53 GAS site. IFN-alpha enhanced tyrosine phosphorylation of STAT1, STAT3, STAT4, STAT5a, and STAT5b. IL-12 induced STAT4 and IL-2 and IL-15 induced STAT5 binding to the GAS elements. Taken together, our results suggest that IFN-alpha, IL-2, IL-12, and IL-15 have overlapping activities on human T cells. These findings thus emphasize the importance of IFN-alpha as a T-cell regulatory cytokine. " ], "offsets": [ [ 0, 1563 ] ] } ]

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[]

[ { "id": "10454636__text", "type": "abstract", "text": [ "Dopamine stimulates expression of the human immunodeficiency virus type 1 via NF-kappaB in cells of the immune system. \nRecent studies have reported that lymphocytes produce, transport and bind dopamine present in plasma. However, the action of dopamine on HIV-1 gene expression in cells of the immune system has not yet been examined. Here, we have investigated the regulation of HIV-1 expression by dopamine in Jurkat T cells and in primary blood mononuclear cells (PBMC). HIV-1 replication was increased by dopamine, which correlated with the increased levels of HIV-1 transactivation. Our transient expression data revealed that dopamine stimulated transcription through the NF-kappaB element present in the long terminal repeat. The importance of NF-kappaB sites was confirmed by using vectors containing wild-type or mutant kappaB sites in a heterologous promoter. Consistent with the role of NF-kappaB in mediating dopamine responsiveness, the proteasome inhibitor MG132 abolished dopamine-induced transcriptional activation. We further explored the effect of dopamine in the presence of phorbol esters or tumor necrosis factor-alpha (TNF-alpha) known to activate NF-kappaB. The combination of dopamine and TNF-alpha led to a stimulation of HIV-1 transcription and replication. However, in contrast with TNF-alpha, dopamine treatment did not affect NF-kappaB DNA binding activity nor the concentrations of p50, p65 and IkappaB-alpha proteins, which suggests a distinct NF-kappaB activation mechanism. These results reveal a new link between the dopamine system, cytokine signaling pathway and regulation of gene expression via the involvement of NF-kappaB in T cells and PBMC. " ], "offsets": [ [ 0, 1684 ] ] } ]

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[]

[ { "id": "10381655__text", "type": "abstract", "text": [ "NF-kappaB functions as both a proapoptotic and antiapoptotic regulatory factor within a single cell type. \nRecently NF-kappaB has been shown to have both proapoptotic and antiapoptotic functions. In T cell hybridomas, both T cell activators and glucocorticoids induce apoptosis. Here we show that blockade of NF-kappaB activity, using a dominant negative IkappaBalpha, has opposite effects on these two apoptotic signals. Treatment with PMA plus ionomycin (P/I) results in the upregulation of Fas Ligand (FasL) and induction of apoptosis. Inhibition of NF-kappaB activity inhibits the P/I mediated induction of FasL mRNA and decreases the level of apoptosis in these cultures, thus establishing NF-kappaB as a proapoptotic factor in this context. Conversely, inhibition of NF-kappaB confers a tenfold increase in glucocorticoid mediated apoptosis, establishing that NF-kappaB also functions as an antiapoptotic factor. We conclude that NF-kappaB is a context-dependent apoptosis regulator. Our data suggests that NF-kappaB may function as an antiapoptotic factor in thymocytes while functioning as a proapoptotic factor in mature peripheral T cells. " ], "offsets": [ [ 0, 1150 ] ] } ]

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[ { "id": "10381655_E1", "type": "Positive_regulation", "trigger": { "text": [ "upregulation" ], "offsets": [ [ 477, 489 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10381655_T3" } ] }, { "id": "10381655_E2", "type": "Negative_regulation", "trigger": { "text": [ "inhibits" ], "offsets": [ [ 572, 580 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10381655_E4" } ] }, { "id": "10381655_E3", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 589, 597 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10381655_E4" } ] }, { "id": "10381655_E4", "type": "Transcription", "trigger": { "text": [ "induction" ], "offsets": [ [ 598, 607 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10381655_T4" } ] } ]

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[]

[ { "id": "1429562__text", "type": "abstract", "text": [ "The regulation of the human tumor necrosis factor alpha promoter region in macrophage, T cell, and B cell lines. \nThe 1311-base pair human tumor necrosis factor (TNF) alpha promoter region was fused to the luciferase (Luc) reporter gene and studied in a transient transfection system in three TNF producing cell lines, the U937 macrophage cell line, the MLA 144 T cell line, and the 729-6 B cell line. This full length promoter construct can be induced by phorbol 13-myristate acetate (PMA) in each of these cell types. Analysis of a series of 5'-truncations showed several peaks of basal and PMA induced activity suggesting the presence of several positive and negative regulatory elements. A PMA responsive element was localized to a region between -95 and -36 bp relative to the transcription start site. Within this region, single AP-2- and AP-1- like consensus sequences were noted. These AP-2 and AP-1 sites were each modified with a double point mutation. A modest (20-50%) reduction in TNF promoter activity was observed with the AP-2 site mutation. However, mutation of the AP-1 site markedly diminished both the basal and PMA-activated promoter activity. Also co-transfections of the wild-type promoter construct with an AP-1/c-jun expression vector resulted in augmented basal and PMA-induced promoter activity. " ], "offsets": [ [ 0, 1323 ] ] } ]

[ { "id": "1429562_T1", "type": "Protein", "text": [ "tumor necrosis factor alpha" ], "offsets": [ [ 28, 55 ] ], "normalized": [] }, { "id": "1429562_T2", "type": "Protein", "text": [ "tumor necrosis factor (TNF) alpha" ], "offsets": [ [ 139, 172 ] ], "normalized": [] }, { "id": "1429562_T3", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 994, 997 ] ], "normalized": [] }, { "id": "1429562_T4", "type": "Protein", "text": [ "c-jun" ], "offsets": [ [ 1236, 1241 ] ], "normalized": [] }, { "id": "1429562_T6", "type": "Entity", "text": [ "promoter region" ], "offsets": [ [ 56, 71 ] ], "normalized": [] }, { "id": "1429562_T7", "type": "Entity", "text": [ "promoter region" ], "offsets": [ [ 173, 188 ] ], "normalized": [] }, { "id": "1429562_T10", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 998, 1006 ] ], "normalized": [] } ]

[ { "id": "1429562_E1", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 4, 14 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1429562_T1" }, { "role": "Site", "ref_id": "1429562_T6" } ] }, { "id": "1429562_E2", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 445, 452 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1429562_T2" }, { "role": "Site", "ref_id": "1429562_T7" } ] }, { "id": "1429562_E3", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 981, 990 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1429562_T3" }, { "role": "Site", "ref_id": "1429562_T10" } ] }, { "id": "1429562_E4", "type": "Negative_regulation", "trigger": { "text": [ "diminished" ], "offsets": [ [ 1102, 1112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1429562_E6" } ] }, { "id": "1429562_E5", "type": "Negative_regulation", "trigger": { "text": [ "diminished" ], "offsets": [ [ 1102, 1112 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1429562_T3" }, { "role": "Site", "ref_id": "1429562_T10" } ] }, { "id": "1429562_E6", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1136, 1145 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1429562_T3" }, { "role": "Site", "ref_id": "1429562_T10" } ] }, { "id": "1429562_E7", "type": "Gene_expression", "trigger": { "text": [ "co-transfections" ], "offsets": [ [ 1170, 1186 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1429562_T4" } ] }, { "id": "1429562_E8", "type": "Positive_regulation", "trigger": { "text": [ "co-transfections" ], "offsets": [ [ 1170, 1186 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1429562_E7" } ] }, { "id": "1429562_E9", "type": "Positive_regulation", "trigger": { "text": [ "augmented" ], "offsets": [ [ 1272, 1281 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1429562_T3" }, { "role": "Cause", "ref_id": "1429562_E8" }, { "role": "Site", "ref_id": "1429562_T10" } ] }, { "id": "1429562_E10", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1296, 1303 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1429562_T3" }, { "role": "Site", "ref_id": "1429562_T10" } ] } ]

[]

[]

[ { "id": "9070319__text", "type": "abstract", "text": [ "Possible role of nuclear factor-kappa B activity in germline C epsilon transcription in a human Burkitt lymphoma B cell line. \nNuclear factor-kappa B (NF-kappa B) plays a broad role in gene regulation, but it is not evident whether NF-kappa B acts as a messenger system for germline C epsilon transcription. We report here that the signaling cascade triggered by interleukin-4 (IL-4) or anti-CD40 monoclonal antibody (mAb) participates in NF-kappa B activation responsible for germline C epsilon transcription in a human Burkitt lymphoma B cell line, DND39. Both IL-4 and anti-CD40 mAb induced activation of phosphatidylinositol 3-kinase (PI3-kinase), translocation of a zeta isoform of protein kinase C, and nuclear expression of NF-kappa B. All such events were abrogated by treatment with LY294002, a specific inhibitor of PI3-kinase. In addition, N-acetyl-L-cysteine (NAC), a potent antioxidant, decreased NF-kappa B activation caused by IL-4, anti-CD40 mAb, or their combination. NAC was also effective in diminishing germline C epsilon transcription, and its potency was higher in cultures costimulated with IL-4 and anti-CD40 mAb than in those stimulated with IL-4 alone. These results indicate that IL-4 and ligation of CD40 induce NF-kappa B expression via at least a mechanism dependent on the PI3-kinase pathway and suggest that NF-kappa B sensitive to NAC may play a role in regulating germline C epsilon transcription. " ], "offsets": [ [ 0, 1432 ] ] } ]

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[]

[ { "id": "10197731__text", "type": "abstract", "text": [ "Studies into the effect of tyrosine phosphatase inhibitor phenylarsine oxide on NFkappaB activation in T lymphocytes during aging: evidence for altered IkappaB-alpha phosphorylation and degradation. \nNuclear Factor kappa B (NFkappaB) is a critical regulator of several genes involved in immune and inflammatory responses. Treatment of T cells with a variety of stimuli, including TNF-alpha, leads to the translocation of the active p65-50 heterodimer to the nucleus, albeit at a lower level in T cells from the elderly. We demonstrate here that pretreatment with PAO results in the inhibition of NFkappaB induction in TNF-alpha treated T cells, suggesting a role for PAO-sensitive phosphatase in the activation of the NFkappaB via this pathway in human T cells. Furthermore, it demonstrates that aging does not influence the sensitivity of this phosphatase. Treatment with DMP prior to treatment with PAO and TNF abolishes the inhibition induced by PAO, in T cells from both young and old donors, alike. Finally, we demonstrate that a failure to degrade IkappaB-alpha in cytosols of TNF-treated T cells pretreated with PAO is due to its interference with the phosphorylation of IkappaB-alpha and not due to its inhibitory effect on proteasomal degradation. These data collectively suggest that PAO interferes with the phosphorylation and the regulated degradation of IkappaB-alpha, induced by TNF, without affecting the chymotryptic activity of the proteasome, independent of age. " ], "offsets": [ [ 0, 1481 ] ] } ]

[ { "id": "10197731_T1", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 152, 165 ] ], "normalized": [] }, { "id": "10197731_T2", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 380, 389 ] ], "normalized": [] }, { "id": "10197731_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 618, 627 ] ], "normalized": [] }, { "id": "10197731_T4", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1054, 1067 ] ], "normalized": [] }, { "id": "10197731_T5", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1178, 1191 ] ], "normalized": [] }, { "id": "10197731_T6", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1367, 1380 ] ], "normalized": [] } ]

[ { "id": "10197731_E1", "type": "Regulation", "trigger": { "text": [ "altered" ], "offsets": [ [ 144, 151 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10197731_E4" } ] }, { "id": "10197731_E2", "type": "Regulation", "trigger": { "text": [ "altered" ], "offsets": [ [ 144, 151 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10197731_E3" } ] }, { "id": "10197731_E3", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 166, 181 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10197731_T1" } ] }, { "id": "10197731_E4", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 186, 197 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10197731_T1" } ] }, { "id": "10197731_E5", "type": "Protein_catabolism", "trigger": { "text": [ "degrade" ], "offsets": [ [ 1046, 1053 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10197731_T4" } ] }, { "id": "10197731_E6", "type": "Positive_regulation", "trigger": { "text": [ "due" ], "offsets": [ [ 1126, 1129 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10197731_E5" }, { "role": "Cause", "ref_id": "10197731_E7" } ] }, { "id": "10197731_E7", "type": "Negative_regulation", "trigger": { "text": [ "interference" ], "offsets": [ [ 1137, 1149 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10197731_E8" } ] }, { "id": "10197731_E8", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1159, 1174 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10197731_T5" } ] }, { "id": "10197731_E9", "type": "Regulation", "trigger": { "text": [ "due" ], "offsets": [ [ 1200, 1203 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10197731_E5" } ] }, { "id": "10197731_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1318, 1333 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10197731_T6" } ] }, { "id": "10197731_E11", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 1352, 1363 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10197731_T6" } ] } ]

[]

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[ { "id": "10022897__text", "type": "abstract", "text": [ "Activation-dependent transcriptional regulation of the human Fas promoter requires NF-kappaB p50-p65 recruitment. \nFas (CD95) and Fas ligand (CD95L) are an interacting receptor-ligand pair required for immune homeostasis. Lymphocyte activation results in the upregulation of Fas expression and the acquisition of sensitivity to FasL-mediated apoptosis. Although Fas upregulation is central to the preservation of immunologic tolerance, little is known about the molecular machinery underlying this process. To investigate the events involved in activation-induced Fas upregulation, we have examined mRNA accumulation, fas promoter activity, and protein expression in the Jurkat T-cell line treated with phorbol myristate acetate and ionomycin (P/I), pharmacological mimics of T-cell receptor activation. Although resting Jurkat cells express Fas, Fas mRNA was induced approximately 10-fold in 2 h upon P/I stimulation. Using sequential deletion mutants of the human fas promoter in transient transfection assays, we identified a 47-bp sequence (positions -306 to -260 relative to the ATG) required for activation-driven fas upregulation. Sequence analysis revealed the presence of a previously unrecognized composite binding site for both the Sp1 and NF-kappaB transcription factors at positions -295 to -286. Electrophoretic mobility shift assay (EMSA) and supershift analyses of this region documented constitutive binding of Sp1 in unactivated nuclear extracts and inducible binding of p50-p65 NF-kappaB heterodimers after P/I activation. Sp1 and NF-kappaB transcription factor binding was shown to be mutually exclusive by EMSA displacement studies with purified recombinant Sp1 and recombinant p50. The functional contribution of the kappaB-Sp1 composite site in P/I-inducible fas promoter activation was verified by using kappaB-Sp1 concatamers (-295 to -286) in a thymidine kinase promoter-driven reporter construct and native promoter constructs in Jurkat cells overexpressing IkappaB-alpha. Site-directed mutagenesis of the critical guanine nucleotides in the kappaB-Sp1 element documented the essential role of this site in activation-dependent fas promoter induction. " ], "offsets": [ [ 0, 2179 ] ] } ]

[ { "id": "10022897_T1", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 61, 64 ] ], "normalized": [] }, { "id": "10022897_T2", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 93, 96 ] ], "normalized": [] }, { "id": "10022897_T3", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 97, 100 ] ], "normalized": [] }, { "id": "10022897_T4", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 115, 118 ] ], "normalized": [] }, { "id": "10022897_T5", "type": "Protein", "text": [ "CD95" ], "offsets": [ [ 120, 124 ] ], "normalized": [] }, { "id": "10022897_T6", "type": "Protein", "text": [ "Fas ligand" ], "offsets": [ [ 130, 140 ] ], "normalized": [] }, { "id": "10022897_T7", "type": "Protein", "text": [ "CD95L" ], "offsets": [ [ 142, 147 ] ], "normalized": [] }, { "id": "10022897_T8", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 275, 278 ] ], "normalized": [] }, { "id": "10022897_T9", "type": "Protein", "text": [ "FasL" ], "offsets": [ [ 328, 332 ] ], "normalized": [] }, { "id": "10022897_T10", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 362, 365 ] ], "normalized": [] }, { "id": "10022897_T11", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 564, 567 ] ], "normalized": [] }, { "id": "10022897_T12", "type": "Protein", "text": [ "fas" ], "offsets": [ [ 618, 621 ] ], "normalized": [] }, { "id": "10022897_T13", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 842, 845 ] ], "normalized": [] }, { "id": "10022897_T14", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 847, 850 ] ], "normalized": [] }, { "id": "10022897_T15", "type": "Protein", "text": [ "fas" ], "offsets": [ [ 966, 969 ] ], "normalized": [] }, { "id": "10022897_T16", "type": "Protein", "text": [ "fas" ], "offsets": [ [ 1120, 1123 ] ], "normalized": [] }, { "id": "10022897_T17", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1243, 1246 ] ], "normalized": [] }, { "id": "10022897_T18", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1428, 1431 ] ], "normalized": [] }, { "id": "10022897_T19", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1489, 1492 ] ], "normalized": [] }, { "id": "10022897_T20", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1493, 1496 ] ], "normalized": [] }, { "id": "10022897_T21", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1542, 1545 ] ], "normalized": [] }, { "id": "10022897_T22", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1679, 1682 ] ], "normalized": [] }, { "id": "10022897_T23", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1699, 1702 ] ], "normalized": [] }, { "id": "10022897_T24", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1746, 1749 ] ], "normalized": [] }, { "id": "10022897_T25", "type": "Protein", "text": [ "fas" ], "offsets": [ [ 1782, 1785 ] ], "normalized": [] }, { "id": "10022897_T26", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1835, 1838 ] ], "normalized": [] }, { "id": "10022897_T27", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1985, 1998 ] ], "normalized": [] }, { "id": "10022897_T28", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 2076, 2079 ] ], "normalized": [] }, { "id": "10022897_T29", "type": "Protein", "text": [ "fas" ], "offsets": [ [ 2155, 2158 ] ], "normalized": [] }, { "id": "10022897_T32", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 65, 73 ] ], "normalized": [] }, { "id": "10022897_T51", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1786, 1794 ] ], "normalized": [] }, { "id": "10022897_T54", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 2159, 2167 ] ], "normalized": [] } ]

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[ { "id": "9190901__text", "type": "abstract", "text": [ "ETS1, NFkappaB and AP1 synergistically transactivate the human GM-CSF promoter. \nActivation of helper T cells results in coordinate expression of a number of cytokines involved in differentiation, proliferation and activation of the haematopoietic system. Granulocyte-macrophage colony stimulating factor (GM-CSF) is one such cytokine, whose increased expression results mostly from increases in transcription. Cis-acting elements with NFkappaB, AP1 and ETS-like binding motifs have been identified in the promoter region of the GM-CSF gene, and are important or essential for transcriptional activity following T cell activation. ETS1 is a transcription factor of the ETS family that is expressed in T cells. We have previously shown that ETS1 can transactivate GM-CSF in Jurkat T cells, but only after the cells have been stimulated by treatment with PMA and ionomycin, agents that mimic T cell activation. Thus we proposed that ETS1, which is expressed constitutively in Jurkat cells, may act in concert with PMA/ionomycin inducible factors. Here we show that ETS1 can transactivate a GM-CSF reporter construct in unstimulated Jurkat cells, providing that either NFkappaB or AP1 transcription factors are supplied by co-transfection. We confirm that binding of endogenous NFkappaB and AP1 is induced following PMA/ionomycin treatment of T cells. Transactivation by ETS1, NFkappaB and AP1 is synergistic, and mutation of the individual binding sites reveals that the transcriptional activities of these factors are interdependent. Our results suggest that constitutive ETS1, and inducible NFkappaB and AP1, cooperate as part of a higher order transcriptional complex in activated T cells. " ], "offsets": [ [ 0, 1691 ] ] } ]

[ { "id": "9190901_T1", "type": "Protein", "text": [ "ETS1" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "9190901_T2", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 63, 69 ] ], "normalized": [] }, { "id": "9190901_T3", "type": "Protein", "text": [ "Granulocyte-macrophage colony stimulating factor" ], "offsets": [ [ 256, 304 ] ], "normalized": [] }, { "id": "9190901_T4", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 306, 312 ] ], "normalized": [] }, { "id": "9190901_T5", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 529, 535 ] ], "normalized": [] }, { "id": "9190901_T6", "type": "Protein", "text": [ "ETS1" ], "offsets": [ [ 631, 635 ] ], "normalized": [] }, { "id": "9190901_T7", "type": "Protein", "text": [ "ETS1" ], "offsets": [ [ 740, 744 ] ], "normalized": [] }, { "id": "9190901_T8", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 763, 769 ] ], "normalized": [] }, { "id": "9190901_T9", "type": "Protein", "text": [ "ETS1" ], "offsets": [ [ 931, 935 ] ], "normalized": [] }, { "id": "9190901_T10", "type": "Protein", "text": [ "ETS1" ], "offsets": [ [ 1063, 1067 ] ], "normalized": [] }, { "id": "9190901_T11", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 1088, 1094 ] ], "normalized": [] }, { "id": "9190901_T12", "type": "Protein", "text": [ "ETS1" ], "offsets": [ [ 1368, 1372 ] ], "normalized": [] }, { "id": "9190901_T13", "type": "Protein", "text": [ "ETS1" ], "offsets": [ [ 1571, 1575 ] ], "normalized": [] }, { "id": "9190901_T15", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 70, 78 ] ], "normalized": [] }, { "id": "9190901_T20", "type": "Entity", "text": [ "Cis-acting elements" ], "offsets": [ [ 411, 430 ] ], "normalized": [] } ]

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[]

[ { "id": "7532282__text", "type": "abstract", "text": [ "Transcription-independent turnover of I kappa B alpha during monocyte adherence: implications for a translational component regulating I kappa B alpha/MAD-3 mRNA levels. \nWe identified I kappa B alpha/MAD-3 as an immediate-early gene in human monocytes that is expressed in response to a variety of signals, including adhesion, lipopolysaccharide, and phorbol myristate acetate. Within 5 min of monocyte adhesion, the level of the I kappa B alpha protein is markedly diminished but is rapidly replaced in a cycloheximide-sensitive manner within 20 min. Accompanying the rapid turnover of the I kappa B alpha protein is simultaneous translocation of NF-kappa B-related transcription factors to nuclei of adhered monocytes. The demonstration that NF-kappa B can regulate I kappa B alpha/MAD-3 gene transcription in other cell types suggested that the rapid increase in steady-state I kappa B alpha/MAD-3 mRNA levels we observed within 30 min of monocyte adherence would result from NF-kappa B-dependent transcriptional stimulation of the I kappa B alpha/MAD-3 gene. Nuclear run-on analyses indicated that, instead, while several immediate-early cytokine genes, such as the interleukin 1 beta (IL-1 beta) gene, were transcriptionally activated during monocyte adhesion, the rate of I kappa B alpha/MAD-3 gene transcription remained constant. The adherence-dependent increase in I kappa B alpha/MAD-3 mRNA levels was also not a consequence of mRNA stabilization events. Interestingly, while increases in both IL-1 beta and I kappa B alpha/MAD-3 mRNA levels were detected in nuclei of adherent monocytes, cytoplasmic levels of IL-1 beta mRNA increased during adherence whereas those of I kappa B alpha/MAD-3 mRNA did not. Taken together, our data suggest that two interactive mechanisms regulate monocytic I kappa B alpha/MAD-3 mRNA levels. We propose that adherent monocytes regulate nuclear processing (or decay) of I kappa B alpha/MAD-3 mRNA, thereby increasing mRNA levels without stimulating I kappa B alpha/MAD-3 gene transcription. Moreover, since inhibition of protein synthesis leads to accumulation of I kappa B alpha/MAD-3 mRNA without stimulating I kappa B alpha/MAD-3 gene transcription, we suggest that low cytoplasmic levels of I kappa B alpha/MAD-3 mRNA are maintained by a translation-dependent degradation mechanism. " ], "offsets": [ [ 0, 2330 ] ] } ]

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1444, 1457 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7532282_T18" } ] }, { "id": "7532282_E17", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 1487, 1496 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7532282_T21" } ] }, { "id": "7532282_E18", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 1487, 1496 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7532282_T20" } ] }, { "id": "7532282_E19", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1637, 1646 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7532282_T23" } ] }, { "id": "7532282_E20", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1637, 1646 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7532282_T24" } ] }, { "id": "7532282_E21", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 1782, 1790 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7532282_T26" } ] }, { "id": "7532282_E22", "type": "Positive_regulation", "trigger": { "text": [ "increasing" ], "offsets": [ [ 1949, 1959 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7532282_T28" } ] }, { "id": "7532282_E23", "type": "Positive_regulation", "trigger": { "text": [ "without stimulating" ], "offsets": [ [ 1972, 1991 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7532282_E24" } ] }, { "id": "7532282_E24", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 2019, 2032 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7532282_T30" } ] }, { "id": "7532282_E25", "type": "Positive_regulation", "trigger": { "text": [ "leads" ], "offsets": [ [ 2082, 2087 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7532282_E26" } ] }, { "id": "7532282_E26", "type": "Positive_regulation", "trigger": { "text": [ "accumulation" ], "offsets": [ [ 2091, 2103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7532282_T32" } ] }, { "id": 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[ { "id": "10080875__text", "type": "abstract", "text": [ "Involvement of NF-kappaB p50/p65 heterodimer in activation of the human pro-interleukin-1beta gene at two subregions of the upstream enhancer element. \nA region between-3134 and -2729 bp upstream from the transcription site of the human pro-interleukin 1beta (proIL-1beta) gene was identified as an LPS-responsive enhancer element. In this study, the influence of the sequences located between -3134 and -2987 on the transcriptional activity of the proIL-1beta gene in LPS-stimulated Raw 264.7 cells was examined in detail. The results obtained by transient transfection of fos -CAT constructs that contained serial 5'-deletion mutations showed that the region between -3134 and -3059 appears to be required for the induction of transcription by LPS. Gel shift assay studies with synthetic oligonucleotides corresponding to partial sequences of the latter region and nuclear extracts from stimulated cells revealed specific protein binding sites between -3110 and -3090 and between -3079 and -3059. These specific bindings were time and LPS dose dependent. The results of supershift analysis using specific antibodies against transcription factors suggested that both binding complexes contained the NF-kappaB components p50 and p65, and did not contain other NF-kappaB proteins (p52, c-Rel, Rel B), AP-1 proteins (c-Fos, C-Jun), CREB or C/EBPbeta (NF-IL6). Mutation of either of the putative NF-kappaB-binding sites in the enhancer element decreased the LPS-stimulated transcriptional activity. These data indicated that two NF-kappaB-binding sites, which are located between -3134 and -3059, are critical for the activation of proIL-1beta gene transcription. Copyright 1999 Academic Press. " ], "offsets": [ [ 0, 1692 ] ] } ]

[ { "id": "10080875_T1", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 25, 28 ] ], "normalized": [] }, { "id": "10080875_T2", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 29, 32 ] ], "normalized": [] }, { "id": "10080875_T3", "type": "Protein", "text": [ "pro-interleukin-1beta" ], "offsets": [ [ 72, 93 ] ], "normalized": [] }, { "id": "10080875_T4", "type": "Protein", "text": [ "pro-interleukin 1beta" ], "offsets": [ [ 237, 258 ] ], "normalized": [] }, { "id": "10080875_T5", "type": "Protein", "text": [ "proIL-1beta" ], "offsets": [ [ 260, 271 ] ], "normalized": [] }, { "id": "10080875_T6", "type": "Protein", "text": [ "proIL-1beta" ], "offsets": [ [ 449, 460 ] ], "normalized": [] }, { "id": "10080875_T7", "type": "Protein", "text": [ "fos" ], "offsets": [ [ 574, 577 ] ], "normalized": [] }, { "id": "10080875_T8", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 579, 582 ] ], "normalized": [] }, { "id": "10080875_T9", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1221, 1224 ] ], "normalized": [] }, { "id": "10080875_T10", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1229, 1232 ] ], "normalized": [] }, { "id": "10080875_T11", "type": "Protein", "text": [ "p52" ], "offsets": [ [ 1280, 1283 ] ], "normalized": [] }, { "id": "10080875_T12", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 1285, 1290 ] ], "normalized": [] }, { "id": "10080875_T13", "type": "Protein", "text": [ "Rel B" ], "offsets": [ [ 1292, 1297 ] ], "normalized": [] }, { "id": "10080875_T14", "type": "Protein", "text": [ "c-Fos" ], "offsets": [ [ 1315, 1320 ] ], "normalized": [] }, { "id": "10080875_T15", "type": "Protein", "text": [ "C-Jun" ], "offsets": [ [ 1322, 1327 ] ], "normalized": [] }, { "id": "10080875_T16", "type": "Protein", "text": [ "C/EBPbeta" ], "offsets": [ [ 1338, 1347 ] ], "normalized": [] }, { "id": "10080875_T17", "type": "Protein", "text": [ "NF-IL6" ], "offsets": [ [ 1349, 1355 ] ], "normalized": [] }, { "id": "10080875_T18", "type": "Protein", "text": [ "proIL-1beta" ], "offsets": [ [ 1629, 1640 ] ], "normalized": [] } ]

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[ { "id": "1541828__text", "type": "abstract", "text": [ "T cell-specific negative regulation of transcription of the human cytokine IL-4. \nIL-4 secreted by activated T cells is a pleiotropic cytokine affecting growth and differentiation of diverse cell types such as T cells, B cells, and mast cells. We investigated the upstream regulatory elements of the human IL-4 promoter. A novel T cell-specific negative regulatory element (NRE) composed of two protein-binding sites were mapped in the 5' flanking region of the IL-4 gene: -311CTCCCTTCT-303 (NRE-I) and -288CTTTTTGCTT-TGC-300 (NRE-II). A T cell-specific protein Neg-1 and a ubiquitous protein Neg-2 binding to NRE-I and NRE-II, respectively, were identified. Furthermore, a positive regulatory element was found 45 bp downstream of the NRE. The enhancer activity of the PRE was completely suppressed when the NRE was present. These data suggest that IL-4 promoter activity is normally down-regulated by an NRE via repression of the enhancer positive regulatory element. These data may have implications for the stringent control of IL-4 expression in T cells. " ], "offsets": [ [ 0, 1060 ] ] } ]

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[]

[]

[ { "id": "9872676__text", "type": "abstract", "text": [ "Interleukin-10 stabilizes inhibitory kappaB-alpha in human monocytes. \nInterleukin-10 (IL-10) protects animals from lethal endotoxemia. This beneficial effect is mediated, in part, by inhibition of inflammatory cytokine production, including tumor necrosis factor-alpha (TNF-alpha). Evidence suggests that IL-10 may inhibit activation of the transcription factor nuclear factor-kappaB (NF-kappaB) through an unknown mechanism. NF-kappaB activation in response to inflammatory signals is dependent upon degradation of its associated inhibitory peptide, inhibitory kappaB-alpha (IkappaB-alpha). We hypothesized that IL-10 prevents human monocyte NF-kappaB activation and resultant TNF-alpha production by stabilization of IkappaB-alpha. The purpose of this study was to determine the effect of IL-10 on lipopolysaccharide (LPS)-induced human monocyte TNF-alpha production, NF-kappaB activation, and IkappaB-alpha degradation. Monocytes were isolated from human donors. Cells were stimulated with endotoxin (LPS, 100 ng/mL) with and without human IL-10 (10 ng/mL). Following stimulation, TNF-alpha was measured in cell supernatants by ELISA, NF-kappaB activity by electrophoretic mobility shift assay, and IkappaB-alpha levels by Western blot. We observed that after LPS stimulation of human monocytes, TNF-alpha increased to 798+/-67 pg/mL (p < .001 versus control). IL-10 attenuated LPS-stimulated TNF-alpha production (297+/-54; p < .001 versus LPS alone). After LPS stimulation in human monocytes, IkappaB-alpha protein levels decreased, and NF-kappaB DNA binding increased. IL-10 pretreatment prevented LPS-induced decreases in IkappaB-alpha protein levels and attenuated NF-kappaB DNA binding. IL-10 appears to prevent activation of NF-kappaB by preserving IkappaB-alpha protein levels, leading to a reduction in TNF-alpha release. " ], "offsets": [ [ 0, 1835 ] ] } ]

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"ref_id": "9872676_T13" } ] }, { "id": "9872676_E11", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 782, 788 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9872676_E14" }, { "role": "Cause", "ref_id": "9872676_T13" } ] }, { "id": "9872676_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 826, 833 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9872676_E15" } ] }, { "id": "9872676_E13", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 826, 833 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9872676_E14" } ] }, { "id": "9872676_E14", "type": "Gene_expression", "trigger": { "text": [ "production" ], "offsets": [ [ 859, 869 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9872676_T14" } ] }, { "id": "9872676_E15", "type": "Protein_catabolism", "trigger": { "text": [ "degradation" ], "offsets": [ [ 911, 922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9872676_T15" } ] }, { 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"preserving" ], "offsets": [ [ 1749, 1759 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9872676_T26" }, { "role": "Cause", "ref_id": "9872676_T25" } ] }, { "id": "9872676_E27", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 1803, 1812 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9872676_E28" } ] }, { "id": "9872676_E28", "type": "Localization", "trigger": { "text": [ "release" ], "offsets": [ [ 1826, 1833 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9872676_T27" } ] } ]

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[]

[ { "id": "9136989__text", "type": "abstract", "text": [ "Inhibitor (IK) of IFN-gamma induced HLA class II antigens expression also inhibits HLA class II constitutive expression in the human Raji B cell line. \nThe expression of major histocompatibility complex (MHC) class II antigens is constitutive in professional antigen presenting cells (APCs) but can also be induced by interferon-gamma (IFN-gamma) on the majority of the non professional APCs (e.g. fibroblasts). We have recently characterised a new factor called IK which is an efficient inhibitor of IFN-gamma induction of MHC class II antigens expression. Here, we demonstrate a novel role for IK in MHC class II expression since over-expression of this protein by stable transfection into human B cells led to a total disappearance of constitutive MHC class II mRNA expression. The class II transactivator (CIITA) is necessary for both constitutive and IFN-gamma induced MHC class II expressions. Examination of CIITA mRNA in IK stably transfected clones revealed a marked reduction of CIITA mRNA transcription. Taken together these results demonstrate that the IK protein plays a key role in the constitutive expression of MHC class II antigens and that inhibition induced by IK is upstream of CIITA in this regulatory pathway. " ], "offsets": [ [ 0, 1232 ] ] } ]

[ { "id": "9136989_T1", "type": "Protein", "text": [ "IK" ], "offsets": [ [ 11, 13 ] ], "normalized": [] }, { "id": "9136989_T2", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 18, 27 ] ], "normalized": [] }, { "id": "9136989_T3", "type": "Protein", "text": [ "interferon-gamma" ], "offsets": [ [ 318, 334 ] ], "normalized": [] }, { "id": "9136989_T4", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 336, 345 ] ], "normalized": [] }, { "id": "9136989_T5", "type": "Protein", "text": [ "IK" ], "offsets": [ [ 463, 465 ] ], "normalized": [] }, { "id": "9136989_T6", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 501, 510 ] ], "normalized": [] }, { "id": "9136989_T7", "type": "Protein", "text": [ "IK" ], "offsets": [ [ 596, 598 ] ], "normalized": [] }, { "id": "9136989_T8", "type": "Protein", "text": [ "class II transactivator" ], "offsets": [ [ 785, 808 ] ], "normalized": [] }, { "id": "9136989_T9", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 810, 815 ] ], "normalized": [] }, { "id": "9136989_T10", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 856, 865 ] ], "normalized": [] }, { "id": "9136989_T11", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 915, 920 ] ], "normalized": [] }, { "id": "9136989_T12", "type": "Protein", "text": [ "IK" ], "offsets": [ [ 929, 931 ] ], "normalized": [] }, { "id": "9136989_T13", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 989, 994 ] ], "normalized": [] }, { "id": "9136989_T14", "type": "Protein", "text": [ "IK" ], "offsets": [ [ 1065, 1067 ] ], "normalized": [] }, { "id": "9136989_T15", "type": "Protein", "text": [ "IK" ], "offsets": [ [ 1180, 1182 ] ], "normalized": [] }, { "id": "9136989_T16", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1198, 1203 ] ], "normalized": [] } ]

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[]

[ { "id": "8600942__text", "type": "abstract", "text": [ "Surfactant suppresses NF-kappa B activation in human monocytic cells. \nIn addition to biophysical properties, pulmonary surfactant has immunomodulatory activity. We previously demonstrated that both synthetic (Exosurf) and modified natural surfactant (Survanta) downregulated endotoxin-stimulated inflammatory cytokine mRNA levels and protein products (tumor necrosis factor-alpha [TNF], interleukin-1-beta [IL-1], interleukin-6 [IL-6]) in human alveolar macrophages. In this study, we report that both Exosurf and Survanta suppress TNF mRNA and secretion (85 +/- 4% mean percent inhibition +/- SEM by Exosurf; 71 +/- 6% by Survanta) by endotoxin-stimulated THP-1, a human monocytic cell line. Because surfactant downregulated inflammatory cytokine production similarly in both normal human alveolar macrophages and the THP-1 cell line, we used this cell line to investigate whether surfactant affected transcriptional mechanisms. Specifically, we examined nuclear factor-kappa B (NF-kappa B) activation because it is crucial in transcriptional regulation of many inflammatory cytokine genes including TNF, IL-1, and IL-6. Electrophoretic mobility shift assays showed that both surfactants decreased activation of NF-kappa B. The presence of both p65 and p50 NF-kappa B components in LPS-activated THP-1 cells was confirmed by specific antibody induction of supershifts in mobility assays. These results are the first to suggest that surfactant's suppressive effects on inflammatory cytokine production may involve transcriptional regulation through inhibition of NF-kappa B activation. " ], "offsets": [ [ 0, 1587 ] ] } ]

[ { "id": "8600942_T1", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 353, 380 ] ], "normalized": [] }, { "id": "8600942_T2", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 382, 385 ] ], "normalized": [] }, { "id": "8600942_T3", "type": "Protein", "text": [ "interleukin-1-beta" ], "offsets": [ [ 388, 406 ] ], "normalized": [] }, { "id": "8600942_T4", "type": "Protein", "text": [ "IL-1" ], "offsets": [ [ 408, 412 ] ], "normalized": [] }, { "id": "8600942_T5", "type": "Protein", "text": [ "interleukin-6" ], "offsets": [ [ 415, 428 ] ], "normalized": [] }, { "id": "8600942_T6", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 430, 434 ] ], "normalized": [] }, { "id": "8600942_T7", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 533, 536 ] ], "normalized": [] }, { "id": "8600942_T8", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 1102, 1105 ] ], "normalized": [] }, { "id": "8600942_T9", "type": "Protein", "text": [ "IL-1" ], "offsets": [ [ 1107, 1111 ] ], "normalized": [] }, { "id": "8600942_T10", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 1117, 1121 ] ], "normalized": [] }, { "id": "8600942_T11", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1247, 1250 ] ], "normalized": [] }, { "id": "8600942_T12", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1255, 1258 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "7788861__text", "type": "abstract", "text": [ "Expression of Ah receptor (TCDD receptor) during human monocytic differentiation. \nWe have previously found a high expression of human Ah receptor (TCDD receptor) mRNA in peripheral blood cells of individuals. In this paper, the expression of this gene in blood cells was first investigated in fractions of nucleated cells, revealing predominant expression of the Ah receptor gene in the monocyte fraction. Then the expression levels of AhR mRNA in various hematopoietic cell lines were examined together with those of Arnt and P450IA1. AhR was expressed at high levels in monocytoid U937, THP1, and HEL/S cells, and at moderate levels in promyelocytic HL60 cells and erythroblastic HEL cells. However, it was not detected in lymphoid cells MOLT4 (T cell) and BALL1 (B cell), nor in K562 erythroblasts. Furthermore, a specific induction of AhR during monocytic differentiation was investigated in HL60 and HEL cells. HL60 cells were induced to differentiate toward monocytes-macrophages by incubation with phorbol ester, showing a 5- to 2-fold increase of AhR mRNA. The incubation with transforming growth factor beta 1 and 1 alpha,25-dihydroxyvitamin D3 resulted in a 5- to 7-fold increase of AhR mRNA. The HEL cells also exhibited a similar elevation of AhR mRNA level, when they had differentiated toward monocyte-macrophage cells by these combined inducers, but little change in the mRNA level was observed when the cells were induced to differentiate into other cell types. Treatment of the differentiated HL60 cells with 3-methylcholanthrene, a ligand of AhR, induced the expression of the P450IA1 gene. These results indicated that expression of AhR mRNA was significantly induced during monocytic differentiation and that the differentiated cells were responsive to xenobiotics. Our results suggest that AhR may play an important role in the function of monocytes and also in the eventual activation of environmental carcinogens. " ], "offsets": [ [ 0, 1938 ] ] } ]

[ { "id": "7788861_T1", "type": "Protein", "text": [ "Ah receptor" ], "offsets": [ [ 14, 25 ] ], "normalized": [] }, { "id": "7788861_T2", "type": "Protein", "text": [ "TCDD receptor" ], "offsets": [ [ 27, 40 ] ], "normalized": [] }, { "id": "7788861_T3", "type": "Protein", "text": [ "Ah receptor" ], "offsets": [ [ 135, 146 ] ], "normalized": [] }, { "id": "7788861_T4", "type": "Protein", "text": [ "TCDD receptor" ], "offsets": [ [ 148, 161 ] ], "normalized": [] }, { "id": "7788861_T5", "type": "Protein", "text": [ "Ah receptor" ], "offsets": [ [ 364, 375 ] ], "normalized": [] }, { "id": "7788861_T6", "type": "Protein", "text": [ "AhR" ], "offsets": [ [ 437, 440 ] ], "normalized": [] }, { "id": "7788861_T7", "type": "Protein", "text": [ "P450IA1" ], "offsets": [ [ 528, 535 ] ], "normalized": [] }, { "id": "7788861_T8", "type": "Protein", "text": [ "AhR" ], "offsets": [ [ 537, 540 ] ], "normalized": [] }, { "id": "7788861_T9", "type": "Protein", "text": [ "AhR" ], "offsets": [ [ 840, 843 ] ], "normalized": [] }, { "id": "7788861_T10", "type": "Protein", "text": [ "AhR" ], "offsets": [ [ 1056, 1059 ] ], "normalized": [] }, { "id": "7788861_T11", "type": "Protein", "text": [ "transforming growth factor beta 1" ], "offsets": [ [ 1086, 1119 ] ], "normalized": [] }, { "id": "7788861_T12", "type": "Protein", "text": [ "AhR" ], "offsets": [ [ 1194, 1197 ] ], "normalized": [] }, { "id": "7788861_T13", "type": "Protein", "text": [ "AhR" ], "offsets": [ [ 1256, 1259 ] ], "normalized": [] }, { "id": "7788861_T14", "type": "Protein", "text": [ "AhR" ], "offsets": [ [ 1561, 1564 ] ], "normalized": [] }, { "id": "7788861_T15", "type": "Protein", "text": [ "P450IA1" ], "offsets": [ [ 1596, 1603 ] ], "normalized": [] }, { "id": "7788861_T16", "type": "Protein", "text": [ "AhR" ], "offsets": [ [ 1653, 1656 ] ], "normalized": [] }, { "id": "7788861_T17", "type": "Protein", "text": [ "AhR" ], "offsets": [ [ 1812, 1815 ] ], "normalized": [] } ]

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[]

[ { "id": "9144218__text", "type": "abstract", "text": [ "An enhancer-blocking element between alpha and delta gene segments within the human T cell receptor alpha/delta locus. \nT cell receptor (TCR) alpha and delta gene segments are organized within a single genetic locus but are differentially regulated during T cell development. An enhancer-blocking element (BEAD-1, for blocking element alpha/delta 1) was localized to a 2.0-kb region 3' of TCR delta gene segments and 5' of TCR alpha joining gene segments within this locus. BEAD-1 blocked the ability of the TCR delta enhancer (Edelta) to activate a promoter when located between the two in a chromatin-integrated construct. We propose that BEAD-1 functions as a boundary that separates the TCR alpha/delta locus into distinct regulatory domains controlled by Edelta and the TCR alpha enhancer, and that it prevents Edelta from opening the chromatin of the TCR alpha joining gene segments for VDJ recombination at an early stage of T cell development. " ], "offsets": [ [ 0, 952 ] ] } ]

[]

[]

[]

[]

[ { "id": "7890777__text", "type": "abstract", "text": [ "Mapping of the interaction site of the defective transcription factor in the class II major histocompatibility complex mutant cell line clone-13 to the divergent X2-box. \nWe have previously described a mutant B lymphoblastoid cell line, Clone-13, that expresses HLA-DQ in the absence of HLA-DR and -DP. Several criteria indicated that the defect in this cell line influences the activity of an isotype-specific transcription factor. Indeed, transient transfection of HLA-DRA and DQB reporter constructs indicated that the affected factor operates via cis-elements located between -141 base pairs and the transcription initiation site. A series of hybrid DRA/DQB reporter constructs was generated to further map the relevant cis-elements in this system. Insertion of oligonucleotides spanning the DQB X-box (but not the DQB-W region or the DQB Y-box) upstream of -141 in a DRA reporter plasmid rescued expression to nearly wild-type levels. Substitution promoters were then generated where the entire X-box, or only the X1- or X2-boxes of HLA-DRA were replaced with the analogous regions of HLA-DQB. The DQB X2-box was able to restore expression to the silent DRA reporter construct. Moreover, replacement of the DQB X2-box with the DRA X2-box markedly diminished the activity of the DQB promoter in the mutant cell. None of the hybrid reporter constructs were defective when transfected into the wild-type, HLA-DR/-DQ positive parental cell line, Jijoye. These studies suggest that the divergent X2-box of the class II major histocompatibility complex promoters plays an important role in influencing differential expression of the human class II isotypes. " ], "offsets": [ [ 0, 1657 ] ] } ]

[ { "id": "7890777_T1", "type": "Protein", "text": [ "HLA-DRA" ], "offsets": [ [ 1038, 1045 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "1653950__text", "type": "abstract", "text": [ "USF-related transcription factor, HIV-TF1, stimulates transcription of human immunodeficiency virus-1. \nThe transcription factor HIV-TF1, which binds to a region about 60 bp upstream from the enhancer of the human immunodeficiency virus-1 (HIV-1), was purified from human B cells. HIV-TF1 had a molecular weight of 39,000. Binding of HIV-TF1 to the HIV long terminal repeat (LTR) activated transcription from the HIV promoter in vitro. The HIV-TF1-binding site in HIV LTR was similar to the site recognized by upstream stimulatory factor (USF) in the adenovirus major late promoter. DNA-binding properties of HIV-TF1 suggested that HIV-TF1 might be identical or related to USF. Interestingly, treatment of purified HIV-TF1 by phosphatase greatly reduced its DNA-binding activity, suggesting that phosphorylation of HIV-TF1 was essential for DNA binding. The disruption of HIV-TF1-binding site induced a 60% decrease in the level of transcription from the HIV promoter in vivo. These results suggest that HIV-TF1 is involved in transcriptional regulation of HIV-1. " ], "offsets": [ [ 0, 1064 ] ] } ]

[ { "id": "1653950_T1", "type": "Protein", "text": [ "USF" ], "offsets": [ [ 0, 3 ] ], "normalized": [] }, { "id": "1653950_T2", "type": "Protein", "text": [ "HIV-TF1" ], "offsets": [ [ 34, 41 ] ], "normalized": [] }, { "id": "1653950_T3", "type": "Protein", "text": [ "HIV-TF1" ], "offsets": [ [ 129, 136 ] ], "normalized": [] }, { "id": "1653950_T4", "type": "Protein", "text": [ "HIV-TF1" ], "offsets": [ [ 281, 288 ] ], "normalized": [] }, { "id": "1653950_T5", "type": "Protein", "text": [ "HIV-TF1" ], "offsets": [ [ 334, 341 ] ], "normalized": [] }, { "id": "1653950_T6", "type": "Protein", "text": [ "HIV-TF1" ], "offsets": [ [ 440, 447 ] ], "normalized": [] }, { "id": "1653950_T7", "type": "Protein", "text": [ "upstream stimulatory factor" ], "offsets": [ [ 510, 537 ] ], "normalized": [] }, { "id": "1653950_T8", "type": "Protein", "text": [ "USF" ], "offsets": [ [ 539, 542 ] ], "normalized": [] }, { "id": "1653950_T9", "type": "Protein", "text": [ "HIV-TF1" ], "offsets": [ [ 609, 616 ] ], "normalized": [] }, { "id": "1653950_T10", "type": "Protein", "text": [ "HIV-TF1" ], "offsets": [ [ 632, 639 ] ], "normalized": [] }, { "id": "1653950_T11", "type": "Protein", "text": [ "USF" ], "offsets": [ [ 673, 676 ] ], "normalized": [] }, { "id": "1653950_T12", "type": "Protein", "text": [ "HIV-TF1" ], "offsets": [ [ 715, 722 ] ], "normalized": [] }, { "id": "1653950_T13", "type": "Protein", "text": [ "HIV-TF1" ], "offsets": [ [ 815, 822 ] ], "normalized": [] }, { "id": "1653950_T14", "type": "Protein", "text": [ "HIV-TF1" ], "offsets": [ [ 872, 879 ] ], "normalized": [] }, { "id": "1653950_T15", "type": "Protein", "text": [ "HIV-TF1" ], "offsets": [ [ 1004, 1011 ] ], "normalized": [] } ]

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[ { "id": "9858618__text", "type": "abstract", "text": [ "Interactions between the class II transactivator and CREB binding protein increase transcription of major histocompatibility complex class II genes. \nClass II major histocompatibility (class II) genes are regulated in a B-cell-specific and gamma interferon-inducible fashion. The master switch for the expression of these genes is the class II transactivator (CIITA). In this report, we demonstrate that one of the functions of CIITA is to recruit the CREB binding protein (CBP) to class II promoters. Not only functional but also specific binding interactions between CIITA and CBP were demonstrated. Moreover, a dominant negative form of CBP decreased the activity of class II promoters and levels of class II determinants on the surface of cells. Finally, the inhibition of class II gene expression by the glucocorticoid hormone could be attributed to the squelching of CBP by the glucocorticoid receptor. We conclude that CBP, a histone acetyltransferase, plays an important role in the transcription of class II genes. " ], "offsets": [ [ 0, 1024 ] ] } ]

[ { "id": "9858618_T1", "type": "Protein", "text": [ "class II transactivator" ], "offsets": [ [ 25, 48 ] ], "normalized": [] }, { "id": "9858618_T2", "type": "Protein", "text": [ "CREB binding protein" ], "offsets": [ [ 53, 73 ] ], "normalized": [] }, { "id": "9858618_T3", "type": "Protein", "text": [ "gamma interferon" ], "offsets": [ [ 240, 256 ] ], "normalized": [] }, { "id": "9858618_T4", "type": "Protein", "text": [ "class II transactivator" ], "offsets": [ [ 335, 358 ] ], "normalized": [] }, { "id": "9858618_T5", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 360, 365 ] ], "normalized": [] }, { "id": "9858618_T6", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 428, 433 ] ], "normalized": [] }, { "id": "9858618_T7", "type": "Protein", "text": [ "CREB binding protein" ], "offsets": [ [ 452, 472 ] ], "normalized": [] }, { "id": "9858618_T8", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 474, 477 ] ], "normalized": [] }, { "id": "9858618_T9", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 569, 574 ] ], "normalized": [] }, { "id": "9858618_T10", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 579, 582 ] ], "normalized": [] }, { "id": "9858618_T11", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 640, 643 ] ], "normalized": [] }, { "id": "9858618_T12", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 873, 876 ] ], "normalized": [] }, { "id": "9858618_T13", "type": "Protein", "text": [ "glucocorticoid receptor" ], "offsets": [ [ 884, 907 ] ], "normalized": [] }, { "id": "9858618_T14", "type": "Protein", "text": [ "CBP" ], "offsets": [ [ 926, 929 ] ], "normalized": [] } ]

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[ { "id": "7802642__text", "type": "abstract", "text": [ "Platelet-activating factor (PAF) positively auto-regulates the expression of human PAF receptor transcript 1 (leukocyte-type) through NF-kappa B. \nThe human platelet-activating factor receptor (PAFR) gene is transcribed by two distinct promoters (promoter 1 and promoter 2) to generate two transcripts (designated as PAFR transcript 1 and PAFR transcript 2), though their open reading frames are identical. By primer extension analysis to discriminate two transcripts, we found that the levels of PAFR transcript 1 (leukocyte-type), but not PAFR transcript 2 (tissue-type), are upregulated by PAF as well as by 12-O-tetradecanoylphorbol-13-acetate (TPA) in the human stomach cancer cell line (JR-St cells) which expresses both functional PAFR transcript 1 and PAFR transcript 2 endogenously. Functional analysis of the promoter 1 with a transient expression assay using chloramphenicol acetyltransferase (CAT) gene as a reporter showed that both PAF and TPA activated the promoter 1 but not the deleted promoter lacking the three consensus binding sites for NF-kappa B located from -571 bp to -459 bp. These findings suggest a molecular mechanism of positive regulation of PAFR gene expression by PAF through NF-kappa B, possibly by a phosphorylation reaction involving protein kinase C by PAF. " ], "offsets": [ [ 0, 1295 ] ] } ]

[ { "id": "7802642_T1", "type": "Protein", "text": [ "PAF receptor" ], "offsets": [ [ 83, 95 ] ], "normalized": [] }, { "id": "7802642_T2", "type": "Protein", "text": [ "platelet-activating factor receptor" ], "offsets": [ [ 157, 192 ] ], "normalized": [] }, { "id": "7802642_T3", "type": "Protein", "text": [ "PAFR" ], "offsets": [ [ 194, 198 ] ], "normalized": [] }, { "id": "7802642_T4", "type": "Protein", "text": [ "PAFR" ], "offsets": [ [ 317, 321 ] ], "normalized": [] }, { "id": "7802642_T5", "type": "Protein", "text": [ "PAFR" ], "offsets": [ [ 339, 343 ] ], "normalized": [] }, { "id": "7802642_T6", "type": "Protein", "text": [ "PAFR" ], "offsets": [ [ 497, 501 ] ], "normalized": [] }, { "id": "7802642_T7", "type": "Protein", "text": [ "PAFR" ], "offsets": [ [ 541, 545 ] ], "normalized": [] }, { "id": "7802642_T8", "type": "Protein", "text": [ "PAFR" ], "offsets": [ [ 738, 742 ] ], "normalized": [] }, { "id": "7802642_T9", "type": "Protein", "text": [ "PAFR" ], "offsets": [ [ 760, 764 ] ], "normalized": [] }, { "id": "7802642_T10", "type": "Protein", "text": [ "chloramphenicol acetyltransferase" ], "offsets": [ [ 870, 903 ] ], "normalized": [] }, { "id": "7802642_T11", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 905, 908 ] ], "normalized": [] }, { "id": "7802642_T12", "type": "Protein", "text": [ "PAFR" ], "offsets": [ [ 1173, 1177 ] ], "normalized": [] } ]

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[]

[ { "id": "1911548__text", "type": "abstract", "text": [ "A nuclear factor NF-GM2 that interacts with a regulatory region of the GM-CSF gene essential for its induction in responses to T-cell activation: purification from human T-cell leukemia line Jurkat cells and similarity to NF-kappa B. \nActivation of T cells by antigen, lectin, or a combination of phorbol-12-myristate acetate (PMA) and calcium ionophore (A23187) leads to the induction of genes for a set of lymphokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF). We demonstrated in earlier studies that the upstream region of the mouse GM-CSF promoter at positions between -95 and -73 is essential for transcriptional activation in response to PMA/A23187. This region contains two DNA-binding motifs, GM2 and GC-box. The GM2 sequence (GGTAGTTCCC) is recognized by an inducible factor NF-GM2; the other (CCGCCC) by constitutive factors A1, A2, and B. To elucidate the mechanism of GM-CSF gene activation, we have purified the inducible factor NF-GM2 from the nuclear extract of stimulated Jurkat cells on the basis of specific DNA-binding activity. The purified NF-GM2 consists of 50 (p50) and 65 kDa (p65) polypeptides and has a binding activity specific for both the GM-CSF and immunoglobulin kappa (GGAAAGTCCC) enhancers. Electrophoretically purified p50 alone can form a protein-DNA complex, but in the mixture, p50 associates preferentially with p65 to form the NF-GM2 complex. In addition, p65 gave per se, with low affinity, a protein-DNA complex that migrated more slowly than native NF-GM2 complex. Furthermore, an antiserum against KBF1 (identical to 50 kDa NF-kappa B protein) reacted with the p50 of NF-GM2, indicating that the NF-GM2 polypeptide cannot be immunologically differentiated from the 50 kDa subunit of NF-kappa B. The purified NF-GM2 activated in vitro transcription from the kappa B enhancer, while it failed to stimulate transcription from the GM-CSF promoter harboring the GM2 sequence. This suggests that the activation mechanism of the GM-CSF gene through the GM2/GC-box sequence is different from that of genes carrying the kappa B enhancer alone. " ], "offsets": [ [ 0, 2105 ] ] } ]

[ { "id": "1911548_T1", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 71, 77 ] ], "normalized": [] }, { "id": "1911548_T2", "type": "Protein", "text": [ "granulocyte-macrophage colony-stimulating factor" ], "offsets": [ [ 431, 479 ] ], "normalized": [] }, { "id": "1911548_T3", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 481, 487 ] ], "normalized": [] }, { "id": "1911548_T4", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 563, 569 ] ], "normalized": [] }, { "id": "1911548_T5", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 907, 913 ] ], "normalized": [] }, { "id": "1911548_T6", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1111, 1114 ] ], "normalized": [] }, { "id": "1911548_T7", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1128, 1131 ] ], "normalized": [] }, { "id": "1911548_T8", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 1195, 1201 ] ], "normalized": [] }, { "id": "1911548_T9", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1280, 1283 ] ], "normalized": [] }, { "id": "1911548_T10", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1342, 1345 ] ], "normalized": [] }, { "id": "1911548_T11", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1377, 1380 ] ], "normalized": [] }, { "id": "1911548_T12", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1422, 1425 ] ], "normalized": [] }, { "id": "1911548_T13", "type": "Protein", "text": [ "KBF1" ], "offsets": [ [ 1568, 1572 ] ], "normalized": [] }, { "id": "1911548_T14", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1631, 1634 ] ], "normalized": [] }, { "id": "1911548_T15", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 1897, 1903 ] ], "normalized": [] }, { "id": "1911548_T16", "type": "Protein", "text": [ "GM-CSF" ], "offsets": [ [ 1992, 1998 ] ], "normalized": [] }, { "id": "1911548_T26", "type": "Entity", "text": [ "enhancers" ], "offsets": [ [ 1240, 1249 ] ], "normalized": [] } ]

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[ { "id": "10206983__text", "type": "abstract", "text": [ "Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP). \nActivation of T lymphocytes to produce cytokines is regulated by the counterbalance of protein-tyrosine kinases and protein-tyrosine phosphatases, many of which have a high degree of substrate specificity because of physical association with their targets. Overexpression of hematopoietic protein-tyrosine phosphatase (HePTP) results in suppression of T lymphocyte activation as measured by T cell antigen receptor-induced activation of transcription factors binding to the 5' promoter of the interleukin-2 gene. Efforts to pinpoint the exact site of action and specificity of HePTP in the signaling cascade revealed that HePTP acts directly on the mitogen-activated protein (MAP) kinases Erk1 and 2 and consequently reduces the magnitude and duration of their catalytic activation in intact T cells. In contrast, HePTP had no effects on N-terminal c-Jun kinase or on events upstream of the MAP kinases. The specificity of HePTP correlated with its physical association through its noncatalytic N terminus with Erk and another MAP kinase, p38, but not Jnk or other proteins. We propose that HePTP plays a negative role in antigen receptor signaling by specifically regulating MAP kinases in the cytosol and at early time points of T cell activation before the activation-induced expression of nuclear dual-specific MAP kinase phosphatases. " ], "offsets": [ [ 0, 1461 ] ] } ]

[ { "id": "10206983_T1", "type": "Protein", "text": [ "hematopoietic tyrosine phosphatase" ], "offsets": [ [ 76, 110 ] ], "normalized": [] }, { "id": "10206983_T2", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 112, 117 ] ], "normalized": [] }, { "id": "10206983_T3", "type": "Protein", "text": [ "hematopoietic protein-tyrosine phosphatase" ], "offsets": [ [ 396, 438 ] ], "normalized": [] }, { "id": "10206983_T4", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 440, 445 ] ], "normalized": [] }, { "id": "10206983_T5", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 614, 627 ] ], "normalized": [] }, { "id": "10206983_T6", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 698, 703 ] ], "normalized": [] }, { "id": "10206983_T7", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 743, 748 ] ], "normalized": [] }, { "id": "10206983_T8", "type": "Protein", "text": [ "Erk1" ], "offsets": [ [ 810, 814 ] ], "normalized": [] }, { "id": "10206983_T9", "type": "Protein", "text": [ "2" ], "offsets": [ [ 819, 820 ] ], "normalized": [] }, { "id": "10206983_T10", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 935, 940 ] ], "normalized": [] }, { "id": "10206983_T11", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 1044, 1049 ] ], "normalized": [] }, { "id": "10206983_T12", "type": "Protein", "text": [ "HePTP" ], "offsets": [ [ 1212, 1217 ] ], "normalized": [] } ]

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[]

[ { "id": "10233875__text", "type": "abstract", "text": [ "NF-kappaB activation is required for C5a-induced interleukin-8 gene expression in mononuclear cells. \nC5a, a potent peptide chemoattractant, stimulates interleukin-8 (IL-8) secretion from peripheral blood mononuclear cells (PBMC). Experiments were conducted to understand the mechanisms for C5a-induced IL-8 production, which was 14-fold greater than that in unstimulated cells by 2 hours. IL-8 secretion was accompanied by accumulation of IL-8 mRNA in the cytosol and by nuclear expression of a kappaB DNA binding activity within 30 minutes. AP-1 but not NF-IL-6 DNA binding activity was also detected in C5a-stimulated PBMC; however, its delayed expression (maximal at 4 hours) suggested a less important role in the rapid production of IL-8. The correlation between C5a-induced kappaB binding activity and IL-8 gene expression was examined in the RAW264.7 macrophage cells using reporter genes directed by the kappaB sequence from IkappaBalpha and IL-8 promoter regions. C5a-induced reporter gene expression was abolished by introducing mutations into the kappaB sites and by coexpression of a dominant negative IkappaBalpha construct resistant to agonist-induced phosphorylation. Pertussis toxin, which ADP-ribosylates the Gi proteins known to couple to the C5a receptor, produced minimal inhibition of C5a-induced IL-8 expression and had little effect on C5a-induced calcium mobilization in RAW264.7 cells. These results suggest that NF-kappaB activation is required for C5a-induced IL-8 gene expression and that this response is mediated primarily through a pertussis toxin-insensitive pathway. " ], "offsets": [ [ 0, 1601 ] ] } ]

[ { "id": "10233875_T1", "type": "Protein", "text": [ "interleukin-8" ], "offsets": [ [ 49, 62 ] ], "normalized": [] }, { "id": "10233875_T2", "type": "Protein", "text": [ "interleukin-8" ], "offsets": [ [ 152, 165 ] ], "normalized": [] }, { "id": "10233875_T3", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 167, 171 ] ], "normalized": [] }, { "id": "10233875_T4", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 303, 307 ] ], "normalized": [] }, { "id": "10233875_T5", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 390, 394 ] ], "normalized": [] }, { "id": "10233875_T6", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 440, 444 ] ], "normalized": [] }, { "id": "10233875_T7", "type": "Protein", "text": [ "NF-IL-6" ], "offsets": [ [ 556, 563 ] ], "normalized": [] }, { "id": "10233875_T8", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 739, 743 ] ], "normalized": [] }, { "id": "10233875_T9", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 809, 813 ] ], "normalized": [] }, { "id": "10233875_T10", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 934, 946 ] ], "normalized": [] }, { "id": "10233875_T11", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 951, 955 ] ], "normalized": [] }, { "id": "10233875_T12", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 1115, 1127 ] ], "normalized": [] }, { "id": "10233875_T13", "type": "Protein", "text": [ "C5a receptor" ], "offsets": [ [ 1262, 1274 ] ], "normalized": [] }, { "id": "10233875_T14", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1319, 1323 ] ], "normalized": [] }, { "id": "10233875_T15", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1488, 1492 ] ], "normalized": [] } ]

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[ { "id": "10233875_1", "entity_ids": [ "10233875_T2", "10233875_T3" ] } ]

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[ { "id": "9479628__text", "type": "abstract", "text": [ "Oxidants, transcription factors, and intestinal inflammation. \nIt is now well appreciated that chronic gut inflammation is characterized by enhanced production of reactive metabolites of oxygen and nitrogen. Some of these oxidants are known to modulate the expression of a variety of genes that are involved in the immune and inflammatory responses. For example, certain oxidants are known to activate the nuclear transcription factor kappa B, which regulates the expression of a variety of different adhesion molecules, cytokines, and enzymes. Oxidants are also known to activate another transcription factor, activator protein-1. This transcription factor is composed of products from the fos and jun proto-oncogene family and is believed to be important in regulating cell growth and proliferation. Finally, oxidants are believed to promote intestinal epithelial cell apoptosis, and the B-cell lymphoma/leukemia-2 gene product is believed to inhibit this phenomenon in an antioxidant-dependent manner. Taken together, these observations suggest that nontoxic concentrations of reactive metabolites of oxygen and nitrogen play an important role in regulating the expression of genes involved in the inflammatory response and in modulating apoptosis. " ], "offsets": [ [ 0, 1252 ] ] } ]

[ { "id": "9479628_T1", "type": "Protein", "text": [ "fos" ], "offsets": [ [ 691, 694 ] ], "normalized": [] }, { "id": "9479628_T2", "type": "Protein", "text": [ "jun" ], "offsets": [ [ 699, 702 ] ], "normalized": [] }, { "id": "9479628_T3", "type": "Protein", "text": [ "B-cell lymphoma/leukemia-2" ], "offsets": [ [ 890, 916 ] ], "normalized": [] } ]

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[ { "id": "9724034__text", "type": "abstract", "text": [ "Glucocorticoid-induced apoptosis and regulation of NF-kappaB activity in human leukemic T cells. \nGlucocorticoid-induced apoptosis was investigated in glucocorticoid-sensitive 6TG1.1 and resistant ICR27TK.3 human leukemic T cells. Following glucocorticoid treatment of 6TG1.1 cells, chromatin fragmentation was observed after a delay of 24 h. Fragmentation was not observed in ICR27TK.3 cells containing mutant glucocorticoid receptors (L753F) that are activation-deficient but retain the ability to repress AP-1 activity. Nor was fragmentation observed after treatment with RU38486, indicating that repression of AP-1 activity is not involved. As described in other systems, fragmentation required ongoing protein synthesis. However, inhibition of protein synthesis with cycloheximide anytime during the first 18 h of steroid treatment was as effective in blocking chromatin fragmentation as inhibition for the entire period, suggesting that synthesis of a component with a rapid turnover rate is required. Dexamethasone treatment completely blocked 12-O-tetradecanoylphorbol 13-acetate induction of nuclear factor-kappaB (NF-kappaB) activity and elicited an increase in the amount of immunoreactive IkappaB alpha in sensitive 6TG1.1 cells but not in resistant ICR27TK.3 cells. In addition, mild detergent treatment of cell extracts indicated that a substantial amount of cytoplasmic NF-kappaB is complexed with IkappaB alpha or some other inhibitory factor. These results suggest that induction of a labile inhibitory factor such as IkappaB alpha may contribute to glucocorticoid-induced apoptosis. " ], "offsets": [ [ 0, 1601 ] ] } ]

[ { "id": "9724034_T1", "type": "Protein", "text": [ "IkappaB alpha" ], "offsets": [ [ 1201, 1214 ] ], "normalized": [] }, { "id": "9724034_T2", "type": "Protein", "text": [ "IkappaB alpha" ], "offsets": [ [ 1413, 1426 ] ], "normalized": [] }, { "id": "9724034_T3", "type": "Protein", "text": [ "IkappaB alpha" ], "offsets": [ [ 1535, 1548 ] ], "normalized": [] } ]

[ { "id": "9724034_E1", "type": "Positive_regulation", "trigger": { "text": [ "increase" ], "offsets": [ [ 1160, 1168 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9724034_T1" } ] }, { "id": "9724034_E2", "type": "Binding", "trigger": { "text": [ "complexed" ], "offsets": [ [ 1398, 1407 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9724034_T2" } ] }, { "id": "9724034_E3", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1487, 1496 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9724034_T3" } ] } ]

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[ { "id": "9343406__text", "type": "abstract", "text": [ "Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells. \nDithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants. " ], "offsets": [ [ 0, 2095 ] ] } ]

[ { "id": "9343406_T1", "type": "Protein", "text": [ "interleukin 2" ], "offsets": [ [ 505, 518 ] ], "normalized": [] }, { "id": "9343406_T2", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 520, 524 ] ], "normalized": [] }, { "id": "9343406_T3", "type": "Protein", "text": [ "c-Jun" ], "offsets": [ [ 678, 683 ] ], "normalized": [] }, { "id": "9343406_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 775, 779 ] ], "normalized": [] }, { "id": "9343406_T5", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 1308, 1313 ] ], "normalized": [] }, { "id": "9343406_T6", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 1384, 1389 ] ], "normalized": [] }, { "id": "9343406_T7", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 1547, 1552 ] ], "normalized": [] }, { "id": "9343406_T8", "type": "Protein", "text": [ "c-Jun NH2-terminal kinase" ], "offsets": [ [ 1902, 1927 ] ], "normalized": [] }, { "id": "9343406_T9", "type": "Protein", "text": [ "JNK" ], "offsets": [ [ 1929, 1932 ] ], "normalized": [] }, { "id": "9343406_T10", "type": "Protein", "text": [ "NFATp" ], "offsets": [ [ 1970, 1975 ] ], "normalized": [] } ]

[ { "id": "9343406_E1", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 490, 499 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9343406_E2" } ] }, { "id": "9343406_E2", "type": "Gene_expression", "trigger": { "text": [ "synthesis" ], "offsets": [ [ 526, 535 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9343406_T2" } ] }, { "id": "9343406_E3", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 664, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9343406_E4" } ] }, { "id": "9343406_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 714, 724 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9343406_T3" } ] }, { "id": "9343406_E5", "type": "Regulation", "trigger": { "text": [ "targeted" ], "offsets": [ [ 1294, 1302 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9343406_T5" } ] }, { "id": "9343406_E6", "type": "Positive_regulation", "trigger": { "text": [ "promoted" ], "offsets": [ [ 1503, 1511 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9343406_E7" } ] }, { "id": "9343406_E7", "type": "Localization", "trigger": { "text": [ "shuttling" ], "offsets": [ [ 1534, 1543 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9343406_T7" } ] }, { "id": "9343406_E8", "type": "Positive_regulation", "trigger": { "text": [ "leading to their accelerated" ], "offsets": [ [ 1564, 1592 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9343406_E9" }, { "role": "Cause", "ref_id": "9343406_E6" } ] }, { "id": "9343406_E9", "type": "Localization", "trigger": { "text": [ "export" ], "offsets": [ [ 1593, 1599 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9343406_T7" } ] }, { "id": "9343406_E10", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylating" ], "offsets": [ [ 1954, 1969 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9343406_T10" } ] }, { "id": "9343406_E11", "type": "Positive_regulation", "trigger": { "text": [ "phosphorylating" ], "offsets": [ [ 1954, 1969 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9343406_E10" }, { "role": "Cause", "ref_id": "9343406_T9" } ] } ]

[ { "id": "9343406_1", "entity_ids": [ "9343406_T1", "9343406_T2" ] }, { "id": "9343406_2", "entity_ids": [ "9343406_T8", "9343406_T9" ] } ]

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[ { "id": "9570512__text", "type": "abstract", "text": [ "Human immunodeficiency virus type 1 long terminal repeat quasispecies differ in basal transcription and nuclear factor recruitment in human glial cells and lymphocytes. \nThe generation of genomic diversity during the course of infection has the potential to affect all aspects of HIV-1 replication, including expression of the proviral genome. To gain a better understanding of the impact of long terminal repeat (LTR) sequence diversity on LTR-directed gene expression in cells of the central nervous system (CNS) and immune system, we amplified and cloned LTRs from proviral DNA in HIV-1-infected peripheral blood. Sequence analysis of nineteen LTRs cloned from 2 adult and 3 pediatric patients revealed an average of 33 nucleotide changes (with respect to the sequence of the LAI LTR) within the 455-bp U3 region. Transient expression analyses in cells of neuroglial and lymphocytic origin demonstrated that some of these LTRs had activities which varied significantly from the LAI LTR in U-373 MG cells (an astrocytoma cell line) as well as in Jurkat cells (a CD4-positive lymphocyte cell line). While LTRs which demonstrated the highest activities in U-373 MG cells also yielded high activities in Jurkat cells, the LTRs were generally more active in Jurkat cells when compared to the LAI LTR. Differences in LTR sequence also resulted in differences in transcription factor recruitment to cis-acting sites within the U3 region of the LTR, as demonstrated by electrophoretic mobility shift assays. In particular, naturally occurring sequence variation impacted transcription factor binding to an activating transcription factor/cAMP response element binding (ATF/CREB) binding site (located between the LEF-1 and distal NF-kappaB transcription factor binding sites) that we identified in previous studies of the HIV-1 LTR. These findings suggest that LTR sequence changes can significantly affect basal LTR function and transcription factor recruitment, which may, in turn, alter the course of viral replication in cells of CNS and immune system origin. " ], "offsets": [ [ 0, 2059 ] ] } ]

[ { "id": "9570512_T1", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1064, 1067 ] ], "normalized": [] }, { "id": "9570512_T2", "type": "Protein", "text": [ "LEF-1" ], "offsets": [ [ 1708, 1713 ] ], "normalized": [] } ]

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[ { "id": "7523507__text", "type": "abstract", "text": [ "Inducible binding to the c-fos serum response element during T cell activation is regulated by a phosphotyrosine-containing protein. \nThe proto-oncogene c-fos is an immediate-early gene, and one of the first genes transcribed after stimulation of most cells with a variety of ligands. Fos expression may be a pivotal event in converting ligand-receptor interactions at the membrane into functional modulation of cell phenotype. The serum response element (SRE) in the c-fos regulatory region participates in induction of transcription by various growth factors and by phorbol esters and subsequent squelching of transcription. We show that an inducible protein complex (Band A) binds to SRE DNA within 10 min after mitogenic stimulation of human PBL-T, and becomes nondetectable by 60 min. Band A contains the serum response factor plus additional factor(s). A protein that is phosphorylated on a tyrosine residue in resting PBL-T suppresses binding of a component of Band A to the SRE motif. Upon stimulation of the cells, this protein no longer prevents binding of DNA by Band A, and suppression of binding is restored within 30 min. The phosphorylated tyrosine residue itself is important for the protein-protein interaction. " ], "offsets": [ [ 0, 1229 ] ] } ]

[ { "id": "7523507_T1", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 25, 30 ] ], "normalized": [] }, { "id": "7523507_T2", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 153, 158 ] ], "normalized": [] }, { "id": "7523507_T3", "type": "Protein", "text": [ "Fos" ], "offsets": [ [ 285, 288 ] ], "normalized": [] }, { "id": "7523507_T4", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 468, 473 ] ], "normalized": [] } ]

[ { "id": "7523507_E1", "type": "Transcription", "trigger": { "text": [ "transcribed" ], "offsets": [ [ 214, 225 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7523507_T2" } ] }, { "id": "7523507_E2", "type": "Positive_regulation", "trigger": { "text": [ "after" ], "offsets": [ [ 226, 231 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7523507_E1" } ] }, { "id": "7523507_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 289, 299 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7523507_T3" } ] } ]

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