Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human class II MHC Ag are a family of cell surface glycoproteins. Their constitutive expression is limited to B lymphocytes and thymic epithelial cells. In many other cells their expression can be induced by IFN-gamma. Conserved upstream promoter sequences regulate this tissue-specific expression of class II genes. In the DRA promoter, one of these cis-acting regulatory motifs is the X2-box to which nuclear factor X2 (NF-X2) binds. Here, we present the isolation and characterization of the full-length cDNA clone encoding NF-X2. This cDNA clone was isolated by expression cDNA cloning, and encodes the human c-Jun protein, which together with c-Fos forms the heterodimeric activator protein-1 transcription complex. Whereas c-Fos/c-Jun heterodimers do not exist in B cells, they form and bind to the X2-box in class II nonexpressing cells. Thus, c-Fos/c-Jun heterodimers might contribute to the repression of DRA gene expression.
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PMID:NF-X2 that binds to the DRA X2-box is activator protein 1. Expression cloning of c-Jun. 170 11

Mouse MHC class I-specific mAbs recognizing the alpha 1/alpha 2, but not those directed against the alpha 3 domain of the molecule, inhibited RNA, protein, and DNA synthesis of splenic T cells in response to stimulation through the TCR/CD3 complex. Similar inhibition was seen with LFA-1-specific mAbs under the same stimulation conditions. The effect of class I- and LFA-1-specific mAbs reflected a decrease of both IL-2 and IFN-gamma synthesis and IL-2 receptor alpha chain induction. IL-2, IL-2 receptor alpha chain, IFN-gamma, c-fos, c-jun, and c-myc mRNAs were not detected. Activation of AP-1 (c-Fos and c-Jun proteins) and NF-kappa B transcription factors were also inhibited. Inhibition was observed both after treatment of cells in culture and after intravenous injection of Abs in mice. Although bulk phosphorylation was inhibited, early tyrosine phosphorylation and calcium ion influx were normally induced. Protein phosphatase inhibitors did not reverse this inhibition, ruling out an enhanced activation of these enzymes in the observed inhibition. Cell surface expression of one of early PKC activation marker, CD69 was also inhibited. Phorbol esters that directly activate PKC prevented inhibition. Thus, class I molecules are implicated in signal transduction involved at an early stage for T cell activation in a manner that suggests their implication in accessory signal transmission that contributes to the regulation of PKC activity.
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PMID:MHC class I molecules are implicated in costimulatory signals during TCR/CD3-induced activation. 859 31

It has been demonstrated that CNS levels of the cytokine IFN-gamma are elevated in association with a number of neuro-inflammatory diseases. In the present study, we have examined the effect of this cytokine on human brain derived cells. We show that prolonged treatment (22 h) of such cells with IFN-gamma inhibits the DNA binding activity of transcription factor AP-1. Furthermore, we show that this effect can be reversed by either N(G)-monomethyl-L-arginine (L-NMMA) or L-N5-(1-iminoethyl)ornithine (L-NIO), competitive inhibitors of nitric oxide synthase activity [Rees et al., 1990]. In addition, we show that treatment of brain-derived cells with the nitric oxide donor 3-morpholinosydnonimine, HCl (SIN-1), or [N-(b-D-glucopyranosyl)-N2-acetyl-S-nitroso-D,L-penicillaminamide] (glyco-SNAP-1), also inhibits the binding activity of AP-1. Together, these results suggest that IFN-gamma can inhibit AP-1 binding activity through a nitric oxide dependent mechanism.
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PMID:IFN-gamma inhibits AP-1 binding activity in human brain-derived cells through a nitric oxide dependent mechanism. 968 22

The expression of inducible nitric oxide synthase (iNOS) by macrophages is stimulated by coexposure to IFN-gamma and a number of stimuli, including TNF-alpha. Recent work has shown that TNF-alpha activates members of the mitogen-activated protein kinase family that subsequently trans-activate transcription factors implicated in the regulation of iNOS expression. The objective of this study was to systematically evaluate the role of: 1) p42mapk/erk2, 2) p46 c-Jun NH2-terminal kinase/stress-activated protein kinase (p46 JNK/SAPK), and 3) p38mapk in the induction of iNOS expression during costimulation of mouse macrophages with IFN-gamma and TNF-alpha. All three kinases were activated during costimulation with IFN-gamma and TNF-alpha. However, specific antagonism of the p42mapk/erk2 and p38mapk with PD98059 and SKF86002, respectively, had no effect on the induction of iNOS expression. In contrast, blockade of all three kinases with N-acetylcysteine completely blocked the induction of iNOS expression. In addition, specific antagonism of the JNK/SAPK upstream kinases MEKK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase) and MKK4 (mitogen-activated protein kinase kinase 4) with dominant inhibitory mutants blocked transcriptional activation of the iNOS promoter in response to costimulation with IFN-gamma and TNF-alpha. Collectively, these findings support the involvement of p46 JNK/SAPK and its upstream kinases in regulating the induction of iNOS following ligation of the TNF-alpha receptor CD120a (p55) in the presence of IFN-gamma.
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PMID:Evaluation of the role of mitogen-activated protein kinases in the expression of inducible nitric oxide synthase by IFN-gamma and TNF-alpha in mouse macrophages. 988 15

A toxic dose of the nitric oxide (NO) donor S-nitrosoglutathione (GSNO; 1 mM) promoted apoptotic cell death of RAW 264.7 macrophages, which was attenuated by cellular preactivation with a nontoxic dose of GSNO (200 microM) or with lipopolysaccharide, interferon-gamma, and NG-monomethyl-L-arginine (LPS/IFN-gamma/NMMA) for 15 h. Protection from apoptosis was achieved by expression of cyclooxygenase-2 (Cox-2). Here we investigated the underlying mechanisms leading to Cox-2 expression. LPS/IFN-gamma/NMMA prestimulation activated nuclear factor (NF)-kappaB and promoted Cox-2 expression. Cox-2 induction by low-dose GSNO demanded activation of both NF-kappaB and activator protein-1 (AP-1). NF-kappaB supershift analysis implied an active p50/p65 heterodimer, and a luciferase reporter construct, containing four copies of the NF-kappaB site derived from the murine Cox-2 promoter, confirmed NF-kappaB activation after NO addition. An NF-kappaB decoy approach abrogated not only Cox-2 expression after low-dose NO or after LPS/IFN-gamma/NMMA but also inducible protection. The importance of AP-1 for Cox-2 expression and cell protection by low-level NO was substantiated by using the extracellular signal-regulated kinase inhibitor PD98059, blocking NO-elicited Cox-2 expression, but leaving the cytokine signal unaltered. Transient transfection of a dominant-negative c-Jun mutant further attenuated Cox-2 expression by low-level NO. Whereas cytokine-mediated Cox-2 induction relies on NF-kappaB activation, a low-level NO-elicited Cox-2 response required activation of both NF-kappaB and AP-1.
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PMID:NF-kappaB and AP-1 activation by nitric oxide attenuated apoptotic cell death in RAW 264.7 macrophages. 995 Jun 82

Interleukin (IL)-18 is functionally similar to IL-12 in mediating T helper cell type 1 (Th1) response and natural killer (NK) cell activity but is related to IL-1 in protein structure and signaling, including recruitment of IL-1 receptor-associated kinase (IRAK) to the receptor and activation of c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-kappaB. The role of IRAK in IL-18-induced responses was studied in IRAK-deficient mice. Significant defects in JNK induction and partial impairment in NF-kappaB activation were found in IRAK-deficient Th1 cells, resulting in a dramatic decrease in interferon (IFN)-gamma mRNA expression. In vivo Th1 response to Propionibacterium acnes and lipopolysaccharide in IFN-gamma production and induction of NK cytotoxicity by IL-18 were severely impaired in IRAK-deficient mice. IFN-gamma production by activated NK cells in an acute murine cytomegalovirus infection was significantly reduced despite normal induction of NK cytotoxicity. These results demonstrate that IRAK plays an important role in IL-18-induced signaling and function.
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PMID:Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. 1019 Sep 4

Optimal T cell activation requires two signals, one generated by TCR and another by the CD28 costimulatory receptor. In this study, we investigated the regulation of costimulation-induced mitogen-activated protein kinase (MAPK) activation in primary mouse T cells. In contrast to that reported for human Jurkat T cells, we found that p38 MAPK, but not Jun NH2-terminal kinase (JNK), is weakly activated upon stimulation with either anti-CD3 or anti-CD28 in murine thymocytes and splenic T cells. However, p38 MAPK is activated strongly and synergistically by either CD3/CD28 coligation or PMA/Ca2+ ionophore stimulation, which mimics TCR-CD3/CD28-mediated signaling. Activation of p38 MAPK correlates closely with the stimulation of T cell proliferation. In contrast, PMA-induced JNK activation is inhibited by Ca2+ ionophore. T cell proliferation and production of IL-2, IL-4, and IFN-gamma induced by both CD3 and CD3/CD28 ligation and the nuclear expression of the c-Jun and ATF-2 proteins are each blocked by the p38 MAPK inhibitor SB203580. Our findings demonstrate that p38 MAPK 1) plays an important role in signal integration during costimulation of primary mouse T cells, 2) may be involved in the induction of c-Jun activation and augmentation of AP-1 transcriptional activity, and 3) regulates whether T cells enter a state of functional unresponsiveness.
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PMID:p38 mitogen-activated protein kinase mediates signal integration of TCR/CD28 costimulation in primary murine T cells. 1020 99

Activation of the sphingomyelin/ceramide pathway may mediate interleukin-1-induced beta-cell death (Welsh, N: Interleuken-1beta-induced ceramide and diacylglycerol generation may lead to activation of the c-Jun NH2-terminal kinase and the transcription factor ATF-2 in the insulin-producing cell line RINm5F. J Biol Chem 271: 8307-8312, 1996). In this report, we have examined this pathway in more detail. Culture of beta-TC3 cells with 25 micromol/l ceramide analogs (N-acetyl- and N-hexanoylsphingosine) for 72 h did not significantly affect glucose- and carbachol-induced insulin secretion. Dihydroceramide (N-acetyl- or N-hexanoylsphinganine), a structurally similar analog, had no effect on agonist-induced secretion. However, ceramide analogs both time- and dose-dependently decreased cell viability, while the dihydroceramide analog had no effect. The ceramide effect on cell viability mimicked the effect of the cytokines TNF-alpha, IL-1beta, and IFN-gamma, reported stimulators of sphingomyelin hydrolysis. Cytokines, however, failed to stimulate sphingomyelin metabolism. Furthermore, using two different methods to quantitate ceramide, cytokines failed to cause an increase in beta-cell ceramide content versus unstimulated or time-matched vehicle controls. Taken together, these data suggest that although ceramide analogs mimic the cytotoxic effect of cytokines, activation of the sphingomyelin/ceramide signaling pathway is not involved in cytokine-induced beta-cell death.
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PMID:Activation of the sphingomyelinase/ceramide signal transduction pathway in insulin-secreting beta-cells: role in cytokine-induced beta-cell death. 1038 41

IFN-gamma is a key regulatory cytokine of the immune system. Reporter transgenic mice expressing the luciferase gene under the control of separate TCR-response elements (TCR-RE) from the IFN-gamma promoter or expressing the green fluorescent protein gene under the control of an IFN-gamma "minigene" were employed to explore the basis for IL-12 regulation of IFN-gamma gene transcription. In the absence of TCR stimulation, IL-12 did not activate the TCR-REs but did induce green fluorescent protein expression. TCR plus IL-12R stimulation of effector Th cells resulted in: 1) enhanced activation of the proximal, but not the distal, TCR-RE, and 2) increased induction of cJun-proximal TCR-RE complexes and c-Jun protein expression. Overexpression of cJun, but not cFos, increased activity of the proximal TCR-RE in T cells. These results suggest that IL-12R signaling affects IFN-gamma gene transcription by at least two separate mechanisms; IL-12R signaling without TCR signaling targets promoter regions outside of the approximately 100-bp IFN-gamma TCR-RE, and IL-12R signaling also stimulates TCR-induced activity of the proximal TCR-RE.
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PMID:TCR and IL-12 receptor signals cooperate to activate an individual response element in the IFN-gamma promoter in effector Th cells. 1039 64

Extracellular purines, including adenosine and ATP, are potent endogenous immunomodulatory molecules. Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or ischemia. In the present study, we investigated whether extracellular inosine can affect inflammatory/immune processes. In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1alpha, and IFN-gamma, but failed to alter the production of the anti-inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by nucleoside transporters and was partially reversed by blockade of adenosine A1 and A2 receptors. Inosine inhibited cytokine production by a posttranscriptional mechanism. The activity of inosine was independent of activation of the p38 and p42/p44 mitogen-activated protein kinases, the phosphorylation of the c-Jun terminal kinase, the degradation of inhibitory factor kappaB, and elevation of intracellular cAMP. Inosine suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model. Taken together, inosine has multiple anti-inflammatory effects. These findings, coupled with the fact that inosine has very low toxicity, suggest that this agent may be useful in the treatment of inflammatory/ischemic diseases.
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PMID:Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. 1062 51


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