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)

The objective of this study was to determine if the increase in the induction of interleukin-2 (IL-2) expression with caloric restriction correlates with changes in binding activity of the IL-2-specific transcription factor NFAT (nuclear factor of activated T cells) and/or the ubiquitous transcription factor AP-1 in T cells from male Fischer 344 rats. Splenic T cells were isolated from young (6-month) and old (24-month) rats fed ad libitum and from old (24-month) rats fed a restricted diet (40% caloric restriction) that began at 6 weeks of age. T cells were stimulated with concanavalin A (Con A) and the expression of IL-2 and the DNA binding activity of the transcription factors NFAT and AP-1 were measured in these cells. We found that the induction of IL-2 activity and mRNA levels decreased with age and that caloric restriction significantly (P < 0.05) reduced the age-related decline in IL-2 expression. The ability of nuclear extracts from T cells isolated from old rats fed ad libitum and restricted old rats to bind to the NFAT oligonucleotide or AP-1 oligonucleotide decreased with age. Caloric restriction significantly (P < 0.05) reduced the age-related decline in NFAT but had no significant effect on AP-1 binding activity. We also measured the induction of c-fos and c-jun expression by Con A in T cells from young and old rats fed ad libitum or caloric-restricted diet. The induction of c-fos protein and mRNA levels but not c-jun protein or mRNA levels decreased significantly with age. Caloric restriction significantly (P < 0.05) reduced the age-related decline in c-fos expression but had no significant effect on c-jun expression. Therefore, the increase in IL-2 expression with caloric restriction correlates with an increase in binding activity of transcription factor NFAT and an increase in the expression of c-fos, which is a component of the NFAT-protein complex.
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PMID:The increase in the induction of IL-2 expression with caloric restriction is correlated to changes in the transcription factor NFAT. 931 34

p38/CSBP, a subgroup member of mitogen-activated protein kinase (MAPK) superfamily molecules, is known to be activated by proinflammatory cytokines and environmental stresses. We report here that p38 is specifically activated by signals that lead to interleukin-2 (IL-2) production in T lymphocytes. A p38 activator MKK6 was also markedly activated by the same stimulation. Pretreatment of cells with SB203580, a specific inhibitor of p38, as well as expression of a dominant-negative mutant of MKK6, suppressed the transcriptional activation of the IL-2 promoter. We also demonstrated that MKK7, a recently described MAPK kinase family member, plays a major role in the activation of stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK) in T lymphocytes. Moreover, a dominant-negative mutant of MKK7 abrogated the transcriptional activation of the distal nuclear factor of activated T cells response element in the IL-2 promoter. Cyclosporin A, a potent immunosuppressant, inhibited activation of both p38 and SAPK/JNK pathways but not the MAPK/extracellular signal-regulated kinase (ERK) pathway. Our results indicate that both MKK6 to p38 and MKK7 to SAPK/JNK signaling pathways are activated in a cyclosporin A-sensitive manner and contribute to IL-2 gene expression in T lymphocytes.
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PMID:T lymphocyte activation signals for interleukin-2 production involve activation of MKK6-p38 and MKK7-SAPK/JNK signaling pathways sensitive to cyclosporin A. 957 91

The hematopoietic tyrosine phosphatase (HePTP) is predominantly expressed in thymocytes and T lymphocytes and at lower levels in other hematopoietic cells. Expression of the gene is enhanced by the T cell growth factor interleukin-2, suggesting a role for HePTP in T cell proliferation or differentiation. We report that HePTP blocks T cell antigen receptor (TCR)-induced transcriptional activation of a reporter gene driven by a nuclear factor of activated T cells(NFAT)/AP-1 element taken from the interleukin-2 gene promoter. This effect was specific to HePTP and was abolished by a mutation (C270S) that impaired its phosphatase activity. Co-expression of HePTP also reduced TCR-induced activation of the mitogen-activated protein kinase Erk2 and the TCR-induced appearance of phosphorylated Erk. In contrast, HePTP did not affect the activation of the N-terminal c-Jun kinase, Jnk. Together these findings suggest that HePTP plays an active negative role in TCR signaling by dephosphorylating one or several signaling molecules between the receptor and the mitogen-activated protein kinase pathway.
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PMID:Negative regulation of T cell antigen receptor signal transduction by hematopoietic tyrosine phosphatase (HePTP). 962 14

Signaling pathways that stabilize interleukin-2 (IL-2) messenger RNA (mRNA) in activated T cells were examined. IL-2 mRNA contains at least two cis elements that mediated its stabilization in response to different signals, including activation of c-Jun amino-terminal kinase (JNK). This response was mediated through a cis element encompassing the 5' untranslated region (UTR) and the beginning of the coding region. IL-2 transcripts lacking this 5' element no longer responded to JNK activation but were still responsive to other signals generated during T cell activation, which were probably sensed through the 3' UTR. Thus, multiple elements within IL-2 mRNA modulate its stability in a combinatorial manner, and the JNK pathway controls turnover as well as synthesis of IL-2 mRNA.
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PMID:Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway. 963 95

The p56 Src family non-receptor tyrosine kinase has been shown to be critical for T lymphocyte differentiation and activation. Hence in the absence of p56, T cell receptor triggered activation does not occur. We now provide evidence for a CD2-based signaling pathway which, in contrast to that of the T cell receptor, is independent of p56. CD2-mediated interleukin-2 production occurs via activation of Jun kinase in cell lines lacking p56. Jun kinase then facilitates the binding of c-Jun/c-Fos heterodimers to the AP-1 consensus site and the subsequent transcriptional activity of the interleukin-2 promoter. These data elucidate differences between TCR and CD2 signaling pathways in the same T cells.
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PMID:A p56lck-independent pathway of CD2 signaling involves Jun kinase. 972 49

POU domain proteins have been implicated as key regulators during development and lymphocyte activation. The POU domain protein T-cell factor beta1 (TCFbeta1), which binds octamer and octamer-related sequences, is a potent transactivator. In this study, we showed that TCFbeta1 is phosphorylated following activation via the T-cell receptor or by stress-induced signals. Phosphorylation of TCFbeta1 occurred predominantly at serine and threonine residues. Signals which upregulate Jun kinase (JNK)/stress-activated protein kinase activity also lead to association of JNK with TCFbeta1. JNK associates with the activation domain of TCFbeta1 and phosphorylates its DNA binding domain. The phosphorylation of recombinant TCFbeta1 by recombinant JNK enhances the ability of TCFbeta1 to bind to a consensus octamer motif. Consistent with this conclusion, TCFbeta1 upregulates reporter gene transcription in an activation- and JNK-dependent manner. In addition, inhibition of JNK activity by catalytically inactive MEKK (in which methionine was substituted for the lysine at position 432) also inhibits the ability of TCFbeta1 to drive inducible transcription from the interleukin-2 promoter. These results suggest that stress-induced signals and T-cell activation induce JNK, which then acts on multiple cis sequences by modulating distinct transactivators like c-Jun and TCFbeta1. This demonstrates a coupling between the JNK activation pathway and POU domain proteins and implicates TCFbeta1 as a physiological target in the JNK signal transduction pathway leading to coordinated biological responses.
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PMID:Jun kinase phosphorylates and regulates the DNA binding activity of an octamer binding protein, T-cell factor beta1. 1002 89

The Janus kinase, JAK3 plays an important role in interleukin-2 (IL-2)-dependent signal transduction and proliferation of T lymphocytes. Our findings show that prostaglandin E2 (PGE2) can inhibit upregulation of JAK3 protein in naive T cells and can downregulate its expression in primed cells. Reduction in JAK3 was selective because expression of other tyrosine kinases (JAK1, p56(lck), and p59(fyn)) and signal transducer and activator of transcription (STAT)5, which are linked to IL-2 receptor (IL-2R) signaling pathway, were not affected. Inhibition of JAK3 may be controlled by intracellular cyclic adenosine monophosphate (cAMP) levels, as forskolin, a direct activator of adenylate cyclase and dibutyryl cAMP (dbcAMP), a membrane permeable analogue of cAMP suppressed JAK3 expression. Moreover, 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of cAMP phosphodiesterase, potentiated PGE2-induced suppression of JAK3. In naive T cells, but not primed T cells, PGE2 and other cAMP elevating agents also caused a modest reduction in surface expression of the common gamma chain (gammac) that associates with JAK3. The absence of JAK3, but not IL-2R in T cells correlated with impaired IL-2-dependent signal transduction and proliferation. The alteration in IL-2 signaling included decreased tyrosine phosphorylation and DNA binding activity of STAT5 and poor induction of the c-Myc and c-Jun pathways. In contrast, IL-2-dependent induction of Bcl-2 was unaffected. These findings suggest that suppression of JAK3 levels may represent one mechanism by which PGE2 and other cAMP elevating agents can inhibit T-cell proliferation.
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PMID:Downregulation of JAK3 protein levels in T lymphocytes by prostaglandin E2 and other cyclic adenosine monophosphate-elevating agents: impact on interleukin-2 receptor signaling pathway. 1009 Sep 41

Activation of T lymphocytes to produce cytokines is regulated by the counterbalance of protein-tyrosine kinases and protein-tyrosine phosphatases, many of which have a high degree of substrate specificity because of physical association with their targets. Overexpression of hematopoietic protein-tyrosine phosphatase (HePTP) results in suppression of T lymphocyte activation as measured by T cell antigen receptor-induced activation of transcription factors binding to the 5' promoter of the interleukin-2 gene. Efforts to pinpoint the exact site of action and specificity of HePTP in the signaling cascade revealed that HePTP acts directly on the mitogen-activated protein (MAP) kinases Erk1 and 2 and consequently reduces the magnitude and duration of their catalytic activation in intact T cells. In contrast, HePTP had no effects on N-terminal c-Jun kinase or on events upstream of the MAP kinases. The specificity of HePTP correlated with its physical association through its noncatalytic N terminus with Erk and another MAP kinase, p38, but not Jnk or other proteins. We propose that HePTP plays a negative role in antigen receptor signaling by specifically regulating MAP kinases in the cytosol and at early time points of T cell activation before the activation-induced expression of nuclear dual-specific MAP kinase phosphatases.
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PMID:Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP). 1020 83

Exposure of an interleukin-2 (IL-2)-dependent murine T-cell line (CTLL-2) to mercuric chloride in in vitro culture induced a low but definite level of DNA synthesis in the absence of exogenous IL-2, and further enhanced the IL-2-induced DNA synthesis. Addition of anti-IL-2 or anti-IL-4 antibody to the culture, which neutralized all of the IL-2 or IL-4 activity, respectively, never inhibited the mercuric chloride-mediated DNA synthesis. Correspondingly, no detectable level of IL-2, IL-4, and IL-15 mRNA was found in mercuric chloride-treated CTLL-2 cells in our test condition. Stimulation of CTLL-2 cells with IL-2 induced phosphorylation on extracellular signal-regulated kinases more intensively than on c-Jun NH2-terminal kinases (JNKs), and provoked tyrosine phosphorylation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). In contrast, by mercuric chloride stimulation, JNKs and c-Jun were preferentially phosphorylated, but no detectable level of phosphorylation was induced on JAKs and STATs. These findings provided a possibility that mercuric chloride promoted lymphocyte proliferation through a JNK-linked signal cascade in CTLL-2 cells, which differs from that triggered by IL-2.
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PMID:Mercuric chloride stimulates distinct signal transduction pathway for DNA synthesis in a T-cell line, CTLL-2. 1086 47

Although numerous reports document a role for CD43 in T cell signaling, the direct participation of this molecule in cell activation has been questioned. In this study we show that CD43 ligation on human normal peripheral T cells was sufficient to induce interleukin-2, CD69, and CD40-L gene expression, without requiring signals provided by additional receptor molecules. This response was partially inhibited by cyclosporin A and staurosporine, suggesting the participation of both the Ca(2+) and the protein kinase C pathways in CD43 signaling. Consistent with the transient CD43-dependent intracellular Ca(2+) peaks reported by others, signals generated through the CD43 molecule resulted in the induction of NF-AT DNA binding activity. CD43-dependent signals resulted also in AP-1 and NFkappaB activation, probably as a result of protein kinase C involvement. AP-1 complexes bound to the AP-1 sequence contained c-Jun, and those bound to the NF-AT-AP-1 composite site contained c-Jun and Fos. NFkappaB complexes containing p65 could be found as early as 1 h after CD43 cross-linking, suggesting that CD43 participates in early events of T cell activation. The induction of the interleukin-2, CD69, and CD-40L genes and the participation of AP-1, NF-AT, and NFkappaB in the CD43-mediated signaling cascade implicate an important role for this molecule in the regulation of gene expression and cell function.
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PMID:CD43-mediated signals induce DNA binding activity of AP-1, NF-AT, and NFkappa B transcription factors in human T lymphocytes. 1090 70


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