Datasets:

bigbio

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bionlp_shared_task_2009

like 2

[ { "id": "10352279__text", "type": "abstract", "text": [ "CD28 costimulation augments IL-2 secretion of activated lamina propria T cells by increasing mRNA stability without enhancing IL-2 gene transactivation. \nThe pathways leading to activation in lamina propria (LP) T cells are different from peripheral T cells. LP T cells exhibit enhanced IL-2 secretion when activated through the CD2 pathway. Coligation of CD28 leads to synergistic enhancement of IL-2 secretion. Previous studies have characterized the CD28 augmentation of TCR-mediated signaling in peripheral blood T cells through transcriptional activation of an IL-2 promoter CD28 response element (CD28RE), along with enhanced mRNA stability. This study characterized molecular events involved in CD28 costimulation of IL-2 production in LP mononuclear cells (LPMC). LPMC exhibited increased IL-2 production in response to CD28 costimulation, compared with cells activated through CD2 alone. IL-2 secretion was paralleled by increased expression of IL-2 mRNA, resulting from enhanced IL-2 mRNA stability. In contrast to transcriptional activation in PBMC, EMSA revealed that CD28 coligation of CD2-activated LPMC does not result in increased binding of trans-factors to the CD28RE, nor did Western blots detect changes in I-kappaBalpha or I-kappaBbeta levels following CD28 coligation. Furthermore, CD28 coligation fails to enhance IL-2 promoter-reporter or RE/AP construct expression in CD2-activated LPMC. The results reported herein indicate that the molecular mechanisms involved in CD28 cosignaling and regulation of IL-2 secretion in LP T cells are unique to that compartment and differ from those seen in peripheral blood T cells. These observations suggest a biological significance for different mechanisms of IL-2 activation in initiation and maintenance of the cytokine repertoire found in the mucosa. " ], "offsets": [ [ 0, 1818 ] ] } ]

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[ { "id": "9886419__text", "type": "abstract", "text": [ "Regulation of IL-6 synthesis in human peripheral blood mononuclear cells by C3a and C3a(desArg). \nThe anaphylatoxin C3a has been reported to have immunomodulatory effects on a number of different cell types. In this study we investigated the effects of C3a and C3a(desArg) on gene expression and protein secretion of IL-6 in human PBMCs, either alone or in combination with LPS or IL-1beta. C3a or C3a(desArg) alone exhibited no effect on the expression or secretion of IL-6. However, when PBMC were stimulated with LPS or IL-1beta, both C3a and C3a(desArg) were found to enhance IL-6 release by PBMC in a dose-dependent manner. Since C3a has been shown to induce PGE2 production by monocytes, and PGE2 has been shown to influence cytokine production, we investigated the potential role of PGE2 in C3a-mediated enhancement of LPS- and IL-1beta-induced IL-6 production. Indomethacin blocked PGE2 release, but had no influence on the observed effects of C3a, suggesting that the effects of C3a on IL-6 production are independent of PGE2 formation by monocytes. Northern blot analysis showed that C3a as well as C3a(desArg) enhanced LPS-induced mRNA levels for IL-6. Pretreatment of PBMCs with pertussis toxin blocked the functions of C3a and C3a(desArg), indicating that the actions of these two molecules are mediated by a G protein-coupled pathway. Furthermore, we investigated the effects of C3a and C3a(desArg) on induction of NF-kappaB and activating protein-1 binding. Both molecules enhanced LPS-induced NF-kappaB and activating protein-1 binding activity. These results demonstrate the capacity of intact C3a and its circulating des-Arg form to exert immunmodulatory effects in vitro. " ], "offsets": [ [ 0, 1691 ] ] } ]

[ { "id": "9886419_T1", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 14, 18 ] ], "normalized": [] }, { "id": "9886419_T2", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 76, 79 ] ], "normalized": [] }, { "id": "9886419_T3", "type": "Protein", "text": [ "C3a(desArg)" ], "offsets": [ [ 84, 95 ] ], "normalized": [] }, { "id": "9886419_T4", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 116, 119 ] ], "normalized": [] }, { "id": "9886419_T5", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 253, 256 ] ], "normalized": [] }, { "id": "9886419_T6", "type": "Protein", "text": [ "C3a(desArg)" ], "offsets": [ [ 261, 272 ] ], "normalized": [] }, { "id": "9886419_T7", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 317, 321 ] ], "normalized": [] }, { "id": "9886419_T8", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 381, 389 ] ], "normalized": [] }, { "id": "9886419_T9", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 391, 394 ] ], "normalized": [] }, { "id": "9886419_T10", "type": "Protein", "text": [ "C3a(desArg)" ], "offsets": [ [ 398, 409 ] ], "normalized": [] }, { "id": "9886419_T11", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 470, 474 ] ], "normalized": [] }, { "id": "9886419_T12", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 523, 531 ] ], "normalized": [] }, { "id": "9886419_T13", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 538, 541 ] ], "normalized": [] }, { "id": "9886419_T14", "type": "Protein", "text": [ "C3a(desArg)" ], "offsets": [ [ 546, 557 ] ], "normalized": [] }, { "id": "9886419_T15", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 580, 584 ] ], "normalized": [] }, { "id": "9886419_T16", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 635, 638 ] ], "normalized": [] }, { "id": "9886419_T17", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 798, 801 ] ], "normalized": [] }, { "id": "9886419_T18", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 835, 843 ] ], "normalized": [] }, { "id": "9886419_T19", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 852, 856 ] ], "normalized": [] }, { "id": "9886419_T20", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 952, 955 ] ], "normalized": [] }, { "id": "9886419_T21", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 988, 991 ] ], "normalized": [] }, { "id": "9886419_T22", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 995, 999 ] ], "normalized": [] }, { "id": "9886419_T23", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 1094, 1097 ] ], "normalized": [] }, { "id": "9886419_T24", "type": "Protein", "text": [ "C3a(desArg)" ], "offsets": [ [ 1109, 1120 ] ], "normalized": [] }, { "id": "9886419_T25", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 1158, 1162 ] ], "normalized": [] }, { "id": "9886419_T26", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 1232, 1235 ] ], "normalized": [] }, { "id": "9886419_T27", "type": "Protein", "text": [ "C3a(desArg)" ], "offsets": [ [ 1240, 1251 ] ], "normalized": [] }, { "id": "9886419_T28", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 1393, 1396 ] ], "normalized": [] }, { "id": "9886419_T29", "type": "Protein", "text": [ "C3a(desArg)" ], "offsets": [ [ 1401, 1412 ] ], "normalized": [] }, { "id": "9886419_T30", "type": "Protein", "text": [ "C3a" ], "offsets": [ [ 1611, 1614 ] ], "normalized": [] } ]

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"ref_id": "9886419_T25" } ] }, { "id": "9886419_E35", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1207, 1214 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9886419_E33" } ] }, { "id": "9886419_E36", "type": "Negative_regulation", "trigger": { "text": [ "blocked" ], "offsets": [ [ 1207, 1214 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9886419_E32" } ] }, { "id": "9886419_E37", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1308, 1316 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9886419_E33" } ] }, { "id": "9886419_E38", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 1308, 1316 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9886419_E32" } ] } ]

[]

[]

[ { "id": "9271352__text", "type": "abstract", "text": [ "CholecystokininB receptor from human Jurkat lymphoblastic T cells is involved in activator protein-1-responsive gene activation. \nThe aim of this study was to analyze the role of cholecystokinin (CCK(B)) receptor in human lymphoblastic Jurkat T cells. We investigated the trophic effect resulting from activation of such a receptor by using the reporter gene strategy. For this purpose, we transiently transfected Jurkat T cells with the reporter plasmid p[(TRE)3-tk-Luc] and found that CCK-8 was able to dose-dependently induce luciferase expression related to activator protein-1 (AP-1) activation with a maximal response identical to that obtained with compounds known to activate AP-1 complex (quantitatively, the same level of induction was obtained with 1 nM 12-O-tetradecanoylphorbol-13-acetate, 100 microM diacylglycerol, or 4 nM epidermal growth factor). The involvement of the CCK(B) receptor in such a stimulation was demonstrated by the inhibiting effect of the selective CCK(B) receptor antagonist PD-135,158. This effect was confirmed in COS-7 cells transfected with the cDNA of CCK(B) receptor cloned from Jurkat T cells. To better understand the AP-1-dependent luciferase expression in Jurkat T cells, we tested two specific inhibitors of serine/threonine phosphatases-1 and -2A: okadaic acid and calyculin A. These compounds strongly increased the phorbol-12-myristate-13-acetate response, whereas we have not observed a contribution of phosphatase inhibitors on a CCK-8-induced luciferase activity. To confirm that CCK(B) receptors are involved in AP-1 response, we investigated the CCK-8 effect on interleukin-2 expression, a natural endogenous gene regulated by several factors, including AP-1. In Jurkat T cells activated by phorbol-12-myristate-13-acetate and phytohemagglutinin, CCK-8 induced IL-2 expression. This induction was abolished by PD-135,158. Our results indicate that CCK-8 exerts a trophic effect in Jurkat T cells through stimulation of CCK(B) receptors by modulation of expression of AP-1-regulated genes. " ], "offsets": [ [ 0, 2044 ] ] } ]

[ { "id": "9271352_T1", "type": "Protein", "text": [ "CholecystokininB receptor" ], "offsets": [ [ 0, 25 ] ], "normalized": [] }, { "id": "9271352_T2", "type": "Protein", "text": [ "(CCK(B)) receptor" ], "offsets": [ [ 195, 212 ] ], "normalized": [] }, { "id": "9271352_T3", "type": "Protein", "text": [ "luciferase" ], "offsets": [ [ 529, 539 ] ], "normalized": [] }, { "id": "9271352_T4", "type": "Protein", "text": [ "CCK(B) receptor" ], "offsets": [ [ 887, 902 ] ], "normalized": [] }, { "id": "9271352_T5", "type": "Protein", "text": [ "CCK(B) receptor" ], "offsets": [ [ 984, 999 ] ], "normalized": [] }, { "id": "9271352_T6", "type": "Protein", "text": [ "CCK(B) receptor" ], "offsets": [ [ 1093, 1108 ] ], "normalized": [] }, { "id": "9271352_T7", "type": "Protein", "text": [ "luciferase" ], "offsets": [ [ 1177, 1187 ] ], "normalized": [] }, { "id": "9271352_T8", "type": "Protein", "text": [ "serine/threonine phosphatases-1" ], "offsets": [ [ 1255, 1286 ] ], "normalized": [] }, { "id": "9271352_T9", "type": "Protein", "text": [ "-2A" ], "offsets": [ [ 1291, 1294 ] ], "normalized": [] }, { "id": "9271352_T10", "type": "Protein", "text": [ "luciferase" ], "offsets": [ [ 1496, 1506 ] ], "normalized": [] }, { "id": "9271352_T11", "type": "Protein", "text": [ "CCK(B) receptors" ], "offsets": [ [ 1533, 1549 ] ], "normalized": [] }, { "id": "9271352_T12", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 1617, 1630 ] ], "normalized": [] }, { "id": "9271352_T13", "type": "Protein", "text": [ "phytohemagglutinin" ], "offsets": [ [ 1782, 1800 ] ], "normalized": [] }, { "id": "9271352_T14", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1816, 1820 ] ], "normalized": [] }, { "id": "9271352_T15", "type": "Protein", "text": [ "CCK(B) receptors" ], "offsets": [ [ 1974, 1990 ] ], "normalized": [] } ]

[ { "id": "9271352_E1", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 302, 312 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_T2" } ] }, { "id": "9271352_E2", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 522, 528 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_E3" } ] }, { "id": "9271352_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 540, 550 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_T3" } ] }, { "id": "9271352_E4", "type": "Positive_regulation", "trigger": { "text": [ "induction was obtained" ], "offsets": [ [ 732, 754 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_E3" } ] }, { "id": "9271352_E5", "type": "Regulation", "trigger": { "text": [ "involvement" ], "offsets": [ [ 868, 879 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_E2" }, { "role": "Cause", "ref_id": "9271352_T4" } ] }, { "id": "9271352_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibiting effect" ], "offsets": [ [ 949, 966 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_E2" } ] }, { "id": "9271352_E7", "type": "Negative_regulation", "trigger": { "text": [ "antagonist" ], "offsets": [ [ 1000, 1010 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_T5" } ] }, { "id": "9271352_E8", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 1167, 1176 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_E9" } ] }, { "id": "9271352_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1188, 1198 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_T7" } ] }, { "id": "9271352_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 1241, 1251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_T8" } ] }, { "id": "9271352_E11", "type": "Negative_regulation", "trigger": { "text": [ "inhibitors" ], "offsets": [ [ 1241, 1251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_T9" } ] }, { "id": "9271352_E12", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1488, 1495 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_T10" } ] }, { "id": "9271352_E13", "type": "Regulation", "trigger": { "text": [ "effect" ], "offsets": [ [ 1607, 1613 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_E14" } ] }, { "id": "9271352_E14", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1631, 1641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_T12" } ] }, { "id": "9271352_E15", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 1669, 1678 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_T12" } ] }, { "id": "9271352_E16", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1808, 1815 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_E17" } ] }, { "id": "9271352_E17", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1821, 1831 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_T14" } ] }, { "id": "9271352_E18", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 1852, 1861 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_E16" } ] }, { "id": "9271352_E19", "type": "Positive_regulation", "trigger": { "text": [ "stimulation" ], "offsets": [ [ 1959, 1970 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9271352_T15" } ] } ]

[]

[]

[ { "id": "10329626__text", "type": "abstract", "text": [ "Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. \nJagged1 belongs to the DSL family of ligands for Notch receptors that control the proliferation and differentiation of various cell lineages. However, little is known about the transcription factors that regulate its expression. Here, we show that Jagged1 is a Rel/NF-kappaB-responsive gene. Both c-Rel and RelA induced jagged1 gene expression, whereas a mutant defective for transactivation did not. Importantly, jagged1 transcripts were also upregulated by endogenous NF-kappaB activation and this effect was inhibited by a dominant mutant of IkappaBalpha, a physiological inhibitor of NF-kappaB. Cell surface expression of Jagged1 in c-Rel-expressing cell monolayers led to a functional interaction with lymphocytes expressing the Notch1/TAN-1 receptor. This correlated with the initiation of signaling downstream of Notch, as evidenced by increased levels of HES-1 transcripts in co-cultivated T cells and of CD23 transcripts in co-cultivated B cells. Consistent with its Rel/NF-kappaB-dependent induction, Jagged1 was found to be highly expressed in splenic B cells where c-Rel is expressed constitutively. These results demonstrate that c-Rel can trigger the Notch signaling pathway in neighboring cells by inducing jagged1 gene expression, and suggest a role for Jagged1 in B-cell activation, differentiation or function. These findings also highlight the potential for an interplay between the Notch and NF-kappaB signaling pathways in the immune system. " ], "offsets": [ [ 0, 1587 ] ] } ]

[ { "id": "10329626_T1", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 84, 91 ] ], "normalized": [] }, { "id": "10329626_T2", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 124, 131 ] ], "normalized": [] }, { "id": "10329626_T3", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 372, 379 ] ], "normalized": [] }, { "id": "10329626_T4", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 421, 426 ] ], "normalized": [] }, { "id": "10329626_T5", "type": "Protein", "text": [ "RelA" ], "offsets": [ [ 431, 435 ] ], "normalized": [] }, { "id": "10329626_T6", "type": "Protein", "text": [ "jagged1" ], "offsets": [ [ 444, 451 ] ], "normalized": [] }, { "id": "10329626_T7", "type": "Protein", "text": [ "jagged1" ], "offsets": [ [ 538, 545 ] ], "normalized": [] }, { "id": "10329626_T8", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 669, 681 ] ], "normalized": [] }, { "id": "10329626_T9", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 750, 757 ] ], "normalized": [] }, { "id": "10329626_T10", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 761, 766 ] ], "normalized": [] }, { "id": "10329626_T11", "type": "Protein", "text": [ "Notch1" ], "offsets": [ [ 858, 864 ] ], "normalized": [] }, { "id": "10329626_T12", "type": "Protein", "text": [ "TAN-1" ], "offsets": [ [ 865, 870 ] ], "normalized": [] }, { "id": "10329626_T13", "type": "Protein", "text": [ "HES-1" ], "offsets": [ [ 987, 992 ] ], "normalized": [] }, { "id": "10329626_T14", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 1037, 1041 ] ], "normalized": [] }, { "id": "10329626_T15", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 1135, 1142 ] ], "normalized": [] }, { "id": "10329626_T16", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 1201, 1206 ] ], "normalized": [] }, { "id": "10329626_T17", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 1267, 1272 ] ], "normalized": [] }, { "id": "10329626_T18", "type": "Protein", "text": [ "jagged1" ], "offsets": [ [ 1346, 1353 ] ], "normalized": [] }, { "id": "10329626_T19", "type": "Protein", "text": [ "Jagged1" ], "offsets": [ [ 1394, 1401 ] ], "normalized": [] } ]

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[ { "id": "10329626_1", "entity_ids": [ "10329626_T11", "10329626_T12" ] } ]

[]

[ { "id": "7665588__text", "type": "abstract", "text": [ "Ubiquitin-mediated processing of NF-kappa B transcriptional activator precursor p105. Reconstitution of a cell-free system and identification of the ubiquitin-carrier protein, E2, and a novel ubiquitin-protein ligase, E3, involved in conjugation. \nIn most cases, the transcriptional factor NF-kappa B is a heterodimer consisting of two subunits, p50 and p65, which are encoded by two distinct genes of the Rel family. p50 is translated as a precursor of 105 kDa. The C-terminal domain of the precursor is rapidly degraded, forming the mature p50 subunit consisted of the N-terminal region of the molecule. The mechanism of generation of p50 is not known. It has been suggested that the ubiquitin-proteasome system is involved in the process; however, the specific enzymes involved and the mechanism of limited proteolysis, in which half of the molecule is spared, have been obscure. Palombella and colleagues (Palombella, V.J., Rando, O.J., Goldberg, A.L., and Maniatis, T.(1994) Cell 78, 773-785) have shown that ubiquitin is required for the processing in a cell-free system of a truncated, artificially constructed, 60-kDa precursor. They have also shown that proteasome inhibitors block the processing both in vitro and in vivo. In this study, we demonstrate reconstitution of a cell-free processing system and demonstrate directly that: (a) the ubiquitin-proteasome system is involved in processing of the intact p105 precursor, (b) conjugation of ubiquitin to the precursor is an essential intermediate step in the processing, (c) the recently discovered novel species of the ubiquitin-carrier protein, E2-F1, that is involved in the conjugation and degradation of p53, is also required for the limited processing of the p105 precursor, and (d) a novel, approximately 320-kDa species of ubiquitin-protein ligase, is involved in the process. This novel enzyme is distinct from E6-AP, the p53-conjugating ligase, and from E3 alpha, the \"N-end rule\" ligase. " ], "offsets": [ [ 0, 1961 ] ] } ]

[ { "id": "7665588_T1", "type": "Protein", "text": [ "Ubiquitin" ], "offsets": [ [ 0, 9 ] ], "normalized": [] }, { "id": "7665588_T2", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 80, 84 ] ], "normalized": [] }, { "id": "7665588_T3", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 149, 158 ] ], "normalized": [] }, { "id": "7665588_T4", "type": "Protein", "text": [ "E2" ], "offsets": [ [ 176, 178 ] ], "normalized": [] }, { "id": "7665588_T5", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 192, 201 ] ], "normalized": [] }, { "id": "7665588_T6", "type": "Protein", "text": [ "E3" ], "offsets": [ [ 218, 220 ] ], "normalized": [] }, { "id": "7665588_T7", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 346, 349 ] ], "normalized": [] }, { "id": "7665588_T8", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 354, 357 ] ], "normalized": [] }, { "id": "7665588_T9", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 418, 421 ] ], "normalized": [] }, { "id": "7665588_T10", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 542, 545 ] ], "normalized": [] }, { "id": "7665588_T11", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 637, 640 ] ], "normalized": [] }, { "id": "7665588_T12", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 686, 695 ] ], "normalized": [] }, { "id": "7665588_T13", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1014, 1023 ] ], "normalized": [] }, { "id": "7665588_T14", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1350, 1359 ] ], "normalized": [] }, { "id": "7665588_T15", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 1418, 1422 ] ], "normalized": [] }, { "id": "7665588_T16", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1582, 1591 ] ], "normalized": [] }, { "id": "7665588_T17", "type": "Protein", "text": [ "E2-F1" ], "offsets": [ [ 1609, 1614 ] ], "normalized": [] }, { "id": "7665588_T18", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1671, 1674 ] ], "normalized": [] }, { "id": "7665588_T19", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 1727, 1731 ] ], "normalized": [] }, { "id": "7665588_T20", "type": "Protein", "text": [ "ubiquitin" ], "offsets": [ [ 1793, 1802 ] ], "normalized": [] }, { "id": "7665588_T21", "type": "Protein", "text": [ "E6-AP" ], "offsets": [ [ 1882, 1887 ] ], "normalized": [] }, { "id": "7665588_T22", "type": "Protein", "text": [ "p53" ], "offsets": [ [ 1893, 1896 ] ], "normalized": [] }, { "id": "7665588_T23", "type": "Protein", "text": [ "E3 alpha" ], "offsets": [ [ 1926, 1934 ] ], "normalized": [] } ]

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[ { "id": "9428796__text", "type": "abstract", "text": [ "Estrogen receptor diminishes DNA-binding activities of chicken GATA-1 and CACCC-binding proteins. \nThe estrogen receptor (ER) repressed erythroid differentiation and erythroid-specific gene expression. In this study, we investigated the effect of ER alpha (referred to throughout as ER) on DNA-binding activities of transcription factors involved in regulating the expression of erythroid-specific genes, and, in particular, the histone H5 gene. Using electrophoretic mobility shift assays, we found that in the presence of rabbit reticulocyte lysate, human ER reduced the binding activities of chicken immature erythrocyte nuclear extracted proteins to GATA and CACCC sites in the H5 promoter and enhancer. In contrast, the binding activities of NF1 and Sp1 were not affected by ER. Binding of ER to an estrogen response element was enhanced by addition of rabbit reticulocyte lysate. This lysate was also necessary for ER to diminish the DNA-binding activity of GATA-1. These results suggest that additional factor(s) are necessary for full ER function. Both GATA-1 and CACCC-binding proteins are critical for the developmentally regulated expression of erythroid-specific genes. We hypothesize that interference in DNA-binding activities of GATA-1 and CACCC-binding proteins is the mechanism by which the ER inhibits regulation of these genes. " ], "offsets": [ [ 0, 1347 ] ] } ]

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[ { "id": "10482545__text", "type": "abstract", "text": [ "Induction of Bcl-x(L) expression by human T-cell leukemia virus type 1 Tax through NF-kappaB in apoptosis-resistant T-cell transfectants with Tax. \nHuman T-cell leukemia virus type 1 (HTLV-1) Tax is thought to play a pivotal role in immortalization of T cells. We have recently shown that the expression of Tax protected the mouse T-cell line CTLL-2 against apoptosis induced by interleukin-2 (IL-2) deprivation and converted its growth from being IL-2 dependent to being IL-2 independent. In this study, we demonstrate that constitutive expression of bcl-xl but not bcl-2, bcl-xs, bak, bad, or bax was associated with apoptosis resistance after IL-2 deprivation in CTLL-2 cells that expressed Tax. Transient-transfection assays showed that bcl-x promoter was transactivated by wild-type Tax. Similar effects were observed in mutant Tax retaining transactivating ability through NF-kappaB. Deletion or substitution of a putative NF-kappaB binding site identified in the bcl-x promoter significantly decreased Tax-induced transactivation. This NF-kappaB-like element was able to form a complex with NF-kappaB family proteins in vitro. Furthermore, Tax-induced transactivation of the bcl-x promoter was also diminished by the mutant IkappaBalpha, which specifically inhibits NF-kappaB activity. Our findings suggest that constitutive expression of Bcl-x(L) induced by Tax through the NF-kappaB pathway contributes to the inhibition of apoptosis in CTLL-2 cells after IL-2 deprivation. " ], "offsets": [ [ 0, 1483 ] ] } ]

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[ { "id": "10482545_1", "entity_ids": [ "10482545_T6", "10482545_T7" ] } ]

[]

[ { "id": "9045614__text", "type": "abstract", "text": [ "Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway. \nHuman immunodeficiency virus-type 1 (HIV-1) infection is characterized by a chronic state of immune hyperactivation in patients. Infection of human peripheral blood lymphocytes with HIV-1 in vitro resulted in increased interleukin-2 (IL-2) secretion in response to T cell activation via the CD3 and CD28 receptors. Expression of the HIV-1 transactivator Tat recapitulated this phenotype and was associated with increased IL-2 secretion in response to costimulation with CD3 plus CD28. IL-2 superinduction by Tat occurred at the transcriptional level, was mediated by the CD28-responsive element in the IL-2 promoter, and was exclusively dependent on the 29 amino acids encoded by the second exon of Tat. " ], "offsets": [ [ 0, 792 ] ] } ]

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[ { "id": "9045614_E1", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 297, 306 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9045614_E3" } ] }, { "id": "9045614_E2", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 328, 337 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9045614_T3" } ] }, { "id": "9045614_E3", "type": "Positive_regulation", "trigger": { "text": [ "in response to" ], "offsets": [ [ 338, 352 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9045614_E2" } ] }, { "id": "9045614_E4", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 499, 508 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9045614_E5" }, { "role": "Cause", "ref_id": "9045614_T5" } ] }, { "id": "9045614_E5", "type": "Localization", "trigger": { "text": [ "secretion" ], "offsets": [ [ 514, 523 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9045614_T4" } ] }, { "id": "9045614_E6", "type": "Positive_regulation", "trigger": { "text": [ "superinduction" ], "offsets": [ [ 578, 592 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9045614_T6" } ] }, { "id": "9045614_E7", "type": "Positive_regulation", "trigger": { "text": [ "mediated" ], "offsets": [ [ 643, 651 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9045614_E6" } ] }, { "id": "9045614_E8", "type": "Positive_regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 725, 734 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9045614_E6" } ] } ]

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[ { "id": "8562512__text", "type": "abstract", "text": [ "Cross-linking of Fc gamma receptors activates HIV-1 long terminal repeat-driven transcription in human monocytes. \nElevation of the levels of circulating immune complexes frequently accompanies HIV-1 infection and is a prognostic indicator of clinical progression from asymptomatic infection to AIDS. Here we report that cross-linking of Fc gamma RI or Fc gamma RII by adherent human IgG or by specific anti-Fc gamma R mAb activates HIV-1 gene expression in the human monocytic cell line BF24 and increased HIV RNA expression in monocytes from HIV infected patients as assayed by reverse transcription-PCR. In THP-1 cells, Fc gamma R cross-linking induced NF-kappa B, which is known to bind to the regulatory region of the long terminal repeat (LTR) of HIV-1 and to activate HIV-1 transcription. Anti-TNF-alpha antibody but not anti-IL-1 beta antibody strongly inhibited both the induction of HIV-1-LTR-driven transcription and the induction of NF-kappa B by Fc gamma R cross-linking. These results indicate that Fc gamma R can mediate a TNF-alpha-dependent induction of HIV-1 gene transcription and suggest that immune complexes may contribute to the pathophysiology of HIV-1 infection by augmenting viral replication in monocytes. " ], "offsets": [ [ 0, 1233 ] ] } ]

[ { "id": "8562512_T1", "type": "Protein", "text": [ "Fc gamma RI" ], "offsets": [ [ 338, 349 ] ], "normalized": [] }, { "id": "8562512_T2", "type": "Protein", "text": [ "Fc gamma RII" ], "offsets": [ [ 353, 365 ] ], "normalized": [] }, { "id": "8562512_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 801, 810 ] ], "normalized": [] }, { "id": "8562512_T4", "type": "Protein", "text": [ "IL-1 beta" ], "offsets": [ [ 833, 842 ] ], "normalized": [] }, { "id": "8562512_T5", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1038, 1047 ] ], "normalized": [] } ]

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[ { "id": "9317131__text", "type": "abstract", "text": [ "Cooperation of binding sites for STAT6 and NF kappa B/rel in the IL-4-induced up-regulation of the human IgE germline promoter. \nIg heavy chain class switching is directed by cytokines inducing transcription from unrearranged CH genes. Subsequently, such primed cells can undergo switch recombination to express the selected new isotype. In the case of IgE class switching, IL-4 activates the IgE germline promoter by inducing the interaction of the transcription factor STAT6 (IL-4STAT) with a responsive DNA element in the proximal region of the promoter. This study describes the characterization of two additional cis-acting elements that interact with members of the NF kappa B/rel transcription factor family in an IL-4-independent fashion. Electrophoretic mobility shift assays show that the nucleoprotein complex formed on the upstream site (NF kappa B1) contains the classical p50/p65 heterodimer. The complex on the proximal site (NF kappa B2) appears to be composed of p50 and relB. IgE germline promoter reporter gene constructs carrying point mutations in the NF kappa B2 site were largely unresponsive to IL-4 stimulation in transient transfection experiments, while plasmids with similar mutations in the NF kappa B1 site responded to cytokine stimulation better than the wild-type promoter. The NF kappa B2 effect was dependent on the presence of the STAT6 binding site, demonstrating that the NF kappa B2 motif is necessary but not sufficient for mediating cytokine up-regulation. In addition, the combination of a NF kappa B/rel binding site and the STAT6 response element conferred IL-4 inducibility to a heterologous minimal promoter, while the individual sites had no effect. The available data suggest that the NF kappa B2 nucleoprotein complex may cooperate with DNA-bound STAT6 to achieve IL-4-dependent activation of the human IgE germline gene. " ], "offsets": [ [ 0, 1871 ] ] } ]

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[ { "id": "7579328__text", "type": "abstract", "text": [ "The myeloid zinc finger gene, MZF-1, regulates the CD34 promoter in vitro. \nMZF-1 is a C2H2 zinc finger gene encoding a putative transcriptional regulator of myeloid differentiation. The MZF-1 protein contains 13 C2H2 zinc fingers arranged in bipartite DNA binding domains containing zinc fingers through 4 and, in the carboxy-terminus, 5 through 13. We previously identified the DNA consensus binding site recognized by the two DNA binding domains. To assess the transcription regulatory function of MZF-1, the full-length MZF-1 coding region was fused to the DNA binding domain of the yeast transactivator GAL4. The expression vector was cotransfected with the chloramphenicol acetyl transferase (CAT) reporter gene regulated by the thymidine kinase promoter containing GAL4 DNA binding sites into NIH 3T3, 293, K562, and Jurkat cell lines. MZF-1 represses CAT reporter gene expression via GAL4 binding sites in the nonhematopoietic cell lines NIH 3T3 and 293. In contrast, MZF-1 activates CAT reporter gene expression in the hematopoietic cell lines K562 and Jurkat. The MZF-1 binding sites are present in the promoters of several genes expressed during myeloid differentiation, including the CD34 promoter. MZF-1 transcriptional regulation of this physiologically relevant promoter was assessed in both hematopoietic and nonhematopoietic cell lines. Recombinant MZF-1 protein specifically binds to the consensus binding sites in the CD34 promoter in mobility shift assays. MZF-1 expression vectors were cotransfected with the luciferase reporter plasmids regulated by the CD34 promoter into both nonhematopoietic and hematopoietic cell lines. As with the heterologous DNA binding domain, MZF-1 represses reporter gene expression in nonhematopoietic cell lines and activates expression in hematopoietic cell lines. Activation of CD34 expression in hematopoietic cell lines is dependent on the presence of intact MZF-1 binding sites. The cell type-specific regulation of the CD34 promoter by MZF-1 suggests the presence of tissue-specific regulators/adapters or differential MZF-1 modifications that determine MZF-1 transcriptional regulatory function. " ], "offsets": [ [ 0, 2155 ] ] } ]

[ { "id": "7579328_T1", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 30, 35 ] ], "normalized": [] }, { "id": "7579328_T2", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 51, 55 ] ], "normalized": [] }, { "id": "7579328_T3", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 76, 81 ] ], "normalized": [] }, { "id": "7579328_T4", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 187, 192 ] ], "normalized": [] }, { "id": "7579328_T5", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 501, 506 ] ], "normalized": [] }, { "id": "7579328_T6", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 524, 529 ] ], "normalized": [] }, { "id": "7579328_T7", "type": "Protein", "text": [ "GAL4" ], "offsets": [ [ 608, 612 ] ], "normalized": [] }, { "id": "7579328_T8", "type": "Protein", "text": [ "chloramphenicol acetyl transferase" ], "offsets": [ [ 663, 697 ] ], "normalized": [] }, { "id": "7579328_T9", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 699, 702 ] ], "normalized": [] }, { "id": "7579328_T10", "type": "Protein", "text": [ "thymidine kinase" ], "offsets": [ [ 735, 751 ] ], "normalized": [] }, { "id": "7579328_T11", "type": "Protein", "text": [ "GAL4" ], "offsets": [ [ 772, 776 ] ], "normalized": [] }, { "id": "7579328_T12", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 843, 848 ] ], "normalized": [] }, { "id": "7579328_T13", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 859, 862 ] ], "normalized": [] }, { "id": "7579328_T14", "type": "Protein", "text": [ "GAL4" ], "offsets": [ [ 892, 896 ] ], "normalized": [] }, { "id": "7579328_T15", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 976, 981 ] ], "normalized": [] }, { "id": "7579328_T16", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 992, 995 ] ], "normalized": [] }, { "id": "7579328_T17", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 1074, 1079 ] ], "normalized": [] }, { "id": "7579328_T18", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 1196, 1200 ] ], "normalized": [] }, { "id": "7579328_T19", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 1211, 1216 ] ], "normalized": [] }, { "id": "7579328_T20", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 1366, 1371 ] ], "normalized": [] }, { "id": "7579328_T21", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 1437, 1441 ] ], "normalized": [] }, { "id": "7579328_T22", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 1477, 1482 ] ], "normalized": [] }, { "id": "7579328_T23", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 1576, 1580 ] ], "normalized": [] }, { "id": "7579328_T24", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 1692, 1697 ] ], "normalized": [] }, { "id": "7579328_T25", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 1832, 1836 ] ], "normalized": [] }, { "id": "7579328_T26", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 1915, 1920 ] ], "normalized": [] }, { "id": "7579328_T27", "type": "Protein", "text": [ "CD34" ], "offsets": [ [ 1977, 1981 ] ], "normalized": [] }, { "id": "7579328_T28", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 1994, 1999 ] ], "normalized": [] }, { "id": "7579328_T29", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 2077, 2082 ] ], "normalized": [] }, { "id": "7579328_T30", "type": "Protein", "text": [ "MZF-1" ], "offsets": [ [ 2112, 2117 ] ], "normalized": [] }, { "id": "7579328_T32", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 56, 64 ] ], "normalized": [] }, { "id": "7579328_T36", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 752, 760 ] ], "normalized": [] }, { "id": "7579328_T43", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1201, 1209 ] ], "normalized": [] }, { "id": "7579328_T46", "type": "Entity", "text": [ "consensus binding sites" ], "offsets": [ [ 1406, 1429 ] ], "normalized": [] }, { "id": "7579328_T51", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1982, 1990 ] ], "normalized": [] } ]

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[]

[ { "id": "8496329__text", "type": "abstract", "text": [ "Expression levels of the thyrotropin receptor gene in autoimmune thyroid disease: coregulation with parameters of thyroid function and inverse relation to major histocompatibility complex classes I and II. \nUsing a human TSH receptor (TSH-R) cDNA probe, we investigated TSH-R transcript levels in 13 human thyroid fragments by Northern blot analysis; 7 Graves' disease, 2 Hashimoto's disease, 3 endemic goiter, and 1 healthy thyroid gland were studied. TSH-R expression levels were variable, but displayed a close correlation to the expression of thyroid peroxidase (r = 0.703; P < 0.05), thyroglobulin (r = 0.817; P < 0.01), and the nuclear oncogene c-fos (r = 0.935; P < 0.001), but not c-myc. Overall, TSH-R transcript levels were low or absent in those thyroids in which expression of the major histocompatibility complex class I or II (MHC I or II) was high, thus establishing an inverse relation (MHC I, r = -0.791; P < 0.01; MHC II, r = -0.784; P < 0.01). In situ hybridization showed that apart from lymphocytes, thyroid cells themselves were the source of MHC II transcripts. gamma-Interferon expression was only detectable in 1 Hashimoto's goiter. Our findings suggest that next to lymphocyte infiltration, active regulatory events in the thyrocyte are responsible for the inverse relation between functional parameters (TSH-R, thyroid peroxidase, thyroglobulin, and c-fos) and immunological markers (MHC I and II). " ], "offsets": [ [ 0, 1426 ] ] } ]

[ { "id": "8496329_T1", "type": "Protein", "text": [ "thyrotropin receptor" ], "offsets": [ [ 25, 45 ] ], "normalized": [] }, { "id": "8496329_T2", "type": "Protein", "text": [ "TSH receptor" ], "offsets": [ [ 221, 233 ] ], "normalized": [] }, { "id": "8496329_T3", "type": "Protein", "text": [ "TSH-R" ], "offsets": [ [ 235, 240 ] ], "normalized": [] }, { "id": "8496329_T4", "type": "Protein", "text": [ "TSH-R" ], "offsets": [ [ 270, 275 ] ], "normalized": [] }, { "id": "8496329_T5", "type": "Protein", "text": [ "TSH-R" ], "offsets": [ [ 453, 458 ] ], "normalized": [] }, { "id": "8496329_T6", "type": "Protein", "text": [ "thyroid peroxidase" ], "offsets": [ [ 547, 565 ] ], "normalized": [] }, { "id": "8496329_T7", "type": "Protein", "text": [ "thyroglobulin" ], "offsets": [ [ 589, 602 ] ], "normalized": [] }, { "id": "8496329_T8", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 651, 656 ] ], "normalized": [] }, { "id": "8496329_T9", "type": "Protein", "text": [ "c-myc" ], "offsets": [ [ 689, 694 ] ], "normalized": [] }, { "id": "8496329_T10", "type": "Protein", "text": [ "TSH-R" ], "offsets": [ [ 705, 710 ] ], "normalized": [] }, { "id": "8496329_T11", "type": "Protein", "text": [ "gamma-Interferon" ], "offsets": [ [ 1085, 1101 ] ], "normalized": [] }, { "id": "8496329_T12", "type": "Protein", "text": [ "TSH-R" ], "offsets": [ [ 1331, 1336 ] ], "normalized": [] }, { "id": "8496329_T13", "type": "Protein", "text": [ "thyroid peroxidase" ], "offsets": [ [ 1338, 1356 ] ], "normalized": [] }, { "id": "8496329_T14", "type": "Protein", "text": [ "thyroglobulin" ], "offsets": [ [ 1358, 1371 ] ], "normalized": [] }, { "id": "8496329_T15", "type": "Protein", "text": [ "c-fos" ], "offsets": [ [ 1377, 1382 ] ], "normalized": [] } ]

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[ { "id": "1315834__text", "type": "abstract", "text": [ "Interferon-gamma potentiates the antiviral activity and the expression of interferon-stimulated genes induced by interferon-alpha in U937 cells. \nBinding of type I interferon (IFN-alpha/beta) to specific receptors results in the rapid transcriptional activation, independent of protein synthesis, of IFN-alpha-stimulated genes (ISGs) in human fibroblasts and HeLa and Daudi cell lines. The binding of ISGF3 (IFN-stimulated gene factor 3) to the conserved IFN-stimulated response element (ISRE) results in transcriptional activation. This factor is composed of a DNA-binding protein (ISGF3 gamma), which normally is present in the cytoplasm, and other IFN-alpha-activated proteins which preexist as latent cytoplasmic precursors (ISGF3 alpha). We have found that ISG expression in the monocytic U937 cell line differs from most cell lines previously examined. U937 cells express both type I and type II IFN receptors, but only IFN-alpha is capable of inducing antiviral protection in these cells. Pretreatment with IFN-gamma potentiates the IFN-alpha-induced protection, but IFN-gamma alone does not have any antiviral activity. ISG15 mRNA accumulation in U937 cells is not detectable before 6 h of IFN-alpha treatment, peaks at 24 h, and requires protein synthesis. Although IFN-gamma alone does not induce ISG expression, IFN-gamma pretreatment markedly increases and hastens ISG expression and transcriptional induction. Nuclear extracts assayed for the presence of ISRE binding factors by electrophoretic mobility shift assays show that ISGF3 is induced by IFN-alpha within 6 h from undetectable basal levels in untreated U937 cells. Activation of ISGF3 alpha, the latent component of ISGF3, occurs rapidly. However, the increase in ISGF3 activity ultimately correlates with the accumulation of ISGF3 gamma induced by IFN-alpha or IFN-gamma. (ABSTRACT TRUNCATED AT 250 WORDS) " ], "offsets": [ [ 0, 1879 ] ] } ]

[ { "id": "1315834_T1", "type": "Protein", "text": [ "Interferon-gamma" ], "offsets": [ [ 0, 16 ] ], "normalized": [] }, { "id": "1315834_T2", "type": "Protein", "text": [ "ISGF3 gamma" ], "offsets": [ [ 583, 594 ] ], "normalized": [] }, { "id": "1315834_T3", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1014, 1023 ] ], "normalized": [] }, { "id": "1315834_T4", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1074, 1083 ] ], "normalized": [] }, { "id": "1315834_T5", "type": "Protein", "text": [ "ISG15" ], "offsets": [ [ 1128, 1133 ] ], "normalized": [] }, { "id": "1315834_T6", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1275, 1284 ] ], "normalized": [] }, { "id": "1315834_T7", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1323, 1332 ] ], "normalized": [] }, { "id": "1315834_T8", "type": "Protein", "text": [ "ISGF3 gamma" ], "offsets": [ [ 1798, 1809 ] ], "normalized": [] }, { "id": "1315834_T9", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1834, 1843 ] ], "normalized": [] }, { "id": "1315834_T11", "type": "Entity", "text": [ "cytoplasm" ], "offsets": [ [ 630, 639 ] ], "normalized": [] } ]

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[ { "id": "8739563__text", "type": "abstract", "text": [ "Involvement of tyrosine phosphorylation in endothelial adhesion molecule induction. \nInduction of endothelial adhesion molecules by the cytokine tumor necrosis factor-alpha (TNF) can occur independently of protein kinase C and activation of a protein tyrosine kinase (PTK) has recently been implicated in the upregulation of vascular cell adhesion molecule 1 (VCAM-1) by interleukin-4 (IL-4) on endothelial cells. We demonstrate that the PTK inhibitors herbimycin A or genistein suppress induction of endothelial VCAM-1 and E-selectin, as well as subsequent monocytic cell adhesion to endothelial cells stimulated by TNF. Inhibition studies indicate that specific tyrosine phosphorylation following PTK activation is involved in the mobilization of the transcription factor, nuclear factor kappa B, and VCAM-1 mRNA expression. This may have implications for pathophysiological conditions that involve the upregulation of these molecules (e.g. inflammation and atherosclerosis). " ], "offsets": [ [ 0, 978 ] ] } ]

[ { "id": "8739563_T1", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 145, 172 ] ], "normalized": [] }, { "id": "8739563_T2", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 174, 177 ] ], "normalized": [] }, { "id": "8739563_T3", "type": "Protein", "text": [ "vascular cell adhesion molecule 1" ], "offsets": [ [ 325, 358 ] ], "normalized": [] }, { "id": "8739563_T4", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 360, 366 ] ], "normalized": [] }, { "id": "8739563_T5", "type": "Protein", "text": [ "interleukin-4" ], "offsets": [ [ 371, 384 ] ], "normalized": [] }, { "id": "8739563_T6", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 386, 390 ] ], "normalized": [] }, { "id": "8739563_T7", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 513, 519 ] ], "normalized": [] }, { "id": "8739563_T8", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 524, 534 ] ], "normalized": [] }, { "id": "8739563_T9", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 617, 620 ] ], "normalized": [] }, { "id": "8739563_T10", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 803, 809 ] ], "normalized": [] } ]

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[ { "id": "2172166__text", "type": "abstract", "text": [ "Characterization of defensin resistance phenotypes associated with mutations in the phoP virulence regulon of Salmonella typhimurium. \nThe defensin sensitivities of Salmonella typhimurium strains with mutations in the phoP/phoQ two-component virulence regulon were tested by using purified defensins NP-1 and NP-2. Strains with mutations in either gene of the regulatory pair (phoP [transcriptional activator] or phoQ [membrane sensor kinase]) had increased sensitivities to defensin. The predicted periplasmic domain of the PhoQ protein contained a markedly anionic domain that could interact with cationic proteins and that could be responsible for resistance to defensin. Because insertion mutations in phoP are polar on phoQ, we constructed strains that expressed the PhoQ protein in the absence of PhoP to test whether resistance to defensin requires only the phoQ gene product. We found that resistance to defensin requires the function of both components of this regulatory system, because strains expressing PhoQ without PhoP were still markedly sensitive to defensins. This implied that a pag (phoP-activated gene) product is responsible for defensin resistance. We also tested for the ability of defensins NP-1, NP-5, and HNP-1 to activate pag expression and found that these peptides have no effect. Defensin resistance is not the only virulence characteristic controlled by the PhoP-PhoQ regulon because mutations in pagC, as well as ones in the phoP locus that resulted in constitutive pag activation (phenotype PhoPc), had no effect on defensin resistance, even though they rendered the organism avirulent and deficient in survival within macrophages. The virulence defect conferred by mutations in the phoP-phoQ two-component regulatory system is not completely explained by alterations in resistance to cationic proteins and involves the control of other proteins necessary for S. typhimurium survival within macrophages. " ], "offsets": [ [ 0, 1938 ] ] } ]

[ { "id": "2172166_T1", "type": "Protein", "text": [ "phoP" ], "offsets": [ [ 218, 222 ] ], "normalized": [] }, { "id": "2172166_T2", "type": "Protein", "text": [ "phoQ" ], "offsets": [ [ 223, 227 ] ], "normalized": [] }, { "id": "2172166_T3", "type": "Protein", "text": [ "NP-1" ], "offsets": [ [ 300, 304 ] ], "normalized": [] }, { "id": "2172166_T4", "type": "Protein", "text": [ "NP-2" ], "offsets": [ [ 309, 313 ] ], "normalized": [] }, { "id": "2172166_T5", "type": "Protein", "text": [ "phoP" ], "offsets": [ [ 377, 381 ] ], "normalized": [] }, { "id": "2172166_T6", "type": "Protein", "text": [ "phoQ" ], "offsets": [ [ 413, 417 ] ], "normalized": [] }, { "id": "2172166_T7", "type": "Protein", "text": [ "PhoQ" ], "offsets": [ [ 525, 529 ] ], "normalized": [] }, { "id": "2172166_T8", "type": "Protein", "text": [ "phoP" ], "offsets": [ [ 706, 710 ] ], "normalized": [] }, { "id": "2172166_T9", "type": "Protein", "text": [ "phoQ" ], "offsets": [ [ 724, 728 ] ], "normalized": [] }, { "id": "2172166_T10", "type": "Protein", "text": [ "PhoQ" ], "offsets": [ [ 772, 776 ] ], "normalized": [] }, { "id": "2172166_T11", "type": "Protein", "text": [ "PhoP" ], "offsets": [ [ 803, 807 ] ], "normalized": [] }, { "id": "2172166_T12", "type": "Protein", "text": [ "phoQ" ], "offsets": [ [ 865, 869 ] ], "normalized": [] }, { "id": "2172166_T13", "type": "Protein", "text": [ "PhoQ" ], "offsets": [ [ 1016, 1020 ] ], "normalized": [] }, { "id": "2172166_T14", "type": "Protein", "text": [ "PhoP" ], "offsets": [ [ 1029, 1033 ] ], "normalized": [] }, { "id": "2172166_T15", "type": "Protein", "text": [ "NP-1" ], "offsets": [ [ 1216, 1220 ] ], "normalized": [] }, { "id": "2172166_T16", "type": "Protein", "text": [ "NP-5" ], "offsets": [ [ 1222, 1226 ] ], "normalized": [] }, { "id": "2172166_T17", "type": "Protein", "text": [ "HNP-1" ], "offsets": [ [ 1232, 1237 ] ], "normalized": [] }, { "id": "2172166_T18", "type": "Protein", "text": [ "PhoP" ], "offsets": [ [ 1390, 1394 ] ], "normalized": [] }, { "id": "2172166_T19", "type": "Protein", "text": [ "PhoQ" ], "offsets": [ [ 1395, 1399 ] ], "normalized": [] }, { "id": "2172166_T20", "type": "Protein", "text": [ "pagC" ], "offsets": [ [ 1429, 1433 ] ], "normalized": [] }, { "id": "2172166_T21", "type": "Protein", "text": [ "phoP" ], "offsets": [ [ 1458, 1462 ] ], "normalized": [] }, { "id": "2172166_T22", "type": "Protein", "text": [ "phoP" ], "offsets": [ [ 1717, 1721 ] ], "normalized": [] }, { "id": "2172166_T23", "type": "Protein", "text": [ "phoQ" ], "offsets": [ [ 1722, 1726 ] ], "normalized": [] } ]

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[ { "id": "9400372__text", "type": "abstract", "text": [ "Molecular mechanisms of anoxia/reoxygenation-induced neutrophil adherence to cultured endothelial cells. \nThe objectives of this study were to (1) determine the time course of neutrophil adhesion to monolayers of human umbilical vein endothelial cells (HUVECs) that were exposed to 60 minutes of anoxia followed by 30 to 600 minutes of reoxygenation and (2) define the mechanisms responsible for both the early (minutes) and late (hours) hyperadhesivity of postanoxic HUVECs to human neutrophils. The results clearly demonstrate that anoxia/reoxygenation (A/R) leads to a biphasic increase in neutrophil adhesion to HUVECs, with peak responses occurring at 30 minutes (phase 1) and 240 minutes (phase 2) after reoxygenation. Oxypurinol and catalase inhibited phase-1 adhesion, suggesting a role for xanthine oxidase and H2O2. In comparison, platelet activating factor (PAF) contributed to both phases of neutrophil adhesion. Anti-intercellular adhesion molecule-1 (ICAM-1) and anti-P-selectin antibodies (monoclonal antibodies [mAbs]) attenuated phase-1 neutrophil adhesion, consistent with roles for constitutively expressed ICAM-1 and enhanced surface expression of preformed P-selectin. Phase-2 neutrophil adhesion was attenuated by an anti-E-selectin mAb, indicating a dominant role of this adhesion molecule in the late phase response. Pretreatment with actinomycin D and cycloheximide or with competing ds-oligonucleotides containing the nuclear factor-kappa B or activator protein-1 cognate DNA sequences significantly attenuated phase-2 response, suggesting a role for de novo macromolecule synthesis. Surface expression of ICAM-1, P-selectin, and E-selectin on HUVECs correlated with the phase-1 and -2 neutrophil adhesion responses. Collectively, these findings indicate that A/R elicits a two-phase neutrophil-endothelial cell adhesion response that involves transcription-independent and transcription-dependent surface expression of different endothelial cell adhesion molecules. " ], "offsets": [ [ 0, 1993 ] ] } ]

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[ { "id": "10378895__text", "type": "abstract", "text": [ "Downregulation of Wilms' tumor gene (WT1) is not a prerequisite for erythroid or megakaryocytic differentiation of the leukemic cell line K562. \nThe Wilms' tumor gene (WT1) encodes a transcription factor of the zinc finger type. A high expression of WT1 has been detected in a range of acute leukemias, and WT1 is downregulated during induced differentiation of some leukemic cell lines. Overexpression of WT1 in some myeloid cell lines confers resistance to differentiation induction. These observations suggest that a high WT1 expression in hematopoietic cells is incompatible with differentiation. In this study, each of the four different isoforms of WT1 was constitutively overexpressed in the leukemic cell line K562. K562 cells express endogenous WT1, which is downregulated as a response to induced differentiation along the erythroid and megakaryocytic pathways. We now demonstrate that a forced exogenous expression of the four different isoforms of WT1 in K562 does not affect the differentiation response, as judged by accumulation of hemoglobin in response to hemin or the expression of megakaryocytic cell surface markers in response to 12-O-tetradecanoylphorbol-13-acetate (TPA). We conclude that downregulation of WT1 during induced differentiation of K562 cells is not a prerequisite for erythroid or megakaryocytic differentiation of these cells. " ], "offsets": [ [ 0, 1365 ] ] } ]

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[ { "id": "10330189__text", "type": "abstract", "text": [ "Nuclear localization and formation of beta-catenin-lymphoid enhancer factor 1 complexes are not sufficient for activation of gene expression. \nIn response to activation of the Wnt signaling pathway, beta-catenin accumulates in the nucleus, where it cooperates with LEF/TCF (for lymphoid enhancer factor and T-cell factor) transcription factors to activate gene expression. The mechanisms by which beta-catenin undergoes this shift in location and participates in activation of gene transcription are unknown. We demonstrate here that beta-catenin can be imported into the nucleus independently of LEF/TCF binding, and it may also be exported from nuclei. We have introduced a small deletion within beta-catenin (Delta19) that disrupts binding to LEF-1, E-cadherin, and APC but not axin. This Delta19 beta-catenin mutant localizes to the nucleus because it may not be efficiently sequestered in the cytoplasm. The nuclear localization of Delta19 definitively demonstrates that the mechanisms by which beta-catenin localizes in the nucleus are completely independent of LEF/TCF factors. beta-Catenin and LEF-1 complexes can activate reporter gene expression in a transformed T-lymphocyte cell line (Jurkat) but not in normal T lymphocytes, even though both factors are nuclear. Thus, localization of both factors to the nucleus is not sufficient for activation of gene expression. Excess beta-catenin can squelch reporter gene activation by LEF-1-beta-catenin complexes but not activation by the transcription factor VP16. Taken together, these data suggest that a third component is necessary for gene activation and that this third component may vary with cell type. " ], "offsets": [ [ 0, 1667 ] ] } ]

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[ { "id": "10082473__text", "type": "abstract", "text": [ "Molecular mechanisms of neutrophil-endothelial cell adhesion induced by redox imbalance. \nPrevious studies have implicated a role for intracellular thiols in the activation of nuclear factor-kappaB and transcriptional regulation of endothelial cell adhesion molecules. This study was designed to determine whether changes in endothelial cell glutathione (GSH) or oxidized glutathione (GSSG) can alter neutrophil adhesivity and to define the molecular mechanism that underlies this GSSG/GSH-induced adhesion response. Treatment of human umbilical vein endothelial cell (HUVEC) monolayers for 6 hours with 0.2 mmol/L diamide and 1 mmol/L buthionine sulfoximine (BSO) decreased GSH levels and increased the ratio of GSSG to GSH without cell toxicity. These redox changes are similar to those observed with anoxia/reoxygenation. Diamide plus BSO-induced thiol/disulfide imbalance was associated with a biphasic increase in neutrophil adhesion to HUVECs with peak responses observed at 15 minutes (phase 1) and 240 minutes (phase 2). N-Acetylcysteine treatment attenuated neutrophil adhesion in both phases, which indicated a role for GSH in the adhesion responses. Interestingly, phase 1 adhesion was inversely correlated with GSH levels but not with the GSSG/GSH ratio, whereas phase 2 neutrophil adhesion was positively correlated with GSSG/GSH ratio but not with GSH levels. Intercellular adhesion molecule-1 and P-selectin-specific monoclonal antibodies attenuated the increased neutrophil adhesion during both phases, whereas an anti-E-selectin monoclonal antibody also attenuated the phase 2 response. Pretreatment with actinomycin D and cycloheximide or with competing ds-oligonucleotides that contained nuclear factor-kappaB or activator protein-1 cognate DNA sequences significantly attenuated the phase 2 response, which implicated a role for de novo protein synthesis. Surface expression of intercellular adhesion molecule-1, P-selectin, and E-selectin on HUVECs correlated with the phase 1 and 2 neutrophil adhesion responses. This study demonstrates that changes in endothelial cell GSSG/GSH cause transcription-independent and transcription-dependent surface expression of different endothelial cell adhesion molecules, which leads to a 2-phase neutrophil-endothelial adhesion response. " ], "offsets": [ [ 0, 2297 ] ] } ]

[ { "id": "10082473_T1", "type": "Protein", "text": [ "Intercellular adhesion molecule-1" ], "offsets": [ [ 1374, 1407 ] ], "normalized": [] }, { "id": "10082473_T2", "type": "Protein", "text": [ "P-selectin" ], "offsets": [ [ 1412, 1422 ] ], "normalized": [] }, { "id": "10082473_T3", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 1535, 1545 ] ], "normalized": [] }, { "id": "10082473_T4", "type": "Protein", "text": [ "intercellular adhesion molecule-1" ], "offsets": [ [ 1898, 1931 ] ], "normalized": [] }, { "id": "10082473_T5", "type": "Protein", "text": [ "P-selectin" ], "offsets": [ [ 1933, 1943 ] ], "normalized": [] }, { "id": "10082473_T6", "type": "Protein", "text": [ "E-selectin" ], "offsets": [ [ 1949, 1959 ] ], "normalized": [] } ]

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[ { "id": "9311830__text", "type": "abstract", "text": [ "The ability of BHRF1 to inhibit apoptosis is dependent on stimulus and cell type. \nThe development of resistance to host defense mechanisms such as tumor necrosis factor (TNF)- and Fas-mediated apoptosis of transformed or virus-infected cells may be a critical component in the development of disease. To find genes that protect cells from apoptosis, we used an expression cloning strategy and identified BHRF1, an Epstein-Barr virus (EBV) early-lytic-cycle protein with distant homology to Bcl-2, as an anti-apoptosis protein. Expression of BHRF1 in MCF-Fas cells conferred nearly complete resistance against both anti-Fas antibody and TNF-mediated apoptosis. In addition, BHRF1 protected these cells from monocyte-mediated killing but failed to protect them from killing mediated by lymphokine-activated killer cells. The ability of BHRF1 to protect MCF-Fas cells from apoptosis induced by various stimuli was identical to that of Bcl-2 and Bcl-xL. Moreover, the mechanism of action of BHRF1 resembled that of Bcl-2 and Bcl-xL as it inhibited TNF- and anti-Fas-induced activation of two enzymes participating in the apoptosis pathway, cytosolic phospholipase A2 and caspase-3/CPP32, but did not interfere with the activation of NF-kappaB-like transcription factors. A putative function of BHRF1 in EBV-infected epithelial cells may be to protect virus-infected cells from TNF- and/or anti-Fas- induced cell death in order to maximize virus production. Surprisingly, expression of neither BHRF1 nor Bcl-2 in a B-cell line, BJAB, protected the cells from anti-Fas-mediated apoptosis even though they increased the survival of serum-starved cells. Thus, the protective role of BHRF1 against apoptosis resembles that of Bcl-2 in being cell type specific and dependent on the apoptotic stimulus. " ], "offsets": [ [ 0, 1793 ] ] } ]

[ { "id": "9311830_T1", "type": "Protein", "text": [ "BHRF1" ], "offsets": [ [ 15, 20 ] ], "normalized": [] }, { "id": "9311830_T2", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 181, 184 ] ], "normalized": [] }, { "id": "9311830_T3", "type": "Protein", "text": [ "BHRF1" ], "offsets": [ [ 405, 410 ] ], "normalized": [] }, { "id": "9311830_T4", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 491, 496 ] ], "normalized": [] }, { "id": "9311830_T5", "type": "Protein", "text": [ "BHRF1" ], "offsets": [ [ 542, 547 ] ], "normalized": [] }, { "id": "9311830_T6", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 620, 623 ] ], "normalized": [] }, { "id": "9311830_T7", "type": "Protein", "text": [ "BHRF1" ], "offsets": [ [ 674, 679 ] ], "normalized": [] }, { "id": "9311830_T8", "type": "Protein", "text": [ "BHRF1" ], "offsets": [ [ 835, 840 ] ], "normalized": [] }, { "id": "9311830_T9", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 933, 938 ] ], "normalized": [] }, { "id": "9311830_T10", "type": "Protein", "text": [ "Bcl-xL" ], "offsets": [ [ 943, 949 ] ], "normalized": [] }, { "id": "9311830_T11", "type": "Protein", "text": [ "BHRF1" ], "offsets": [ [ 988, 993 ] ], "normalized": [] }, { "id": "9311830_T12", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1012, 1017 ] ], "normalized": [] }, { "id": "9311830_T13", "type": "Protein", "text": [ "Bcl-xL" ], "offsets": [ [ 1022, 1028 ] ], "normalized": [] }, { "id": "9311830_T14", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 1059, 1062 ] ], "normalized": [] }, { "id": "9311830_T15", "type": "Protein", "text": [ "cytosolic phospholipase A2" ], "offsets": [ [ 1137, 1163 ] ], "normalized": [] }, { "id": "9311830_T16", "type": "Protein", "text": [ "caspase-3" ], "offsets": [ [ 1168, 1177 ] ], "normalized": [] }, { "id": "9311830_T17", "type": "Protein", "text": [ "CPP32" ], "offsets": [ [ 1178, 1183 ] ], "normalized": [] }, { "id": "9311830_T18", "type": "Protein", "text": [ "BHRF1" ], "offsets": [ [ 1291, 1296 ] ], "normalized": [] }, { "id": "9311830_T19", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 1391, 1394 ] ], "normalized": [] }, { "id": "9311830_T20", "type": "Protein", "text": [ "BHRF1" ], "offsets": [ [ 1490, 1495 ] ], "normalized": [] }, { "id": "9311830_T21", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1500, 1505 ] ], "normalized": [] }, { "id": "9311830_T22", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 1560, 1563 ] ], "normalized": [] }, { "id": "9311830_T23", "type": "Protein", "text": [ "BHRF1" ], "offsets": [ [ 1676, 1681 ] ], "normalized": [] }, { "id": "9311830_T24", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1718, 1723 ] ], "normalized": [] } ]

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[ { "id": "9311830_1", "entity_ids": [ "9311830_T16", "9311830_T17" ] } ]

[]

[ { "id": "9115810__text", "type": "abstract", "text": [ "NF-kappa B-independent suppression of HIV expression by ascorbic acid. \nAscorbic acid (ascorbate or vitamin C) has been shown to suppress the induction of HIV in latently infected T lymphocytic cells following stimulation with a tumor promoter (PMA) and inflammatory cytokine (TNF-alpha). To assess whether this inhibition was mediated via modulation of the cellular transcription factor, NF-kappa B, we carried out gel shift analysis on nuclear extracts prepared under different conditions of cell stimulation in the presence or absence of ascorbate, N-acetylcysteine (NAC), or zidovudine (AZT). Pretreatment of ACH-2 T cells by NAC followed by stimulation with PMA, TNF-alpha, or hydrogen peroxide (H2O2) resulted in strong suppression of NF-kappa B activation. In contrast, neither ascorbate nor AZT affected NF-kappa B activity under all three induction conditions in the ACH-2 cell line. Ascorbate and AZT also had no effect on NF-kappa B activation following TNF-alpha- or PMA-induced stimulation of U1 promonocytic cells. These results suggest that the molecular mechanism of HIV inhibition by ascorbate is not mediated via NF-kappa B inhibition, unlike that seen with other antioxidants. " ], "offsets": [ [ 0, 1196 ] ] } ]

[ { "id": "9115810_T1", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 277, 286 ] ], "normalized": [] }, { "id": "9115810_T2", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 668, 677 ] ], "normalized": [] }, { "id": "9115810_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 965, 974 ] ], "normalized": [] } ]

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[ { "id": "9074948__text", "type": "abstract", "text": [ "Suppression by azelastine hydrochloride of NF-kappa B activation involved in generation of cytokines and nitric oxide. \nThe influence of the anti-allergy agent azelastine hydrochloride (Azeptin) on NF-kappa B activation associated with the generation of cytokines and nitric oxide (NO) was investigated in various kinds of human and mouse cells. Azeptin dose-dependently suppressed both DNA and protein synthesis in human gingival fibroblasts (HF) and also suppressed blastogenesis of human peripheral blood lymphocytes (PBL). Generation of tumor necrosis factor-alpha, interleukin 1-beta, granulocyte-macrophage colony-stimulating factor and interleukin-6 from 10(-5) M Azeptin-treated PBL and human monocytes (HM) was decreased to approximately 1/3 to 2/3 of the control levels. In parallel with the decreased cytokine generation, each cytokine mRNA was less expressed in the presence of 10(-5) M Azeptin. In addition, both inducible nitric oxide synthase-mRNA level and NO generation in mouse peritoneal macrophages were suppressed by 10(-5) M Azeptin. Being compatible with those results, Azeptin (10(-5) M) suppressed activation of NF-kappa B in PBL, HM and HF. These results appear to indicate that suppression of cytokine and NO generation by Azeptin results at least partially from the inhibition of NF-kappa B activation. " ], "offsets": [ [ 0, 1331 ] ] } ]

[ { "id": "9074948_T1", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 541, 568 ] ], "normalized": [] }, { "id": "9074948_T2", "type": "Protein", "text": [ "interleukin 1-beta" ], "offsets": [ [ 570, 588 ] ], "normalized": [] }, { "id": "9074948_T3", "type": "Protein", "text": [ "granulocyte-macrophage colony-stimulating factor" ], "offsets": [ [ 590, 638 ] ], "normalized": [] }, { "id": "9074948_T4", "type": "Protein", "text": [ "interleukin-6" ], "offsets": [ [ 643, 656 ] ], "normalized": [] }, { "id": "9074948_T5", "type": "Protein", "text": [ "nitric oxide synthase" ], "offsets": [ [ 936, 957 ] ], "normalized": [] } ]

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[ { "id": "1903417__text", "type": "abstract", "text": [ "Transforming growth factor-beta suppresses human B lymphocyte Ig production by inhibiting synthesis and the switch from the membrane form to the secreted form of Ig mRNA. \nTransforming growth factor-beta (TGF-beta) inhibits B cell Ig secretion and reduces B cell membrane Ig expression. The addition of TGF-beta to human B lymphocyte cultures stimulated with Staphylococcus aureus Cowan strain I and IL-2 completely inhibited B cell Ig secretion (greater than 90%) and decreased B cell surface IgM, IgD, kappa L chain, and lambda L chain expression. In contrast, TGF-beta had only minimal effects on two other B cell membrane proteins, HLA-DR and CD20. Internal labeling with [35S]methionine and immunoprecipitation with anti-IgM, anti-kappa, and anti-lambda antibodies revealed a striking reduction in kappa L chain in the presence of TGF-beta. A less pronounced reduction in lambda L chain and microH chain was also noted. Northern blot analysis of RNA purified from B cells treated with TGF-beta for varying time intervals revealed a significant decrease in steady state kappa and lambda L chain mRNA levels. Furthermore, a significant decrease in the switch from the membrane forms of mu and gamma to their respective secreted forms was noted in the presence of TGF-beta. Nuclear run-on experiments demonstrated decreased transcription of kappa L chain. The effects of TGF-beta on two transcriptional regulatory factors, Oct-2 and nuclear factor (NF) kappa B, known to be important in Ig gene transcription were examined. Oct-2 mRNA levels and both Oct-2 and NF-kappa B proteins in nuclear extracts were not altered by treatment with TGF-beta. In contrast, levels of the transcriptional factor AP-1, which is not known to be important in B cell Ig production, were reduced by TGF-beta. These findings demonstrate that TGF-beta decreases B lymphocyte Ig secretion by inhibiting the synthesis of Ig mRNA and inhibiting the switch from the membrane form to the secreted forms of mu and gamma mRNA. The mechanism by which TGF-beta inhibits Ig chain synthesis is unclear although it does not involve inhibition of the binding of NF-kappa B or Oct-2 to their respective target sequences. " ], "offsets": [ [ 0, 2186 ] ] } ]

[ { "id": "1903417_T1", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 400, 404 ] ], "normalized": [] }, { "id": "1903417_T2", "type": "Protein", "text": [ "kappa L chain" ], "offsets": [ [ 504, 517 ] ], "normalized": [] }, { "id": "1903417_T3", "type": "Protein", "text": [ "lambda L chain" ], "offsets": [ [ 523, 537 ] ], "normalized": [] }, { "id": "1903417_T4", "type": "Protein", "text": [ "CD20" ], "offsets": [ [ 647, 651 ] ], "normalized": [] }, { "id": "1903417_T5", "type": "Protein", "text": [ "kappa" ], "offsets": [ [ 736, 741 ] ], "normalized": [] }, { "id": "1903417_T6", "type": "Protein", "text": [ "lambda" ], "offsets": [ [ 752, 758 ] ], "normalized": [] }, { "id": "1903417_T7", "type": "Protein", "text": [ "kappa L chain" ], "offsets": [ [ 803, 816 ] ], "normalized": [] }, { "id": "1903417_T8", "type": "Protein", "text": [ "lambda L chain" ], "offsets": [ [ 877, 891 ] ], "normalized": [] }, { "id": "1903417_T9", "type": "Protein", "text": [ "kappa" ], "offsets": [ [ 1074, 1079 ] ], "normalized": [] }, { "id": "1903417_T10", "type": "Protein", "text": [ "lambda L chain" ], "offsets": [ [ 1084, 1098 ] ], "normalized": [] }, { "id": "1903417_T11", "type": "Protein", "text": [ "kappa L chain" ], "offsets": [ [ 1343, 1356 ] ], "normalized": [] }, { "id": "1903417_T12", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 1425, 1430 ] ], "normalized": [] }, { "id": "1903417_T13", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 1526, 1531 ] ], "normalized": [] }, { "id": "1903417_T14", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 1553, 1558 ] ], "normalized": [] }, { "id": "1903417_T15", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 2142, 2147 ] ], "normalized": [] } ]

[ { "id": "1903417_E1", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 469, 478 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_E3" } ] }, { "id": "1903417_E2", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 469, 478 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_E4" } ] }, { "id": "1903417_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 538, 548 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_T2" } ] }, { "id": "1903417_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 538, 548 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_T3" } ] }, { "id": "1903417_E5", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 589, 596 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_T4" } ] }, { "id": "1903417_E6", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 790, 799 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_T7" } ] }, { "id": "1903417_E7", "type": "Negative_regulation", "trigger": { "text": [ "reduction" ], "offsets": [ [ 864, 873 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_T8" } ] }, { "id": "1903417_E8", "type": "Negative_regulation", "trigger": { "text": [ "levels" ], "offsets": [ [ 1104, 1110 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_T9" } ] }, { "id": "1903417_E9", "type": "Negative_regulation", "trigger": { "text": [ "levels" ], "offsets": [ [ 1104, 1110 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_T10" } ] }, { "id": "1903417_E10", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 1316, 1325 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_E11" } ] }, { "id": "1903417_E11", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1326, 1339 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_T11" } ] }, { "id": "1903417_E12", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 1362, 1369 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_T12" } ] }, { "id": "1903417_E13", "type": "Regulation", "trigger": { "text": [ "altered" ], "offsets": [ [ 1612, 1619 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_T14" } ] }, { "id": "1903417_E14", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 2099, 2109 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_E15" } ] }, { "id": "1903417_E15", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 2117, 2124 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1903417_T15" } ] } ]

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[]

[ { "id": "9915863__text", "type": "abstract", "text": [ "Role of Egr-2 in up-regulation of Fas ligand in normal T cells and aberrant double-negative lpr and gld T cells. \nWe previously identified a Fas ligand regulatory element (FLRE) in the Fas ligand (fasL) promoter that binds Egr family proteins and demonstrated that Egr-3 (PILOT) but not Egr-1 (NGFI-A, Krox-24, Tis-8, and Zif-268) induces transcription of fasL. The aberrant CD4(-)CD8(-) T cells from lpr/lpr and gld/gld mice, which have mutations in the genes encoding Fas and FasL, respectively, have an activated phenotype and constitutively express high levels of fasL mRNA, prompting us to ask what role if any the FLRE and Egr family proteins have in this aberrant expression of fasL. Unstimulated MRL-lpr/lpr and C3H-gld/gld CD4(-)CD8(-) T cells constitutively contained high levels of two proteins that bound to the FLRE. Supershift analysis revealed these proteins to be Egr-1 and Egr-2 (Krox-20); Egr-3 was not detected. Activation of normal lymph node cells resulted in increased expression of Egr-1, -2, and -3. As with egr-3, expression of egr-2 was blocked by cyclosporin A. Although overexpressed Egr-1 was ineffective, overexpressed Egr-2 was as potent as Egr-3 in inducing fasL promoter-dependent reporter constructs in T cell hybridomas and HeLa cells, and both up-regulated endogenous fasL mRNA in HeLa cells. FasL-dependent reporter constructs in MRL-lpr/lpr and C3H-gld/gld CD4(-)CD8(-) T cells were constitutively active, and this activity was largely prevented by mutation of the critical Egr family binding element. Thus, Egr-2, in addition to Egr-3, regulates FasL expression in activated normal T cells, and Egr-2 is likely to play a direct role in aberrant fasL up-regulation in lpr/lpr and gld/gld CD4(-)CD8(-) T cells. " ], "offsets": [ [ 0, 1748 ] ] } ]

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[ { "id": "9028949__text", "type": "abstract", "text": [ "Characterization of the human platelet/endothelial cell adhesion molecule-1 promoter: identification of a GATA-2 binding element required for optimal transcriptional activity. \nPlatelet/endothelial cell adhesion molecule-1 (PECAM-1) is a 130-kD member of the Ig gene superfamily that is expressed on platelets, endothelial cells, and certain leukocyte subsets. To examine the factors controlling vascular-specific expression of PECAM-1, we cloned the 5'-flanking region of the PECAM-1 gene and analyzed its transcriptional activity. 5'-Rapid amplification of cDNA ends (5'-RACE) analysis showed that transcription initiation occurred at several closely spaced nearby sites originating approximately 204 bp upstream from the translation start site. Analysis of the sequence immediately upstream from the transcription initiation site (TIS) showed no canonical TATA or CAAT elements, however an initiator element commonly found in TATA-less promoters encompassed the TIS. 5'-serially truncated PECAM-1 promoter segments cloned in front of a luciferase reporter drove transcription in both a lineage- and orientation-specific manner. Putative cis-acting control elements present within a 300-bp core promoter included two ets sites, an Sp1 site, tandem E-box domains, two GATA-associated sites (CACCC), an AP-2 binding site, and a GATA element at -24. Mutational analysis showed that optimal transcriptional activity required the GATA sequence at position -24, and gel-shift assays further showed that the GATA-2 transcription factor, but not GATA-1, bound to this region of the PECAM-1 promoter. Understanding the cis- and transacting factors that regulate the tissue-specific expression of PECAM-1 should increase our understanding of the mechanisms by which vascular-specific gene expression is achieved. " ], "offsets": [ [ 0, 1805 ] ] } ]

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[ { "id": "10235509__text", "type": "abstract", "text": [ "HIV-1 reactivation in resting peripheral blood mononuclear cells of infected adults upon in vitro CD4 cross-linking by ligands of the CDR2-loop in extracellular domain 1. \nHIV-1 infects resting peripheral blood mononuclear cells (PBMCs) but remains inactive state until subsequent cell activation. We have demonstrated that the cross-linking of cell surface CD4 by gp120-anti-gp120 immune complexes or heat-inactivated HIV-1 (iHIV-1) is sufficient to trigger activation signals leading to virus reactivation (9). In this study, we demonstrate that NF-kappaB nuclear translocation and stimulation of virus production by iHIV-1 were strictly linked to the concentrations of viral proteins used as exogenous stimuli. Moreover, we further investigated the physiologic relevance of these observations. When submitted to an in vitro CD4 cross-linking by iHIV-1, PBMCs from HIV-1-infected patients were found to produce virus. This viral reactivation was associated with increased NF-kappaB nuclear translocation in patients' PBMCs. Additionally, virus reactivation in resting PBMCs infected in vitro with HIV-1 was found to be specifically induced by ligands of the CDR2-loop in domain 1 (D1) of CD4 (virus envelope and anti-CD4 monoclonal antibodies). In contrast, virus reactivation was not observed following CD4 oligomerization by antibodies that bind other epitopes in D1, including the D1/CDR3-loop. Finally, soluble CD4 (sCD4) prevented virus reactivation by D1/CDR2-loop ligands. Our results indicate that the signaling events initiated in PBMCs by oligomerization of CD4 at the D1/CDR2-loop can trigger HIV-1 upregulation in infected individuals. " ], "offsets": [ [ 0, 1650 ] ] } ]

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[]

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[ { "id": "8444885__text", "type": "abstract", "text": [ "Suppression of a cellular differentiation program by phorbol esters coincides with inhibition of binding of a cell-specific transcription factor (NF-E2) to an enhancer element required for expression of an erythroid-specific gene. \nInduction by hemin increases, while induction with 12-O-tetradecanoylphorbol-13-acetate (TPA) represses, erythroid-specific gene expression in the human cell line K562. We analyzed the effects of hemin or TPA induction on the binding and activity of transcription factors at a regulatory element found within the transcriptional regulatory sequences of many erythroid-specific genes. TPA induction increases the binding of ubiquitous AP-1 factors to this element. TPA induction inhibits the binding of the lineage limited transcription factor NF-E2 to this transcriptional control element. Hemin induction of K562 cells does not facilitate the binding of NF-E2 to its recognition site. Hemin induction appears to nonspecifically increase the expression of transiently transfected genes in K562 cells. Beyond this nonspecific increase in gene expression, hemin induction acts to increase the activity of the lineage limited transcription factor NF-E2. The divergent effects of hemin and TPA on gene expression in K562 cells are mediated, in part, by their contrasting effects on the transcription factor NF-E2. " ], "offsets": [ [ 0, 1342 ] ] } ]

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[ { "id": "7869038__text", "type": "abstract", "text": [ "Calcium/calmodulin-dependent protein kinase II downregulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells. \nEngagement of the T cell receptor for antigen activates phospholipase C resulting in an increase in intracellular free calcium concentration ([Ca2+]i) and activation of protein kinase C (PKC). Increased [Ca2+]i activates Ca2+/calmodulin-dependent kinases including the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM-K II), as well as calcineurin, a type 2B protein phosphatase. Recent studies have identified calcineurin as a key enzyme for interleukin (IL)-2 and IL-4 promoter activation. However, the role of CaM-K II remains unknown. We have used mutants of these kinases and phosphatases (gamma B*CaM-K and delta CaM-AI, respectively) to explore their relative role in cytokine gene transcription and their interactions with PKC-dependent signaling systems. gamma B*CaM-K and delta CaM-AI, known to exhibit constitutive Ca(2+)-independent activity, were cotransfected (alone or in combination) in Jurkat T cells with a plasmid containing the intact IL-2 promoter driving the expression of the chloramphenicol acetyltransferase reporter gene. Cotransfection of gamma B*CaM-K with the IL-2 promoter construct downregulated its transcription in response to stimulation with ionomycin and phorbol myristate acetate (PMA). The inhibitory effect of CaM-K II on IL-2 promoter was associated with decreased transcription of its AP-1 and NF-AT transactivating pathways. Under the same conditions, delta CaM-AI superinduced IL-2 promoter activity (approximately twofold increase). When both mutants were used in combination, gamma B*CaM-K inhibited the induction of the IL-2 promoter by delta CaM-AI. Similar results were obtained when a construct containing the IL-4 promoter also was used. gamma B*CaM-K also downregulated the activation of AP-1 in response to transfection with a constitutively active mutant of PKC or stimulation with PMA. These results suggest that CaM-K II may exert negative influences on cytokine gene transcription in human T cells, and provide preliminary evidence for negative cross-talk with the calcineurin- and PKC- dependent signaling systems. " ], "offsets": [ [ 0, 2256 ] ] } ]

[ { "id": "7869038_T1", "type": "Protein", "text": [ "calmodulin" ], "offsets": [ [ 394, 404 ] ], "normalized": [] }, { "id": "7869038_T2", "type": "Protein", "text": [ "interleukin (IL)-2" ], "offsets": [ [ 627, 645 ] ], "normalized": [] }, { "id": "7869038_T3", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 650, 654 ] ], "normalized": [] }, { "id": "7869038_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1139, 1143 ] ], "normalized": [] }, { "id": "7869038_T5", "type": "Protein", "text": [ "chloramphenicol acetyltransferase" ], "offsets": [ [ 1183, 1216 ] ], "normalized": [] }, { "id": "7869038_T6", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1273, 1277 ] ], "normalized": [] }, { "id": "7869038_T7", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1445, 1449 ] ], "normalized": [] }, { "id": "7869038_T8", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1604, 1608 ] ], "normalized": [] }, { "id": "7869038_T9", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1750, 1754 ] ], "normalized": [] }, { "id": "7869038_T10", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1843, 1847 ] ], "normalized": [] }, { "id": "7869038_T12", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 655, 663 ] ], "normalized": [] }, { "id": "7869038_T15", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1450, 1458 ] ], "normalized": [] }, { "id": "7869038_T20", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1609, 1617 ] ], "normalized": [] }, { "id": "7869038_T23", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1755, 1763 ] ], "normalized": [] } ]

[ { "id": "7869038_E1", "type": "Positive_regulation", "trigger": { "text": [ "key enzyme" ], "offsets": [ [ 612, 622 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7869038_E3" } ] }, { "id": "7869038_E2", "type": "Positive_regulation", "trigger": { "text": [ "key enzyme" ], "offsets": [ [ 612, 622 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7869038_E4" } ] }, { "id": "7869038_E3", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 664, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7869038_T3" }, { "role": "Site", "ref_id": "7869038_T12" } ] }, { "id": "7869038_E4", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 664, 674 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7869038_T2" }, { "role": "Site", "ref_id": "7869038_T12" } ] }, { "id": "7869038_E5", "type": "Negative_regulation", "trigger": { "text": [ "inhibitory effect" ], "offsets": [ [ 1412, 1429 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7869038_T7" }, { "role": "Site", "ref_id": "7869038_T15" } ] }, { "id": "7869038_E6", "type": "Negative_regulation", "trigger": { "text": [ "decreased" ], "offsets": [ [ 1479, 1488 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7869038_E8" } ] }, { "id": "7869038_E7", "type": "Transcription", "trigger": { "text": [ "transcription" ], "offsets": [ [ 1489, 1502 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7869038_T7" } ] }, { "id": "7869038_E8", "type": "Positive_regulation", "trigger": { "text": [ "transactivating pathways" ], "offsets": [ [ 1525, 1549 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7869038_E7" } ] }, { "id": "7869038_E9", "type": "Positive_regulation", "trigger": { "text": [ "superinduced" ], "offsets": [ [ 1591, 1603 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7869038_T8" }, { "role": "Site", "ref_id": "7869038_T20" } ] }, { "id": "7869038_E10", "type": "Negative_regulation", "trigger": { "text": [ "inhibited" ], "offsets": [ [ 1719, 1728 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7869038_E11" } ] }, { "id": "7869038_E11", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1733, 1742 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7869038_T9" }, { "role": "Site", "ref_id": "7869038_T23" } ] } ]

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[ { "id": "1655897__text", "type": "abstract", "text": [ "Nuclear transcription factors that bind to elements of the IL-2 promoter. Induction requirements in primary human T cells. \nPrior studies have identified several elements that contribute to the activity of the IL-2 promoter in the stimulated T cell line, Jurkat. The sites and their corresponding nuclear binding factors include: NF-kappa B, AP-1, AP-3, OCT-1, and NF-AT. The latter \"nuclear factor for activated T cells\" likely contributes to the tissue specificity of IL-2 gene expression. Using electrophoretic mobility shift assays, we have studied these transcription factors in primary T cells from human blood to verify their presence in a physiologic setting and to identify the signals that stimulate factor activity. All factors are induced in the nuclei of T cells upon activation with mitogens but not with exogenous IL-2 growth factor. However, the signaling requirements and sensitivity to protein synthesis inhibitors differ considerably. Only the activities for NF-AT and AP-1 sites require two signals for optimal induction, i.e., PMA plus either lectin or antibody to the CD3 or CD28 surface molecules. Other factors are induced by lectin, antibody, and/or PMA alone. After appropriate stimulation, both NF-AT and AP-1 are peculiarly sensitive to the protein synthesis inhibitor anisomycin. Our data correlate the activity of NF-AT and AP-1 in gel shift assays with the two signals requirements for IL-2 gene expression. " ], "offsets": [ [ 0, 1439 ] ] } ]

[ { "id": "1655897_T1", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 59, 63 ] ], "normalized": [] }, { "id": "1655897_T2", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 210, 214 ] ], "normalized": [] }, { "id": "1655897_T3", "type": "Protein", "text": [ "OCT-1" ], "offsets": [ [ 354, 359 ] ], "normalized": [] }, { "id": "1655897_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 470, 474 ] ], "normalized": [] }, { "id": "1655897_T5", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 829, 833 ] ], "normalized": [] }, { "id": "1655897_T6", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1097, 1101 ] ], "normalized": [] }, { "id": "1655897_T7", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1417, 1421 ] ], "normalized": [] }, { "id": "1655897_T9", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 64, 72 ] ], "normalized": [] }, { "id": "1655897_T11", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 215, 223 ] ], "normalized": [] } ]

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[ { "id": "9847292__text", "type": "abstract", "text": [ "Interleukin-10 and transforming growth factor-beta promoter polymorphisms in allergies and asthma. \nInterleukin-10 (IL-10) and transforming growth factor beta (TGF-beta) are inhibitory for B and T cells, IgE production, and mast cell proliferation, and they induce apoptosis in eosinophils. These cytokines are therefore candidate genes which could contribute to the development of asthma or allergies. We investigated the hypothesis that polymorphic nucleotides within the IL-10 and TGF-beta gene promoters would link to the expression of allergies and asthma. DNA taken from families with an asthmatic proband was examined for base exchanges by single-stranded conformational polymorphism (SSCP). We demonstrated the presence of a polymorphism in the promoter region of the IL-10 gene and four in the TGF-beta gene promoters (3 in TGF-beta1 and 1 in TGF-beta2). The IL-10 gene polymorphism was a C-to-A exchange 571 base pairs upstream from the translation start site and was present between consensus binding sequences for Sp1 and elevated total serum. This polymorphism was associated with elevated total serum IgE in subjects heterozygotic or homozygotic for this base exchange (p < 0.009). The base exchange at -509 (from the transcription initiation site) in the TGF-beta promoter also linked to elevated total IgE (p < 0.01). This polymorphism represented a C-to-T base exchange which induced a YY1 consensus sequence and is present in a region of the promoter associated with negative transcription regulation. " ], "offsets": [ [ 0, 1520 ] ] } ]

[ { "id": "9847292_T1", "type": "Protein", "text": [ "Interleukin-10" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "9847292_T2", "type": "Protein", "text": [ "Interleukin-10" ], "offsets": [ [ 100, 114 ] ], "normalized": [] }, { "id": "9847292_T3", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 116, 121 ] ], "normalized": [] }, { "id": "9847292_T4", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 474, 479 ] ], "normalized": [] }, { "id": "9847292_T5", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 776, 781 ] ], "normalized": [] }, { "id": "9847292_T6", "type": "Protein", "text": [ "TGF-beta1" ], "offsets": [ [ 833, 842 ] ], "normalized": [] }, { "id": "9847292_T7", "type": "Protein", "text": [ "TGF-beta2" ], "offsets": [ [ 852, 861 ] ], "normalized": [] }, { "id": "9847292_T8", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 868, 873 ] ], "normalized": [] }, { "id": "9847292_T9", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 1026, 1029 ] ], "normalized": [] } ]

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[ { "id": "9847292_1", "entity_ids": [ "9847292_T2", "9847292_T3" ] } ]

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[ { "id": "9242431__text", "type": "abstract", "text": [ "Bcl-2 protein inhibits bufalin-induced apoptosis through inhibition of mitogen-activated protein kinase activation in human leukemia U937 cells. \nIn a previous study, we demonstrated that bufalin, which is an active principle of Chinese medicine, chan'su, caused apoptosis in human leukemia U937 cells by anomalous activation of mitogen-activated protein kinase (MAPK) via the signaling pathway of Ras, Raf-1, and MAPK kinase-1. Here, we report the effect of overexpression of bcl-2 in U937 cells on the signaling pathway of apoptosis that is induced by bufalin. The results indicated that the apoptosis induced by bufalin in U937 cells was significantly inhibited by overexpression of the Bcl-2 protein. No significant difference was detected in the activation of MAPK kinase-1 that is induced by bufalin in wild-type or Bcl-2-overexpressed U937 cells; however, the activation of MAPK by bufalin was significantly attenuated in the cells overexpressing Bcl-2. Bufalin treatment activated activator protein-1 transcriptional activity; however, this activation was decreased to 40% in bcl-2-overexpressed U937 cells. These results indicate that Bcl-2 acts downstream of MAPK kinase-1 but upstream of MAPK and suggest that, in the signaling pathway of the apoptotic process induced by bufalin, the transcriptional activity of activator protein-1 may be down-regulated through the inhibition of MAPK activity by Bcl-2. " ], "offsets": [ [ 0, 1416 ] ] } ]

[ { "id": "9242431_T1", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "9242431_T2", "type": "Protein", "text": [ "Raf-1" ], "offsets": [ [ 403, 408 ] ], "normalized": [] }, { "id": "9242431_T3", "type": "Protein", "text": [ "MAPK kinase-1" ], "offsets": [ [ 414, 427 ] ], "normalized": [] }, { "id": "9242431_T4", "type": "Protein", "text": [ "bcl-2" ], "offsets": [ [ 477, 482 ] ], "normalized": [] }, { "id": "9242431_T5", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 690, 695 ] ], "normalized": [] }, { "id": "9242431_T6", "type": "Protein", "text": [ "MAPK kinase-1" ], "offsets": [ [ 765, 778 ] ], "normalized": [] }, { "id": "9242431_T7", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 822, 827 ] ], "normalized": [] }, { "id": "9242431_T8", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 954, 959 ] ], "normalized": [] }, { "id": "9242431_T9", "type": "Protein", "text": [ "bcl-2" ], "offsets": [ [ 1084, 1089 ] ], "normalized": [] }, { "id": "9242431_T10", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1144, 1149 ] ], "normalized": [] }, { "id": "9242431_T11", "type": "Protein", "text": [ "MAPK kinase-1" ], "offsets": [ [ 1169, 1182 ] ], "normalized": [] }, { "id": "9242431_T12", "type": "Protein", "text": [ "Bcl-2" ], "offsets": [ [ 1409, 1414 ] ], "normalized": [] } ]

[ { "id": "9242431_E1", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 459, 473 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_T4" } ] }, { "id": "9242431_E2", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 459, 473 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_E1" } ] }, { "id": "9242431_E3", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 668, 682 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_T5" } ] }, { "id": "9242431_E4", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 668, 682 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_E3" } ] }, { "id": "9242431_E5", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 751, 761 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_T6" } ] }, { "id": "9242431_E6", "type": "Positive_regulation", "trigger": { "text": [ "overexpressed" ], "offsets": [ [ 828, 841 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_E7" } ] }, { "id": "9242431_E7", "type": "Gene_expression", "trigger": { "text": [ "overexpressed" ], "offsets": [ [ 828, 841 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_T7" } ] }, { "id": "9242431_E8", "type": "Positive_regulation", "trigger": { "text": [ "overexpressing" ], "offsets": [ [ 939, 953 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_E9" } ] }, { "id": "9242431_E9", "type": "Gene_expression", "trigger": { "text": [ "overexpressing" ], "offsets": [ [ 939, 953 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_T8" } ] }, { "id": "9242431_E10", "type": "Positive_regulation", "trigger": { "text": [ "overexpressed" ], "offsets": [ [ 1090, 1103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_E11" } ] }, { "id": "9242431_E11", "type": "Gene_expression", "trigger": { "text": [ "overexpressed" ], "offsets": [ [ 1090, 1103 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_T9" } ] }, { "id": "9242431_E12", "type": "Regulation", "trigger": { "text": [ "acts" ], "offsets": [ [ 1150, 1154 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9242431_T10" }, { "role": "Cause", "ref_id": "9242431_T11" } ] } ]

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[ { "id": "7912114__text", "type": "abstract", "text": [ "Pentoxifylline for the treatment of infection with human immunodeficiency virus. \nCytokine dysregulation in human immunodeficiency virus type 1 (HIV-1) infection has been documented in numerous studies and has been cited as an important component in the pathogenesis of this retroviral infection. Pharmacological modification of cytokine dysregulation, therefore, has been suggested as a therapeutic modality for HIV-1 infection. Dr. Dezube of Beth Israel Hospital (Boston) concisely reviews the state of our knowledge regarding the effects of pentoxifylline on expression of tumor necrosis factor-alpha, a cytokine known to influence HIV-1 replication and to play a possible role in the clinical manifestations of advanced infection with this virus. Pentoxifylline, a trisubstituted xanthine derivative, has been used to decrease blood viscosity and is reasonably well tolerated by most recipients of the drug. Results of preliminary studies, many of which were conducted by Dr. Dezube, suggest that use of this agent in combination with antiretroviral compounds may prove useful in the treatment of patients with HIV-1 infection. " ], "offsets": [ [ 0, 1132 ] ] } ]

[ { "id": "7912114_T1", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 576, 603 ] ], "normalized": [] } ]

[ { "id": "7912114_E1", "type": "Regulation", "trigger": { "text": [ "effects" ], "offsets": [ [ 533, 540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7912114_E2" } ] }, { "id": "7912114_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 562, 572 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7912114_T1" } ] } ]

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[ { "id": "8386664__text", "type": "abstract", "text": [ "Human CD3-CD16+ natural killer cells express the hGATA-3 T cell transcription factor and an unrearranged 2.3-kb TcR delta transcript. \nIn this study we analyzed the T cell receptor(TcR) delta transcripts expressed by CD3-CD16+ cells and we investigated whether these cells expressed the hGATA-3 T cell transcription factor and the recombination-activating gene (RAG)-1. Multiple TcR delta transcripts deriving from an unrearranged TcR delta gene were detected in both polyclonal and clonal CD3-CD16+ natural killer(NK) cell lines. Two unrearranged TcR delta transcripts had a size similar to that of the functional TcR delta mRNA (2.3 and 1.3 kb) found in TcR gamma/delta+ T lymphocytes. Sequence analysis of nine different 2.3-kb cDNA clones obtained from NK-derived polyA+ RNA confirmed that they corresponded to an unrearranged TcR delta gene. These cDNA were 2343 bp long and their transcription initiation site was located 814 bp upstream from the J delta 1 segment. The sequence located upstream of the J delta 1 segment corresponded to the previously reported germ-line sequence. The J delta 1 segment was correctly spliced to C delta; in addition the four C delta exons were found to be already assembled. Two polyadenylation sites were present in the fourth C delta exon. However, only that located at the 3' end appeared to be utilized in the 2.3-kb cDNA. The expression of hGATA-3, a T cell-specific factor known to be involved in the regulation of the transcription of TcR delta locus, was analyzed by Northern blot, in cultured NK cell population and clones (but not in freshly derived cell populations). All NK clones and cell lines studied were found to express hGATA-3-specific mRNA, suggesting that hGATA-3 may be involved in the regulation of the unrearranged TcR delta gene expression in NK cells. Finally, no transcription of the RAG-1 gene could be detected in all NK cell lines or clones analyzed. " ], "offsets": [ [ 0, 1920 ] ] } ]

[ { "id": "8386664_T1", "type": "Protein", "text": [ "CD3" ], "offsets": [ [ 6, 9 ] ], "normalized": [] }, { "id": "8386664_T2", "type": "Protein", "text": [ "CD16" ], "offsets": [ [ 10, 14 ] ], "normalized": [] }, { "id": "8386664_T3", "type": "Protein", "text": [ "hGATA-3" ], "offsets": [ [ 49, 56 ] ], "normalized": [] }, { "id": "8386664_T4", "type": "Protein", "text": [ "TcR delta" ], "offsets": [ [ 112, 121 ] ], "normalized": [] }, { "id": "8386664_T5", "type": "Protein", "text": [ "T cell receptor(TcR) delta" ], "offsets": [ [ 165, 191 ] ], "normalized": [] }, { "id": "8386664_T6", "type": "Protein", "text": [ "CD3" ], "offsets": [ [ 217, 220 ] ], "normalized": [] }, { "id": "8386664_T7", "type": "Protein", "text": [ "CD16" ], "offsets": [ [ 221, 225 ] ], "normalized": [] }, { "id": "8386664_T8", "type": "Protein", "text": [ "hGATA-3" ], "offsets": [ [ 287, 294 ] ], "normalized": [] }, { "id": "8386664_T9", "type": "Protein", "text": [ "recombination-activating gene (RAG)-1" ], "offsets": [ [ 331, 368 ] ], "normalized": [] }, { "id": "8386664_T10", "type": "Protein", "text": [ "TcR delta" ], "offsets": [ [ 379, 388 ] ], "normalized": [] }, { "id": "8386664_T11", "type": "Protein", "text": [ "TcR delta" ], "offsets": [ [ 431, 440 ] ], "normalized": [] }, { "id": "8386664_T12", "type": "Protein", "text": [ "CD3" ], "offsets": [ [ 490, 493 ] ], "normalized": [] }, { "id": "8386664_T13", "type": "Protein", "text": [ "CD16" ], "offsets": [ [ 494, 498 ] ], "normalized": [] }, { "id": "8386664_T14", "type": "Protein", "text": [ "TcR delta" ], "offsets": [ [ 548, 557 ] ], "normalized": [] }, { "id": "8386664_T15", "type": "Protein", "text": [ "TcR delta" ], "offsets": [ [ 615, 624 ] ], "normalized": [] }, { "id": "8386664_T16", "type": "Protein", "text": [ "TcR gamma" ], "offsets": [ [ 656, 665 ] ], "normalized": [] }, { "id": "8386664_T17", "type": "Protein", "text": [ "delta" ], "offsets": [ [ 666, 671 ] ], "normalized": [] }, { "id": "8386664_T18", "type": "Protein", "text": [ "TcR delta" ], "offsets": [ [ 831, 840 ] ], "normalized": [] }, { "id": "8386664_T19", "type": "Protein", "text": [ "hGATA-3" ], "offsets": [ [ 1384, 1391 ] ], "normalized": [] }, { "id": "8386664_T20", "type": "Protein", "text": [ "TcR delta" ], "offsets": [ [ 1481, 1490 ] ], "normalized": [] }, { "id": "8386664_T21", "type": "Protein", "text": [ "hGATA-3" ], "offsets": [ [ 1677, 1684 ] ], "normalized": [] }, { "id": "8386664_T22", "type": "Protein", "text": [ "hGATA-3" ], "offsets": [ [ 1716, 1723 ] ], "normalized": [] }, { "id": "8386664_T23", "type": "Protein", "text": [ "TcR delta" ], "offsets": [ [ 1778, 1787 ] ], "normalized": [] }, { "id": "8386664_T24", "type": "Protein", "text": [ "RAG-1" ], "offsets": [ [ 1850, 1855 ] ], "normalized": [] } ]

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[ { "id": "9663467__text", "type": "abstract", "text": [ "Thrombopoietin supports in vitro erythroid differentiation via its specific receptor c-Mpl in a human leukemia cell line. \nThrombopoietin (TPO) acts on megakaryopoiesis and erythropoiesis in vitro and in vivo. We isolated a novel subline, UT-7/GMT, from the human leukemia cell line UT-7/GM (N. Komatsu, et al., Blood, 89: 4021-4033, 1997). A small population of UT-7/GM cells positively stained for hemoglobin (Hb) after a 7-day exposure to TPO. More than 50% of TPO-treated UT-7/GMT cells positively stained for Hb. Using UT-7/GMT cells, we examined how TPO promotes hemoglobinization. TPO induced tyrosine phosphorylation of the TPO receptor but not the erythropoietin (EPO) receptor. There was no competition between TPO and EPO for binding to EPO receptor. These findings suggest that TPO has a direct effect on hemoglobinization via a specific receptor on UT-7/GMT cells. Isoelectric focusing demonstrated that TPO induced fetal and adult Hb synthesis, whereas EPO induced embryonic, fetal, and adult Hb synthesis. Thus, our data suggest that TPO has a distinct action on erythropoiesis. " ], "offsets": [ [ 0, 1094 ] ] } ]

[ { "id": "9663467_T1", "type": "Protein", "text": [ "Thrombopoietin" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "9663467_T2", "type": "Protein", "text": [ "c-Mpl" ], "offsets": [ [ 85, 90 ] ], "normalized": [] }, { "id": "9663467_T3", "type": "Protein", "text": [ "Thrombopoietin" ], "offsets": [ [ 123, 137 ] ], "normalized": [] }, { "id": "9663467_T4", "type": "Protein", "text": [ "TPO" ], "offsets": [ [ 139, 142 ] ], "normalized": [] }, { "id": "9663467_T5", "type": "Protein", "text": [ "TPO" ], "offsets": [ [ 442, 445 ] ], "normalized": [] }, { "id": "9663467_T6", "type": "Protein", "text": [ "TPO" ], "offsets": [ [ 464, 467 ] ], "normalized": [] }, { "id": "9663467_T7", "type": "Protein", "text": [ "TPO" ], "offsets": [ [ 556, 559 ] ], "normalized": [] }, { "id": "9663467_T8", "type": "Protein", "text": [ "TPO" ], "offsets": [ [ 588, 591 ] ], "normalized": [] }, { "id": "9663467_T9", "type": "Protein", "text": [ "TPO receptor" ], "offsets": [ [ 632, 644 ] ], "normalized": [] }, { "id": "9663467_T10", "type": "Protein", "text": [ "erythropoietin (EPO) receptor" ], "offsets": [ [ 657, 686 ] ], "normalized": [] }, { "id": "9663467_T11", "type": "Protein", "text": [ "TPO" ], "offsets": [ [ 721, 724 ] ], "normalized": [] }, { "id": "9663467_T12", "type": "Protein", "text": [ "EPO" ], "offsets": [ [ 729, 732 ] ], "normalized": [] }, { "id": "9663467_T13", "type": "Protein", "text": [ "EPO receptor" ], "offsets": [ [ 748, 760 ] ], "normalized": [] }, { "id": "9663467_T14", "type": "Protein", "text": [ "TPO" ], "offsets": [ [ 790, 793 ] ], "normalized": [] }, { "id": "9663467_T15", "type": "Protein", "text": [ "TPO" ], "offsets": [ [ 917, 920 ] ], "normalized": [] }, { "id": "9663467_T16", "type": "Protein", "text": [ "EPO" ], "offsets": [ [ 967, 970 ] ], "normalized": [] }, { "id": "9663467_T17", "type": "Protein", "text": [ "TPO" ], "offsets": [ [ 1049, 1052 ] ], "normalized": [] }, { "id": "9663467_T20", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 600, 608 ] ], "normalized": [] } ]

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[ { "id": "10452760__text", "type": "abstract", "text": [ "Signal transduction pathways triggered by the FcepsilonRIIb receptor (CD23) in human monocytes lead to nuclear factor-kappaB activation. \nBACKGROUND: Alveolar macrophages play a key role in the initiation of the inflammatory reaction of allergic asthma. Alveolar macrophages and peripheral blood monocytes are activated when IgE/allergen immune complexes bind to the CD23 receptor, which leads to the production of inflammatory cytokines. OBJECTIVE: We sought to investigate the molecular mechanisms regulating this early inflammatory response. We have focused on the study of the signal transduction pathways triggered by CD23 in human monocytes and the promonocytic cell line U937. METHODS: CD23 was cross-linked in human monocytes and U937 cells with IgE immune complexes. Surface expression of CD23 was determined by FACS analysis. Transcription factor activation and gene transcription were studied by gel-shift assays and Northern blot analysis, respectively. IkappaBalpha phosphorylation and degradation was analyzed by Western blot. RESULTS: Nuclear factor (NF)-kappaB is the main transcription factor involved in the gene activation that follows CD23 cross-linking in monocytes. CD23-induced NF-kappaB is a heterodimer composed of p65/p50 subunits. NF-kappaB nuclear translocation is secondary to the phosphorylation and subsequent degradation of the NF-kappaB inhibitory molecule IkappaBalpha. Tyrosine kinase-dependent, and not protein kinase C-dependent, pathways mediate CD23-triggered NF-kappaB activation but do not participate in the direct phosphorylation of IkappaBalpha. IkappaBalpha degradation and NF-kappaB nuclear translocation correlate with transcriptional activation of the inflammatory cytokines TNF-alpha and IL-1beta. CONCLUSIONS: NF-kappaB is the main transcription factor involved in the signal transduction pathway of CD23 in monocytes. " ], "offsets": [ [ 0, 1869 ] ] } ]

[ { "id": "10452760_T1", "type": "Protein", "text": [ "FcepsilonRIIb receptor" ], "offsets": [ [ 46, 68 ] ], "normalized": [] }, { "id": "10452760_T2", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 70, 74 ] ], "normalized": [] }, { "id": "10452760_T3", "type": "Protein", "text": [ "CD23 receptor" ], "offsets": [ [ 367, 380 ] ], "normalized": [] }, { "id": "10452760_T4", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 623, 627 ] ], "normalized": [] }, { "id": "10452760_T5", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 693, 697 ] ], "normalized": [] }, { "id": "10452760_T6", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 798, 802 ] ], "normalized": [] }, { "id": "10452760_T7", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 966, 978 ] ], "normalized": [] }, { "id": "10452760_T8", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 1155, 1159 ] ], "normalized": [] }, { "id": "10452760_T9", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 1188, 1192 ] ], "normalized": [] }, { "id": "10452760_T10", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1240, 1243 ] ], "normalized": [] }, { "id": "10452760_T11", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1244, 1247 ] ], "normalized": [] }, { "id": "10452760_T12", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 1390, 1402 ] ], "normalized": [] }, { "id": "10452760_T13", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 1484, 1488 ] ], "normalized": [] }, { "id": "10452760_T14", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 1576, 1588 ] ], "normalized": [] }, { "id": "10452760_T15", "type": "Protein", "text": [ "IkappaBalpha" ], "offsets": [ [ 1590, 1602 ] ], "normalized": [] }, { "id": "10452760_T16", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1723, 1732 ] ], "normalized": [] }, { "id": "10452760_T17", "type": "Protein", "text": [ "IL-1beta" ], "offsets": [ [ 1737, 1745 ] ], "normalized": [] }, { "id": "10452760_T18", "type": "Protein", "text": [ "CD23" ], "offsets": [ [ 1850, 1854 ] ], "normalized": [] } ]

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[ { "id": "9744863__text", "type": "abstract", "text": [ "Altered DNA-binding specificity mutants of EKLF and Sp1 show that EKLF is an activator of the beta-globin locus control region in vivo. \nThe locus control region of the beta-globin cluster contains five DNase I hypersensitive sites (5'HS1-5) required for locus activation. 5'HS3 contains six G-rich motifs that are essential for its activity. Members of a protein family, characterized by three zinc fingers highly homologous to those found in transcription factor Sp1, interact with these motifs. Because point mutagenesis cannot distinguish between family members, it is not known which protein activates 5'HS3. We show that the function of such closely related proteins can be distinguished in vivo by matching point mutations in 5'HS3 with amino acid changes in the zinc fingers of Sp1 and EKLF. Testing their activity in transgenic mice shows that EKLF is a direct activator of 5'HS3. " ], "offsets": [ [ 0, 890 ] ] } ]

[ { "id": "9744863_T1", "type": "Protein", "text": [ "EKLF" ], "offsets": [ [ 43, 47 ] ], "normalized": [] }, { "id": "9744863_T2", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 52, 55 ] ], "normalized": [] }, { "id": "9744863_T3", "type": "Protein", "text": [ "EKLF" ], "offsets": [ [ 66, 70 ] ], "normalized": [] }, { "id": "9744863_T4", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 94, 105 ] ], "normalized": [] }, { "id": "9744863_T5", "type": "Protein", "text": [ "beta-globin" ], "offsets": [ [ 169, 180 ] ], "normalized": [] }, { "id": "9744863_T6", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 465, 468 ] ], "normalized": [] }, { "id": "9744863_T7", "type": "Protein", "text": [ "Sp1" ], "offsets": [ [ 786, 789 ] ], "normalized": [] }, { "id": "9744863_T8", "type": "Protein", "text": [ "EKLF" ], "offsets": [ [ 794, 798 ] ], "normalized": [] }, { "id": "9744863_T9", "type": "Protein", "text": [ "EKLF" ], "offsets": [ [ 853, 857 ] ], "normalized": [] } ]

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[]

[]

[ { "id": "8858156__text", "type": "abstract", "text": [ "Human TAFII 105 is a cell type-specific TFIID subunit related to hTAFII130. \nWe previously characterized Drosophila and human TAF subunits that make up the core TFIID complex found in all cells. Here, we report that differentiated B cells contain a novel substoichiometric TAF of 105 kDa not found associated with TFIID isolated from other cell types. The cDNA encoding hTAFII105 reveals a highly conserved C-terminal domain shared by hTAFII130 and oTAFII110, while the N-terminal coactivator domain has diverged significantly. All cells tested express TAFII105 mRNA, but only B cells contain significant levels of protein associated with TFIID. Transient overexpression of hTAFII105 selectively squelches the transcription of some genes in B cells. These properties suggest that TAFII105 is a cell type-specific subunit of TFIID that may be responsible for mediating transcription by a subset of activators in B cells. " ], "offsets": [ [ 0, 920 ] ] } ]

[ { "id": "8858156_T1", "type": "Protein", "text": [ "TAFII 105" ], "offsets": [ [ 6, 15 ] ], "normalized": [] }, { "id": "8858156_T2", "type": "Protein", "text": [ "hTAFII130" ], "offsets": [ [ 65, 74 ] ], "normalized": [] }, { "id": "8858156_T3", "type": "Protein", "text": [ "hTAFII105" ], "offsets": [ [ 370, 379 ] ], "normalized": [] }, { "id": "8858156_T4", "type": "Protein", "text": [ "hTAFII130" ], "offsets": [ [ 435, 444 ] ], "normalized": [] }, { "id": "8858156_T5", "type": "Protein", "text": [ "oTAFII110" ], "offsets": [ [ 449, 458 ] ], "normalized": [] }, { "id": "8858156_T6", "type": "Protein", "text": [ "TAFII105" ], "offsets": [ [ 553, 561 ] ], "normalized": [] }, { "id": "8858156_T7", "type": "Protein", "text": [ "hTAFII105" ], "offsets": [ [ 674, 683 ] ], "normalized": [] }, { "id": "8858156_T8", "type": "Protein", "text": [ "TAFII105" ], "offsets": [ [ 780, 788 ] ], "normalized": [] } ]

[ { "id": "8858156_E1", "type": "Transcription", "trigger": { "text": [ "express" ], "offsets": [ [ 545, 552 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8858156_T6" } ] }, { "id": "8858156_E2", "type": "Binding", "trigger": { "text": [ "associated" ], "offsets": [ [ 623, 633 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8858156_T6" } ] }, { "id": "8858156_E3", "type": "Positive_regulation", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 656, 670 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8858156_E4" } ] }, { "id": "8858156_E4", "type": "Gene_expression", "trigger": { "text": [ "overexpression" ], "offsets": [ [ 656, 670 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8858156_T7" } ] } ]

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[ { "id": "7964483__text", "type": "abstract", "text": [ "One gene, two transcripts: isolation of an alternative transcript encoding for the autoantigen La/SS-B from a cDNA library of a patient with primary Sjogrens' syndrome. \nA cDNA library was prepared from peripheral blood lymphocytes of an autoimmune patient with primary Sjogrens' syndrome. The cDNA library was screened with the patients own autoimmune serum being monospecific for the nuclear autoantigen La/SS-B. Thereby an alternative type of La mRNA was identified that differed from the known La mRNA due to an exchange of the exon 1. Sequencing of the genomic region between the exons 1 and 2 showed that the alternative 5'-end is a part of the intron. In addition, the presence of an alternative promoter site, which exists within the intron downstream of the exon 1, became evident. In consequence, the alternative La mRNA is the result of a promoter switching combined with an alternative splicing mechanism. In the intron, further transcription factor binding sites, including a NF-kappa B element, were identified leading to the suggestion that the expression of the gene encoding for the nuclear autoantigen La/SS-B alters in dependence on disease conditions. " ], "offsets": [ [ 0, 1172 ] ] } ]

[ { "id": "7964483_T1", "type": "Protein", "text": [ "autoantigen La" ], "offsets": [ [ 83, 97 ] ], "normalized": [] }, { "id": "7964483_T2", "type": "Protein", "text": [ "SS-B" ], "offsets": [ [ 98, 102 ] ], "normalized": [] }, { "id": "7964483_T3", "type": "Protein", "text": [ "autoantigen La" ], "offsets": [ [ 394, 408 ] ], "normalized": [] }, { "id": "7964483_T4", "type": "Protein", "text": [ "SS-B" ], "offsets": [ [ 409, 413 ] ], "normalized": [] }, { "id": "7964483_T5", "type": "Protein", "text": [ "La" ], "offsets": [ [ 446, 448 ] ], "normalized": [] }, { "id": "7964483_T6", "type": "Protein", "text": [ "La" ], "offsets": [ [ 498, 500 ] ], "normalized": [] }, { "id": "7964483_T7", "type": "Protein", "text": [ "La" ], "offsets": [ [ 823, 825 ] ], "normalized": [] }, { "id": "7964483_T8", "type": "Protein", "text": [ "autoantigen La" ], "offsets": [ [ 1108, 1122 ] ], "normalized": [] }, { "id": "7964483_T9", "type": "Protein", "text": [ "SS-B" ], "offsets": [ [ 1123, 1127 ] ], "normalized": [] } ]

[ { "id": "7964483_E1", "type": "Positive_regulation", "trigger": { "text": [ "result" ], "offsets": [ [ 838, 844 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7964483_T7" } ] }, { "id": "7964483_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1060, 1070 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7964483_T8" } ] }, { "id": "7964483_E3", "type": "Regulation", "trigger": { "text": [ "alters" ], "offsets": [ [ 1128, 1134 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7964483_E2" } ] } ]

[ { "id": "7964483_1", "entity_ids": [ "7964483_T1", "7964483_T2" ] }, { "id": "7964483_2", "entity_ids": [ "7964483_T8", "7964483_T9" ] }, { "id": "7964483_3", "entity_ids": [ "7964483_T3", "7964483_T4" ] } ]

[]

[ { "id": "10430908__text", "type": "abstract", "text": [ "NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. \nActivation of CD40 is essential for thymus-dependent humoral immune responses and rescuing B cells from apoptosis. Many of the effects of CD40 are believed to be achieved through altered gene expression. In addition to Bcl-x, a known CD40-regulated antiapoptotic molecule, we identified a related antiapoptotic molecule, A1/Bfl-1, as a CD40-inducible gene. Inhibition of the NF-kappaB pathway by overexpression of a dominant-active inhibitor of NF-kappaB abolished CD40-induced up-regulation of both the Bfl-1 and Bcl-x genes and also eliminated the ability of CD40 to rescue Fas-induced cell death. Within the upstream promoter region of Bcl-x, a potential NF-kappaB-binding sequence was found to support NF-kappaB-dependent transcriptional activation. Furthermore, expression of physiological levels of Bcl-x protected B cells from Fas-mediated apoptosis in the absence of NF-kappaB signaling. Thus, our results suggest that CD40-mediated cell survival proceeds through NF-kappaB-dependent up-regulation of Bcl-2 family members. " ], "offsets": [ [ 0, 1145 ] ] } ]

[ { "id": "10430908_T1", "type": "Protein", "text": [ "Bcl-x" ], "offsets": [ [ 36, 41 ] ], "normalized": [] }, { "id": "10430908_T2", "type": "Protein", "text": [ "Bfl-1/A1" ], "offsets": [ [ 46, 54 ] ], "normalized": [] }, { "id": "10430908_T3", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 71, 75 ] ], "normalized": [] }, { "id": "10430908_T4", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 128, 132 ] ], "normalized": [] }, { "id": "10430908_T5", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 252, 256 ] ], "normalized": [] }, { "id": "10430908_T6", "type": "Protein", "text": [ "Bcl-x" ], "offsets": [ [ 333, 338 ] ], "normalized": [] }, { "id": "10430908_T7", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 348, 352 ] ], "normalized": [] }, { "id": "10430908_T8", "type": "Protein", "text": [ "A1/Bfl-1" ], "offsets": [ [ 435, 443 ] ], "normalized": [] }, { "id": "10430908_T9", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 450, 454 ] ], "normalized": [] }, { "id": "10430908_T10", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 579, 583 ] ], "normalized": [] }, { "id": "10430908_T11", "type": "Protein", "text": [ "Bfl-1" ], "offsets": [ [ 618, 623 ] ], "normalized": [] }, { "id": "10430908_T12", "type": "Protein", "text": [ "Bcl-x" ], "offsets": [ [ 628, 633 ] ], "normalized": [] }, { "id": "10430908_T13", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 675, 679 ] ], "normalized": [] }, { "id": "10430908_T14", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 690, 693 ] ], "normalized": [] }, { "id": "10430908_T15", "type": "Protein", "text": [ "Bcl-x" ], "offsets": [ [ 753, 758 ] ], "normalized": [] }, { "id": "10430908_T16", "type": "Protein", "text": [ "Bcl-x" ], "offsets": [ [ 919, 924 ] ], "normalized": [] }, { "id": "10430908_T17", "type": "Protein", "text": [ "Fas" ], "offsets": [ [ 948, 951 ] ], "normalized": [] }, { "id": "10430908_T18", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 1041, 1045 ] ], "normalized": [] } ]

[ { "id": "10430908_E1", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 19, 32 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10430908_T2" } ] }, { "id": "10430908_E2", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 19, 32 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10430908_T1" } ] }, { "id": "10430908_E3", "type": "Positive_regulation", "trigger": { "text": [ "Activation" ], "offsets": [ [ 114, 124 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10430908_T4" } ] }, { "id": "10430908_E4", "type": "Regulation", "trigger": { "text": [ "regulated" ], "offsets": [ [ 353, 362 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10430908_T6" }, { "role": "Cause", "ref_id": "10430908_T7" } ] }, { "id": "10430908_E5", "type": "Positive_regulation", "trigger": { "text": [ "inducible" ], "offsets": [ [ 455, 464 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10430908_T8" }, { "role": "Cause", "ref_id": "10430908_T9" } ] }, { "id": "10430908_E6", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 569, 578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10430908_E9" } ] }, { "id": "10430908_E7", "type": "Negative_regulation", "trigger": { "text": [ "abolished" ], "offsets": [ [ 569, 578 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10430908_E8" } ] }, { "id": "10430908_E8", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 592, 605 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10430908_T11" }, { "role": "Cause", "ref_id": "10430908_T10" } ] }, { "id": "10430908_E9", "type": "Positive_regulation", "trigger": { "text": [ "up-regulation" ], "offsets": [ [ 592, 605 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10430908_T12" }, { "role": "Cause", "ref_id": "10430908_T10" } ] }, { "id": "10430908_E10", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 881, 891 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10430908_T16" } ] } ]

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[ { "id": "1375324__text", "type": "abstract", "text": [ "The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP. \nThe CD19 protein is expressed on the surface of all B-lymphoid cells with the exception of terminally differentiated plasma cells and has been implicated as a signal-transducing receptor in the control of proliferation and differentiation. Here we demonstrate complete correlation between the expression pattern of the CD19 gene and the B-cell-specific transcription factor BSAP in a large panel of B-lymphoid cell lines. The human CD19 gene has been cloned, and several BSAP-binding sites have been mapped by in vitro protein-DNA binding studies. In particular, a high-affinity BSAP-binding site instead of a TATA sequence is located in the -30 promoter region upstream of a cluster of heterogeneous transcription start sites. Moreover, this site is occupied by BSAP in vivo in a CD19-expressing B-cell line but not in plasma or HeLa cells. This high-affinity site has been conserved in the promoters of both human and mouse CD19 genes and was furthermore shown to confer B-cell specificity to a beta-globin reporter gene in transient transfection experiments. In addition, BSAP was found to be the only abundant DNA-binding activity of B-cell nuclear extracts that interacts with the CD19 promoter. Together, this evidence strongly implicates BSAP in the regulation of the CD19 gene. " ], "offsets": [ [ 0, 1380 ] ] } ]

[ { "id": "1375324_T1", "type": "Protein", "text": [ "CD19" ], "offsets": [ [ 20, 24 ] ], "normalized": [] }, { "id": "1375324_T2", "type": "Protein", "text": [ "BSAP" ], "offsets": [ [ 87, 91 ] ], "normalized": [] }, { "id": "1375324_T3", "type": "Protein", "text": [ "CD19" ], "offsets": [ [ 98, 102 ] ], "normalized": [] }, { "id": "1375324_T4", "type": "Protein", "text": [ "CD19" ], "offsets": [ [ 413, 417 ] ], "normalized": [] }, { "id": "1375324_T5", "type": "Protein", "text": [ "BSAP" ], "offsets": [ [ 468, 472 ] ], "normalized": [] }, { "id": "1375324_T6", "type": "Protein", "text": [ "CD19" ], "offsets": [ [ 526, 530 ] ], "normalized": [] }, { "id": "1375324_T7", "type": "Protein", "text": [ "BSAP" ], "offsets": [ [ 565, 569 ] ], "normalized": [] }, { "id": "1375324_T8", "type": "Protein", "text": [ "BSAP" ], "offsets": [ [ 673, 677 ] ], "normalized": [] }, { "id": "1375324_T9", "type": "Protein", "text": [ "BSAP" ], "offsets": [ [ 857, 861 ] ], "normalized": [] }, { "id": "1375324_T10", "type": "Protein", "text": [ "CD19" ], "offsets": [ [ 875, 879 ] ], "normalized": [] }, { "id": "1375324_T11", "type": "Protein", "text": [ "CD19" ], "offsets": [ [ 1020, 1024 ] ], "normalized": [] }, { "id": "1375324_T12", "type": "Protein", "text": [ "beta-globin reporter" ], "offsets": [ [ 1091, 1111 ] ], "normalized": [] }, { "id": "1375324_T13", "type": "Protein", "text": [ "BSAP" ], "offsets": [ [ 1169, 1173 ] ], "normalized": [] }, { "id": "1375324_T14", "type": "Protein", "text": [ "CD19" ], "offsets": [ [ 1280, 1284 ] ], "normalized": [] }, { "id": "1375324_T15", "type": "Protein", "text": [ "BSAP" ], "offsets": [ [ 1339, 1343 ] ], "normalized": [] }, { "id": "1375324_T16", "type": "Protein", "text": [ "CD19" ], "offsets": [ [ 1369, 1373 ] ], "normalized": [] }, { "id": "1375324_T17", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 4, 12 ] ], "normalized": [] }, { "id": "1375324_T24", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1285, 1293 ] ], "normalized": [] } ]

[ { "id": "1375324_E1", "type": "Binding", "trigger": { "text": [ "target" ], "offsets": [ [ 35, 41 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1375324_T1" }, { "role": "Theme", "ref_id": "1375324_T2" }, { "role": "Site", "ref_id": "1375324_T17" } ] }, { "id": "1375324_E2", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 114, 123 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1375324_T3" } ] }, { "id": "1375324_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 387, 397 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1375324_T4" } ] }, { "id": "1375324_E4", "type": "Binding", "trigger": { "text": [ "occupied" ], "offsets": [ [ 845, 853 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1375324_T9" } ] }, { "id": "1375324_E5", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1212, 1219 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1375324_T13" } ] }, { "id": "1375324_E6", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 1261, 1270 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1375324_T13" }, { "role": "Theme", "ref_id": "1375324_T14" }, { "role": "Site", "ref_id": "1375324_T24" } ] }, { "id": "1375324_E7", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1351, 1361 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "1375324_T16" }, { "role": "Cause", "ref_id": "1375324_T15" } ] } ]

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[ { "id": "10364191__text", "type": "abstract", "text": [ "Potent and stable attenuation of live-HIV-1 by gain of a proteolysis-resistant inhibitor of NF-kappaB (IkappaB-alphaS32/36A) and the implications for vaccine development. \nLive-attenuated human immunodeficiency viruses (HIVs) are candidates for Acquired Immunodeficiency Syndrome (AIDS) vaccine. Based on the simian immunodeficiency virus (SIV) model for AIDS, loss-of-function (e.g. deletion of accessory genes such as nef) has been forwarded as a primary approach for creating enfeebled, but replication-competent, HIV-1/SIV. Regrettably, recent evidence suggests that loss-of-function alone is not always sufficient to prevent the emergence of virulent mutants. New strategies that attenuate via mechanisms distinct from loss-of-function are needed for enhancing the safety phenotype of viral genome. Here, we propose gain-of-function to be used simultaneously with loss-of-function as a novel approach for attenuating HIV-1. We have constructed an HIV-1 genome carrying the cDNA of a proteolysis-resistant nuclear factor-kappaB inhibitor (IkappaB-alphaS32/36A) in the nef region. HIV-1 expressing IkappaB-alphaS32/36A down-regulates viral expression and is highly attenuated in both Jurkat and peripheral blood mononuclear cells. We provide formal proof that the phenotypic and attenuating characteristics of IkappaB-alphaS32/36A permit its stable maintenance in a live, replicating HIV-1 despite 180 days of forced ex vivo passaging in tissue culture. As compared with other open-reading frames embedded into HIV/SIV genome, this degree of stability is unprecedented. Thus, IkappaB-alphaS32/36A offers proof-of-principle that artifactually gained functions, when used to attenuate the replication of live HIV-1, can be stable. These findings illustrate gain-of-function as a feasible strategy for developing safer live-attenuated HIVs to be tested as candidates for AIDS vaccine. " ], "offsets": [ [ 0, 1885 ] ] } ]

[ { "id": "10364191_T1", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 103, 116 ] ], "normalized": [] }, { "id": "10364191_T2", "type": "Protein", "text": [ "nef" ], "offsets": [ [ 420, 423 ] ], "normalized": [] }, { "id": "10364191_T3", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1043, 1056 ] ], "normalized": [] }, { "id": "10364191_T4", "type": "Protein", "text": [ "nef" ], "offsets": [ [ 1072, 1075 ] ], "normalized": [] }, { "id": "10364191_T5", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1101, 1114 ] ], "normalized": [] }, { "id": "10364191_T6", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1313, 1326 ] ], "normalized": [] }, { "id": "10364191_T7", "type": "Protein", "text": [ "IkappaB-alpha" ], "offsets": [ [ 1579, 1592 ] ], "normalized": [] } ]

[ { "id": "10364191_E1", "type": "Protein_catabolism", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 57, 68 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10364191_T1" } ] }, { "id": "10364191_E2", "type": "Protein_catabolism", "trigger": { "text": [ "proteolysis" ], "offsets": [ [ 988, 999 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10364191_T3" } ] }, { "id": "10364191_E3", "type": "Negative_regulation", "trigger": { "text": [ "resistant" ], "offsets": [ [ 1000, 1009 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10364191_E2" } ] }, { "id": "10364191_E4", "type": "Gene_expression", "trigger": { "text": [ "expressing" ], "offsets": [ [ 1090, 1100 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10364191_T5" } ] }, { "id": "10364191_E5", "type": "Negative_regulation", "trigger": { "text": [ "attenuated" ], "offsets": [ [ 1168, 1178 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10364191_E4" } ] }, { "id": "10364191_E6", "type": "Positive_regulation", "trigger": { "text": [ "maintenance" ], "offsets": [ [ 1352, 1363 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10364191_T6" } ] } ]

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[ { "id": "7949138__text", "type": "abstract", "text": [ "Distinct DNase-I hypersensitive sites are associated with TAL-1 transcription in erythroid and T-cell lines. \nThe tal-1 gene, frequently activated in human T-cell acute lymphoblastic leukemia (T-ALL), is expressed in the erythroid, megakaryocytic, and mast cell lineages during normal hematopoiesis. To gain further insight into the molecular mechanisms that control tal-1 expression, we investigated tal-1 chromatin structure in erythroid/megakaryocytic cell lines and in T-cell lines either with or without tal-1 rearrangements. Tal-1 transcription was shown to be monoallelic in Jurkat, a T-cell line that expresses tal-1 in the absence of apparent genomic alteration of the locus. Methylation studies indicated that the tal-15' GC-rich region behaves like a CpG island, hypomethylated in normal cells, and methylated de novo on transcriptionally inactive alleles in established cell lines. Five major DNase-I hypersensitive sites (HS) were mapped in the tal-1 locus. HS I, IV, and V were exclusively observed in the erythroid/megakaryocytic cell lines that express tal-1 from the promoters 1a and 1b. HS II was weak in hematopoietic cell lines, absent in Hela, and greatly enhanced in Jurkat, suggesting that this region might be implicated in the cis-activation of tal-1 promoter 1b in this cell line. HS III was weak in HEL and Jurkat, and greatly enhanced in DU528, a T-cell line that bears a t (1;14) and initiates tal-1 transcription within exon 4. These results suggest that distinct regulatory elements are associated with the use of the different tal-1 promoters. " ], "offsets": [ [ 0, 1576 ] ] } ]

[ { "id": "7949138_T1", "type": "Protein", "text": [ "DNase-I" ], "offsets": [ [ 9, 16 ] ], "normalized": [] }, { "id": "7949138_T2", "type": "Protein", "text": [ "TAL-1" ], "offsets": [ [ 58, 63 ] ], "normalized": [] }, { "id": "7949138_T3", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 114, 119 ] ], "normalized": [] }, { "id": "7949138_T4", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 367, 372 ] ], "normalized": [] }, { "id": "7949138_T5", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 401, 406 ] ], "normalized": [] }, { "id": "7949138_T6", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 509, 514 ] ], "normalized": [] }, { "id": "7949138_T7", "type": "Protein", "text": [ "Tal-1" ], "offsets": [ [ 531, 536 ] ], "normalized": [] }, { "id": "7949138_T8", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 619, 624 ] ], "normalized": [] }, { "id": "7949138_T9", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 724, 729 ] ], "normalized": [] }, { "id": "7949138_T10", "type": "Protein", "text": [ "DNase-I" ], "offsets": [ [ 905, 912 ] ], "normalized": [] }, { "id": "7949138_T11", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 958, 963 ] ], "normalized": [] }, { "id": "7949138_T12", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 1069, 1074 ] ], "normalized": [] }, { "id": "7949138_T13", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 1270, 1275 ] ], "normalized": [] }, { "id": "7949138_T14", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 1423, 1428 ] ], "normalized": [] }, { "id": "7949138_T15", "type": "Protein", "text": [ "tal-1" ], "offsets": [ [ 1559, 1564 ] ], "normalized": [] }, { "id": "7949138_T26", "type": "Entity", "text": [ "promoter 1b" ], "offsets": [ [ 1276, 1287 ] ], "normalized": [] } ]

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[ { "id": "10480426__text", "type": "abstract", "text": [ "Neutrophil maturation and the role of retinoic acid. \nNeutrophil maturation occurs in well defined morphological stages that correlate with the acquisition of molecular markers associated with neutrophil function. A variety of factors are known to play a role in terminal neutrophil maturation, including the vitamin A derivative, retinoic acid. Retinoic acid can directly modulate gene expression via binding to its nuclear receptors, which can, in turn, activate transcription of target genes. A role for retinoic acid during neutrophil maturation has been suggested from a variety of sources. Here we present a review of the mechanism of retinoic acid receptor action and the major evidence showing that normal retinoid signaling is required for neutrophil maturation. " ], "offsets": [ [ 0, 772 ] ] } ]

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[ { "id": "1658795__text", "type": "abstract", "text": [ "Clone pAT 133 identifies a gene that encodes another human member of a class of growth factor-induced genes with almost identical zinc-finger domains. \nWe report the structure and regulation of a gene represented by clone pAT 133, which is induced upon transition from a resting state (G0) through the early phase of the cell cycle (G1). The pAT 133 gene is immediately induced, with FOS-like kinetics, in human T cells and in fibroblasts. Primary structure analysis showed that the encoded protein contains three tandem zinc-finger sequences of the type Cys2-Xaa12-His2. This zinc-finger region, which is thought to bind DNA in a sequence-specific manner, is similar (greater than 80% on the amino acid level) to two previously described transcription factors pAT 225/EGR1 and pAT 591/EGR2. Except for the conserved zinc-finger domains, the amino acid sequences of the three proteins are distinct. This structural similarity suggests that the pAT 133 gene encodes a transcription factor with a specific biological function. Comparing the regulation of these related zinc-finger-encoding genes showed coordinate induction upon mitogenic stimulation of resting T lymphocytes and of resting fibroblasts. However, upon transition from a proliferating (G1) to a resting state of the cell cycle the three genes were differently regulated. In human histiocytic U937 cells mRNA of clone pAT 133 was constitutively expressed, whereas mRNA of pAT 225/EGR1 was induced upon induction of terminal differentiation. In contrast mRNA representing pAT 591/EGR2 was not expressed in these cells. This difference in gene regulation suggests distinct biological roles in the control of cell proliferation for the respective proteins. " ], "offsets": [ [ 0, 1716 ] ] } ]

[ { "id": "1658795_T1", "type": "Protein", "text": [ "EGR1" ], "offsets": [ [ 769, 773 ] ], "normalized": [] }, { "id": "1658795_T2", "type": "Protein", "text": [ "EGR2" ], "offsets": [ [ 786, 790 ] ], "normalized": [] }, { "id": "1658795_T3", "type": "Protein", "text": [ "EGR1" ], "offsets": [ [ 1442, 1446 ] ], "normalized": [] }, { "id": "1658795_T4", "type": "Protein", "text": [ "EGR2" ], "offsets": [ [ 1541, 1545 ] ], "normalized": [] } ]

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[ { "id": "9916709__text", "type": "abstract", "text": [ "T cell priming enhances IL-4 gene expression by increasing nuclear factor of activated T cells. \nThe repetitive activation of T cells (priming) enhances the expression of many cytokines, such as IL-4, but not others, such as IL-2. Molecular mechanisms underlying selective expression of cytokines by T cells remain poorly understood. Here we show that priming of CD4 T cells selectively enhances IL-4 expression relative to IL-2 expression by a transcriptional mechanism involving nuclear factor of activated T cells (NFAT) proteins. As detected by in vivo footprinting, priming markedly increases the activation-dependent engagement of the P0 and P1 NFAT-binding elements of the IL-4 promoter. Moreover, each proximal P element is essential for optimal IL-4 promoter activity. Activated primed CD4 T cells contain more NFAT1 and support greater NFAT-directed transcription than unprimed CD4 T cells, while activator protein 1 binding and activator protein 1-mediated transcription by both cell types is similar. Increased expression of wild-type NFAT1 substantially increases IL-4 promoter activity in unprimed CD4 T cells, suggesting NFAT1 may be limiting for IL-4 gene expression in this cell type. Furthermore, a truncated form of NFAT1 acts as a dominant-negative, reducing IL-4 promoter activity in primed CD4 T cells and confirming the importance of endogenous NFAT to increased IL-4 gene expression by effector T cells. NFAT1 appears to be the major NFAT family member responsible for the initial increased expression of IL-4 by primed CD4 T cells. " ], "offsets": [ [ 0, 1557 ] ] } ]

[ { "id": "9916709_T1", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 24, 28 ] ], "normalized": [] }, { "id": "9916709_T2", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 195, 199 ] ], "normalized": [] }, { "id": "9916709_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 225, 229 ] ], "normalized": [] }, { "id": "9916709_T4", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 363, 366 ] ], "normalized": [] }, { "id": "9916709_T5", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 396, 400 ] ], "normalized": [] }, { "id": "9916709_T6", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 424, 428 ] ], "normalized": [] }, { "id": "9916709_T7", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 680, 684 ] ], "normalized": [] }, { "id": "9916709_T8", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 754, 758 ] ], "normalized": [] }, { "id": "9916709_T9", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 795, 798 ] ], "normalized": [] }, { "id": "9916709_T10", "type": "Protein", "text": [ "NFAT1" ], "offsets": [ [ 820, 825 ] ], "normalized": [] }, { "id": "9916709_T11", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 888, 891 ] ], "normalized": [] }, { "id": "9916709_T12", "type": "Protein", "text": [ "NFAT1" ], "offsets": [ [ 1047, 1052 ] ], "normalized": [] }, { "id": "9916709_T13", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1077, 1081 ] ], "normalized": [] }, { "id": "9916709_T14", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1112, 1115 ] ], "normalized": [] }, { "id": "9916709_T15", "type": "Protein", "text": [ "NFAT1" ], "offsets": [ [ 1136, 1141 ] ], "normalized": [] }, { "id": "9916709_T16", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1162, 1166 ] ], "normalized": [] }, { "id": "9916709_T17", "type": "Protein", "text": [ "NFAT1" ], "offsets": [ [ 1235, 1240 ] ], "normalized": [] }, { "id": "9916709_T18", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1279, 1283 ] ], "normalized": [] }, { "id": "9916709_T19", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1312, 1315 ] ], "normalized": [] }, { "id": "9916709_T20", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1386, 1390 ] ], "normalized": [] }, { "id": "9916709_T21", "type": "Protein", "text": [ "NFAT1" ], "offsets": [ [ 1428, 1433 ] ], "normalized": [] }, { "id": "9916709_T22", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 1529, 1533 ] ], "normalized": [] }, { "id": "9916709_T23", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1544, 1547 ] ], "normalized": [] }, { "id": "9916709_T33", "type": "Entity", "text": [ "P0" ], "offsets": [ [ 641, 643 ] ], "normalized": [] }, { "id": "9916709_T34", "type": "Entity", "text": [ "P1 NFAT-binding elements" ], "offsets": [ [ 648, 672 ] ], "normalized": [] }, { "id": "9916709_T35", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 685, 693 ] ], "normalized": [] }, { "id": "9916709_T37", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 759, 767 ] ], "normalized": [] }, { "id": "9916709_T42", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1082, 1090 ] ], "normalized": [] }, { "id": "9916709_T46", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 1284, 1292 ] ], "normalized": [] } ]

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"expression" ], "offsets": [ [ 157, 167 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T3" } ] }, { "id": "9916709_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 429, 439 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T6" } ] }, { "id": "9916709_E8", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 588, 597 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_E14" } ] }, { "id": "9916709_E9", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 588, 597 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_E13" } ] }, { "id": "9916709_E10", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 602, 612 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T7" }, { "role": "Site", "ref_id": "9916709_T35" } ] }, { "id": "9916709_E11", "type": "Regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 613, 622 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_E13" }, { "role": "Cause", "ref_id": "9916709_E10" } ] }, { "id": "9916709_E12", "type": "Regulation", "trigger": { "text": [ "dependent" ], "offsets": [ [ 613, 622 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_E14" }, { "role": "Cause", "ref_id": "9916709_E10" } ] }, { "id": "9916709_E13", "type": "Binding", "trigger": { "text": [ "engagement" ], "offsets": [ [ 623, 633 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T7" }, { "role": "Site", "ref_id": "9916709_T34" } ] }, { "id": "9916709_E14", "type": "Binding", "trigger": { "text": [ "engagement" ], "offsets": [ [ 623, 633 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T7" }, { "role": "Site", "ref_id": "9916709_T33" } ] }, { "id": "9916709_E15", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 732, 741 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T8" }, { "role": "Cause", "ref_id": "9916709_T7" }, { "role": "Site", "ref_id": "9916709_T37" }, { "role": "CSite", "ref_id": "9916709_T34" } ] }, { "id": "9916709_E16", "type": "Positive_regulation", "trigger": { "text": [ "essential" ], "offsets": [ [ 732, 741 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T8" }, { "role": "Cause", "ref_id": "9916709_T7" }, { "role": "Site", "ref_id": "9916709_T37" }, { "role": "CSite", "ref_id": "9916709_T33" } ] }, { "id": "9916709_E17", "type": "Gene_expression", "trigger": { "text": [ "contain" ], "offsets": [ [ 807, 814 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T10" } ] }, { "id": "9916709_E18", "type": "Positive_regulation", "trigger": { "text": [ "more" ], "offsets": [ [ 815, 819 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_E17" } ] }, { "id": "9916709_E19", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1023, 1033 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T12" } ] }, { "id": "9916709_E20", "type": "Positive_regulation", "trigger": { "text": [ "increases" ], "offsets": [ [ 1067, 1076 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T13" }, { "role": "Cause", "ref_id": "9916709_E19" }, { "role": "Site", "ref_id": "9916709_T42" } ] }, { "id": "9916709_E21", "type": "Negative_regulation", "trigger": { "text": [ "limiting" ], "offsets": [ [ 1149, 1157 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_E22" }, { "role": "Cause", "ref_id": "9916709_T15" } ] }, { "id": "9916709_E22", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 1167, 1182 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T13" } ] }, { "id": "9916709_E23", "type": "Negative_regulation", "trigger": { "text": [ "reducing" ], "offsets": [ [ 1270, 1278 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T18" }, { "role": "Site", "ref_id": "9916709_T46" } ] }, { "id": "9916709_E24", "type": "Regulation", "trigger": { "text": [ "importance" ], "offsets": [ [ 1343, 1353 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_E25" } ] }, { "id": "9916709_E25", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1376, 1385 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_E26" } ] }, { "id": "9916709_E26", "type": "Gene_expression", "trigger": { "text": [ "gene expression" ], "offsets": [ [ 1391, 1406 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T20" } ] }, { "id": "9916709_E27", "type": "Regulation", "trigger": { "text": [ "responsible" ], "offsets": [ [ 1477, 1488 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_E28" }, { "role": "Cause", "ref_id": "9916709_T21" } ] }, { "id": "9916709_E28", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 1505, 1514 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_E29" } ] }, { "id": "9916709_E29", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1515, 1525 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9916709_T22" } ] } ]

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[ { "id": "8978306__text", "type": "abstract", "text": [ "Engagement of the Lewis X antigen (CD15) results in monocyte activation. \nWe previously reported that monocyte adhesion to tumor necrosis factor-alpha (TNF-alpha)-treated endothelial cells increased expression of tissue factor and CD36 on monocytes. Using immunological cross-linking to mimic receptor engagement by natural ligands, we now show that CD15 (Lewis X), a monocyte counter-receptor for endothelial selectins may participate in this response. We used cytokine production as a readout for monocyte activation and found that CD15 cross-linking induced TNF-alpha release from peripheral blood monocytes and cells from the monocytic cell line MM6. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) showed an increase in steady-state TNF-alpha mRNA after 3 to 4 hours of cross-linking. CD15 cross-linking also concomitantly increased interleukin-1 beta (IL-1 beta) mRNA, while no apparent change was observed in the levels of beta-actin mRNA, indicating specificity. To examine transcriptional regulation of cytokine genes by CD15 engagement, a CAT plasmid reporter construct containing IL-1 beta promoter/enhancer sequences was introduced into MM6. Subsequent cross-linking of CD15 increased CAT activity. CD15 engagement by monoclonal antibody also attenuated IL-1 beta transcript degradation, demonstrating that signaling via CD15 also had posttranscriptional effects. Nuclear extracts of anti-CD15 cross-linked cells demonstrated enhanced levels of the transcriptional factor activator protein-1, minimally changed nuclear factor-kappa B, and did not affect SV40 promoter specific protein-1. We conclude that engagement of CD15 on monocytes results in monocyte activation. In addition to its well-recognized adhesive role, CD15 may function as an important signaling molecule capable of initiating proinflammatory events in monocytes that come into contact with activated endothelium. " ], "offsets": [ [ 0, 1915 ] ] } ]

[ { "id": "8978306_T1", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 123, 150 ] ], "normalized": [] }, { "id": "8978306_T2", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 152, 161 ] ], "normalized": [] }, { "id": "8978306_T3", "type": "Protein", "text": [ "tissue factor" ], "offsets": [ [ 213, 226 ] ], "normalized": [] }, { "id": "8978306_T4", "type": "Protein", "text": [ "CD36" ], "offsets": [ [ 231, 235 ] ], "normalized": [] }, { "id": "8978306_T5", "type": "Protein", "text": [ "endothelial selectins" ], "offsets": [ [ 398, 419 ] ], "normalized": [] }, { "id": "8978306_T6", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 561, 570 ] ], "normalized": [] }, { "id": "8978306_T7", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 760, 769 ] ], "normalized": [] }, { "id": "8978306_T8", "type": "Protein", "text": [ "interleukin-1 beta" ], "offsets": [ [ 860, 878 ] ], "normalized": [] }, { "id": "8978306_T9", "type": "Protein", "text": [ "IL-1 beta" ], "offsets": [ [ 880, 889 ] ], "normalized": [] }, { "id": "8978306_T10", "type": "Protein", "text": [ "beta-actin" ], "offsets": [ [ 952, 962 ] ], "normalized": [] }, { "id": "8978306_T11", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 1071, 1074 ] ], "normalized": [] }, { "id": "8978306_T12", "type": "Protein", "text": [ "IL-1 beta" ], "offsets": [ [ 1113, 1122 ] ], "normalized": [] }, { "id": "8978306_T13", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 1219, 1222 ] ], "normalized": [] }, { "id": "8978306_T14", "type": "Protein", "text": [ "IL-1 beta" ], "offsets": [ [ 1288, 1297 ] ], "normalized": [] }, { "id": "8978306_T15", "type": "Protein", "text": [ "SV40 promoter specific protein-1" ], "offsets": [ [ 1588, 1620 ] ], "normalized": [] } ]

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[]

[ { "id": "9715838__text", "type": "abstract", "text": [ "Inhibition of HIV-1 replication by combination of a novel inhibitor of TNF-alpha with AZT. \nThe small molecule S9a was derived from an established tumor necrosis factor-alpha (TNF-alpha) inhibitor (Canventol) by replacement of the isopropylidine group with a phenyl ring. S9a at 10 to 100 nM inhibited HIV production as potently as 3'-azido-3'-deoxythymidine (AZT), an inhibitor of viral reverse transcriptase. Furthermore, S9a and AZT in combination, at noncytoxic concentrations strongly inhibited HIV-1 replication that was more than additive and substantially prolonged the appearance of virus both in acutely infected CD4+ lymphocytes (SupT) in culture and in peripheral blood mononuclear cells (PBMCs) infected with a primary HIV-1 isolate. S9a inhibited TNF-alpha promoter-driven reporter gene activity. It was proposed that the mechanism of antiviral action of S9a was on the host cell, by blocking TNF-alpha transcription via a Tat-induced tar-independent loop, which decreases downstream NF-kappaB activation of HIV-1 long terminal repeat (LTR). S9a was superior to the first generation compound Canventol, which was superior to the natural compound sarcophytol A, demonstrating that further structure-based enhancement of potency of these compounds is feasible. This study suggests a therapeutic approach against AIDS by application of two drugs, one against a cellular and the other a viral target, which may provide an approach to the problem of frequent emergence of resistant variants to combinations of drugs that target only HIV genes. " ], "offsets": [ [ 0, 1553 ] ] } ]

[ { "id": "9715838_T1", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 71, 80 ] ], "normalized": [] }, { "id": "9715838_T2", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 147, 174 ] ], "normalized": [] }, { "id": "9715838_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 176, 185 ] ], "normalized": [] }, { "id": "9715838_T4", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 623, 626 ] ], "normalized": [] }, { "id": "9715838_T5", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 761, 770 ] ], "normalized": [] }, { "id": "9715838_T6", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 907, 916 ] ], "normalized": [] }, { "id": "9715838_T7", "type": "Protein", "text": [ "Tat" ], "offsets": [ [ 937, 940 ] ], "normalized": [] } ]

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[ { "id": "10221658__text", "type": "abstract", "text": [ "CIITA-induced occupation of MHC class II promoters is independent of the cooperative stabilization of the promoter-bound multi-protein complexes. \nPrecise regulation of MHC class II expression plays a crucial role in the control of the immune response. The transactivator CIITA behaves as a master controller of constitutive and inducible MHC class II gene activation, but its exact mechanism of action is not known. Activation of MHC class II promoters requires binding of at least three distinct multi-protein complexes (RFX, X2BP and NF-Y). It is known that the stability of this binding results from cooperative interactions between these proteins. We show here that expression of CIITA in MHC class II- cells triggers occupation of the promoters by these complexes. This observation raised the possibility that the effect of CIITA on promoter occupation is mediated by an effect on the cooperative stabilization of the DNA-bound multi-protein complexes. We show, however, that the presence of CIITA does not affect the stability of the higher-order protein complex formed on DNA by RFX, X2BP and NF-Y. This suggests other mechanisms for CIITA-induced promoter occupancy, such as an effect on chromatin structure leading to increased accessibility of MHC class II promoters. This ability of CIITA to facilitate promoter occupation is undissociable from its transactivation potential. Finally, we conclude that this effect of CIITA is cell-type specific, since expression of CIITA is not required for normal occupation of MHC class II promoters in B lymphocytes. " ], "offsets": [ [ 0, 1566 ] ] } ]

[ { "id": "10221658_T1", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "10221658_T2", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 272, 277 ] ], "normalized": [] }, { "id": "10221658_T3", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 685, 690 ] ], "normalized": [] }, { "id": "10221658_T4", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 830, 835 ] ], "normalized": [] }, { "id": "10221658_T5", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 998, 1003 ] ], "normalized": [] }, { "id": "10221658_T6", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1142, 1147 ] ], "normalized": [] }, { "id": "10221658_T7", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1295, 1300 ] ], "normalized": [] }, { "id": "10221658_T8", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1429, 1434 ] ], "normalized": [] }, { "id": "10221658_T9", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1478, 1483 ] ], "normalized": [] } ]

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[ { "id": "1782151__text", "type": "abstract", "text": [ "Stimulation of interferon beta gene transcription in vitro by purified NF-kappa B and a novel TH protein. \nThe human interferon beta (IFN-beta) regulatory element consists of multiple enhanson domains which are targets for transcription factors involved in inducible expression of the promoter. To further characterize the protein-DNA interactions mediating IFN-beta induction, positive regulatory domain (PRD) II binding proteins were purified from phorbol ester induced Jurkat T-cells and from IFN primed, cycloheximide/polyinosinic-polycytidylic acid treated HeLa S3 cells. From HeLa cells, two major proteins of 52 and 45 kilodaltons (kD) copurified with DNA binding activity, whereas from T-cells, four proteins--a major protein of 52 kD and three minor proteins of 82, 67, and 43-47 kD--were purified. Also, an induction specific DNA binding protein was purified from HeLa cells that interacted with the (AAGTGA)4 tetrahexamer sequence and the PRDI domain. This protein is immunologically distinct from IRF-1/ISGF2. Uninduced or Sendai virus induced HeLa extracts were used to examine transcription in vitro using a series of IFN beta promoter deletions. Deletions upstream of the PRDII element increased transcription in the uninduced extract, indicating predominantly negative regulation of the promoter. A 2-4-fold increase in IFN-beta promoter transcription was observed in Sendai virus induced extracts, and deletion of PRDI and PRDII elements decreased this induced level of transcription. When purified PRDII and tetrahexamer binding proteins were added to the induced extract, a 4-fold increase in transcription was observed. These experiments demonstrate that it is possible to modulate IFN-beta transcription in vitro but indicate that additional proteins may be required to fully activate IFN-beta transcription. " ], "offsets": [ [ 0, 1830 ] ] } ]

[ { "id": "1782151_T1", "type": "Protein", "text": [ "interferon beta" ], "offsets": [ [ 15, 30 ] ], "normalized": [] }, { "id": "1782151_T2", "type": "Protein", "text": [ "interferon beta" ], "offsets": [ [ 117, 132 ] ], "normalized": [] }, { "id": "1782151_T3", "type": "Protein", "text": [ "IFN-beta" ], "offsets": [ [ 134, 142 ] ], "normalized": [] }, { "id": "1782151_T4", "type": "Protein", "text": [ "IFN-beta" ], "offsets": [ [ 358, 366 ] ], "normalized": [] }, { "id": "1782151_T5", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 1009, 1014 ] ], "normalized": [] }, { "id": "1782151_T6", "type": "Protein", "text": [ "ISGF2" ], "offsets": [ [ 1015, 1020 ] ], "normalized": [] }, { "id": "1782151_T7", "type": "Protein", "text": [ "IFN beta" ], "offsets": [ [ 1132, 1140 ] ], "normalized": [] }, { "id": "1782151_T8", "type": "Protein", "text": [ "IFN-beta" ], "offsets": [ [ 1336, 1344 ] ], "normalized": [] }, { "id": "1782151_T9", "type": "Protein", "text": [ "IFN-beta" ], "offsets": [ [ 1702, 1710 ] ], "normalized": [] }, { "id": "1782151_T10", "type": "Protein", "text": [ "IFN-beta" ], "offsets": [ [ 1806, 1814 ] ], "normalized": [] }, { "id": "1782151_T13", "type": "Entity", "text": [ "enhanson domains" ], "offsets": [ [ 184, 200 ] ], "normalized": [] } ]

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[ { "id": "8325322__text", "type": "abstract", "text": [ "Occurrence of a silencer of the interleukin-2 gene in naive but not in memory resting T helper lymphocytes. \nIn the immune system the first activation of a naive T cell by antigen is a key step in the shaping of the peripheral T cell specificity repertoire and maintenance of self-tolerance. In the present study, analysis of the interleukin-2 (IL-2) gene activation shows that naive human helper T cells (cord blood CD4+ T cells, adult CD4+CD45RO- T cells) regulate IL-2 transcription by a mechanism involving both a silencer and an activator acting on the purine-rich IL-2 promoter elements (NF-AT binding sites). By contrast, memory cells, either in vitro activated helper T cells reverting to a resting state, or CD4+ T (memory) clones, or CD4+CD45RO+ T cells isolated ex vivo, no longer have a silencer. Their IL-2 transcription seems to be controlled solely by the transition from inactive to active functional state of a positive transcription factor binding to these promoter elements as well as its cytoplasmic or nuclear location: in resting memory T cells the activator is located in the cytoplasm and is inactive, whereas in stimulated cells it is functional in promoting transcription and now resides in the nucleus. Thus, the regulation of the gene coding for the main T cell growth factor changes irreversibly after the first encounter of T cells with antigen. It is most likely that the presence of a silencer contributes to the more stringent activation requirements of naive CD4+ T cells. " ], "offsets": [ [ 0, 1507 ] ] } ]

[ { "id": "8325322_T1", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 32, 45 ] ], "normalized": [] }, { "id": "8325322_T2", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 330, 343 ] ], "normalized": [] }, { "id": "8325322_T3", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 345, 349 ] ], "normalized": [] }, { "id": "8325322_T4", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 417, 420 ] ], "normalized": [] }, { "id": "8325322_T5", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 437, 440 ] ], "normalized": [] }, { "id": "8325322_T6", "type": "Protein", "text": [ "CD45" ], "offsets": [ [ 441, 445 ] ], "normalized": [] }, { "id": "8325322_T7", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 467, 471 ] ], "normalized": [] }, { "id": "8325322_T8", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 570, 574 ] ], "normalized": [] }, { "id": "8325322_T9", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 717, 720 ] ], "normalized": [] }, { "id": "8325322_T10", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 744, 747 ] ], "normalized": [] }, { "id": "8325322_T11", "type": "Protein", "text": [ "CD45" ], "offsets": [ [ 748, 752 ] ], "normalized": [] }, { "id": "8325322_T12", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 815, 819 ] ], "normalized": [] }, { "id": "8325322_T13", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1493, 1496 ] ], "normalized": [] }, { "id": "8325322_T18", "type": "Entity", "text": [ "NF-AT binding sites" ], "offsets": [ [ 594, 613 ] ], "normalized": [] } ]

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[]

[ { "id": "10029571__text", "type": "abstract", "text": [ "Interleukin-10 inhibits expression of both interferon alpha- and interferon gamma- induced genes by suppressing tyrosine phosphorylation of STAT1. \nInterleukin-10 (IL-10) helps maintain polarized T-helper cells in a T-helper lymphocyte 2 (Th2) phenotype. Part of this process involves the prevention of the development of Th1 cells, which are a primary source of interferon gamma (IFNgamma), a potent activator of monocytes and an inhibitor of Th2 proliferation. Because monocytes and macrophages are important mediators of Th1-type responses, such as delayed-type hypersensitivity, we sought to determine if IL-10 could directly mediate inhibition of IFNgamma- and IFNalpha-induced gene expression in these cells. Highly purified monocytes were incubated with IL-10 for 60 to 90 minutes before the addition of IFNgamma or IFNalpha. IL-10 preincubation resulted in the inhibition of gene expression for several IFN-induced genes, such as IP-10, ISG54, and intercellular adhesion molecule-1. The reduction in gene expression resulted from the ability of IL-10 to suppress IFN-induced assembly of signal transducer and activator of transcription (STAT) factors to specific promoter motifs on IFNalpha- and IFNgamma-inducible genes. This was accomplished by preventing the IFN-induced tyrosine phosphorylation of STAT1, a component of both IFNalpha- and IFNgamma-induced DNA binding complexes. Therefore, IL-10 can directly inhibit STAT-dependent early response gene expression induced by both IFNalpha and IFNgamma in monocytes by suppressing the tyrosine phosphorylation of STAT1. This may occur through the ability of IL-10 to induce expression of the gene, suppressor of cytokine signaling 3 (SOCS3). " ], "offsets": [ [ 0, 1702 ] ] } ]

[ { "id": "10029571_T1", "type": "Protein", "text": [ "Interleukin-10" ], "offsets": [ [ 0, 14 ] ], "normalized": [] }, { "id": "10029571_T2", "type": "Protein", "text": [ "interferon gamma" ], "offsets": [ [ 65, 81 ] ], "normalized": [] }, { "id": "10029571_T3", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 140, 145 ] ], "normalized": [] }, { "id": "10029571_T4", "type": "Protein", "text": [ "Interleukin-10" ], "offsets": [ [ 148, 162 ] ], "normalized": [] }, { "id": "10029571_T5", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 164, 169 ] ], "normalized": [] }, { "id": "10029571_T6", "type": "Protein", "text": [ "interferon gamma" ], "offsets": [ [ 363, 379 ] ], "normalized": [] }, { "id": "10029571_T7", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 381, 389 ] ], "normalized": [] }, { "id": "10029571_T8", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 609, 614 ] ], "normalized": [] }, { "id": "10029571_T9", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 652, 660 ] ], "normalized": [] }, { "id": "10029571_T10", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 761, 766 ] ], "normalized": [] }, { "id": "10029571_T11", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 811, 819 ] ], "normalized": [] }, { "id": "10029571_T12", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 833, 838 ] ], "normalized": [] }, { "id": "10029571_T13", "type": "Protein", "text": [ "IP-10" ], "offsets": [ [ 938, 943 ] ], "normalized": [] }, { "id": "10029571_T14", "type": "Protein", "text": [ "ISG54" ], "offsets": [ [ 945, 950 ] ], "normalized": [] }, { "id": "10029571_T15", "type": "Protein", "text": [ "intercellular adhesion molecule-1" ], "offsets": [ [ 956, 989 ] ], "normalized": [] }, { "id": "10029571_T16", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1053, 1058 ] ], "normalized": [] }, { "id": "10029571_T17", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1204, 1212 ] ], "normalized": [] }, { "id": "10029571_T18", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1310, 1315 ] ], "normalized": [] }, { "id": "10029571_T19", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1351, 1359 ] ], "normalized": [] }, { "id": "10029571_T20", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1402, 1407 ] ], "normalized": [] }, { "id": "10029571_T21", "type": "Protein", "text": [ "IFNgamma" ], "offsets": [ [ 1504, 1512 ] ], "normalized": [] }, { "id": "10029571_T22", "type": "Protein", "text": [ "STAT1" ], "offsets": [ [ 1573, 1578 ] ], "normalized": [] }, { "id": "10029571_T23", "type": "Protein", "text": [ "IL-10" ], "offsets": [ [ 1618, 1623 ] ], "normalized": [] }, { "id": "10029571_T24", "type": "Protein", "text": [ "suppressor of cytokine signaling 3" ], "offsets": [ [ 1658, 1692 ] ], "normalized": [] }, { "id": "10029571_T25", "type": "Protein", "text": [ "SOCS3" ], "offsets": [ [ 1694, 1699 ] ], "normalized": [] }, { "id": "10029571_T27", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 112, 120 ] ], "normalized": [] }, { "id": "10029571_T37", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 1282, 1290 ] ], "normalized": [] }, { "id": "10029571_T41", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 1545, 1553 ] ], "normalized": [] } ]

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"Theme", "ref_id": "10029571_E9" } ] }, { "id": "10029571_E6", "type": "Negative_regulation", "trigger": { "text": [ "inhibition" ], "offsets": [ [ 869, 879 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_E8" } ] }, { "id": "10029571_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 888, 898 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_T15" } ] }, { "id": "10029571_E8", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 888, 898 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_T14" } ] }, { "id": "10029571_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 888, 898 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_T13" } ] }, { "id": "10029571_E10", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 915, 922 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_T15" } ] }, { "id": "10029571_E11", 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"accomplished" ], "offsets": [ [ 1239, 1251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_E13" }, { "role": "Cause", "ref_id": "10029571_E19" } ] }, { "id": "10029571_E17", "type": "Positive_regulation", "trigger": { "text": [ "accomplished" ], "offsets": [ [ 1239, 1251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_E15" }, { "role": "Cause", "ref_id": "10029571_E19" } ] }, { "id": "10029571_E18", "type": "Positive_regulation", "trigger": { "text": [ "accomplished" ], "offsets": [ [ 1239, 1251 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_E14" }, { "role": "Cause", "ref_id": "10029571_E19" } ] }, { "id": "10029571_E19", "type": "Negative_regulation", "trigger": { "text": [ "preventing" ], "offsets": [ [ 1255, 1265 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_E20" } ] }, { "id": "10029571_E20", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1274, 1281 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_E21" } ] }, { "id": "10029571_E21", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1291, 1306 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_T18" }, { "role": "Site", "ref_id": "10029571_T37" } ] }, { "id": "10029571_E22", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1360, 1367 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_T18" } ] }, { "id": "10029571_E23", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1360, 1367 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_T18" }, { "role": "Cause", "ref_id": "10029571_T19" } ] }, { "id": "10029571_E24", "type": "Negative_regulation", "trigger": { "text": [ "suppressing" ], "offsets": [ [ 1529, 1540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_E25" }, { "role": "Cause", "ref_id": "10029571_T20" } ] }, { "id": "10029571_E25", "type": "Phosphorylation", "trigger": { "text": [ "phosphorylation" ], "offsets": [ [ 1554, 1569 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_T22" }, { "role": "Site", "ref_id": "10029571_T41" } ] }, { "id": "10029571_E26", "type": "Positive_regulation", "trigger": { "text": [ "induce" ], "offsets": [ [ 1627, 1633 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_E27" }, { "role": "Cause", "ref_id": "10029571_T23" } ] }, { "id": "10029571_E27", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1634, 1644 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10029571_T25" } ] } ]

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[ { "id": "2017258__text", "type": "abstract", "text": [ "Processing of the precursor of NF-kappa B by the HIV-1 protease during acute infection. \nTranscription of the human immunodeficiency virus type-1 (HIV-1) genome is regulated in part by cellular factors and is stimulated by activation of latently infected T cells. T-cell activation also correlates with the induction of the factor NF-kappa B which binds to two adjacent sites in the HIV-1 long terminal repeat. This factor consists of two DNA-binding subunits of relative molecular mass 50,000 (50K) associated with two 65K subunits. It is located in the nucleus in mature B cells, but is present in other cell types as an inactive cytoplasmic complex. External stimuli, including those that activate T cells, result in nuclear translocation of active NF-kappa B. The cloning of the complementary DNA for the 50K subunit helped to identify an exclusively cytoplasmic 105K precursor (p105) (V.B., P.K. and A.I., manuscript submitted). The expression of active NF-kappa B might therefore also be regulated by the extent of processing of p105. Because HIV-1 requires active NF-kappa B for efficient transcription, we tested the effect of HIV-1 infection on the processing of the human 105K precursor. We show here that the HIV-1 protease can process p105 and increases levels of active nuclear NF-kappa B complex. " ], "offsets": [ [ 0, 1311 ] ] } ]

[ { "id": "2017258_T1", "type": "Protein", "text": [ "protease" ], "offsets": [ [ 55, 63 ] ], "normalized": [] }, { "id": "2017258_T2", "type": "Protein", "text": [ "50K subunit" ], "offsets": [ [ 809, 820 ] ], "normalized": [] }, { "id": "2017258_T3", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 883, 887 ] ], "normalized": [] }, { "id": "2017258_T4", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 1035, 1039 ] ], "normalized": [] }, { "id": "2017258_T5", "type": "Protein", "text": [ "protease" ], "offsets": [ [ 1226, 1234 ] ], "normalized": [] }, { "id": "2017258_T6", "type": "Protein", "text": [ "p105" ], "offsets": [ [ 1247, 1251 ] ], "normalized": [] } ]

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[ { "id": "8930131__text", "type": "abstract", "text": [ "The Oct-2 transcription factor. \nThe Oct-2 transcription factor is a member of the POU (Pit-Oct-Unc) family of transcription factors and is expressed only in B lymphocytes and in neuronal cells but not in other cell types. The primary RNA transcript of the gene is subject to alternative splicing to yield different variants which can either activate or repress gene expression. The forms produced in B lymphocytes have a predominantly activating effect on gene expression whereas those produced in neuronal cells have a predominantly inhibitory effect and can repress the expression of both the herpes simplex virus immediate-early genes and the cellular tyrosine hydroxylase gene. Thus Oct-2 plays an important role in the regulation of cellular gene expression in both B cells and neuronal cells as well as in the control of viral latency. " ], "offsets": [ [ 0, 843 ] ] } ]

[ { "id": "8930131_T1", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 4, 9 ] ], "normalized": [] }, { "id": "8930131_T2", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 37, 42 ] ], "normalized": [] }, { "id": "8930131_T3", "type": "Protein", "text": [ "tyrosine hydroxylase" ], "offsets": [ [ 656, 676 ] ], "normalized": [] }, { "id": "8930131_T4", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 688, 693 ] ], "normalized": [] } ]

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[ { "id": "2056282__text", "type": "abstract", "text": [ "Human tumor necrosis factor alpha gene regulation in phorbol ester stimulated T and B cell lines. \nThe minimal region of the human tumor necrosis factor alpha (TNF-alpha) gene promoter necessary for its transcriptional induction by phorbol esters (PMA) in human T and B lymphocyte cell lines has been localized between -52 and +89 nucleotides (nt) relative to the gene's transcriptional start site. Comparison of these sequences to those required to mediate virus or lipopolysaccharide (LPS) induction of the gene reveal significant differences, and thus, the sequence requirements for PMA induction are distinct from those that mediate induction by virus or LPS. Although three sites in the TNF-alpha promoter (kappa 1, kappa 2, and kappa 3) specifically bind the transcription factor NF-kappa B in lymphoid nuclear extracts, TNF-alpha mRNA induction by PMA does not correlate with NF-kappa B binding activities displayed by different T and B cell lines. Moreover, kappa 1-kappa 3 can each be deleted from the TNF-alpha promoter with little effect on the gene's inducibility by PMA. Therefore, TNF-alpha mRNA induction by PMA, like its induction by virus and LPS, is not primarily mediated by NF-kappa B, but rather is mediated through other sequences and protein factors. Surprisingly, multimers of kappa 1-kappa 3 can confer PMA inducibility on a heterologous promoter in a B (Raji), but not a T (HUT78) cell line. However they are not functional on a truncated TNF-alpha promoter, indicating that promoter context and cell type specificity influence the PMA inducible function of these NF-kappa B binding sites. " ], "offsets": [ [ 0, 1616 ] ] } ]

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[ { "id": "2056282_1", "entity_ids": [ "2056282_T2", "2056282_T3" ] } ]

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[ { "id": "1502179__text", "type": "abstract", "text": [ "Simple derivation of TFIID-dependent RNA polymerase II transcription systems from Schizosaccharomyces pombe and other organisms, and factors required for transcriptional activation. \nResolution of whole cell extract through two chromatographic steps yields a single protein fraction requiring only the addition of TFIID for the initiation of transcription at RNA polymerase II promoters. This approach allows the convenient generation of RNA polymerase II transcription systems from Saccharomyces cerevisiae, human lymphocytes, and Schizosaccharomyces pombe. TFIIDs from all three organisms are interchangeable among all three systems. The S. cerevisiae and Sch. pombe systems support effects of acidic activator proteins, provided a further protein fraction from S. cerevisiae is supplied. This further fraction is distinct from the mediator of transcriptional activation described previously and represents a second component in addition to general initiation factors that may facilitate a response to acidic activators. " ], "offsets": [ [ 0, 1023 ] ] } ]

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[ { "id": "10203577__text", "type": "abstract", "text": [ "Suppressive effects of anti-inflammatory agents on human endothelial cell activation and induction of heat shock proteins. \nBACKGROUND: Studies from our laboratory have shown that the earliest stages of atherosclerosis may be mediated by an autoimmune reaction against heat shock protein 60 (Hsp60). The interactions of Hsp60-specific T cells with arterial endothelial cells (EC) require expression of both Hsp60 and certain adhesion molecules shown to be induced simultaneously in EC by mechanical and other types of stress. Recently, it was shown that suppression of T cell-mediated immune responses by cyclosporin A (CyA) enhanced atherosclerotic lesion formation in mice. In contrast, aspirin was found to lower the risk of myocardial infarction in men. These conflicting observations may be due to different effects of anti-inflammatory agents on adhesion molecule and Hsp expression in EC, respectively. MATERIAL AND METHODS: In the present study, we analyzed the effects of CyA, aspirin, and indomethacin on T cell proliferation using a proliferation assay. To explore the expression of adhesion molecules, monocyte chemoattractant protein-1 (MCP-1), and Hsp60 in human umbilical vein endothelial cells (HUVECs), Northern blot analyses were used. To examine the activation status of the transcription factors nuclear factor kappaB (NF-kappaB) and heat shock factor-1 (HSF-1), electrophoretic mobility shift assays were performed. RESULTS: With the exception of indomethacin, the used immunosuppressive and anti-inflammatory agents significantly inhibited T cell proliferation in response to influenza virus antigen in a dose-dependent manner. Interestingly, CyA and indomethacin did not suppress tumor necrosis factor-alpha (TNF-alpha)-induced adhesion molecule expression on HUVECs, whereas aspirin had an inhibitory effect. These observations correlated with the modulation of NF-kappaB activity in EC. All agents tested induced expression of Hsp60 6 hr after application. In addition, aspirin and indomethacin, but not CyA, induced Hsp70 expression in HUVECs that correlated with induction of HSF-1 activity. CONCLUSION: Our results show that the tested agents (except indomethacin) are inhibitors of the T cell-mediated immune response, as expected, that aspirin is an effective suppressor of adhesion molecule expression, and that all three agents can induce Hsp60 in HUVECs. These data provide the molecular basis for the notion that (1) part of the anti-atherogenic effect of aspirin may be due to the prevention of the adhesion of sensitized T cells to stressed EC; (2) that part of the atherosclerosis-promoting effect of CyA may be due to its potential as an inducer of Hsp60 expression and its inability to down-regulate adhesion molecule expression on EC; and (3) that down-regulation of MCP-1 expression by aspirin may result in decreased recruitment of monocytes into the arterial intima beneath stressed EC. " ], "offsets": [ [ 0, 2930 ] ] } ]

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[ { "id": "2017177__text", "type": "abstract", "text": [ "Murine and human T-lymphocyte GATA-3 factors mediate transcription through a cis-regulatory element within the human T-cell receptor delta gene enhancer. \nA family of transcriptional activators has recently been identified in chickens; these transcriptional activators recognize a common consensus motif (WGATAR) through a conserved C4 zinc finger DNA-binding domain. One of the members of this multigene family, cGATA-3, is most abundantly expressed in the T-lymphocyte cell lineage. Analysis of human and murine GATA-3 factors shows a striking degree of amino acid sequence identity and similar patterns of tissue specificity of expression in these three organisms. The murine and human factors are abundantly expressed in a variety of human and murine T-cell lines and can activate transcription through a tissue-specific GATA-binding site identified within the human T-cell receptor delta gene enhancer. We infer that the murine and human GATA-3 proteins play a central and highly conserved role in vertebrate T-cell-specific transcriptional regulation. " ], "offsets": [ [ 0, 1058 ] ] } ]

[ { "id": "2017177_T1", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 30, 36 ] ], "normalized": [] }, { "id": "2017177_T2", "type": "Protein", "text": [ "cGATA-3" ], "offsets": [ [ 413, 420 ] ], "normalized": [] }, { "id": "2017177_T3", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 514, 520 ] ], "normalized": [] }, { "id": "2017177_T4", "type": "Protein", "text": [ "GATA-3" ], "offsets": [ [ 943, 949 ] ], "normalized": [] } ]

[ { "id": "2017177_E1", "type": "Binding", "trigger": { "text": [ "through" ], "offsets": [ [ 67, 74 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2017177_T1" } ] }, { "id": "2017177_E2", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 441, 450 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2017177_T2" } ] }, { "id": "2017177_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 631, 641 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2017177_T3" } ] }, { "id": "2017177_E4", "type": "Gene_expression", "trigger": { "text": [ "expressed" ], "offsets": [ [ 712, 721 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2017177_T3" } ] } ]

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[ { "id": "7554389__text", "type": "abstract", "text": [ "Signalling via CD28 of human naive neonatal T lymphocytes. \nAccessory molecules play a crucial role in the development of the T cell response to antigenic challenge. We have examined the role of CD28 in modulating the 'naive' neonatal T cell response to anti-CD2-mediated activation. To compare the role of CD28, neonatal and adult T cells were stimulated with a pair of mitogenic anti-CD2 antibodies in the presence or absence of anti-CD28 MoAb. With anti-CD2 alone, neonatal T cells proliferated slightly but produced no detectable IL-2, whereas adult T cells proliferated vigorously, with significant IL-2 production. Costimulation with anti-CD28 MoAb greatly enhanced the proliferative response of neonatal T cells to levels equivalent to those of adult T cells, whereas adult T cells showed only slight increases. Although IL-2 secretion was increased in the presence of anti-CD28 MoAb, neonatal T cell IL-2 production remained lower than in adults. In contrast, enhancement of IL-2 mRNA expression in neonates was similar to adult levels. Anti-CD28 MoAb costimulation increased NF kappa B levels in neonates, albeit to levels lower than that of adults. The cellular mechanism governing the diminished proliferative response of neonatal T lymphocytes to anti-CD2 may therefore be due to decreased NF kappa B induction, reduced IL-2 mRNA expression and deficient IL-2 production. Although anti-CD28 MoAb costimulation enhances all of the above signals, NF kappa B and IL-2 levels remain lower than in adults, suggesting the need for further activation requirements in the neonate. " ], "offsets": [ [ 0, 1585 ] ] } ]

[ { "id": "7554389_T1", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 15, 19 ] ], "normalized": [] }, { "id": "7554389_T2", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 195, 199 ] ], "normalized": [] }, { "id": "7554389_T3", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 307, 311 ] ], "normalized": [] }, { "id": "7554389_T4", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 436, 440 ] ], "normalized": [] }, { "id": "7554389_T5", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 534, 538 ] ], "normalized": [] }, { "id": "7554389_T6", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 604, 608 ] ], "normalized": [] }, { "id": "7554389_T7", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 645, 649 ] ], "normalized": [] }, { "id": "7554389_T8", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 828, 832 ] ], "normalized": [] }, { "id": "7554389_T9", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 881, 885 ] ], "normalized": [] }, { "id": "7554389_T10", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 908, 912 ] ], "normalized": [] }, { "id": "7554389_T11", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 983, 987 ] ], "normalized": [] }, { "id": "7554389_T12", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1050, 1054 ] ], "normalized": [] }, { "id": "7554389_T13", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1332, 1336 ] ], "normalized": [] }, { "id": "7554389_T14", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1367, 1371 ] ], "normalized": [] }, { "id": "7554389_T15", "type": "Protein", "text": [ "CD28" ], "offsets": [ [ 1398, 1402 ] ], "normalized": [] }, { "id": "7554389_T16", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 1472, 1476 ] ], "normalized": [] } ]

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[ { "id": "9032344__text", "type": "abstract", "text": [ "Constitutive expression of p50 homodimer in freshly isolated human monocytes decreases with in vitro and in vivo differentiation: a possible mechanism influencing human immunodeficiency virus replication in monocytes and mature macrophages. \nHuman immunodeficiency virus type 1 (HIV-1) replicates more efficiently in vitro in differentiated macrophages than in freshly isolated monocytes. We investigated whether this may be partly explained by changes in expression of NF-kappaB with monocyte differentiation. We demonstrated that constitutive expression of NF-kappaB in primary human monocytes changed significantly with differentiation in vitro to monocyte-derived macrophages (MDMs) and differentiation in vivo to alveolar macrophages (AMs). Freshly isolated monocytes constitutively expressed high levels of transcriptionally inactive p50 homodimer which decreased with time in culture in favor of the transcriptionally active p50/p65 and p50/RelB heterodimers. As in MDMs, AMs constitutively expressed p50/p65 and p50/RelB although at lower levels. HIV infection of fresh monocytes failed to induce p50/p65 as seen in MDMs. The replacement of p50 homodimers with transcriptionally active heterodimers following time in culture may partially explain the progressive increase in susceptibility of monocytes to HIV infection during in vitro culture. The change in NF-kappaB components with monocyte differentiation in vivo may also explain the different transcriptional activities of these cell populations in HIV-infected individuals. " ], "offsets": [ [ 0, 1539 ] ] } ]

[ { "id": "9032344_T1", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 27, 30 ] ], "normalized": [] }, { "id": "9032344_T2", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 840, 843 ] ], "normalized": [] }, { "id": "9032344_T3", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 932, 935 ] ], "normalized": [] }, { "id": "9032344_T4", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 936, 939 ] ], "normalized": [] }, { "id": "9032344_T5", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 944, 947 ] ], "normalized": [] }, { "id": "9032344_T6", "type": "Protein", "text": [ "RelB" ], "offsets": [ [ 948, 952 ] ], "normalized": [] }, { "id": "9032344_T7", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1008, 1011 ] ], "normalized": [] }, { "id": "9032344_T8", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1012, 1015 ] ], "normalized": [] }, { "id": "9032344_T9", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1020, 1023 ] ], "normalized": [] }, { "id": "9032344_T10", "type": "Protein", "text": [ "RelB" ], "offsets": [ [ 1024, 1028 ] ], "normalized": [] }, { "id": "9032344_T11", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1105, 1108 ] ], "normalized": [] }, { "id": "9032344_T12", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1109, 1112 ] ], "normalized": [] }, { "id": "9032344_T13", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1149, 1152 ] ], "normalized": [] } ]

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[ { "id": "1765275__text", "type": "abstract", "text": [ "Transcription factor requirements for U2 snRNA-encoding gene activation in B lymphoid cells. \nTranscription of a human U2 small nuclear RNA(snRNA)-encoding gene in HeLa cells requires a distal enhancer element, which is composed of one octamer motif (Oct) and three Sp 1-binding sites. To study the transcription factor requirement in B-cells, different U2 enhancer constructions were transfected into the lymphoid cell line, BJA-B. The results showed that the activation of U2 snRNA transcription in B-cells also requires an enhancer comprising both the Oct and at least one Sp 1-binding site. Deletion of all the Sp 1-binding sites from the enhancer reduces transcription by 80-90% in HeLa, as well as in BJA-B cells, whereas the removal of the octamer-binding site reduces transcription to levels below detection in both cell types. Enhancers containing a single Oct have, nevertheless, the capacity to partially activate U2 snRNA transcription in both HeLa cells, in which only OTF-1 is expressed, and in BJA-B cells in which OTF-2 is the predominantly expressed octamer-binding factor. The most likely interpretation of our results is that both the ubiquitous transcription factor, OTF-1, and the B-cell-specific transcription factor, OTF-2, can activate U2 snRNA transcription. The results also revealed a similar functional cooperation between the transcription factors which bind to the Oct and the adjacent Sp 1-binding site in BJA-B cells, as has been observed in HeLa cells, since a template which contains a weak binding site for OTFs expresses wild-type levels of U2 snRNA in both cell types when the weak octamer-binding site is combined with a Sp 1-binding site. " ], "offsets": [ [ 0, 1678 ] ] } ]

[ { "id": "1765275_T1", "type": "Protein", "text": [ "Sp 1" ], "offsets": [ [ 266, 270 ] ], "normalized": [] }, { "id": "1765275_T2", "type": "Protein", "text": [ "Sp 1" ], "offsets": [ [ 615, 619 ] ], "normalized": [] }, { "id": "1765275_T3", "type": "Protein", "text": [ "OTF-1" ], "offsets": [ [ 982, 987 ] ], "normalized": [] }, { "id": "1765275_T4", "type": "Protein", "text": [ "OTF-2" ], "offsets": [ [ 1030, 1035 ] ], "normalized": [] }, { "id": "1765275_T5", "type": "Protein", "text": [ "OTF-1" ], "offsets": [ [ 1187, 1192 ] ], "normalized": [] }, { "id": "1765275_T6", "type": "Protein", "text": [ "OTF-2" ], "offsets": [ [ 1240, 1245 ] ], "normalized": [] }, { "id": "1765275_T7", "type": "Protein", "text": [ "Sp 1" ], "offsets": [ [ 1416, 1420 ] ], "normalized": [] }, { "id": "1765275_T8", "type": "Protein", "text": [ "Sp 1" ], "offsets": [ [ 1659, 1663 ] ], "normalized": [] } ]

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[ { "id": "7565811__text", "type": "abstract", "text": [ "An interferon-gamma activation sequence mediates the transcriptional regulation of the IgG Fc receptor type IC gene by interferon-gamma. \nExpression of the IgG Fc receptor type I (Fc gamma RI) on myeloid cells is dramatically increased by treatment with interferon-gamma (IFN-gamma). We observed that Fc gamma RI transcript levels in monoblast-like U937 cells were elevated within 3 hr and peaked 12 hr after exposure to IFN-gamma. Treatment of U937 with IFN-gamma for 9 hr in the presence of cycloheximide led to super-induction of Fc gamma RI expression. Nuclear run-on analysis revealed that the rate of Fc gamma RI transcription was increased by IFN-gamma. Genomic sequence upstream of the Fc gamma RIC gene was cloned and subjected to primer extension analysis, which demonstrated a single transcription initiation site without a TATA box. Transient transfections of CAT reporter gene constructs containing various Fc gamma RIC promoter sequences into U937 cells revealed that a 20-bp region surrounding the transcription start site (-7 to +13) was capable of mediating transcription initiation and that an IFN-gamma responsive element (GIRE) was present within 74 bp upstream of the transcription initiation site. A 17-bp sequence between positions -51 and -35 conferred IFN-gamma responsiveness on a heterologous promoter. Double-stranded GIRE sequence, but not a scrambled sequence, was specifically bound by nuclear proteins from IFN-gamma treated U937 cells. Gel shift experiments further showed that the STAT1 alpha protein bound to the Fc gamma RIC GIRE in response to IFN-gamma treatment of U937 cells. The Fc gamma RIC GIRE is homologous to the IFN-gamma activation sequence (GAS) of the guanylate binding protein and to X box elements of class II MHC genes. Our results demonstrate that transcriptional regulation of the Fc gamma RIC gene by IFN-gamma involves the binding of STAT1 alpha to a 17-bp GAS homology in the proximal promoter. " ], "offsets": [ [ 0, 1953 ] ] } ]

[ { "id": "7565811_T1", "type": "Protein", "text": [ "interferon-gamma" ], "offsets": [ [ 3, 19 ] ], "normalized": [] }, { "id": "7565811_T2", "type": "Protein", "text": [ "IgG Fc receptor type IC" ], "offsets": [ [ 87, 110 ] ], "normalized": [] }, { "id": "7565811_T3", "type": "Protein", "text": [ "interferon-gamma" ], "offsets": [ [ 119, 135 ] ], "normalized": [] }, { "id": "7565811_T4", "type": "Protein", "text": [ "IgG Fc receptor type I" ], "offsets": [ [ 156, 178 ] ], "normalized": [] }, { "id": "7565811_T5", "type": "Protein", "text": [ "Fc gamma RI" ], "offsets": [ [ 180, 191 ] ], "normalized": [] }, { "id": "7565811_T6", "type": "Protein", "text": [ "interferon-gamma" ], "offsets": [ [ 254, 270 ] ], "normalized": [] }, { "id": "7565811_T7", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 272, 281 ] ], "normalized": [] }, { "id": "7565811_T8", "type": "Protein", "text": [ "Fc gamma RI" ], "offsets": [ [ 301, 312 ] ], "normalized": [] }, { "id": "7565811_T9", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 421, 430 ] ], "normalized": [] }, { "id": "7565811_T10", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 455, 464 ] ], "normalized": [] }, { "id": "7565811_T11", "type": "Protein", "text": [ "Fc gamma RI" ], "offsets": [ [ 533, 544 ] ], "normalized": [] }, { "id": "7565811_T12", "type": "Protein", "text": [ "Fc gamma RI" ], "offsets": [ [ 607, 618 ] ], "normalized": [] }, { "id": "7565811_T13", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 650, 659 ] ], "normalized": [] }, { "id": "7565811_T14", "type": "Protein", "text": [ "Fc gamma RIC" ], "offsets": [ [ 694, 706 ] ], "normalized": [] }, { "id": "7565811_T15", "type": "Protein", "text": [ "CAT" ], "offsets": [ [ 872, 875 ] ], "normalized": [] }, { "id": "7565811_T16", "type": "Protein", "text": [ "Fc gamma RIC" ], "offsets": [ [ 920, 932 ] ], "normalized": [] }, { "id": "7565811_T17", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1112, 1121 ] ], "normalized": [] }, { "id": "7565811_T18", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1277, 1286 ] ], "normalized": [] }, { "id": "7565811_T19", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1439, 1448 ] ], "normalized": [] }, { "id": "7565811_T20", "type": "Protein", "text": [ "STAT1 alpha" ], "offsets": [ [ 1515, 1526 ] ], "normalized": [] }, { "id": "7565811_T21", "type": "Protein", "text": [ "Fc gamma RIC" ], "offsets": [ [ 1548, 1560 ] ], "normalized": [] }, { "id": "7565811_T22", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1581, 1590 ] ], "normalized": [] }, { "id": "7565811_T23", "type": "Protein", "text": [ "Fc gamma RIC" ], "offsets": [ [ 1620, 1632 ] ], "normalized": [] }, { "id": "7565811_T24", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1659, 1668 ] ], "normalized": [] }, { "id": "7565811_T25", "type": "Protein", "text": [ "Fc gamma RIC" ], "offsets": [ [ 1836, 1848 ] ], "normalized": [] }, { "id": "7565811_T26", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 1857, 1866 ] ], "normalized": [] }, { "id": "7565811_T27", "type": "Protein", "text": [ "STAT1 alpha" ], "offsets": [ [ 1891, 1902 ] ], "normalized": [] } ]

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[ { "id": "7524762__text", "type": "abstract", "text": [ "Steel factor affects SCL expression during normal erythroid differentiation. \nSteel factor is one of the growth factors that controls the proliferation and differentiation of hematopoietic cells and SCL, also known as Tcl-5 or Tal-1, is a transcription factor involved in erythropoiesis. In this report, we studied the role of SCL in the proliferation of human peripheral blood burst-forming unit-erythroid (BFU-E) and the effects of Steel factor on SCL expression in proliferating erythroid cells. BFU-E-derived colonies increase progressively in size, as determined by cell number, from day 7 to day 14 of culture, with the greatest increase in colony size (10-fold expansion) occurring between day 7 and day 10. SCL protein levels in BFU-E-derived cells were highest in day 7 cells and decreased progressively from day 7 to day 14 of culture, suggesting an association of SCL with erythroid proliferation. In contrast, SCL mRNA levels did not decrease significantly between day 7 and day 14 cells, suggesting that posttranscriptional mechanisms are largely responsible for the decrease in SCL protein observed. The role of SCL in Steel factor-induced erythroid proliferation was then examined. In BFU-E-derived colonies cultured with Steel factor, colony size was significantly increased compared to control. In day 7 and day 10 erythroid precursors cultured with Steel factor, SCL protein was increased significantly compared to control. The increase in SCL protein levels in early erythroid precursors stimulated with Steel factor suggests one mechanism through which Steel factor may enhance normal erythroid proliferation. SCL mRNA levels assessed by Northern blot in day 7 cells did not increase significantly in response to Steel factor stimulation, suggesting that posttranscriptional mechanisms may also be important in the increase in SCL protein observed in response to Steel. " ], "offsets": [ [ 0, 1890 ] ] } ]

[ { "id": "7524762_T1", "type": "Protein", "text": [ "Steel factor" ], "offsets": [ [ 0, 12 ] ], "normalized": [] }, { "id": "7524762_T2", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 21, 24 ] ], "normalized": [] }, { "id": "7524762_T3", "type": "Protein", "text": [ "Steel factor" ], "offsets": [ [ 78, 90 ] ], "normalized": [] }, { "id": "7524762_T4", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 199, 202 ] ], "normalized": [] }, { "id": "7524762_T5", "type": "Protein", "text": [ "Tcl-5" ], "offsets": [ [ 218, 223 ] ], "normalized": [] }, { "id": "7524762_T6", "type": "Protein", "text": [ "Tal-1" ], "offsets": [ [ 227, 232 ] ], "normalized": [] }, { "id": "7524762_T7", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 327, 330 ] ], "normalized": [] }, { "id": "7524762_T8", "type": "Protein", "text": [ "Steel factor" ], "offsets": [ [ 434, 446 ] ], "normalized": [] }, { "id": "7524762_T9", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 450, 453 ] ], "normalized": [] }, { "id": "7524762_T10", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 715, 718 ] ], "normalized": [] }, { "id": "7524762_T11", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 875, 878 ] ], "normalized": [] }, { "id": "7524762_T12", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 922, 925 ] ], "normalized": [] }, { "id": "7524762_T13", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 1092, 1095 ] ], "normalized": [] }, { "id": "7524762_T14", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 1126, 1129 ] ], "normalized": [] }, { "id": "7524762_T15", "type": "Protein", "text": [ "Steel factor" ], "offsets": [ [ 1133, 1145 ] ], "normalized": [] }, { "id": "7524762_T16", "type": "Protein", "text": [ "Steel factor" ], "offsets": [ [ 1237, 1249 ] ], "normalized": [] }, { "id": "7524762_T17", "type": "Protein", "text": [ "Steel factor" ], "offsets": [ [ 1367, 1379 ] ], "normalized": [] }, { "id": "7524762_T18", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 1381, 1384 ] ], "normalized": [] }, { "id": "7524762_T19", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 1458, 1461 ] ], "normalized": [] }, { "id": "7524762_T20", "type": "Protein", "text": [ "Steel factor" ], "offsets": [ [ 1523, 1535 ] ], "normalized": [] }, { "id": "7524762_T21", "type": "Protein", "text": [ "Steel factor" ], "offsets": [ [ 1573, 1585 ] ], "normalized": [] }, { "id": "7524762_T22", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 1630, 1633 ] ], "normalized": [] }, { "id": "7524762_T23", "type": "Protein", "text": [ "Steel factor" ], "offsets": [ [ 1733, 1745 ] ], "normalized": [] }, { "id": "7524762_T24", "type": "Protein", "text": [ "SCL" ], "offsets": [ [ 1847, 1850 ] ], "normalized": [] }, { "id": "7524762_T25", "type": "Protein", "text": [ "Steel" ], "offsets": [ [ 1883, 1888 ] ], "normalized": [] } ]

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[ { "id": "7524762_1", "entity_ids": [ "7524762_T4", "7524762_T5", "7524762_T6" ] } ]

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[ { "id": "2006423__text", "type": "abstract", "text": [ "Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-kappa B [published erratum appears in Science 1991 Oct 4;254(5028):11] \nA DNA probe that spanned a domain conserved among the proto-oncogene c-rel, the Drosophila morphogen dorsal, and the p50 DNA binding subunit of NF-kappa B was generated from Jurkat T cell complementary DNA with the polymerase chain reaction (PCR) and degenerate oligonucleotides. This probe was used to identify a rel-related complementary DNA that hybridized to a 2.6-kilobase messenger RNA present in human T and B lymphocytes. In vitro transcription and translation of the complementary DNA resulted in the synthesis of a protein with an apparent molecular size of 65 kilodaltons (kD). The translated protein showed weak DNA binding with a specificity for the kappa B binding motif. This protein-DNA complex comigrated with the complex obtained with the purified human p65 NF-kappa B subunit and binding was inhibited by I kappa B-alpha and -beta proteins. In addition, the 65-kD protein associated with the p50 subunit of NF-kappa B and the kappa B probe to form a complex with the same electrophoretic mobility as the NF-kappa B-DNA complex. Therefore the rel-related 65-kD protein may represent the p65 subunit of the active NF-kappa B transcription factor complex. " ], "offsets": [ [ 0, 1331 ] ] } ]

[ { "id": "2006423_T1", "type": "Protein", "text": [ "c-rel" ], "offsets": [ [ 228, 233 ] ], "normalized": [] }, { "id": "2006423_T2", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 276, 279 ] ], "normalized": [] }, { "id": "2006423_T3", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 931, 934 ] ], "normalized": [] }, { "id": "2006423_T4", "type": "Protein", "text": [ "I kappa B-alpha" ], "offsets": [ [ 983, 998 ] ], "normalized": [] }, { "id": "2006423_T5", "type": "Protein", "text": [ "-beta" ], "offsets": [ [ 1003, 1008 ] ], "normalized": [] }, { "id": "2006423_T6", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 1070, 1073 ] ], "normalized": [] }, { "id": "2006423_T7", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 1264, 1267 ] ], "normalized": [] } ]

[ { "id": "2006423_E1", "type": "Binding", "trigger": { "text": [ "associated" ], "offsets": [ [ 1050, 1060 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "2006423_T6" } ] } ]

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[ { "id": "7522548__text", "type": "abstract", "text": [ "Antioxidants inhibit monocyte adhesion by suppressing nuclear factor-kappa B mobilization and induction of vascular cell adhesion molecule-1 in endothelial cells stimulated to generate radicals. \nCell adhesion to endothelial cells stimulated by tumor necrosis factor-alpha (TNF) is due to induction of surface receptors, such as vascular cell adhesion molecule-1 (VCAM-1). The antioxidant pyrrolidine dithiocarbamate (PDTC) specifically inhibits activation of nuclear factor-kappa B (NF-kappa B). Since kappa B motifs are present in VCAM-1 and intercellular adhesion molecule-1 (ICAM-1) promoters, we used PDTC to study the regulatory mechanisms of VCAM-1 and ICAM-1 induction and subsequent monocyte adhesion in TNF-treated human umbilical vein endothelial cells (HUVECs). PDTC or N-acetylcysteine dose dependently reduced TNF-induced VCAM-1 but not ICAM-1 surface protein (also in human umbilical arterial endothelial cells) and mRNA expression (by 70% at 100 mumol/L PDTC) in HUVECs as assessed by flow cytometry and polymerase chain reaction. Gel-shift analysis in HUVECs demonstrated that PDTC prevented NF-kappa B mobilization by TNF, suggesting that only VCAM-1 induction was controlled by NF-kappa B. Since HUVECs released superoxide anions in response to TNF, and H2O2 induces VCAM-1, PDTC may act as a radical scavenger. Although ICAM-1 induction was unaffected, inhibitors of NADPH oxidase (apocynin) or cytochrome P-450 (SKF525a) suppressed VCAM-1 induction by TNF, revealing that several radical-generating systems are involved in its regulation. PDTC, apocynin, or SKF525a decreased adhesion of monocytic U937 cells to TNF-treated HUVECs (by 75% at 100 mumol/L PDTC). Inhibition by anti-VCAM-1 monoclonal antibody 1G11 indicated that U937 adhesion was VCAM-1 dependent and suppression by antioxidants was due to reduced VCAM-1 induction. (ABSTRACT TRUNCATED AT 250 WORDS) " ], "offsets": [ [ 0, 1886 ] ] } ]

[ { "id": "7522548_T1", "type": "Protein", "text": [ "vascular cell adhesion molecule-1" ], "offsets": [ [ 107, 140 ] ], "normalized": [] }, { "id": "7522548_T2", "type": "Protein", "text": [ "tumor necrosis factor-alpha" ], "offsets": [ [ 245, 272 ] ], "normalized": [] }, { "id": "7522548_T3", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 274, 277 ] ], "normalized": [] }, { "id": "7522548_T4", "type": "Protein", "text": [ "vascular cell adhesion molecule-1" ], "offsets": [ [ 329, 362 ] ], "normalized": [] }, { "id": "7522548_T5", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 364, 370 ] ], "normalized": [] }, { "id": "7522548_T6", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 533, 539 ] ], "normalized": [] }, { "id": "7522548_T7", "type": "Protein", "text": [ "ntercellular adhesion molecule-1" ], "offsets": [ [ 545, 577 ] ], "normalized": [] }, { "id": "7522548_T8", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 579, 585 ] ], "normalized": [] }, { "id": "7522548_T9", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 649, 655 ] ], "normalized": [] }, { "id": "7522548_T10", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 660, 666 ] ], "normalized": [] }, { "id": "7522548_T11", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 713, 716 ] ], "normalized": [] }, { "id": "7522548_T12", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 824, 827 ] ], "normalized": [] }, { "id": "7522548_T13", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 836, 842 ] ], "normalized": [] }, { "id": "7522548_T14", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 851, 857 ] ], "normalized": [] }, { "id": "7522548_T15", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 1136, 1139 ] ], "normalized": [] }, { "id": "7522548_T16", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1162, 1168 ] ], "normalized": [] }, { "id": "7522548_T17", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 1264, 1267 ] ], "normalized": [] }, { "id": "7522548_T18", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1286, 1292 ] ], "normalized": [] }, { "id": "7522548_T19", "type": "Protein", "text": [ "ICAM-1" ], "offsets": [ [ 1340, 1346 ] ], "normalized": [] }, { "id": "7522548_T20", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1453, 1459 ] ], "normalized": [] }, { "id": "7522548_T21", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 1473, 1476 ] ], "normalized": [] }, { "id": "7522548_T22", "type": "Protein", "text": [ "TNF" ], "offsets": [ [ 1633, 1636 ] ], "normalized": [] }, { "id": "7522548_T23", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1701, 1707 ] ], "normalized": [] }, { "id": "7522548_T24", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1766, 1772 ] ], "normalized": [] }, { "id": "7522548_T25", "type": "Protein", "text": [ "VCAM-1" ], "offsets": [ [ 1834, 1840 ] ], "normalized": [] } ]

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"7522548_E21", "type": "Regulation", "trigger": { "text": [ "controlled" ], "offsets": [ [ 1183, 1193 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7522548_E20" } ] }, { "id": "7522548_E22", "type": "Positive_regulation", "trigger": { "text": [ "induces" ], "offsets": [ [ 1278, 1285 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7522548_T18" } ] }, { "id": "7522548_E23", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1347, 1356 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7522548_T19" }, { "role": "Cause", "ref_id": "7522548_T12" } ] }, { "id": "7522548_E24", "type": "Negative_regulation", "trigger": { "text": [ "unaffected" ], "offsets": [ [ 1361, 1371 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7522548_E23" } ] }, { "id": "7522548_E25", "type": "Negative_regulation", "trigger": { "text": [ "suppressed" ], "offsets": [ [ 1442, 1452 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7522548_E26" } ] }, { "id": "7522548_E26", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1460, 1469 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7522548_T20" }, { "role": "Cause", "ref_id": "7522548_T21" } ] }, { "id": "7522548_E27", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1548, 1558 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7522548_E26" } ] }, { "id": "7522548_E28", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 1826, 1833 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7522548_E29" } ] }, { "id": "7522548_E29", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1841, 1850 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7522548_T25" }, { "role": "Cause", "ref_id": "7522548_T12" } ] } ]

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[ { "id": "8853898__text", "type": "abstract", "text": [ "Transcriptional and posttranscriptional regulation of erythroid gene expression in anthracycline-induced differentiation of human erythroleukemic cells. \nAclacinomycin (ACLA) and doxorubicin (DOX) were used at subtoxic concentrations to induce erythroid differentiation in the human leukemic cell line K562. Cell hemoglobinization was accompanied by the increased expression of genes encoding gamma-globin and porphobilinogen deaminase (PBGD), an enzyme of heme synthesis. By using run-on assays, ACLA was shown to induce an enhancement of the transcription of erythroid genes, including gamma-globin, PBGD, erythropoietin receptor, and GATA-1 transcription factor. In contrast, in DOX-treated cells, the transcription rate of these genes was unchanged in comparison with control cells. In addition, inhibition of mRNA synthesis with actinomycin D indicated that DOX induced an increased stability of PBGD and GATA-1 mRNAs, whereas ACLA did not affect the half-lives of these mRNAs. Because the increase in erythroid mRNA steady-state level in anthracycline-treated cells was inhibited by cycloheximide, this suggests that transcriptional activation in ACLA-treated cells and mRNA stabilization in DOX-treated cells were dependent on de novo protein synthesis. Finally, GATA-1 protein level was shown to be increased in ACLA-treated but not in DOX-treated cells. These two anthracyclines, although closely related in their structures, appeared to act as differentiation inducers by distinct mechanisms. Indeed, erythroid gene expression was demonstrated to be regulated transcriptionally by ACLA and mainly posttranscriptionally by DOX. " ], "offsets": [ [ 0, 1637 ] ] } ]

[ { "id": "8853898_T1", "type": "Protein", "text": [ "porphobilinogen deaminase" ], "offsets": [ [ 410, 435 ] ], "normalized": [] }, { "id": "8853898_T2", "type": "Protein", "text": [ "PBGD" ], "offsets": [ [ 437, 441 ] ], "normalized": [] }, { "id": "8853898_T3", "type": "Protein", "text": [ "PBGD" ], "offsets": [ [ 602, 606 ] ], "normalized": [] }, { "id": "8853898_T4", "type": "Protein", "text": [ "erythropoietin receptor" ], "offsets": [ [ 608, 631 ] ], "normalized": [] }, { "id": "8853898_T5", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 637, 643 ] ], "normalized": [] }, { "id": "8853898_T6", "type": "Protein", "text": [ "PBGD" ], "offsets": [ [ 901, 905 ] ], "normalized": [] }, { "id": "8853898_T7", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 910, 916 ] ], "normalized": [] }, { "id": "8853898_T8", "type": "Protein", "text": [ "GATA-1" ], "offsets": [ [ 1270, 1276 ] ], "normalized": [] } ]

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[ { "id": "10485906__text", "type": "abstract", "text": [ "Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression. \nInterferons (IFNs) inhibit induction by IL-4 of multiple genes in human monocytes. However, the mechanism by which IFNs mediate this inhibition has not been defined. IL-4 activates gene expression by inducing tyrosine phosphorylation, homodimerization, and nuclear translocation of the latent transcription factor, STAT6 (signal transducer and activator of transcription-6). STAT6-responsive elements are characteristically present in the promoters of IL-4-inducible genes. Because STAT6 activation is essential for IL-4-induced gene expression, we examined the ability of type I and type II IFNs to regulate activation of STAT6 by IL-4 in primary human monocytes. Pretreatment of monocytes with IFN-beta or IFN-gamma, but not IL-1, IL-2, macrophage colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, IL-6, or transforming growth factor beta suppressed activation of STAT6 by IL-4. This inhibition was associated with decreased tyrosine phosphorylation and nuclear translocation of STAT6 and was not evident unless the cells were preincubated with IFN for at least 1 hr before IL-4 stimulation. Furthermore, inhibition by IFN could be blocked by cotreatment with actinomycin D and correlated temporally with induction of the JAK/STAT inhibitory gene, SOCS-1. Forced expression of SOCS-1 in a macrophage cell line, RAW264, markedly suppressed trans-activation of an IL-4-inducible reporter as well as IL-6- and IFN-gamma-induced reporter gene activity. These findings demonstrate that IFNs inhibit IL-4-induced activation of STAT6 and STAT6-dependent gene expression, at least in part, by inducing expression of SOCS-1. " ], "offsets": [ [ 0, 1758 ] ] } ]

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[ { "id": "7989745__text", "type": "abstract", "text": [ "Differential regulation of proto-oncogenes c-jun and c-fos in T lymphocytes activated through CD28. \nThe T cell surface molecule CD28 binds to ligands on accessory cells and APCs, playing an important costimulatory role in the response of T cells to Ags. Our knowledge of the intracellular signaling pathways coupled to this receptor is incomplete. In addition to activation of phospholipase C gamma 1, ligation of this receptor also seems to activate a calcium-independent, CD28-specific pathway. In this paper, we report that cross-linking of CD28 (but not CD2, CD5, LFA-1, or CD7) leads to an elevation of c-jun mRNA, with only minimal activation of c-fos expression. CD28-dependent induction of c-jun expression requires protein tyrosine kinase activity, but does not depend on activation of a phorbol ester-responsive protein kinase C or elevation of cytosolic calcium. Furthermore, CD28-dependent elevation of c-jun mRNA does not appear to be mediated at the level of mRNA stability. A mechanism is suggested whereby expression of c-jun and junB, in the absence of members of the fos family, can prevent inappropriate activation of T cells caused by ligation of CD28 in the absence of a specific antigenic stimulus. " ], "offsets": [ [ 0, 1222 ] ] } ]

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[ { "id": "7986199__text", "type": "abstract", "text": [ "Pyrrolidine dithiocarbamate, a potent inhibitor of nuclear factor kappa B (NF-kappa B) activation, prevents apoptosis in human promyelocytic leukemia HL-60 cells and thymocytes. \nWe examined the effect of pyrrolidine dithiocarbamate (PDTC), which potently blocks the activation of nuclear factor kappa B (NF-kappa B), on the induction of apoptosis by a variety of agents. Treatment of a human promyelocytic leukemia cell line, HL-60, with 10 micrograms/mL etoposide or 2 microM 1-beta-D-arabinofuranosylcytosine induced NF-kappa B activation within 1 hr and subsequently caused apoptosis within 3-4 hr. The simultaneous addition of 50-500 microM PDTC with these agents blocked NF-kappa B activation and completely abrogated both morphologically apoptotic changes and internucleosomal DNA fragmentation for up to 6 hr. However, PDTC failed to inhibit the endonuclease activity contained in the whole cell lysates. The inhibitory effect of PDTC was also observed in etoposide- and dexamethasone-induced apoptosis in human thymocytes at a concentration of 1-10 microM. Since PDTC has both antioxidant and metal-ion chelating activities, we tested the effects of N-acetyl-L-cysteine (NAC) (antioxidant) or o-phenanthroline (OP) (metal-ion chelator) on the induction of apoptosis. Pretreatment of HL-60 cells or thymocytes with 100-500 microM OP for 2 hr, but not 10-60 mM NAC, suppressed subsequent occurrence of apoptosis induced by etoposide. These results suggest that the activation of NF-kappa B plays an important role in the apoptotic process of human hematopoietic cells. " ], "offsets": [ [ 0, 1576 ] ] } ]

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[ { "id": "9442374__text", "type": "abstract", "text": [ "Control of NF-kappa B activity by the I kappa B beta inhibitor. \nThe transcription factor NF-kappa B is maintained in an inactive cytoplasmic state by I kappa B inhibitors. In mammalian cells, I kappa B alpha and I kappa B beta proteins have been purified and shown to be the inhibitors of NF-kappa B through their association with the p65 or c-Rel subunits. In addition, we have isolated a third NF-kappa B inhibitor, I kappa B epsilon (1). Upon treatment with a large variety of inducers, I kappa B alpha, I kappa B beta are proteolytically degraded, resulting in NF-kappa B translocation into the nucleus. Here we show that in E29.1 T cell hybridoma I kappa B alpha and I kappa B beta are equally associated with p65 and that I kappa B beta is degraded in response to TNF alpha in contrast to what has been originally published. Our data also suggest that, unlike I kappa B alpha, I kappa B beta is constitutively phosphorylated and resynthesized as a hypophosphorylated form. The absence of slow migrating forms of I kappa B beta following stimulation suggests that the phosphorylation does not necessarily constitute the signal-induced event which targets the molecule for proteolysis. " ], "offsets": [ [ 0, 1191 ] ] } ]

[ { "id": "9442374_T1", "type": "Protein", "text": [ "I kappa B beta" ], "offsets": [ [ 38, 52 ] ], "normalized": [] }, { "id": "9442374_T2", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 193, 208 ] ], "normalized": [] }, { "id": "9442374_T3", "type": "Protein", "text": [ "I kappa B beta" ], "offsets": [ [ 213, 227 ] ], "normalized": [] }, { "id": "9442374_T4", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 336, 339 ] ], "normalized": [] }, { "id": "9442374_T5", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 343, 348 ] ], "normalized": [] }, { "id": "9442374_T6", "type": "Protein", "text": [ "I kappa B epsilon" ], "offsets": [ [ 419, 436 ] ], "normalized": [] }, { "id": "9442374_T7", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 491, 506 ] ], "normalized": [] }, { "id": "9442374_T8", "type": "Protein", "text": [ "I kappa B beta" ], "offsets": [ [ 508, 522 ] ], "normalized": [] }, { "id": "9442374_T9", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 653, 668 ] ], "normalized": [] }, { "id": "9442374_T10", "type": "Protein", "text": [ "I kappa B beta" ], "offsets": [ [ 673, 687 ] ], "normalized": [] }, { "id": "9442374_T11", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 716, 719 ] ], "normalized": [] }, { "id": "9442374_T12", "type": "Protein", "text": [ "I kappa B beta" ], "offsets": [ [ 729, 743 ] ], "normalized": [] }, { "id": "9442374_T13", "type": "Protein", "text": [ "TNF alpha" ], "offsets": [ [ 771, 780 ] ], "normalized": [] }, { "id": "9442374_T14", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 867, 882 ] ], "normalized": [] }, { "id": "9442374_T15", "type": "Protein", "text": [ "I kappa B beta" ], "offsets": [ [ 884, 898 ] ], "normalized": [] }, { "id": "9442374_T16", "type": "Protein", "text": [ "I kappa B beta" ], "offsets": [ [ 1019, 1033 ] ], "normalized": [] } ]

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[ { "id": "9712068__text", "type": "abstract", "text": [ "Inducible nitric oxide: an autoregulatory feedback inhibitor of vascular inflammation. \nInducible nitric oxide (iNO) is produced at sites of vascular inflammation by resident and nonresident vascular wall cells, but its role in the inflammatory process is not known. In this study, we show that a novel function of iNO is to terminate inflammatory processes. We find that iNO produced by murine macrophage-like cells, RAW264.7, can inhibit cytokine-induced endothelial cell activation in a separated and mixed endothelial-RAW264.7 coculture system. Both iNO production and endothelial VCAM-1 expression were induced simultaneously with bacterial LPS and murine-specific IFN-gamma. Inhibition of iNO synthase (iNOS) activity with N omega-monomethyl-L-arginine in endothelial-RAW264.7 cocultures, stimulated with murine-specific IFN-gamma and LPS, decreased iNO production by 86%, augmented VCAM-1 and iNOS expression in endothelial and RAW264.7 cells, respectively, and increased monocyte adhesion to the endothelial cell surface. Transient transfection studies using various VCAM-1 promoter constructs demonstrated that inhibitory effects of iNO on VCAM-1 gene transcription were mediated, in part, by inhibitory effects of iNO on kappa B cis-acting elements. Immunofluorescence studies using an Ab to the RelA (p65) subunit of nuclear factor-kappa B revealed that iNO inhibited the activation of nuclear factor-kappa B. These studies indicate that iNO attenuates iNOS expression in macrophages and inhibits monocyte adhesion to endothelial cells, and suggest that endogenously derived iNO may be an important autoregulatory inhibitor of vascular inflammation. " ], "offsets": [ [ 0, 1661 ] ] } ]

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[ { "id": "9712068_1", "entity_ids": [ "9712068_T3", "9712068_T4" ] }, { "id": "9712068_2", "entity_ids": [ "9712068_T10", "9712068_T11" ] } ]

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[ { "id": "9971788__text", "type": "abstract", "text": [ "High-level replication of human immunodeficiency virus in thymocytes requires NF-kappaB activation through interaction with thymic epithelial cells. \nWe have previously demonstrated that interaction of infected thymocytes with autologous thymic epithelial cells (TEC) is a prerequisite for a high level of human immunodeficiency virus type 1 (HIV-1) replication in thymocytes (M.Rothe, L.Chene, M.Nugeyre, F.Barre-Sinoussi, and N.Israel, J.Virol.72:5852-5861, 1998). We report here that this activation of HIV replication takes place at the transcriptional level through activation of the Rel/NF-kappaB transcription factors. We first demonstrate that an HIV-1 provirus (SF-2 strain) very effectively replicates in thymocytes cocultured with TEC whereas this provirus, with kappaB sites deleted, fails to replicate. We provide evidence that several NF-kappaB complexes are constitutively found in the nuclei of thymocytes either freshly isolated from the thymus or maintained in coculture with autologous or heterologous TEC. The prevalent complex is the heterodimer p50-p65. NF-kappaB activity is tightly correlated with the transcriptional activity of a long terminal repeat (LTR) of HIV-1 transfected in thymocytes. The cotransfection of this LTR with a mutated IkappaBalpha molecule formally demonstrates that LTR transactivation is regulated by members of the Rel/NF-kappaB family in thymocytes. We also showed that tumor necrosis factor (TNF) and to a lesser extent interleukin-1 (IL-1), secreted within the coculture, induce NF-kappaB activity and a correlative LTR transactivation. However IL-7, a crucial factor for thymopoiesis that is secreted mainly by TEC, is a necessary cofactor for NF-kappaB activation elicited by TNF or IL-1. Together, these data indicate that NF-kappaB activation, required for a high level of HIV replication in thymocytes, is regulated in a specific manner in the thymic microenvironment which provides the necessary cytokines: TNF, IL-1, and IL-7. " ], "offsets": [ [ 0, 1987 ] ] } ]

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[ { "id": "10233888__text", "type": "abstract", "text": [ "Unicellular-unilineage erythropoietic cultures: molecular analysis of regulatory gene expression at sibling cell level. \nIn vitro studies on hematopoietic control mechanisms have been hampered by the heterogeneity of the analyzed cell populations, ie, lack of lineage specificity and developmental stage homogeneity of progenitor/precursor cells growing in culture. We developed unicellular culture systems for unilineage differentiation of purified hematopoietic progenitor cells followed by daughter cell analysis at cellular and molecular level. In the culture system reported here, (1) the growth factor (GF) stimulus induces cord blood (CB) progenitor cells to proliferate and differentiate/mature exclusively along the erythroid lineage; (2) this erythropoietic wave is characterized by less than 4% apoptotic cells; (3) asymmetric divisions are virtually absent, ie, nonresponsive hematopoietic progenitors with no erythropoietic potential are forced into apoptosis; (4) the system is cell division controlled (cdc), ie, the number of divisions performed by each cell is monitored. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was applied to this culture system to investigate gene expression of diverse receptors, markers of differentiation, and transcription factors (EKLF, GATA-1, GATA-2, p45 NF-E2, PU.1, and SCL/Tal1) at discrete stages of erythropoietic development. Freshly isolated CD34(+) cells expressed CD34, c-kit, PU.1, and GATA-2 but did not express CD36, erythropoietin receptor (EpoR), SCL/Tal1, EKLF, NF-E2, GATA-1, or glyocophorin A (GPA). In early to intermediate stages of erythroid differentiation we monitored the induction of CD36, Tal1, EKLF, NF-E2, and GATA-1 that preceeded expression of EpoR. In late stages of erythroid maturation, GPA was upregulated, whereas CD34, c-kit, PU.1, and GATA-2 were barely or not detected. In addition, competitive single-cell RT-PCR was used to assay CD34 mRNA transcripts in sibling CD34(+) CD38(-) cells differentiating in unilineage erythroid cultures: this analysis allowed us to semiquantitate the gradual downmodulation of CD34 mRNA from progenitor cells through their differentiating erythroid progeny. It is concluded that this novel culture system, coupled with single-cell RT-PCR analysis, may eliminate the ambiguities intrinsic to molecular studies on heterogeneous populations of hematopoietic progenitors/precursors growing in culture, particularly in the initial stages of development. " ], "offsets": [ [ 0, 2500 ] ] } ]

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"ref_id": "10233888_T21" } ] }, { "id": "10233888_E17", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1676, 1685 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T22" } ] }, { "id": "10233888_E18", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1676, 1685 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T24" } ] }, { "id": "10233888_E19", "type": "Positive_regulation", "trigger": { "text": [ "induction" ], "offsets": [ [ 1676, 1685 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T23" } ] }, { "id": "10233888_E20", "type": "Gene_expression", "trigger": { "text": [ "induction" ], "offsets": [ [ 1676, 1685 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T25" } ] }, { "id": "10233888_E21", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1740, 1750 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T26" } ] }, { "id": "10233888_E22", "type": "Positive_regulation", "trigger": { "text": [ "upregulated" ], "offsets": [ [ 1808, 1819 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T27" } ] }, { "id": "10233888_E23", "type": "Gene_expression", "trigger": { "text": [ "detected" ], "offsets": [ [ 1878, 1886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T30" } ] }, { "id": "10233888_E24", "type": "Gene_expression", "trigger": { "text": [ "detected" ], "offsets": [ [ 1878, 1886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T29" } ] }, { "id": "10233888_E25", "type": "Gene_expression", "trigger": { "text": [ "detected" ], "offsets": [ [ 1878, 1886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T28" } ] }, { "id": "10233888_E26", "type": "Gene_expression", "trigger": { "text": [ "detected" ], "offsets": [ [ 1878, 1886 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T31" } ] }, { "id": "10233888_E27", "type": "Transcription", "trigger": { "text": [ "mRNA transcripts" ], "offsets": [ [ 1955, 1971 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T32" } ] }, { "id": "10233888_E28", "type": "Negative_regulation", "trigger": { "text": [ "downmodulation" ], "offsets": [ [ 2110, 2124 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10233888_T35" } ] } ]

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[ { "id": "9177216__text", "type": "abstract", "text": [ "Transactivation by CIITA, the type II bare lymphocyte syndrome-associated factor, requires participation of multiple regions of the TATA box binding protein. \nCIITA is a positive regulator of class II major histocompatibility complex gene transcription that has been found to be defective in one of the five complementation groups of class II major histocompatibility complex-negative cell lines. Its N-terminal region is capable of activating transcription from a reporter gene when fused to a DNA binding domain. We have investigated the mechanism of transactivation mediated by the CIITA activation domain by studying its role in the process of transcription initiation and elongation. Specifically the altered specificity TBP (TATA box binding protein) assay has been used to analyze the response of the CIITA activation domain to mutations in TBP known to disrupt its interaction with its associated general factors. Transactivation by CIITA was extremely sensitive to a mutation in TBP that in yeast is known to abolish VP16-mediated transcription but leaves basal transcription unaffected. A TBP mutant defective in interaction with TBP-associated factor TAFII250 also failed to mediate transactivation through the CIITA activation domain. Certain interactions between TBP and general factors that are specifically required for acidic activation domains were also required for CIITA-mediated transactivation to reach its full potential. Finally, like VP16, CIITA was able to stimulate elongation of transcription. Overall the mechanism of transactivation by the human B-cell-specific CIITA is very similar to that mediated by the herpes virus transactivator VP16 in the ways that have been tested. " ], "offsets": [ [ 0, 1705 ] ] } ]

[ { "id": "9177216_T1", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 19, 24 ] ], "normalized": [] }, { "id": "9177216_T2", "type": "Protein", "text": [ "TATA box binding protein" ], "offsets": [ [ 132, 156 ] ], "normalized": [] }, { "id": "9177216_T3", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 159, 164 ] ], "normalized": [] }, { "id": "9177216_T4", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 585, 590 ] ], "normalized": [] }, { "id": "9177216_T5", "type": "Protein", "text": [ "TBP" ], "offsets": [ [ 726, 729 ] ], "normalized": [] }, { "id": "9177216_T6", "type": "Protein", "text": [ "TATA box binding protein" ], "offsets": [ [ 731, 755 ] ], "normalized": [] }, { "id": "9177216_T7", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 808, 813 ] ], "normalized": [] }, { "id": "9177216_T8", "type": "Protein", "text": [ "TBP" ], "offsets": [ [ 848, 851 ] ], "normalized": [] }, { "id": "9177216_T9", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 941, 946 ] ], "normalized": [] }, { "id": "9177216_T10", "type": "Protein", "text": [ "TBP" ], "offsets": [ [ 988, 991 ] ], "normalized": [] }, { "id": "9177216_T11", "type": "Protein", "text": [ "VP16" ], "offsets": [ [ 1026, 1030 ] ], "normalized": [] }, { "id": "9177216_T12", "type": "Protein", "text": [ "TBP" ], "offsets": [ [ 1099, 1102 ] ], "normalized": [] }, { "id": "9177216_T13", "type": "Protein", "text": [ "TBP" ], "offsets": [ [ 1140, 1143 ] ], "normalized": [] }, { "id": "9177216_T14", "type": "Protein", "text": [ "TAFII250" ], "offsets": [ [ 1162, 1170 ] ], "normalized": [] }, { "id": "9177216_T15", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1222, 1227 ] ], "normalized": [] }, { "id": "9177216_T16", "type": "Protein", "text": [ "TBP" ], "offsets": [ [ 1276, 1279 ] ], "normalized": [] }, { "id": "9177216_T17", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1384, 1389 ] ], "normalized": [] }, { "id": "9177216_T18", "type": "Protein", "text": [ "VP16" ], "offsets": [ [ 1458, 1462 ] ], "normalized": [] }, { "id": "9177216_T19", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1464, 1469 ] ], "normalized": [] }, { "id": "9177216_T20", "type": "Protein", "text": [ "CIITA" ], "offsets": [ [ 1591, 1596 ] ], "normalized": [] }, { "id": "9177216_T21", "type": "Protein", "text": [ "VP16" ], "offsets": [ [ 1665, 1669 ] ], "normalized": [] } ]

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[ { "id": "9178107__text", "type": "abstract", "text": [ "Reactive oxygen species and antioxidants in inflammatory diseases. \nThis paper aims to review the role of free radical-induced tissue damage and antioxidant defence mechanisms in inflammatory diseases that involve pathogenic processes similar to the periodontal diseases. There is a clearly defined and substantial role for free radicals or reactive oxygen species (ROS) in periodontitis, but little research has been performed in this area. This paper reviews the considerable data available relating ROS activity and antioxidant defence to inflammatory diseases and attempts to draw parallels with periodontitis, in an effort to stimulate more periodontal research in this important area. The recent discovery of the transcription factor nuclear factor kappa B (NF-kappa B) is reviewed and several potential pathways for cytokine-induced periodontal tissue damage, mediated by NF-kappa B1 are discussed. Emphasis is placed on cytokines that have been studied in periodontitis, principally TNF-alpha, IL-1, IL-6, IL-8 and beta-interferon. The link between cellular production of such important mediators of inflammation and the antioxidant (AO) thiols, cysteine and reduced glutathione (GSH), is discussed and it is hypothesised that NF-kappa B antagonists may offer important therapeutic benefits. " ], "offsets": [ [ 0, 1300 ] ] } ]

[ { "id": "9178107_T1", "type": "Protein", "text": [ "NF-kappa B1" ], "offsets": [ [ 879, 890 ] ], "normalized": [] }, { "id": "9178107_T2", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 991, 1000 ] ], "normalized": [] }, { "id": "9178107_T3", "type": "Protein", "text": [ "IL-6" ], "offsets": [ [ 1008, 1012 ] ], "normalized": [] }, { "id": "9178107_T4", "type": "Protein", "text": [ "IL-8" ], "offsets": [ [ 1014, 1018 ] ], "normalized": [] }, { "id": "9178107_T5", "type": "Protein", "text": [ "beta-interferon" ], "offsets": [ [ 1023, 1038 ] ], "normalized": [] } ]

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[ { "id": "7688596__text", "type": "abstract", "text": [ "Cytokine modulation of HIV expression. \nCytokines, the peptide hormones which control the homeostasis of the immune system and also play a fundamental role in inflammatory and immune mediated reactions, have been involved at multiple levels in the pathogenesis of the acquired immune deficiency syndrome (AIDS). Infection with the human immunodeficiency virus (HIV) has been shown to induce production of several cytokines both in vitro and in vivo. Conversely, several cytokines modulate the levels of HIV expression in infected cells of both T lymphocytic and mononuclear phagocytic lineage. Activated mononuclear cells, particularly B cells which are in a state of chronic activation in HIV infected individuals, release HIV-inductive cytokines and thus play a potentially important role in the pathogenesis of HIV infection. " ], "offsets": [ [ 0, 829 ] ] } ]

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[ { "id": "9786883__text", "type": "abstract", "text": [ "Downstream activation of a TATA-less promoter by Oct-2, Bob1, and NF-kappaB directs expression of the homing receptor BLR1 to mature B cells. \nThe chemokine receptor, BLR1, is a major regulator of the microenvironmental homing of B cells in lymphoid organs. In vitro studies identify three essential elements of the TATA-less blr1 core promoter that confer cell type- and differentiation-specific expression in the B cells of both humans and mice, a functional promoter region (-36 with respect to the transcription start site), a NF-kappaB motif (+44), and a noncanonical octamer motif (+157). The importance of these sites was confirmed by in vivo studies in gene-targeted mice deficient of either Oct-2, Bob1, or both NF-kappaB subunits p50 and p52. In all of these animals, the expression of BLR1 was reduced or absent. In mice deficient only of p52/NF-kappaB, BLR1 expression was unaffected. Thus our data demonstrate that BLR1 is a target gene for Oct-2, Bob1, and members of the NF-kappaB/Rel family and provides a link to the impaired B cell functions in mice deficient for these factors. " ], "offsets": [ [ 0, 1097 ] ] } ]

[ { "id": "9786883_T1", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 49, 54 ] ], "normalized": [] }, { "id": "9786883_T2", "type": "Protein", "text": [ "Bob1" ], "offsets": [ [ 56, 60 ] ], "normalized": [] }, { "id": "9786883_T3", "type": "Protein", "text": [ "BLR1" ], "offsets": [ [ 118, 122 ] ], "normalized": [] }, { "id": "9786883_T4", "type": "Protein", "text": [ "BLR1" ], "offsets": [ [ 167, 171 ] ], "normalized": [] }, { "id": "9786883_T5", "type": "Protein", "text": [ "blr1" ], "offsets": [ [ 326, 330 ] ], "normalized": [] }, { "id": "9786883_T6", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 700, 705 ] ], "normalized": [] }, { "id": "9786883_T7", "type": "Protein", "text": [ "Bob1" ], "offsets": [ [ 707, 711 ] ], "normalized": [] }, { "id": "9786883_T8", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 740, 743 ] ], "normalized": [] }, { "id": "9786883_T9", "type": "Protein", "text": [ "p52" ], "offsets": [ [ 748, 751 ] ], "normalized": [] }, { "id": "9786883_T10", "type": "Protein", "text": [ "BLR1" ], "offsets": [ [ 796, 800 ] ], "normalized": [] }, { "id": "9786883_T11", "type": "Protein", "text": [ "p52" ], "offsets": [ [ 850, 853 ] ], "normalized": [] }, { "id": "9786883_T12", "type": "Protein", "text": [ "BLR1" ], "offsets": [ [ 865, 869 ] ], "normalized": [] }, { "id": "9786883_T13", "type": "Protein", "text": [ "BLR1" ], "offsets": [ [ 928, 932 ] ], "normalized": [] }, { "id": "9786883_T14", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 954, 959 ] ], "normalized": [] }, { "id": "9786883_T15", "type": "Protein", "text": [ "Bob1" ], "offsets": [ [ 961, 965 ] ], "normalized": [] } ]

[ { "id": "9786883_E1", "type": "Positive_regulation", "trigger": { "text": [ "directs" ], "offsets": [ [ 76, 83 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_E2" } ] }, { "id": "9786883_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 84, 94 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_T3" } ] }, { "id": "9786883_E3", "type": "Positive_regulation", "trigger": { "text": [ "confer" ], "offsets": [ [ 350, 356 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_E4" } ] }, { "id": "9786883_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 397, 407 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_T5" } ] }, { "id": "9786883_E5", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 782, 792 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_T10" } ] }, { "id": "9786883_E6", "type": "Negative_regulation", "trigger": { "text": [ "reduced" ], "offsets": [ [ 805, 812 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_E5" } ] }, { "id": "9786883_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 870, 880 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_T12" } ] }, { "id": "9786883_E8", "type": "Regulation", "trigger": { "text": [ "unaffected" ], "offsets": [ [ 885, 895 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_E7" } ] }, { "id": "9786883_E9", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 938, 944 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_T13" }, { "role": "Cause", "ref_id": "9786883_T14" } ] }, { "id": "9786883_E10", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 938, 944 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_T13" } ] }, { "id": "9786883_E11", "type": "Regulation", "trigger": { "text": [ "target" ], "offsets": [ [ 938, 944 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_T13" }, { "role": "Cause", "ref_id": "9786883_T15" } ] }, { "id": "9786883_E12", "type": "Gene_expression", "trigger": { "text": [ "deficient" ], "offsets": [ [ 1068, 1077 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_T15" } ] }, { "id": "9786883_E13", "type": "Gene_expression", "trigger": { "text": [ "deficient" ], "offsets": [ [ 1068, 1077 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "9786883_T14" } ] } ]

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[ { "id": "9427533__text", "type": "abstract", "text": [ "Competent transcription initiation by RNA polymerase II in cell-free extracts from xeroderma pigmentosum groups B and D in an optimized RNA transcription assay. \nThe human autosomal recessive disease, xeroderma pigmentosum (XP), can result from mutations in any one of seven genes, designated XPA through XPG. Of these, the XPB and XPD genes encode proteins that are subunits of a general transcription factor, TFIIH, involved in both nucleotide excision repair (NER) and initiation of mRNA transcription by RNA polymerase II. In humans, mutation of the XPB or XPD gene impairs NER, resulting in hyper-sensitivity to sunlight and greatly increased skin tumor formation. However, no transcription deficiency has been demonstrated in either XP-B or XP-D. We have employed an optimized cell-free RNA transcription assay to analyze transcription activity of XP-B and XP-D. Although the growth rate was normal, the XP-B and XP-D cells contained reduced amounts of TFIIH. Extracts prepared from XP-B and XP-D lymphoblastoid cells exhibited similar transcription activity from the adenovirus major late promoter when compared to that in extracts from normal cells. Thus, we conclude that the XP-B and XP-D lymphoblastoid cells do not have impaired RNA transcription activity. We consider the possible consequences of the reduced cellular content of TFIIH for the clinical symptoms in XP-B or XP-D patients, and discuss a 'conditional phenotype' that may involve an impairment of cellular function only under certain growth conditions. " ], "offsets": [ [ 0, 1528 ] ] } ]

[ { "id": "9427533_T1", "type": "Protein", "text": [ "XPA" ], "offsets": [ [ 293, 296 ] ], "normalized": [] }, { "id": "9427533_T2", "type": "Protein", "text": [ "XPG" ], "offsets": [ [ 305, 308 ] ], "normalized": [] }, { "id": "9427533_T3", "type": "Protein", "text": [ "XPB" ], "offsets": [ [ 324, 327 ] ], "normalized": [] }, { "id": "9427533_T4", "type": "Protein", "text": [ "XPD" ], "offsets": [ [ 332, 335 ] ], "normalized": [] }, { "id": "9427533_T5", "type": "Protein", "text": [ "XPB" ], "offsets": [ [ 554, 557 ] ], "normalized": [] }, { "id": "9427533_T6", "type": "Protein", "text": [ "XPD" ], "offsets": [ [ 561, 564 ] ], "normalized": [] }, { "id": "9427533_T7", "type": "Protein", "text": [ "XP-B" ], "offsets": [ [ 739, 743 ] ], "normalized": [] }, { "id": "9427533_T8", "type": "Protein", "text": [ "XP-D" ], "offsets": [ [ 747, 751 ] ], "normalized": [] }, { "id": "9427533_T9", "type": "Protein", "text": [ "XP-B" ], "offsets": [ [ 854, 858 ] ], "normalized": [] }, { "id": "9427533_T10", "type": "Protein", "text": [ "XP-D" ], "offsets": [ [ 863, 867 ] ], "normalized": [] }, { "id": "9427533_T11", "type": "Protein", "text": [ "XP-B" ], "offsets": [ [ 910, 914 ] ], "normalized": [] }, { "id": "9427533_T12", "type": "Protein", "text": [ "XP-D" ], "offsets": [ [ 919, 923 ] ], "normalized": [] }, { "id": "9427533_T13", "type": "Protein", "text": [ "XP-B" ], "offsets": [ [ 989, 993 ] ], "normalized": [] }, { "id": "9427533_T14", "type": "Protein", "text": [ "XP-D" ], "offsets": [ [ 998, 1002 ] ], "normalized": [] }, { "id": "9427533_T15", "type": "Protein", "text": [ "XP-B" ], "offsets": [ [ 1185, 1189 ] ], "normalized": [] }, { "id": "9427533_T16", "type": "Protein", "text": [ "XP-D" ], "offsets": [ [ 1194, 1198 ] ], "normalized": [] }, { "id": "9427533_T17", "type": "Protein", "text": [ "XP-B" ], "offsets": [ [ 1377, 1381 ] ], "normalized": [] }, { "id": "9427533_T18", "type": "Protein", "text": [ "XP-D" ], "offsets": [ [ 1385, 1389 ] ], "normalized": [] } ]

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[ { "id": "8628306__text", "type": "abstract", "text": [ "Identification of an inducible regulator of c-myb expression during T-cell activation. \nResting T cells express very low levels of c-Myb protein. During T-cell activation, c-myb expression is induced and much of the increase in expression occurs at the transcriptional level. We identified a region of the c-myb 5' flanking sequence that increased c-myb expression during T-cell activation. In vivo footprinting by ligation-mediated PCR was performed to correlate in vivo protein binding with functional activity. A protein footprint was visible over this region of the c-myb 5' flanking sequence in activated T cells but not in unactivated T cells. An electrophoretic mobility shift assay (EMSA) with nuclear extract from activated T cells and an oligonucleotide of this binding site demonstrated a new protein-DNA complex, referred to as CMAT for c-myb in activated T cells; this complex was not present in unactivated T cells. Because the binding site showed some sequence similarity with the nuclear factor of activated T cells (NFAT) binding site, we compared the kinetics of induction of the two binding complexes and the molecular masses of the two proteins. Studies of the kinetics of induction showed that the NFAT EMSA binding complex appeared earlier than the CMAT complex. The NFAT protein migrated more slowly in a sodium dodecyl sulfate-polyacrylamide gel than the CMAT protein did. In addition, an antibody against NFAT did not cross-react with the CMAT protein. The appearance of the CMAT binding complex was inhibited by both cyclosporin A and rapamycin. The CMAT protein appears to be a novel inducible protein involved in the regulation of c-myb expression during T-cell activation. " ], "offsets": [ [ 0, 1702 ] ] } ]

[ { "id": "8628306_T1", "type": "Protein", "text": [ "c-myb" ], "offsets": [ [ 44, 49 ] ], "normalized": [] }, { "id": "8628306_T2", "type": "Protein", "text": [ "c-Myb" ], "offsets": [ [ 131, 136 ] ], "normalized": [] }, { "id": "8628306_T3", "type": "Protein", "text": [ "c-myb" ], "offsets": [ [ 172, 177 ] ], "normalized": [] }, { "id": "8628306_T4", "type": "Protein", "text": [ "c-myb" ], "offsets": [ [ 306, 311 ] ], "normalized": [] }, { "id": "8628306_T5", "type": "Protein", "text": [ "c-myb" ], "offsets": [ [ 348, 353 ] ], "normalized": [] }, { "id": "8628306_T6", "type": "Protein", "text": [ "c-myb" ], "offsets": [ [ 570, 575 ] ], "normalized": [] }, { "id": "8628306_T7", "type": "Protein", "text": [ "c-myb" ], "offsets": [ [ 849, 854 ] ], "normalized": [] }, { "id": "8628306_T8", "type": "Protein", "text": [ "c-myb" ], "offsets": [ [ 1659, 1664 ] ], "normalized": [] } ]

[ { "id": "8628306_E1", "type": "Regulation", "trigger": { "text": [ "regulator" ], "offsets": [ [ 31, 40 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8628306_E2" } ] }, { "id": "8628306_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 50, 60 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8628306_T1" } ] }, { "id": "8628306_E3", "type": "Gene_expression", "trigger": { "text": [ "express" ], "offsets": [ [ 104, 111 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8628306_T2" } ] }, { "id": "8628306_E4", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 178, 188 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8628306_T3" } ] }, { "id": "8628306_E5", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 192, 199 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8628306_E4" } ] }, { "id": "8628306_E6", "type": "Positive_regulation", "trigger": { "text": [ "increased" ], "offsets": [ [ 338, 347 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8628306_E7" } ] }, { "id": "8628306_E7", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 354, 364 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8628306_T5" } ] }, { "id": "8628306_E8", "type": "Regulation", "trigger": { "text": [ "regulation" ], "offsets": [ [ 1645, 1655 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8628306_E9" } ] }, { "id": "8628306_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1665, 1675 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8628306_T8" } ] } ]

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[ { "id": "7542591__text", "type": "abstract", "text": [ "Distinct signaling properties identify functionally different CD4 epitopes. \nThe CD4 coreceptor interacts with non-polymorphic regions of major histocompatibility complex class II molecules on antigen-presenting cells and contributes to T cell activation. We have investigated the effect of CD4 triggering on T cell activating signals in a lymphoma model using monoclonal antibodies (mAb) which recognize different CD4 epitopes. We demonstrate that CD4 triggering delivers signals capable of activating the NF-AT transcription factor which is required for interleukin-2 gene expression. Whereas different anti-CD4 mAb or HIV-1 gp120 could all trigger activation of the protein tyrosine kinases p56lck and p59fyn and phosphorylation of the Shc adaptor protein, which mediates signals to Ras, they differed significantly in their ability to activate NF-AT. Lack of full activation of NF-AT could be correlated to a dramatically reduced capacity to induce calcium flux and could be complemented with a calcium ionophore. The results identify functionally distinct epitopes on the CD4 coreceptor involved in activation of the Ras/protein kinase C and calcium pathways. " ], "offsets": [ [ 0, 1165 ] ] } ]

[ { "id": "7542591_T1", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 62, 65 ] ], "normalized": [] }, { "id": "7542591_T2", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 81, 84 ] ], "normalized": [] }, { "id": "7542591_T3", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 291, 294 ] ], "normalized": [] }, { "id": "7542591_T4", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 415, 418 ] ], "normalized": [] }, { "id": "7542591_T5", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 449, 452 ] ], "normalized": [] }, { "id": "7542591_T6", "type": "Protein", "text": [ "interleukin-2" ], "offsets": [ [ 556, 569 ] ], "normalized": [] }, { "id": "7542591_T7", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 610, 613 ] ], "normalized": [] }, { "id": "7542591_T8", "type": "Protein", "text": [ "gp120" ], "offsets": [ [ 627, 632 ] ], "normalized": [] }, { "id": "7542591_T9", "type": "Protein", "text": [ "p56lck" ], "offsets": [ [ 694, 700 ] ], "normalized": [] }, { "id": "7542591_T10", "type": "Protein", "text": [ "p59fyn" ], "offsets": [ [ 705, 711 ] ], "normalized": [] }, { "id": "7542591_T11", "type": "Protein", "text": [ "CD4" ], "offsets": [ [ 1077, 1080 ] ], "normalized": [] }, { "id": "7542591_T15", "type": "Entity", "text": [ "epitopes" ], "offsets": [ [ 419, 427 ] ], "normalized": [] } ]

[ { "id": "7542591_E1", "type": "Binding", "trigger": { "text": [ "interacts" ], "offsets": [ [ 96, 105 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_T2" } ] }, { "id": "7542591_E2", "type": "Positive_regulation", "trigger": { "text": [ "triggering" ], "offsets": [ [ 295, 305 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_T3" } ] }, { "id": "7542591_E3", "type": "Binding", "trigger": { "text": [ "recognize" ], "offsets": [ [ 395, 404 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_T4" }, { "role": "Site", "ref_id": "7542591_T15" } ] }, { "id": "7542591_E4", "type": "Positive_regulation", "trigger": { "text": [ "triggering" ], "offsets": [ [ 453, 463 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_T5" } ] }, { "id": "7542591_E5", "type": "Positive_regulation", "trigger": { "text": [ "required" ], "offsets": [ [ 543, 551 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_E6" } ] }, { "id": "7542591_E6", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 575, 585 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_T6" } ] }, { "id": "7542591_E7", "type": "Positive_regulation", "trigger": { "text": [ "trigger" ], "offsets": [ [ 643, 650 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_E11" } ] }, { "id": "7542591_E8", "type": "Positive_regulation", "trigger": { "text": [ "trigger" ], "offsets": [ [ 643, 650 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_E12" } ] }, { "id": "7542591_E9", "type": "Positive_regulation", "trigger": { "text": [ "trigger" ], "offsets": [ [ 643, 650 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_E12" }, { "role": "Cause", "ref_id": "7542591_T8" } ] }, { "id": "7542591_E10", "type": "Positive_regulation", "trigger": { "text": [ "trigger" ], "offsets": [ [ 643, 650 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_E11" }, { "role": "Cause", "ref_id": "7542591_T8" } ] }, { "id": "7542591_E11", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 651, 661 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_T10" } ] }, { "id": "7542591_E12", "type": "Positive_regulation", "trigger": { "text": [ "activation" ], "offsets": [ [ 651, 661 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "7542591_T9" } ] } ]

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[ { "id": "9013974__text", "type": "abstract", "text": [ "Inhibitory effect of growth hormone on TNF-alpha secretion and nuclear factor-kappaB translocation in lipopolysaccharide-stimulated human monocytes. \nSeveral studies have pointed to a link between immune and endocrine systems, including a regulatory function of GH on monocyte activation. The present study demonstrates that human THP-1 promonocytic cells, engineered by gene transfer to constitutively produce human growth hormone (hGH), secreted depressed amounts of TNF-alpha in response to challenge by LPS. The effect of GH appears to occur in an autocrine fashion, since the inhibitory effect on TNF-alpha secretion by constitutive GH production could be abolished in the presence of anti-hGH mAb. The GH-induced inhibitory effect was also observed using normal human monocytes and monocyte-derived macrophages. Inhibition of TNF-alpha production by THP-1-hGH-transfected cells cultured in the presence of LPS is dependent on a selective pathway, since no inhibition of TNF-alpha production was observed when cells were cultured in the presence of PMA. Inhibition of TNF-alpha secretion by LPS-stimulated THP-1-hGH cells was associated with a decrease in nuclear translocation of nuclear factor-kappaB. The capacity of GH to inhibit LPS-induced TNF-alpha production by monocytes without altering other pathways leading to TNF-alpha production may be of potential relevance in septic shock, since GH is available for clinical use. " ], "offsets": [ [ 0, 1436 ] ] } ]

[ { "id": "9013974_T1", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 39, 48 ] ], "normalized": [] }, { "id": "9013974_T2", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 469, 478 ] ], "normalized": [] }, { "id": "9013974_T3", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 602, 611 ] ], "normalized": [] }, { "id": "9013974_T4", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 832, 841 ] ], "normalized": [] }, { "id": "9013974_T5", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 976, 985 ] ], "normalized": [] }, { "id": "9013974_T6", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1073, 1082 ] ], "normalized": [] }, { "id": "9013974_T7", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1251, 1260 ] ], "normalized": [] }, { "id": "9013974_T8", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 1328, 1337 ] ], "normalized": [] } ]

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[ { "id": "1944294__text", "type": "abstract", "text": [ "Evaluation of the role of ligand and thermal activation of specific DNA binding by in vitro synthesized human glucocorticoid receptor. \nWe have used a DNA-binding/immunoprecipitation assay to analyze the capacity of human glucocorticoid receptor (hGR), generated in rabbit reticulocyte lysates, to bind DNA. In vitro translated hGR was indistinguishable from native hGR, as determined by migration on sodium dodecyl sulfate-polyacrylamide gels, sedimentation on sucrose density gradients, and reactivity with antipeptide antibodies generated against hGR. In addition, cell-free synthesized hGR was capable of specific binding to glucocorticoid response element (GRE)-containing DNA fragments. Using this assay system, we have evaluated the contributions of ligand binding and heat activation to DNA binding by these glucocorticoid receptors. In vitro translated hGR was capable of selective DNA binding even in the absence of glucocorticoid. Treatment with dexamethasone or the antiglucocorticoid RU486 had no additional effect on the DNA-binding capacity when receptor preparations were maintained at 0 C (no activation). In contrast, addition of either ligand or antagonist in combination with a heat activation step promoted DNA binding by approximately 3-fold over that of heat-activated unliganded receptors. Agonist (dexamethasone) was slightly more effective in supporting specific DNA binding than antagonist (RU486). DNA binding by in vitro synthesized GR was blocked by the addition of sodium molybdate to the receptor preparations before steroid addition and thermal activation. Addition of KCl resulted in less DNA binding either due to blockage of DNA-receptor complex formation or disruption of the complexes. The specificity of DNA binding by cell-free synthesized hGR was analyzed further by examining the abilities of various DNAs to compete for binding to a naturally occurring GRE found in the mouse mammary tumor virus-long terminal repeat. Oligonucleotides containing the consensus GRE were the most efficient competitors, and fragments containing regulatory sequences from glucocorticoid-repressible genes were somewhat competitive, whereas single stranded oligonucleotides were unable to compete for mouse mammary tumor virus-long terminal repeat DNA binding, except when competitor was present at extremely high concentrations. Together these studies indicate that hGR synthesized in rabbit reticulocyte lysates displays many of the same properties, including GRE-specific DNA binding, observed for glucocorticoid receptor present in cytosolic extracts of mammalian cells and tissues. Similarities between the effects of dexamethasone and RU486 suggest that the antiglucocorticoid properties of RU486 do not occur at the level of specific DNA binding. " ], "offsets": [ [ 0, 2776 ] ] } ]

[]

[]

[]

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[ { "id": "8977297__text", "type": "abstract", "text": [ "A novel SP-1 site in the human interleukin-1 beta promoter confers preferential transcriptional activity in keratinocytes. \nTo investigate the mechanisms of transcriptional activation of interleukin-1beta (IL-1beta) in non-monocytic cells, we constructed a series of reporter plasmids with the bacterial chloramphenicol acetyltransferase gene linked to various parts of the human IL-1beta promoter and performed transient transfection experiments. We identified a promoter segment that activates transcription most efficiently in keratinocytes. Electrophoretic mobility shift assays (EMSA) with a 43-mer oligonucleotide derived from the functionally identified cis-acting element revealed specific complexes. By competition analysis with transcription factor consensus sequence oligonucleotides and by immunosupershift, transcription factor SP-1 or a closely related protein was shown to bind to this regulatory element. The closest match to the known SP-1 consensus sequence within the respective region is a TCCCCTCCCCT motif. Mutation of this motif almost completely, and specifically, abolished the binding of two low-mobility complexes and led to a 95% decrease of constitutive transcriptional activation of a reporter construct IL-1beta (-170/+108). Likewise, activation of this reporter construct by tumor necrosis factor-alpha depended on the SP-1 site. These observations suggest that a so-far-unrecognized SP-1 site in the human IL-1beta promoter may participate in the transcriptional regulation of this gene in keratinocytes. " ], "offsets": [ [ 0, 1538 ] ] } ]

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[ { "id": "8816424__text", "type": "abstract", "text": [ "Regulation of sialoadhesin expression on rat macrophages. Induction by glucocorticoids and enhancement by IFN-beta, IFN-gamma, IL-4, and lipopolysaccharide. \nSialoadhesin is a macrophage-restricted member of the Ig superfamily that mediates adhesion with lymphoid and myeloid cells. It is expressed on a subpopulation of macrophages in lymphoid tissues and in chronic inflammation (e.g., during autoimmune diseases). We have studied the regulation of sialoadhesin expression in vitro and show that glucocorticoids (GC) induce sialoadhesin expression on freshly isolated rat macrophages and the rat macrophage cell line R2. The cytokines IFN-beta, IFN-gamma, IL-4, and LPS, although unable to induce sialoadhesin expression by themselves, were able to enhance GC-mediated induction of sialoadhesin. Sialoadhesin expression was functional as shown by cell adhesion assays with human RBCs. Northern blotting experiments indicated that regulation predominantly occurred at the mRNA level. Comparison of the different combinations of GC and cytokines/LPS revealed differences in the level of GC-dependent enhancement of sialoadhesin expression, with IFN-beta and IL-4 being more potent than IFN-gamma and LPS. Moreover, the effects of IFN-gamma and LPS could be reproduced by priming, whereas IFN-beta and IL-4 were required simultaneously with GC. The regulation of sialoadhesin expression was mediated by the GC receptor, and not by mineralocorticoid receptor, as shown by inhibition experiments with specific antagonists. Finally, it is demonstrated that macrophages in the adrenal gland, the major site of endogenous GC production, express sialoadhesin. This study demonstrates that GC act as a primary inducer of sialoadhesin expression on rat macrophages, and that the response can be enhanced by IFN-beta, T cell-derived cytokines, or LPS. " ], "offsets": [ [ 0, 1842 ] ] } ]

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"enhanced" ], "offsets": [ [ 1786, 1794 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8816424_E38" }, { "role": "Cause", "ref_id": "8816424_T26" } ] } ]

[]

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[ { "id": "7534293__text", "type": "abstract", "text": [ "E2F-1 and a cyclin-like DNA repair enzyme, uracil-DNA glycosylase, provide evidence for an autoregulatory mechanism for transcription. \nThe cell cycle-dependent transcription factor, E2F-1, regulates the cyclin-like species of the DNA repair enzyme uracil-DNA glycosylase (UDG) gene in human osteosarcoma (Saos-2) cells. We demonstrate, through the deletion of the human UDG promoter sequences, that expression of E2F-1 activates the UDG promoter through several E2F sites. The major putative downstream site for E2F, located in the first exon, serves as a target for E2F-1/DP1 complex binding in vitro. We also provide evidence for the functional relationship between the cyclin-like UDG gene product and E2F. High levels of UDG expression in a transient transfection assay result in the down-regulation of transcriptional activity through elements specific for E2F-mediated transcription. Overexpression of UDG in Saos 2 cells was observed to delay growth late in G1 phase and transiently arrest these cells from progressing into the S phase. This hypothetical model integrates one mechanism of DNA repair with the cell cycle control of gene transcription, likely through E2F. This implicates E2F as a multifunctional target for proteins and enzymes, possibly, responsive to DNA damage through the negative effect of UDG on E2F-mediated transcriptional activity. " ], "offsets": [ [ 0, 1365 ] ] } ]

[ { "id": "7534293_T1", "type": "Protein", "text": [ "E2F-1" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "7534293_T2", "type": "Protein", "text": [ "uracil-DNA glycosylase" ], "offsets": [ [ 43, 65 ] ], "normalized": [] }, { "id": "7534293_T3", "type": "Protein", "text": [ "E2F-1" ], "offsets": [ [ 183, 188 ] ], "normalized": [] }, { "id": "7534293_T4", "type": "Protein", "text": [ "uracil-DNA glycosylase" ], "offsets": [ [ 249, 271 ] ], "normalized": [] }, { "id": "7534293_T5", "type": "Protein", "text": [ "UDG" ], "offsets": [ [ 273, 276 ] ], "normalized": [] }, { "id": "7534293_T6", "type": "Protein", "text": [ "UDG" ], "offsets": [ [ 371, 374 ] ], "normalized": [] }, { "id": "7534293_T7", "type": "Protein", "text": [ "E2F-1" ], "offsets": [ [ 414, 419 ] ], "normalized": [] }, { "id": "7534293_T8", "type": "Protein", "text": [ "UDG" ], "offsets": [ [ 434, 437 ] ], "normalized": [] }, { "id": "7534293_T9", "type": "Protein", "text": [ "E2F-1" ], "offsets": [ [ 568, 573 ] ], "normalized": [] }, { "id": "7534293_T10", "type": "Protein", "text": [ "DP1" ], "offsets": [ [ 574, 577 ] ], "normalized": [] }, { "id": "7534293_T11", "type": "Protein", "text": [ "UDG" ], "offsets": [ [ 685, 688 ] ], "normalized": [] }, { "id": "7534293_T12", "type": "Protein", "text": [ "UDG" ], "offsets": [ [ 726, 729 ] ], "normalized": [] }, { "id": "7534293_T13", "type": "Protein", "text": [ "UDG" ], "offsets": [ [ 909, 912 ] ], "normalized": [] }, { "id": "7534293_T14", "type": "Protein", "text": [ "UDG" ], "offsets": [ [ 1319, 1322 ] ], "normalized": [] }, { "id": "7534293_T18", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 438, 446 ] ], "normalized": [] } ]

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[]

[ { "id": "7569976__text", "type": "abstract", "text": [ "Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis [see comments] \nGlucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of almost all known cytokines and of several cell surface molecules required for immune function, but the mechanism underlying this activity has been unclear. Here it is shown that glucocorticoids are potent inhibitors of nuclear factor kappa B (NF-kappa B) activation in mice and cultured cells. This inhibition is mediated by induction of the I kappa B alpha inhibitory protein, which traps activated NF-kappa B in inactive cytoplasmic complexes. Because NF-kappa B activates many immunoregulatory genes in response to pro-inflammatory stimuli, the inhibition of its activity can be a major component of the anti-inflammatory activity of glucocorticoids. " ], "offsets": [ [ 0, 899 ] ] } ]

[ { "id": "7569976_T1", "type": "Protein", "text": [ "I kappa B alpha" ], "offsets": [ [ 587, 602 ] ], "normalized": [] } ]

[]

[]

[]

[ { "id": "8170476__text", "type": "abstract", "text": [ "Patterns of Pan expression and role of Pan proteins in endocrine cell type-specific complex formation. \nThe Pan gene encodes at least two distinct transcripts, Pan-1 and Pan-2 (also known as E47 and E12, respectively), by the mechanism of alternative RNA splicing. Northern blot analyses performed on rat and mouse tissues have detected ubiquitously expressed Pan transcripts, but the abundance, distribution, and form of Pan proteins have not been clearly defined. Studies of cell lines representing endocrine, fibroblast, and lymphoid lineages using polyclonal antisera to detect E2A proteins have suggested that significant E2A protein expression is restricted to B-lymphocytes. We have developed a monoclonal antibody, Yae, which is specific for Pan/E2A proteins, and have used the Yae antibody to examine a variety of endocrine and nonendocrine cell lineages for differences in Pan/E2A protein expression, subcellular localization, and heteromeric complex formation. In contrast to previous results obtained using polyclonal antiseras to detect Pan/E2A proteins, we report comparable levels of Pan proteins in GH/PRL- and insulin-producing, B- and T-lymphocyte cells. IEF-1, a pancreatic beta-cell type-specific complex believed to regulate insulin expression, is demonstrated to consist of at least two distinct species, one of which does not contain Pan molecules. Although it has been postulated that pituitary endocrine cells and pancreatic endocrine beta-cells share identical Pan/E2A complexes, native-Western analyses of pituitary and endocrine beta-cells detect Pan proteins in distinct cell type-specific complexes. " ], "offsets": [ [ 0, 1630 ] ] } ]

[ { "id": "8170476_T1", "type": "Protein", "text": [ "Pan" ], "offsets": [ [ 108, 111 ] ], "normalized": [] }, { "id": "8170476_T2", "type": "Protein", "text": [ "Pan-1" ], "offsets": [ [ 160, 165 ] ], "normalized": [] }, { "id": "8170476_T3", "type": "Protein", "text": [ "Pan-2" ], "offsets": [ [ 170, 175 ] ], "normalized": [] }, { "id": "8170476_T4", "type": "Protein", "text": [ "E47" ], "offsets": [ [ 191, 194 ] ], "normalized": [] }, { "id": "8170476_T5", "type": "Protein", "text": [ "E12" ], "offsets": [ [ 199, 202 ] ], "normalized": [] }, { "id": "8170476_T6", "type": "Protein", "text": [ "Pan" ], "offsets": [ [ 360, 363 ] ], "normalized": [] }, { "id": "8170476_T7", "type": "Protein", "text": [ "Pan" ], "offsets": [ [ 422, 425 ] ], "normalized": [] }, { "id": "8170476_T8", "type": "Protein", "text": [ "E2A" ], "offsets": [ [ 582, 585 ] ], "normalized": [] }, { "id": "8170476_T9", "type": "Protein", "text": [ "E2A" ], "offsets": [ [ 627, 630 ] ], "normalized": [] }, { "id": "8170476_T10", "type": "Protein", "text": [ "Pan" ], "offsets": [ [ 750, 753 ] ], "normalized": [] }, { "id": "8170476_T11", "type": "Protein", "text": [ "E2A" ], "offsets": [ [ 754, 757 ] ], "normalized": [] }, { "id": "8170476_T12", "type": "Protein", "text": [ "Pan" ], "offsets": [ [ 883, 886 ] ], "normalized": [] }, { "id": "8170476_T13", "type": "Protein", "text": [ "E2A" ], "offsets": [ [ 887, 890 ] ], "normalized": [] }, { "id": "8170476_T14", "type": "Protein", "text": [ "Pan" ], "offsets": [ [ 1050, 1053 ] ], "normalized": [] }, { "id": "8170476_T15", "type": "Protein", "text": [ "E2A" ], "offsets": [ [ 1054, 1057 ] ], "normalized": [] }, { "id": "8170476_T16", "type": "Protein", "text": [ "Pan" ], "offsets": [ [ 1099, 1102 ] ], "normalized": [] }, { "id": "8170476_T17", "type": "Protein", "text": [ "GH" ], "offsets": [ [ 1115, 1117 ] ], "normalized": [] }, { "id": "8170476_T18", "type": "Protein", "text": [ "insulin" ], "offsets": [ [ 1127, 1134 ] ], "normalized": [] }, { "id": "8170476_T19", "type": "Protein", "text": [ "insulin" ], "offsets": [ [ 1246, 1253 ] ], "normalized": [] }, { "id": "8170476_T20", "type": "Protein", "text": [ "Pan" ], "offsets": [ [ 1357, 1360 ] ], "normalized": [] }, { "id": "8170476_T21", "type": "Protein", "text": [ "Pan" ], "offsets": [ [ 1487, 1490 ] ], "normalized": [] }, { "id": "8170476_T22", "type": "Protein", "text": [ "E2A" ], "offsets": [ [ 1491, 1494 ] ], "normalized": [] }, { "id": "8170476_T23", "type": "Protein", "text": [ "Pan" ], "offsets": [ [ 1575, 1578 ] ], "normalized": [] } ]

[ { "id": "8170476_E1", "type": "Transcription", "trigger": { "text": [ "expressed" ], "offsets": [ [ 350, 359 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8170476_T6" } ] }, { "id": "8170476_E2", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 639, 649 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8170476_T9" } ] }, { "id": "8170476_E3", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 899, 909 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8170476_T12" } ] }, { "id": "8170476_E4", "type": "Binding", "trigger": { "text": [ "heteromeric complex formation" ], "offsets": [ [ 941, 970 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8170476_T12" } ] }, { "id": "8170476_E5", "type": "Gene_expression", "trigger": { "text": [ "comparable levels" ], "offsets": [ [ 1078, 1095 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8170476_T16" } ] }, { "id": "8170476_E6", "type": "Gene_expression", "trigger": { "text": [ "producing" ], "offsets": [ [ 1135, 1144 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8170476_T17" } ] }, { "id": "8170476_E7", "type": "Gene_expression", "trigger": { "text": [ "producing" ], "offsets": [ [ 1135, 1144 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8170476_T18" } ] }, { "id": "8170476_E8", "type": "Regulation", "trigger": { "text": [ "regulate" ], "offsets": [ [ 1237, 1245 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8170476_E9" } ] }, { "id": "8170476_E9", "type": "Gene_expression", "trigger": { "text": [ "expression" ], "offsets": [ [ 1254, 1264 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8170476_T19" } ] }, { "id": "8170476_E10", "type": "Gene_expression", "trigger": { "text": [ "detect" ], "offsets": [ [ 1568, 1574 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "8170476_T23" } ] } ]

[ { "id": "8170476_1", "entity_ids": [ "8170476_T3", "8170476_T5" ] }, { "id": "8170476_2", "entity_ids": [ "8170476_T2", "8170476_T4" ] } ]

[]

[ { "id": "10328874__text", "type": "abstract", "text": [ "Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. \nRecent studies have shown that the non-steroidal anti-inflammatory drugs (NSAIDs) activate heat shock transcription factor (HSF1) from a latent cytoplasmic form to a nuclear, DNA binding state. As HSF1 can function as both an activator of heat shock genes and a repressor of non-heat shock genes such as IL1B and c- fos, we have examined the potential role of HSF1 in the effects of NSAIDs on gene expression in a human monocytic cell line THP-1. We found that two members of the NSAIDs, sodium salicylate and sulindac repress the IL1B promoter to similar degree to heat shock or HSF1 overexpression. In addition, sodium salicylate and additional NSAIDs used at concentrations that activate HSF1 also inhibited the expression of other monocytic genes (TNF-alpha, IL-1beta, IL-6, IL-8, IL-10, ICAM-1) activated by exposure to a pro-inflammatory stimulus (lipopolysaccharide, LPS). At least in the case of the IL1B promoter, repression did not seem to involve another factor whose activity is affected by the NSAIDs, NFkappaB as the IL1B promoter fragment used in our studies is not NFkappaB responsive and binds specifically to HSF1. Exposure to NSAIDs had a complex effect on HSP gene expression and while sulindac activated the stress responsive HSP70B promoter, sodium salicylate did not. In addition, only a subset of the NSAIDs induced HSP70 mRNA species. These findings reflect the properties of HSF1 which can be activated to at least two DNA binding forms only one of which activates heat shock promoters and suggest that individual NSAID family members may differentially induce one or other of these forms. Overall therefore, exposure to NSAIDs leads to a profound switch in gene expression in monocytic cells, with suppression of genes involved in macrophage activation and induction of stress genes and HSF1 appears to play a regulatory role in these effects. Copyright 1999 Academic Press. " ], "offsets": [ [ 0, 2014 ] ] } ]

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"ref_id": "10328874_T41" } ] }, { "id": "10328874_E41", "type": "Positive_regulation", "trigger": { "text": [ "induced" ], "offsets": [ [ 1444, 1451 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10328874_T19" } ] }, { "id": "10328874_E42", "type": "Positive_regulation", "trigger": { "text": [ "activated" ], "offsets": [ [ 1531, 1540 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10328874_E43" } ] }, { "id": "10328874_E43", "type": "Binding", "trigger": { "text": [ "binding" ], "offsets": [ [ 1561, 1568 ] ] }, "arguments": [ { "role": "Theme", "ref_id": "10328874_T20" } ] } ]

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[ { "id": "10233879__text", "type": "abstract", "text": [ "Transcriptional targeting of retroviral vectors to the erythroblastic progeny of transduced hematopoietic stem cells. \nTargeted expression to specific tissues or cell lineages is a necessary feature of a gene therapy vector for many clinical applications, such as correction of hemoglobinopathies or thalassemias by transplantation of genetically modified hematopoietic stem cells. We developed retroviral vectors in which the constitutive viral enhancer in the U3 region of the 3' LTR is replaced by an autoregulatory enhancer of the erythroid-specific GATA-1 transcription factor gene. The replaced enhancer is propagated to the 5' LTR upon integration into the target cell genome. The modified vectors were used to transduce human hematopoietic cell lines, cord blood-derived CD34(+) stem/progenitor cells, and murine bone marrow repopulating stem cells. The expression of appropriate reporter genes (triangle upLNGFR, EGFP) was analyzed in the differentiated progeny of transduced stem cells in vitro, in liquid culture as well as in clonogenic assay, and in vivo, after bone marrow transplantation in lethally irradiated mice. The GATA-1 autoregulatory enhancer effectively restricts the expression of the LTR-driven proviral transcription unit to the erythroblastic progeny of both human progenitors and mouse-repopulating stem cells. Packaging of viral particles, integration into the target genome, and stability of the integrated provirus are not affected by the LTR modification. Enhancer replacement is therefore an effective strategy to target expression of a retroviral transgene to a specific progeny of transduced hematopoietic stem cells. " ], "offsets": [ [ 0, 1655 ] ] } ]

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[ { "id": "9060666__text", "type": "abstract", "text": [ "Alteration of a single serine in the basic domain of the Epstein-Barr virus ZEBRA protein separates its functions of transcriptional activation and disruption of latency. \nThe ZEBRA protein from Epstein-Barr virus (EBV) activates a switch from the latent to the lytic expression program of the virus. ZEBRA, a member of the bZIP family of DNA-binding proteins, is a transcriptional activator capable of inducing expression from viral lytic cycle promoters. It had previously been thought that ZEBRA's capacity to disrupt EBV latency resided primarily in its ability to activate transcription of genes that encode products required for lytic replication. We generated a point mutant of ZEBRA, Z(S186A), that was not impaired in its ability to activate transcription; however, this mutation abolished its ability to initiate the viral lytic cascade. The mutant, containing a serine-to-alanine substitution in the DNA-binding domain of the protein, bound to several known ZEBRA-binding sites and activated transcription from reporters bearing known ZEBRA-responsive promoters but did not disrupt latency in EBV-infected cell lines. Therefore, initiation of the EBV lytic cycle by the ZEBRA protein requires a function in addition to transcriptional activation; a change of serine 186 to alanine in the DNA-binding domain of ZEBRA abolished this additional function and uncovered a new role for the ZEBRA protein in disruption of EBV latency. The additional function that is required for initiation of the lytic viral life cycle is likely to require phosphorylation of serine 186 of the ZEBRA protein, which may influence either DNA recognition or transcriptional activation of lytic viral promoters in a chromatinized viral episome. " ], "offsets": [ [ 0, 1730 ] ] } ]

[ { "id": "9060666_T1", "type": "Protein", "text": [ "ZEBRA" ], "offsets": [ [ 76, 81 ] ], "normalized": [] }, { "id": "9060666_T2", "type": "Protein", "text": [ "ZEBRA" ], "offsets": [ [ 176, 181 ] ], "normalized": [] }, { "id": "9060666_T3", "type": "Protein", "text": [ "ZEBRA" ], "offsets": [ [ 301, 306 ] ], "normalized": [] }, { "id": "9060666_T4", "type": "Protein", "text": [ "ZEBRA" ], "offsets": [ [ 493, 498 ] ], "normalized": [] }, { "id": "9060666_T5", "type": "Protein", "text": [ "ZEBRA" ], "offsets": [ [ 685, 690 ] ], "normalized": [] }, { "id": "9060666_T6", "type": "Protein", "text": [ "ZEBRA" ], "offsets": [ [ 969, 974 ] ], "normalized": [] }, { "id": "9060666_T7", "type": "Protein", "text": [ "ZEBRA" ], "offsets": [ [ 1046, 1051 ] ], "normalized": [] }, { "id": "9060666_T8", "type": "Protein", "text": [ "ZEBRA" ], "offsets": [ [ 1181, 1186 ] ], "normalized": [] }, { "id": "9060666_T9", "type": "Protein", "text": [ "ZEBRA" ], "offsets": [ [ 1321, 1326 ] ], "normalized": [] }, { "id": "9060666_T10", "type": "Protein", "text": [ "ZEBRA" ], "offsets": [ [ 1395, 1400 ] ], "normalized": [] }, { "id": "9060666_T11", "type": "Protein", "text": [ "ZEBRA" ], "offsets": [ [ 1583, 1588 ] ], "normalized": [] }, { "id": "9060666_T13", "type": "Entity", "text": [ "serine 186" ], "offsets": [ [ 1565, 1575 ] ], "normalized": [] } ]

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[ { "id": "1527846__text", "type": "abstract", "text": [ "A novel Ets-related transcription factor, Elf-1, binds to human immunodeficiency virus type 2 regulatory elements that are required for inducible trans activation in T cells. \nHuman immunodeficiency virus type 1 (HIV-1) and HIV-2 are structurally related retroviruses which both cause AIDS in humans. Although both viruses establish latency in quiescent human-peripheral-blood T cells, the asymptomatic phase of HIV-2 infection may be more prolonged than that of HIV-1. The latent phases of both HIV-1 and HIV-2 infection have been shown to be disrupted by T-cell activation, a process that requires host cell transcription factors. In the case of HIV-1, the transcription factor NF-kappa B is sufficient for inducible transcriptional activation. In contrast, factors in addition to NF-kappa B are required to activate HIV-2 transcription in infected T cells. In this report, we demonstrate that a novel Ets-related transcription factor, Elf-1, binds specifically to two purine-rich motifs in the HIV-2 enhancer. Mutagenesis experiments demonstrated that these Elf-1 binding sites are required for induction of HIV-2 transcription following T-cell-receptor-mediated T-cell activation. Moreover, Elf-1 is the only factor present in activated T-cell nuclear extracts that binds to these sites in electrophoretic mobility shift assays. Thus, Elf-1 is a novel transcription factor that appears to be required for the T-cell-receptor-mediated trans activation of HIV-2 gene expression. These results may explain differences in the clinical spectra of diseases caused by HIV-1 and HIV-2 and may also have implications for the design of therapeutic approaches to HIV-2 infection. " ], "offsets": [ [ 0, 1673 ] ] } ]

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[ { "id": "8972869__text", "type": "abstract", "text": [ "Octamer independent activation of transcription from the kappa immunoglobulin germline promoter. \nPrevious analyses of immunoglobulin V region promoters has led to the discovery of a common octamer motif which is functionally important in the tissue-specific and developmentally regulated transcriptional activation of immunoglobulin genes. The germline promoters (Ko) located upstream of the J region gene segments of the kappa locus also contain an octamer motif (containing a single base pair mutation and referred to as the variant octamer) which has been shown previously to bind Oct-1 and Oct-2 transcription factors in vitro. To further elucidate the role of this variant octamer motif in the regulation of germline transcription from the unrearranged kappa locus, we have quantitated the relative binding affinity of Oct-1 and Oct-2 for the variant octamer motif and determined the functional role of this octamer motif in transcriptional activation. We find that, although the variant octamer motif binds Oct-1 and Oct-2 in vitro with 5-fold lower affinity than the consensus octamer motif, mutation of the variant octamer motif to either a consensus octamer or non-octamer motif has no effect on transcriptional activation from the germline promoter. We also find significant differences in activation of germline and V region promoters by kappa enhancers. Our results suggest that the germline promoters and V region promoters differ in their dependence on octamer for activation and respond differently to enhancer activation. These findings have important implications in regulation of germline transcription as well as concomitant activation of the V-J recombination of the kappa light chain locus. " ], "offsets": [ [ 0, 1713 ] ] } ]

[ { "id": "8972869_T1", "type": "Protein", "text": [ "Oct-1" ], "offsets": [ [ 585, 590 ] ], "normalized": [] }, { "id": "8972869_T2", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 595, 600 ] ], "normalized": [] }, { "id": "8972869_T3", "type": "Protein", "text": [ "Oct-1" ], "offsets": [ [ 825, 830 ] ], "normalized": [] }, { "id": "8972869_T4", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 835, 840 ] ], "normalized": [] }, { "id": "8972869_T5", "type": "Protein", "text": [ "Oct-1" ], "offsets": [ [ 1014, 1019 ] ], "normalized": [] }, { "id": "8972869_T6", "type": "Protein", "text": [ "Oct-2" ], "offsets": [ [ 1024, 1029 ] ], "normalized": [] } ]

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[ { "id": "1531412__text", "type": "abstract", "text": [ "Transcriptional regulation during T-cell development: the alpha TCR gene as a molecular model. \nThe regulation of gene expression during lymphocyte differentiation is a complex process involving interactions between multiple positive and negative transcriptional regulatory elements. In this article, transcriptional regulation of the archetypal T-cell-specific gene, alpha TCR, is discussed. Major recent developments, including the identification of novel families of transcription factors that regulate multiple T-cell genes during thymocyte ontogeny and T-cell activation, are described. " ], "offsets": [ [ 0, 592 ] ] } ]

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[ { "id": "8543841__text", "type": "abstract", "text": [ "IL-10 cooperates with TNF-alpha to activate HIV-1 from latently and acutely infected cells of monocyte/macrophage lineage. \nIL-10 is elevated in HIV-1-infected individuals and has been implicated in disease progression. In this study, we investigated the effects of IL-10 on the activation of HIV-1 from infected monocytes and macrophages. Although IL-10 alone did not induce HIV-1 replication, in the presence of TNF-alpha, IL-10 markedly enhanced virion production from a chronically infected promonocytic cell line (U1) and in acutely infected monocyte-derived macrophages. Neutralizing mAbs to IL-10 and TNF-alpha indicated that both cytokines were essential for the induction and were required to generate a synergistic increase in virus expression. The effects of the two cytokines were distinguishable functionally since pretreatment with TNF-alpha attenuated the cytokine cooperativity, while pretreatment with IL-10 potentiated their cooperativity, suggesting that IL-10 and TNF-alpha play different roles in the activation of virus. Northern blot analysis as well as Ab blocking and cytokine secretion studies indicated that the induction of either endogenous TNF-alpha or IL-10 was not involved in the cooperativity, nor was an up-regulation of TNF-alpha receptors. In combination with TNF-alpha, IL-10 stimulated activating protein-1 (AP-1) and nuclear factor (NF)-kappa B binding activities and cooperated to increase HIV-1 steady-state mRNA levels and enhance long terminal repeat-directed transcription through activation of the NF-kappa B binding sites, suggesting the IL-10 effect occurs at least in part at the transcriptional level. These results indicate that IL-10, in addition to down-regulating the cellular immune response to HIV-1, may also play a role in TNF-alpha-mediated activation of HIV-1 replication in the monocyte/macrophage lineage. " ], "offsets": [ [ 0, 1868 ] ] } ]

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[ { "id": "7848679__text", "type": "abstract", "text": [ "Association of alterations in NF-kappa B moieties with HIV type 1 proviral latency in certain monocytic cells. \nHuman immunodeficiency virus type 1 (HIV-1) replication is controlled by a complex array of virally encoded and cellular proteins. A wide spectrum of levels of HIV-1 expression have been demonstrated in various cells, both in cell culture and in vivo. Molecular mechanisms leading to restricted HIV-1 replication may differ between certain cell types. It is now demonstrated that HIV-1 proviral latency in the monocytic cell line U1, in which only extremely low levels of HIV-1 expression are detected in the baseline unstimulated state, is associated with alterations in nuclear factor-kappa B (NF-kappa B) moieties demonstrated in these cells by electrophoretic mobility shift assays (EMSAs) and in situ UV cross-linking studies. A predominance of p50 NF-kappa B moieties and possibly p50 homodimers or closely related species, rather than the p50-p56 heterodimer of NF-kappa B that is the predominant NF-kappa B species in most T lymphocytic and monocytic cells, is demonstrated in the nuclei of U1 cells. This pattern of NF-kappa B-related moieties differs from the latently infected T lymphocytic cell line ACH-2, and from the U937 monocytic line, the parental cell line of the U1 cellular clone. As such, these data suggest that different proximal mechanisms may lead to restricted HIV-1 replication in various cell types. " ], "offsets": [ [ 0, 1441 ] ] } ]

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[ { "id": "9680181__text", "type": "abstract", "text": [ "Redox signals and NF-kappaB activation in T cells. \nAccumulating data from a number of laboratories have recently indicated that the response of transcription factor NF-kappaB to alterations in the redox homeostasis of cells may play an important role in modulating immune function. The activation of NF-kappaB has been recognized to regulate a number of genes necessary for normal T cell responses including IL-2, IL-6, IL-8, and several T cell surface receptors. Diminished NF-kappaB activity has been shown to occur in T cells with aging, suggesting that impaired activation of NF-kappaB might occur during cellular senescence. In addition, aberrancies in NF-kappaB activity have been implicated in the immunopathogenesis of diseases involving immune or inflammatory processes such as atherosclerosis and HIV-1 infection. The role of H2O2 and other reactive oxygen species (ROS) as an integratory secondary messenger for divergent T cell signals has been complicated by the fact that various T cell lines and peripheral blood T cells differ markedly in the levels of NF-kappaB activation induced by oxidant stress. Additionally, proposed pathways of NF-kappaB activation have been based on indirect evidence provided by experiments which used antioxidants to inhibit active NF-kappaB formation. Further, complete activation of T cells requires at least two signals, one that stimulates an increase in intracellular calcium and one that stimulates enzymatic processes including kinases. Similarly, substantial evidence indicates that full activation of NF-kappaB requires dual signals. The ability of H2O2 or other ROS to induce T cell signals and functional responses by these two mechanisms is reviewed and the specific response of NF-kappaB to redox changes in T cells is examined. Data are also presented to suggest that the redox regulation in NF-kappaB activation may be relevant to immune-related diseases and to aging. " ], "offsets": [ [ 0, 1929 ] ] } ]

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[ { "id": "10477716__text", "type": "abstract", "text": [ "Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation. \nTumor necrosis factor alpha (TNFalpha) is a pluripotent activator of inflammation by inducing a proinflammatory cytokine cascade. This phenomenon is mediated, in part, through inducible expression of the CXC chemokine, interleukin-8 (IL-8). In this study, we investigate the role of TNFalpha-inducible reactive oxygen species (ROS) in IL-8 expression by \"monocyte-like\" U937 histiocytic lymphoma cells. TNFalpha is a rapid activator of IL-8 gene expression by U937, producing a 50-fold induction of mRNA within 1 hour of treatment. In gene transfection assays, the effect of TNFalpha requires the presence of an inducible nuclear factor-kappaB (NF-kappaB) (Rel A) binding site in the IL-8 promoter. TNFalpha treatment induces a rapid translocation of the 65 kD transcriptional activator NF-kappaB subunit, Rel A, whose binding in the nucleus occurs before changes in intracellular ROS. Pretreatment (or up to 15 minutes posttreatment) relative to TNFalpha with the antioxidant dimethyl sulfoxide (DMSO) (2% [vol/vol]) blocks 80% of NF-kappaB-dependent transcription. Surprisingly, however, DMSO has no effect on inducible Rel A binding. Similar selective effects on NF-kappaB transcription are seen with the unrelated antioxidants, N-acetylcysteine (NAC) and vitamin C. These data indicate that TNFalpha induces a delayed ROS-dependent signalling pathway that is required for NF-kappaB transcriptional activation and is separable from that required for its nuclear translocation. Further definition of this pathway will yield new insights into inflammation initiated by TNFalpha signalling. " ], "offsets": [ [ 0, 1793 ] ] } ]

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[ { "id": "10477716_1", "entity_ids": [ "10477716_T5", "10477716_T6" ] }, { "id": "10477716_2", "entity_ids": [ "10477716_T3", "10477716_T4" ] } ]

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[ { "id": "9834081__text", "type": "abstract", "text": [ "Signaling pathways mediated by the TNF- and cytokine-receptor families target a common cis-element of the IFN regulatory factor 1 promoter. \nCD40 activation of B cells is strongly influenced by the presence of cytokines. However, the molecular basis for the interplay between these distinct stimuli is not clearly delineated. IFN regulatory factor 1 (IRF-1) is a transcription factor activated by either CD40 or cytokines. We have found that these different sets of signals target a common cis-acting element in the promoter of this gene, the IRF-1 gamma-activated site (GAS). Targeting of the IRF-1 GAS is not confined to activation via CD40 but extends to other stimuli that mimic the CD40 signaling cascade, like TNF-alpha and EBV. In contrast to induction of STATs by cytokines, the IRF-1 GAS-binding complex activated by CD40, TNF-alpha, or EBV contains Rel proteins, specifically p50 and p65. In this system, simultaneous exposure to CD40L together with either IL-4 or IFN-gamma does not lead to the activation of novel Rel/STAT complexes. Given the importance of IRF-1 in a variety of biologic functions from proliferation to apoptosis, our findings support the notion that modulation of IRF-1 levels may be a critical control point in B cell activation. " ], "offsets": [ [ 0, 1262 ] ] } ]

[ { "id": "9834081_T1", "type": "Protein", "text": [ "IFN regulatory factor 1" ], "offsets": [ [ 106, 129 ] ], "normalized": [] }, { "id": "9834081_T2", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 141, 145 ] ], "normalized": [] }, { "id": "9834081_T3", "type": "Protein", "text": [ "IFN regulatory factor 1" ], "offsets": [ [ 326, 349 ] ], "normalized": [] }, { "id": "9834081_T4", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 351, 356 ] ], "normalized": [] }, { "id": "9834081_T5", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 404, 408 ] ], "normalized": [] }, { "id": "9834081_T6", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 543, 548 ] ], "normalized": [] }, { "id": "9834081_T7", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 594, 599 ] ], "normalized": [] }, { "id": "9834081_T8", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 638, 642 ] ], "normalized": [] }, { "id": "9834081_T9", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 687, 691 ] ], "normalized": [] }, { "id": "9834081_T10", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 716, 725 ] ], "normalized": [] }, { "id": "9834081_T11", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 787, 792 ] ], "normalized": [] }, { "id": "9834081_T12", "type": "Protein", "text": [ "CD40" ], "offsets": [ [ 826, 830 ] ], "normalized": [] }, { "id": "9834081_T13", "type": "Protein", "text": [ "TNF-alpha" ], "offsets": [ [ 832, 841 ] ], "normalized": [] }, { "id": "9834081_T14", "type": "Protein", "text": [ "p50" ], "offsets": [ [ 886, 889 ] ], "normalized": [] }, { "id": "9834081_T15", "type": "Protein", "text": [ "p65" ], "offsets": [ [ 894, 897 ] ], "normalized": [] }, { "id": "9834081_T16", "type": "Protein", "text": [ "CD40L" ], "offsets": [ [ 940, 945 ] ], "normalized": [] }, { "id": "9834081_T17", "type": "Protein", "text": [ "IL-4" ], "offsets": [ [ 967, 971 ] ], "normalized": [] }, { "id": "9834081_T18", "type": "Protein", "text": [ "IFN-gamma" ], "offsets": [ [ 975, 984 ] ], "normalized": [] }, { "id": "9834081_T19", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 1070, 1075 ] ], "normalized": [] }, { "id": "9834081_T20", "type": "Protein", "text": [ "IRF-1" ], "offsets": [ [ 1195, 1200 ] ], "normalized": [] }, { "id": "9834081_T22", "type": "Entity", "text": [ "promoter" ], "offsets": [ [ 130, 138 ] ], "normalized": [] } ]

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[ { "id": "9047238__text", "type": "abstract", "text": [ "c-Rel is a target of pentoxifylline-mediated inhibition of T lymphocyte activation. \nThe possible clinical use of the methyl xanthine derivative, pentoxifylline (PF), for the treatment of T cell-dependent diseases is being noted with increasing interest. In this paper, we studied the molecular consequences of PF treatment during lymphocyte activation. We found that in T cells, anti-CD3-induced c-Rel expression was blocked by PF, whereas the induction of other NF-kappaB family members was not significantly affected. However, induction of NF-AT, which has the same signaling requirements as c-Rel induction, was not inhibited by PF. Among genes that respond to these transcription factors, IL-2 mRNA induction was suppressed by PF, whereas IL-2R(alpha) chain mRNA induction was not affected. These observations implicated c-Rel as an IL-2 promoter factor, for which experimental support was obtained from transient transfection experiments. In contrast with the observation in T cells, c-Rel induction was not blocked by PF in B cells. The greater selectivity of PF, compared with FK506, at both the molecular and cellular levels may prove advantageous in manipulating T cell responses in vivo. " ], "offsets": [ [ 0, 1199 ] ] } ]

[ { "id": "9047238_T1", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "9047238_T2", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 397, 402 ] ], "normalized": [] }, { "id": "9047238_T3", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 595, 600 ] ], "normalized": [] }, { "id": "9047238_T4", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 694, 698 ] ], "normalized": [] }, { "id": "9047238_T5", "type": "Protein", "text": [ "IL-2R(alpha) chain" ], "offsets": [ [ 744, 762 ] ], "normalized": [] }, { "id": "9047238_T6", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 826, 831 ] ], "normalized": [] }, { "id": "9047238_T7", "type": "Protein", "text": [ "IL-2" ], "offsets": [ [ 838, 842 ] ], "normalized": [] }, { "id": "9047238_T8", "type": "Protein", "text": [ "c-Rel" ], "offsets": [ [ 990, 995 ] ], "normalized": [] } ]

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[ { "id": "10209041__text", "type": "abstract", "text": [ "GrpL, a Grb2-related adaptor protein, interacts with SLP-76 to regulate nuclear factor of activated T cell activation. \nPropagation of signals from the T cell antigen receptor (TCR) involves a number of adaptor molecules. SH2 domain-containing protein 76 (SLP-76) interacts with the guanine nucleotide exchange factor Vav to activate the nuclear factor of activated cells (NF-AT), and its expression is required for normal T cell development. We report the cloning and characterization of a novel Grb2-like adaptor molecule designated as Grb2-related protein of the lymphoid system (GrpL). Expression of GrpL is restricted to hematopoietic tissues, and it is distinguished from Grb2 by having a proline-rich region. GrpL can be coimmunoprecipitated with SLP-76 but not with Sos1 or Sos2 from Jurkat cell lysates. In contrast, Grb2 can be coimmunoprecipitated with Sos1 and Sos2 but not with SLP-76. Moreover, tyrosine-phosphorylated LAT/pp36/38 in detergent lysates prepared from anti-CD3 stimulated T cells associated with Grb2 but not GrpL. These data reveal the presence of distinct complexes involving GrpL and Grb2 in T cells. A functional role of the GrpL-SLP-76 complex is suggested by the ability of GrpL to act alone or in concert with SLP-76 to augment NF-AT activation in Jurkat T cells. " ], "offsets": [ [ 0, 1299 ] ] } ]

[ { "id": "10209041_T1", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 0, 4 ] ], "normalized": [] }, { "id": "10209041_T2", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 8, 12 ] ], "normalized": [] }, { "id": "10209041_T3", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 53, 59 ] ], "normalized": [] }, { "id": "10209041_T4", "type": "Protein", "text": [ "SH2 domain-containing protein 76" ], "offsets": [ [ 222, 254 ] ], "normalized": [] }, { "id": "10209041_T5", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 256, 262 ] ], "normalized": [] }, { "id": "10209041_T6", "type": "Protein", "text": [ "Vav" ], "offsets": [ [ 318, 321 ] ], "normalized": [] }, { "id": "10209041_T7", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 497, 501 ] ], "normalized": [] }, { "id": "10209041_T8", "type": "Protein", "text": [ "Grb2-related protein of the lymphoid system" ], "offsets": [ [ 538, 581 ] ], "normalized": [] }, { "id": "10209041_T9", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 583, 587 ] ], "normalized": [] }, { "id": "10209041_T10", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 604, 608 ] ], "normalized": [] }, { "id": "10209041_T11", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 678, 682 ] ], "normalized": [] }, { "id": "10209041_T12", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 716, 720 ] ], "normalized": [] }, { "id": "10209041_T13", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 754, 760 ] ], "normalized": [] }, { "id": "10209041_T14", "type": "Protein", "text": [ "Sos1" ], "offsets": [ [ 774, 778 ] ], "normalized": [] }, { "id": "10209041_T15", "type": "Protein", "text": [ "Sos2" ], "offsets": [ [ 782, 786 ] ], "normalized": [] }, { "id": "10209041_T16", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 826, 830 ] ], "normalized": [] }, { "id": "10209041_T17", "type": "Protein", "text": [ "Sos1" ], "offsets": [ [ 864, 868 ] ], "normalized": [] }, { "id": "10209041_T18", "type": "Protein", "text": [ "Sos2" ], "offsets": [ [ 873, 877 ] ], "normalized": [] }, { "id": "10209041_T19", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 891, 897 ] ], "normalized": [] }, { "id": "10209041_T20", "type": "Protein", "text": [ "LAT" ], "offsets": [ [ 933, 936 ] ], "normalized": [] }, { "id": "10209041_T21", "type": "Protein", "text": [ "pp36/38" ], "offsets": [ [ 937, 944 ] ], "normalized": [] }, { "id": "10209041_T22", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 1024, 1028 ] ], "normalized": [] }, { "id": "10209041_T23", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 1037, 1041 ] ], "normalized": [] }, { "id": "10209041_T24", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 1106, 1110 ] ], "normalized": [] }, { "id": "10209041_T25", "type": "Protein", "text": [ "Grb2" ], "offsets": [ [ 1115, 1119 ] ], "normalized": [] }, { "id": "10209041_T26", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 1157, 1161 ] ], "normalized": [] }, { "id": "10209041_T27", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 1162, 1168 ] ], "normalized": [] }, { "id": "10209041_T28", "type": "Protein", "text": [ "GrpL" ], "offsets": [ [ 1208, 1212 ] ], "normalized": [] }, { "id": "10209041_T29", "type": "Protein", "text": [ "SLP-76" ], "offsets": [ [ 1245, 1251 ] ], "normalized": [] }, { "id": "10209041_T36", "type": "Entity", "text": [ "tyrosine" ], "offsets": [ [ 909, 917 ] ], "normalized": [] } ]

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[ { "id": "10487715__text", "type": "abstract", "text": [ "Increased IkappaB expression and diminished nuclear NF-kappaB in human mononuclear cells following hydrocortisone injection. \nWe have recently demonstrated that hydrocortisone and other glucocorticoids inhibit reactive oxygen species (ROS) generation by mononuclear (MNC) and polymorphonuclear leucocytes (PMNL). Since NF-kappaB/IkappaB system regulates the transcription of proinflammatory genes, including those responsible for ROS generation, we tested the hypothesis that hydrocortisone may stimulate IkappaB production thus inhibiting NF-kappaB translocation from the cytosol into the nucleus in MNC, in vivo. One hundred milligram of hydrocortisone was injected intravenously into 4 normal subjects. Blood samples were obtained prior to the injection and at 1, 2, 4, 8 and 24 hr after the injection. Nuclear extracts and total cell lysates were prepared from MNC by standard techniques. IkappaB levels in MNC homogenates increased at 1 hr, peaked at 2-4 hr, started to decrease at 8 hr, and returned to baseline levels at 24 hr. NF-kappaB in MNC nuclear extracts decreased at 1 hr, reached a nadir at 4 hr, gradually increased at 8 hr and returned back to baseline levels at 24 hr. The total protein content of NF-kappaB subunit (P65) in MNC lysates also showed a decrease following hydrocortisone injection. This decrease was observed at 2 hr, reached a nadir at 4 hr, and returned to baseline levels at 24 hr. ROS generation inhibition paralleled NF-kappaB levels in the nucleus. It was inhibited at 1 hr, reached a nadir at 2-4 hr, started to increase at 8 hr, and returned to basal levels at 24 hr. Our data demonstrate that hydrocortisone induces IkappaB and suppresses NF-kappaB expression in MNC in parallel. IkappaB further reduces the translocation of NF-kappaB into the nucleus thus preventing the expression of proinflammatory genes. " ], "offsets": [ [ 0, 1851 ] ] } ]

[ { "id": "10487715_T1", "type": "Protein", "text": [ "P65" ], "offsets": [ [ 1236, 1239 ] ], "normalized": [] } ]

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