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 role of monocyte chemoattractant protein-1 (MCP-1) in mediating the infiltration and activation of monocytes/macrophages into the sites of inflammation or tumor growth is well documented, but the molecular mechanism(s) involved in the process is poorly understood. In the current investigation, we demonstrate activation of the p42/44 MAPK-mediated signal transduction in murine peritoneal macrophages on stimulation with MCP-1 (10-100 ng/ml) in vitro. The p42/44 MAPK activation was determined by studying the expression of the phosphorylated p42/44 MAPK (Thr202/Tyr204) in the MCP-1-treated macrophages. This response was found to be rapid and time dependent, detectable within 5 min of MCP-1 stimulation. PD98058 (5-50 microM), a specific inhibitor of MAPK kinase (MEK) inhibited the p42/44 MAPK phosphorylation, indicating the specificity of the response. Furthermore, the MCP-1-induced phosphorylation of p42/44 MAPK was found to be blocked by pertussis toxin (100 ng/ml), tyrosine kinase inhibitor-genestein (10 ng/ml), PI3K inhibitor-wortmannin (20-200 microM), and anti-CCR2 antibody (2.5 microg/ml). Additionally, phosphorylation of JNK and activation of the transcription factor, c-Jun, were also noted in response to MCP-1 treatment. Lastly, the MCP1-induced p42/44 MAPK activity was correlated with the functional activation of macrophages by demonstrating the dose-specific inhibition of actin polymerization, macrophage-mediated tumor cell cytotoxicity, and tumor necrosis factor-alpha (TNF-alpha) transcription/production afforded by PD98059 in the MCP-1-treated macrophages. Taken together, these data suggest the involvement of the p42/44 MAPK/c-Jun pathway in the signal transduction process, leading to activation of murine peritoneal macrophages.
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PMID:Monocyte chemoattractant protein-1-induced activation of p42/44 MAPK and c-Jun in murine peritoneal macrophages: a potential pathway for macrophage activation. 1206 Apr 90

Various toxicants and carcinogens upregulate the expression of small proline-rich protein 1B (SPRR1B), a squamous differentiation marker, in bronchial epithelial cells both in vivo and in vitro. We have recently shown that phorbol 13-myristate 12-acetate (PMA)-stimulated SPRR1B transcription in Clara-like H441 cells is mainly mediated by activator protein-1 (AP-1) and c-Jun N-terminal kinase-1 (JNK1). Though mitogen-activated protein kinase (MAPK) kinase (MEK)-1/2 pathway inhibitors strongly suppressed both basal and PMA-inducible SPRR1B transcription, overexpression of dominant negative (dn) forms of extracellular signal-regulated kinase (ERK)-1 and/or -2 did not have any significant effect indicating the involvement of another ERK-like MAPK in this pathway. Here, we report for the first time the involvement of ERK5 in PMA-inducible SPRR1B transcription in H441 cells. PMA significantly induced ERK5 activation in H441 cells. Overexpression of dn-ERK5 strongly suppressed both basal and PMA-inducible SPRR1B transcription, whereas wild-type ERK5 upregulated it. Consistent with this, a mutant form of MEK-5, an upstream activator of ERK5, strongly suppressed PMA-inducible promoter activity. However, coexpression of c-Jun restored promoter activation suppressed by dn-ERK5. Thus, in addition to JNK1, the activation of MEK5-ERK5 MAPK pathway probably plays a pivotal role in transcriptional regulation of AP-1-mediated SPRR1B expression in the distal bronchiolar region.
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PMID:BMK1 (ERK5) regulates squamous differentiation marker SPRR1B transcription in Clara-like H441 cells. 1209 Dec 47

We studied the activation of MAPKs, such as ERK and JNK, by arsenite in C2C12 mouse skeletal muscle cells as a function of proliferation and differentiation. Data showed that both ERK and JNK were activated by arsenite in proliferated and differentiated cells in a differential manner. The activation of the enzymes was not due to alteration in their concentration. The activities were independent of each other. ERK activation was possibly partly through the activity of Ras, Raf and the MEK cascade, and due to oxidative stress, which possibly led to the activation of the transcription factor, Elk-1. In contrast, the activation of JNK was solely due to the generation of free radicals, resulting in activation of c-Jun and perhaps Elk-1. These results show for the first time that, in skeletal muscle, stress caused by arsenite involves the MAP-kinase signal transduction cascade, perhaps in a cell type-specific regulatory pathway.
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PMID:Differential activation of ERK and JNK by arsenite in mouse muscle cells. 1216 Nov 71

Human pancreatic cancers harbor mutations in the K-ras gene, and these mutations convert the gene oncogenic and constitutively active forms. However, in pancreatic cancer cells little is known about the activation of the downstream pathways of Ras, MEK-ERK and MEKK1-JNK, and their roles in cell survival and proliferation. An analysis of nine pancreatic cancer tissues revealed JNK activation in all tumor samples and ERK activation in three tumor samples. Colony formation assays by transfection of dominant negative mutants of Ras, ERK or MEKK1 into pancreatic cancer cell lines (BxPC-3, PANC-1, MIAPaCa-2 and AsPC-1) and an amnion-derived cell line (FL) revealed that DN-MEKK strongly inhibits the survival of colonies in pancreatic cancer cells, but not in FL cells. In vitro kinase assays and luciferase assays using the Gal4c-Jun system revealed that in pancreatic cancer cells DN-MEKK fails to inhibit JNK activation. In PANC-1 cells, c-Jun was found to be a major component of protein component binding to AP-1 site and CRE, but not in FL cells. The inhibitory effect of DN-MEKK in PANC-1 cells was thought to be the result of the inhibition of c-Jun DNA-binding. The difference of suppression in pancreatic cancer cells and non-pancreatic cancer cells suggested that the MEKK1 pathway mainly contributes to cell survival in pancreatic cancer cells and may provide an advantage for the gene therapy of pancreatic cancers using DN-MEKK expression vectors.
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PMID:Dominant negative MEKK1 inhibits survival of pancreatic cancer cells. 1218 92

We have previously suggested that PKCalpha has a role in 12-O-Tetradecanoylphorbol-13-acetate (TPA)-mediated growth arrest and myogenic differentiation in human embryonal rhabdomyosarcoma cells (RD). Here, by monitoring the signalling pathways triggered by TPA, we demonstrate that PKCalpha mediates these effects by inducing transient activation of c-Jun N-terminal protein kinases (JNKs) and sustained activation of both p38 kinase and extracellular signal-regulated kinases (ERKs) (all referred to as MAPKs). Activation of MAPKs following ectopic expression of constitutively active PKCalpha, but not its dominant-negative form, is also demonstrated. We investigated the selective contribution of MAPKs to growth arrest and myogenic differentiation by monitoring the activation of MAPK pathways, as well as by dissecting MAPK pathways using MEK1/2 inhibitor (UO126), p38 inhibitor (SB203580) and JNK and p38 agonist (anisomycin) treatments. Growth-arresting signals are triggered either by transient and sustained JNK activation (by TPA and anisomycin, respectively) or by preventing both ERK and JNK activation (UO126) and are maintained, rather than induced, by p38. We therefore suggest a key role for JNK in controlling ERK-mediated mitogenic activity. Notably, sarcomeric myosin expression is induced by both TPA and UO126 but is abrogated by the p38 inhibitor. This finding indicates a pivotal role for p38 in controlling the myogenic program. Anisomycin persistently activates p38 and JNKs but prevents myosin expression induced by TPA. In accordance with this negative role, reactivation of JNKs by anisomycin, in UO126-pre-treated cells, also prevents myosin expression. This indicates that, unlike the transient JNK activation that occurs in the TPA-mediated myogenic process, long-lasting JNK activation supports the growth-arrest state but antagonises p38-mediated myosin expression. Lastly, our results with the MEK inhibitor suggest a key role of the ERK pathway in regulating myogenic-related morphology in differentiated RD cells.
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PMID:PKCalpha-mediated ERK, JNK and p38 activation regulates the myogenic program in human rhabdomyosarcoma cells. 1218 45

Glucocorticoid-induced leucine zipper (GILZ) is a leucine zipper protein, whose expression is augmented by dexamethasone (DEX) treatment and downregulated by T-cell receptor (TCR) triggering. Stable expression of GILZ in T cells mimics some of the effects of glucocorticoid hormones (GCH) in GCH-mediated immunosuppressive and anti-inflammatory activity. In fact, GILZ overexpression inhibits TCR-activated NF-kappaB nuclear translocation, interleukin-2 production, FasL upregulation, and the consequent activation-induced apoptosis. We have investigated the molecular mechanism underlying GILZ-mediated regulation of T-cell activation by analyzing the effects of GILZ on the activity of mitogen-activated protein kinase (MAPK) family members, including Raf, MAPK/extracellular signal-regulated kinase (ERK) 1/2 (MEK-1/2), ERK-1/2, and c-Jun NH(2)-terminal protein kinase (JNK). Our results indicate that GILZ inhibited Raf-1 phosphorylation, which resulted in the suppression of both MEK/ERK-1/2 phosphorylation and AP-1-dependent transcription. We demonstrate that GILZ interacts in vitro and in vivo with endogenous Raf-1 and that Raf-1 coimmunoprecipitated with GILZ in murine thymocytes treated with DEX. Mapping of the binding domains and experiments with GILZ mutants showed that GILZ binds the region of Raf interacting with Ras through the NH(2)-terminal region. These data suggest that GILZ contributes, through protein-to-protein interaction with Raf-1 and the consequent inhibition of Raf-MEK-ERK activation, to regulating the MAPK pathway and to providing a further mechanism underlying GCH immunosuppression.
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PMID:Glucocorticoid-induced leucine zipper inhibits the Raf-extracellular signal-regulated kinase pathway by binding to Raf-1. 1239 Nov 60

Previous studies have revealed that p202 (52 kDa), an interferon (IFN) and differentiation-inducible protein, negatively regulates cell proliferation and modulates cell survival. However, the role of p202 in transformed cells remains to be investigated. Here we report that constitutive expression of oncogenic H-Ras (Q61L) in NIH 3T3 cells, which resulted in cell transformation, was associated with increases in the steady-state levels of 202 RNA and protein. Interestingly, the increase in p202 levels in transformed cells correlated with increases in the activity of the transcription factor c-Jun/AP-1, which bound to the two potential AP-1 DNA binding sites (the AP-1CS1 and AP-1CS2) in the 5'-regulatory region of the 202 gene in gel mobility shift assays. Furthermore, the site-directed mutagenesis, coupled with promoter-reporter analyses, revealed that these two AP-1 DNA binding sites contribute to the regulation of the 202 gene in Ras transformed cells. Because treatment of transformed cells with a specific inhibitor of MEK (PD 98059) resulted in significant decreases in the levels of p202, these observations raise the possibility that in transformed cells Ras/Raf/MEK pathway regulates the transcriptional activation of the 202 gene. Significantly, decreases in the levels of p202 in Ras transformed NIH 3T3 cells under reduced serum conditions increased the susceptibility to apoptosis. Collectively, our observations support the idea that the transcriptional increases in the levels of p202 by oncogenic H-Ras in NIH 3T3 cells are needed for cell survival.
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PMID:Induction of p202, a modulator of apoptosis, during oncogenic transformation of NIH 3T3 cells by activated H-Ras (Q61L) contributes to cell survival. 1246 88

This study examines the effects of an increase in passive stretch in endothelium-removed bovine coronary artery on oxidant-induced changes in force generation. Increasing passive stretch on the arterial segments from 5 to 20 g for 20 minutes caused a subsequent increase (P<0.05) in force generation to 30 mmol/L KCl or 0.1 micromol/L serotonin compared with the prestretch control response. Also associated with the passive stretch were increases in superoxide detection by lucigenin and a selective increase in extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase phosphorylation measured by Western analysis. The stretch-induced increase in force generation was eliminated by inhibition of the ERK pathway by the MEK inhibitor PD98059 but not by inhibitors of the p38 MAP kinase pathway (SB202190) or c-Jun N-terminal protein kinase pathway (SP200169). Additionally, stretch-induced increases in both ERK phosphorylation and force generation were attenuated by inhibition of tyrosine kinases (genistein), src (PP2), and specific sites on the epidermal growth factor receptor (EGFR) (AG1478). Probes for oxidant signaling, including NAD(P)H oxidase inhibitors (diphenyliodonium and apocynin) or enhancement of peroxide consumption (ebselen) but not inhibition of xanthine oxidase (allopurinol), attenuated the effects of stretch on both ERK phosphorylation and force generation. Furthermore, stretch caused an increase in EGFR phosphorylation and cytosolic to membrane translocation of the p47phox NAD(P)H oxidase subunit. Hydrogen peroxide also elicited contraction through EGFR phosphorylation and ERK. In summary, stretch seems to enhance force generation via ERK signaling through an EGFR/src-dependent mechanism activated by peroxide derived from a stretch-mediated activation of the NAD(P)H oxidase, a response that may contribute to hypertensive alterations in vascular reactivity.
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PMID:Stretch enhances contraction of bovine coronary arteries via an NAD(P)H oxidase-mediated activation of the extracellular signal-regulated kinase mitogen-activated protein kinase cascade. 1252 17

In skin, the profibrotic protein connective tissue growth factor (CTGF) is not normally expressed. However, when skin cells are exposed to transforming growth factor-beta (TGF-beta), CTGF is induced in fibroblasts but not in epithelial cells. We have begun to investigate the requirements for the fibroblast-selective induction of CTGF by TGF-beta. Previously we found that this response was Smad-dependent. Now we show that protein kinase C and Ras/MEK/ERK are necessary for the TGF-beta induction of the CTGF promoter but not of a generic Smad-responsive promoter (SBE-lux). Induction of the CTGF promoter is antagonized by c-Jun or by MEKK1, suggesting that a proper balance between the Ras/MEK/ERK and JNK MAPK cascades is necessary for TGF-beta induction of CTGF. We identify the minimal CTGF promoter element necessary and sufficient to confer TGF-beta responsiveness to a heterologous promoter and show that a tandem repeat of a consensus transcription enhancer factor binding element, 5'-GAGGAATGG-3', is necessary for this induction. This element has not been previously shown to play a role in TGF-beta induction of gene expression in fibroblasts. Gel shift analysis shows that this sequence binds nuclear factors that are greatly enriched in fibroblasts relative to epithelial cells. Thus Smads, Ras/MEK/ERK, protein kinase C, and fibroblast-enriched factors that bind GAGGAATGG act together to drive the TGF-beta-mediated induction of CTGF in fibroblasts.
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PMID:Connective tissue growth factor gene regulation. Requirements for its induction by transforming growth factor-beta 2 in fibroblasts. 1257 Dec 53

Herpes simplex virus type 1 (HSV-1) triggered apoptosis in hippocampal cultures, as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and immunohistochemistry with antibody specific for the large fragment of activated caspase 3. The levels of phosphorylated (activated) c-Jun N-terminal kinase (JNK) were also increased in HSV-1-infected hippocampal cultures as were the levels of activated c-Jun, its target. JNK activation was involved in HSV-1-induced apoptosis as evidenced by apoptosis inhibition with the JNK inhibitor SP600125. HSV-2 activated the mitogen-activated protein kinase/extracellular regulated protein kinase (MEK/ERK) survival pathway and did not trigger apoptosis in hippocampal cultures. The MEK specific inhibitor U0126 inhibited ERK activation and caused a significant increase in the percent TUNEL(+) cells in HSV-2-infected cultures, indicating that the failure of HSV-2 to trigger apoptosis is due to its ability to activate the MEK/ERK survival pathway. JNK was also activated in brain tissues from patients with HSV-associated acute focal encephalitis (HSE) that were positive for HSV-1 antigen. JNK activation correlated with apoptosis, as determined by immunohistochemistry with antibody to activated caspase 3 or cleaved poly (ADP-ribose) polymerase (PARP). The data suggest that HSE has an apoptotic component that may contribute to disease pathogenesis.
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PMID:Herpes simplex virus type 1-induced encephalitis has an apoptotic component associated with activation of c-Jun N-terminal kinase. 1258 73


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