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

---

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

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.
...
PMID:Negative regulation of T cell antigen receptor signal transduction by hematopoietic tyrosine phosphatase (HePTP). 962 14

We have investigated the mechanisms underlying regulation of the calcitonin gene-related peptide (CGRP) cell-specific enhancer. Recently, we reported that this enhancer is inhibited by serotonin type-1 (5-HT1) agonists, similar to currently used antimigraine drugs. We have now tested whether this repression involves a mitogen-activated protein (MAP) kinase pathway. We first demonstrate that the CGRP enhancer is strongly (10-fold) activated by a constitutively active MAP kinase kinase (MEK1), yielding reporter activities 100-fold above the enhancerless control. The involvement of a MAP kinase pathway was confirmed by down-regulation of reporter activity upon cotransfection of a dominant negative Ras. Activation of the enhancer by MEK1 was blocked in a dose-dependent manner by the 5-HT1 receptor agonist CGS 12066A (CGS). Since it is not known whether the CGRP enhancer factors are immediate targets of MAP kinases, we then used EIk-1- and c-Jun-dependent reporter genes that are directly activated by the ERK (extracellular signal-regulated kinases) and JNK (c-Jun N-terminal kinase) MAP kinases. CGS treatment repressed the activation of both of these reporters, suggesting that at least two MAP kinases are the immediate targets of CGS-mediated repression. We further demonstrate that 5-HT1 agonists inactivate ERK by dephosphorylation, even in the presence of constitutively activated MEK1. This inactivation appears to be due to a marked increase in the level of MAP kinase phosphatase-1. These results have defined a novel and general mechanism by which 5-HT1 receptor agonists can repress MAP kinase activation of target genes, such as CGRP.
...
PMID:Serotonergic repression of mitogen-activated protein kinase control of the calcitonin gene-related peptide enhancer. 965 4

Both extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) have been implicated in mediating the signaling events that precede apoptosis. We studied the activation of these kinases during apoptosis of WEHI 231 B cells. Surface IgM ligation induces apoptosis of WEHI 231 cells. This effect is augmented by simultaneous engagement of CD95 and is inhibited by costimulation with either CD40 or IL-4R. We determined that surface IgM ligation activates ERK2 to a much greater level than JNK, and that IgM-mediated ERK2 activation is enhanced by costimulation with anti-CD95. Costimulation with either IL-4 or anti-CD40 interferes with anti-IgM-stimulated ERK2 activation. Transient expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) inhibits both ERK2 activation and cell death following stimulation with anti-IgM and the combination of anti-IgM plus anti-CD95. CD40 engagement alone activates JNK, but IL-4 stimulation does not. N-acetyl-L-cysteine pretreatment, which blocks CD40-mediated JNK activation, does not affect the ability of CD40 to inhibit anti-IgM-mediated ERK2 activation and apoptosis. Together, these data suggest that JNK activation is not required for CD40 inhibition of surface IgM-induced cell death and that ERK2 plays an active role in mediating anti-IgM-induced apoptosis of WEHI 231 B cells.
...
PMID:Extracellular signal-regulated kinase-2, but not c-Jun NH2-terminal kinase, activation correlates with surface IgM-mediated apoptosis in the WEHI 231 B cell line. 971 25

The tumor suppressor PTEN dephosphorylates focal adhesion kinase (FAK) and inhibits integrin-mediated cell spreading and cell migration. We demonstrate here that expression of PTEN selectively inhibits activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. PTEN expression in glioblastoma cells lacking the protein resulted in inhibition of integrin-mediated MAP kinase activation. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)- induced MAPK activation were also blocked. To determine the specific point of inhibition in the Ras/Raf/ MEK/ERK pathway, we examined these components after stimulation by fibronectin or growth factors. Shc phosphorylation and Ras activity were inhibited by expression of PTEN, whereas EGF receptor autophosphorylation was unaffected. The ability of cells to spread at normal rates was partially rescued by coexpression of constitutively activated MEK1, a downstream component of the pathway. In addition, focal contact formation was enhanced as indicated by paxillin staining. The phosphatase domain of PTEN was essential for all of these functions, because PTEN with an inactive phosphatase domain did not suppress MAP kinase or Ras activity. In contrast to its effects on ERK, PTEN expression did not affect c-Jun NH2-terminal kinase (JNK) or PDGF-stimulated Akt. Our data suggest that a general function of PTEN is to down-regulate FAK and Shc phosphorylation, Ras activity, downstream MAP kinase activation, and associated focal contact formation and cell spreading.
...
PMID:Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. 983 64

Arachidonic acid (AA) and its metabolites play important roles in a variety of biological processes, such as signal transduction, contraction, chemotaxis, and cell proliferation and differentiation. It was demonstrated recently that AA can activate mitogen-activated protein kinases (MAPKs), which are crucial for transducing signals initiating cell growth and apoptosis. Here we studied the effect of AA on the induction of MAPK phosphatase-1 (MKP-1) in vascular smooth muscle cells (VSMCs) and found that AA stimulated induction of MKP-1 mRNA and proteins in VSMCs in a time- and dose-dependent manner. Specific inhibitors of cyclooxygenase-, lipoxygenase-, and cytochrome P450-dependent metabolism did not affect AA-induced MKP-1 expression, indicating that eicosanoid biosynthesis was not involved in this process. The glutathione precursor N-acetylcysteine, an antioxidant, abolished AA-stimulated MKP-1 gene expression, whereas inhibition of protein kinase C by calphostin C had no influence on MKP-1 induction. VSMC pretreatment with genistein, a tyrosine kinase inhibitor, completely blocked AA-stimulated MKP-1 induction. MAPK kinase inhibitor PD 98059 did abolish AA-stimulated activation of extracellular signal-regulated kinases but not MKP-1 induction. Furthermore, agonists that increase AA release stimulated MKP-1 induction and activation of MAPKs, including extracellular signal-regulated kinases and c-Jun NH2-terminal protein kinases or stress-activated protein kinases. Taken together, our findings demonstrate that AA induced MKP-1 expression in VSMCs via activation of tyrosine kinases involving AA-induced free radical generation, suggesting an important role for MKP-1 in the regulation of AA-initiated signal transduction in VSMCs.
...
PMID:Induction of mitogen-activated protein kinase phosphatase-1 by arachidonic acid in vascular smooth muscle cells. 983 5

Collagenase-1 (matrix metalloproteinase-1, MMP-1) is expressed by several types of cells, including fibroblasts, and apparently plays an important role in the remodeling of collagenous extracellular matrix in various physiologic and pathologic situations. Here, we have examined the molecular mechanisms of the activation of fibroblast MMP-1 gene expression by a naturally occurring non-phorbol ester type tumor promoter okadaic acid (OA), a potent inhibitor of serine/threonine protein phosphatase 2A. We show that in fibroblasts OA activates three distinct subgroups of mitogen activated protein kinases (MAPKs): extracellular signal-regulated kinase1,2 (ERK1,2), c-Jun N-terminal-kinase/stress-activated protein kinase (JNK/SAPK) and p38. Activation of MMP-1 promoter by OA is entirely blocked by overexpression of dual-specificity MAPK phosphatase CL100. In addition, expression of kinase-deficient forms of ERK1,2, SAPKbeta, p38, or JNK/SAPK kinase SEK1 strongly inhibited OA-elicited activation of MMP-1 promoter. OA-elicited enhancement of MMP-1 mRNA abundance was also strongly prevented by two chemical MAPK inhibitors: PD 98059, a specific inhibitor of the activation of ERK1,2 kinases MEK1,2; and SB 203580, a selective inhibitor of p38 activity. Results of this study show that MMP-1 gene expression in fibroblasts is coordinately regulated by ERK1,2, JNK/SAPK, and p38 MAPKs and suggest an important role for the stress-activated MAPKs JNK/SAPK and p38 in the activation of MMP-1 gene expression. Based on these observations, it is conceivable that specific inhibition of stress-activated MAPK pathways may serve as a novel therapeutic target for inhibiting degradation of collagenous extracellular matrix.
...
PMID:Enhancement of fibroblast collagenase-1 (MMP-1) gene expression by tumor promoter okadaic acid is mediated by stress-activated protein kinases Jun N-terminal kinase and p38. 992 49

We reported previously that Ro-318220 blocked expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) induced by tumor necrosis factor-alpha (TNF-alpha) and subsequently caused apopotosis in mesangial cells (Y.-L. Guo, B. Kang, and J. R. Williamson. J. Biol. Chem. 273: 10362-10366, 1998). These data support our hypothesis that a TNF-alpha-inducible phosphatase may be responsible for preventing sustained activation of c-Jun NH2-terminal protein kinase (JNK) and consequent cell death in these cells (Y.-L. Guo, K. Baysal, B. Kang, L.-J. Yang, and J. R. Williamson. J. Biol. Chem. 273: 4027-4034, 1998). In this study, we investigated the involvement of protein kinase C (PKC) in regulation of MKP-1 expression in mesangial cells together with effects on viability. Although originally characterized as a PKC inhibitor, Ro-318220 inhibited TNF-alpha-induced MKP-1 expression through a mechanism other than blocking the PKC pathway. Furthermore, inhibition of the PKC pathway neither significantly affected TNF-alpha-induced MKP-1 expression nor made cells susceptible to toxic effect of TNF-alpha. Thus PKC activation is not essential for cells to achieve the resistance to TNF-alpha cytotoxicity displayed by normal mesangial cells. However, activation of PKC by phorbol 12-myristate 13-acetate (PMA) dramatically increased cellular resistance to the apoptotic effect of TNF-alpha. Coincidentally, PMA stimulated MKP-1 expression and suppressed JNK activation. Therefore, PMA-induced MKP-1 expression may contribute to the protective effect of PMA. These results provide a mechanistic explanation for previous documentation that PKC activation can rescue some cells from apopotosis.
...
PMID:Resistance to TNF-alpha cytotoxicity can be achieved through different signaling pathways in rat mesangial cells. 995 Jul 71

FTY720 is a novel immunosuppressive drug derived from a metabolite from Isaria sinclairii that is known to induce apoptosis of rat splenic T cells. In this study, we examined the intracellular signaling pathway triggered by FTY720. Treatment of human Jurkat T lymphocytes with FTY720-induced apoptosis characterized by DNA fragmentation. The same treatment induced activation of protein kinases such as c-Jun NH2-terminal kinase (JNK), p38/CSBP (CSAID-binding protein), and a novel 36-kDa myelin basic protein (MBP) kinase, but not extracellular signal-regulated kinase (ERK). Pretreatment of Jurkat cells with DEVD-CHO blocked FTY720-induced DNA fragmentation as well as the activation of p38/CSBP. However, DEVD-CHO treatment failed to inhibit FTY720-induced activation of JNK and the 36-kDa MBP kinase. We have also demonstrated that activation of the ERK signaling pathway completely suppressed the FTY720-induced apoptotic process including activation of caspase 3 and activation of JNK and the 36-kDa MBP kinase. Furthermore, transient expression of constitutively active mitogen-activated protein kinase/ERK kinase (MEK) protected the cells from FTY720-induced cell death. The effect of MEK was canceled by coexpression of a mitogen-activated protein kinase phosphatase, CL100. These results indicate that JNK and p38 pathways are differentially regulated during FTY720-induced apoptosis and that activation of ERK pathway alone is sufficient to cancel the FTY720-induced death signal.
...
PMID:Differential activation of c-Jun NH2-terminal kinase and p38 pathways during FTY720-induced apoptosis of T lymphocytes that is suppressed by the extracellular signal-regulated kinase pathway. 1009 85

Pathophysiological hypoxia is an important modulator of gene expression in solid tumors and other pathologic conditions. We observed that transcriptional activation of the c-jun proto-oncogene in hypoxic tumor cells correlates with phosphorylation of the ATF2 transcription factor. This finding suggested that hypoxic signals transmitted to c-jun involve protein kinases that target AP-1 complexes (c-Jun and ATF2) that bind to its promoter region. Stress-inducible protein kinases capable of activating c-jun expression include stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and p38 members of the mitogen-activated protein kinase (MAPK) superfamily of signaling molecules. To investigate the potential role of MAPKs in the regulation of c-jun by tumor hypoxia, we focused on the activation SAPK/JNKs in SiHa human squamous carcinoma cells. Here, we describe the transient activation of SAPK/JNKs by tumor-like hypoxia, and the concurrent transcriptional activation of MKP-1, a stress-inducible member of the MAPK phosphatase (MKP) family of dual specificity protein-tyrosine phosphatases. MKP-1 antagonizes SAPK/JNK activation in response to diverse environmental stresses. Together, these findings identify MKP-1 as a hypoxia-responsive gene and suggest a critical role in the regulation of SAPK/JNK activity in the tumor microenvironment.
...
PMID:Mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is induced by low oxygen conditions found in solid tumor microenvironments. A candidate MKP for the inactivation of hypoxia-inducible stress-activated protein kinase/c-Jun N-terminal protein kinase activity. 1021 78

Members of the mitogen activated protein (MAP) kinase family, extracellular signal-regulated kinase, stress-activated protein kinase-1/c-Jun NH2-terminal kinase, and p38, are central elements that transduce the signal generated by growth factors, cytokines, and stressing agents. It is well known that the platelet-derived growth factor (PDGF) activates extracellular signal-regulated kinase, which leads to cellular mitogenic response. On the other hand, the role of the other MAP kinases in mediating the cellular function of PDGF remains unclear. In the present study, we have investigated the functional role of the other MAP kinases in PDGF-mediated cellular responses. We show that ligand stimulation of PDGF receptors leads to the activation of p38 but not stress-activated protein kinase-1/c-Jun NH2-terminal kinase. Experiments using a specific inhibitor of p38, SB203580, show that the activation of p38 is required for PDGF-induced cell motility responses such as cell migration and actin reorganization but not required for PDGF-stimulated DNA synthesis. Analyses of tyrosine residue-mutated PDGF receptors show that Src homology 2 domain-containing proteins including Src family kinases, phosphatidylinositol 3-kinase, the GTPase-activating protein of Ras, the Src homology 2 domain-containing phosphatase SHP-2, phospholipase C-gamma, and Crk do not play a major role in mediating the PDGF-induced activation of p38. Finally, the expression of dominant-negative Ras but not dominant-negative Rac inhibited p38 activation by PDGF, suggesting that Ras is a potent mediator in the p38 activation pathway downstream of PDGF receptors. Taken together, our present study proposes the existence of a Ras-dependent pathway for the activation of p38, which is important for cell motility responses elicited by PDGF stimulation.
...
PMID:Platelet-derived growth factor activates p38 mitogen-activated protein kinase through a Ras-dependent pathway that is important for actin reorganization and cell migration. 1031 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---