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 involvement of p38 in fundamental physiological processes and the fact that deregulation often leads to disease indicates the potential impact of p38 dependent mechanisms. Here we demonstrate a new pathway that includes the induction of the mitogen activated protein kinase p38 by protein kinase C and results in a specific phosphorylation of c-Jun in T-lymphocytes. P38 directly phosphorylates c-Jun within its transactivation domain at serine 63 and serine 73 and thus posttranscriptionally affects the presence of DNA-bound phosphorylated c-Jun, a prerequisite for activator protein 1 dependent gene transcription. Moreover, DNA-binding activity of c-Fos, FosB, and JunB were also dependent on the p38 protein kinase activity, whereas JunD, Fra-1 and Fra-2 were not affected. Although we show that stress induced mitogen activated protein kinases share c-Jun as a substrate for phosphorylation, p38 mediated effects could not be rescued by the c-Jun N-terminal kinases. This demonstrates that the protein kinase p38 plays a unique and non-redundant role in posttranslational c-Jun regulation. The induction of a p38 dependent c-Jun phosphorylation was comparable in both CD4(+) and CD8(+) T-cells, proposing a ubiquitous pathway that is not linked to T-cell subtype and effector function. In contrast, ATF-2 was predominantly phosphorylated in CD8(+) T-cells. Different cell lines show p38-dependent c-Jun phosphorylation upon phorbol ester induction but there is evidence that the simian virus 40 large T-antigen may interfere with this pathway.
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PMID:The mitogen-activated protein kinase p38 regulates activator protein 1 by direct phosphorylation of c-Jun. 1768 31

Ropinirole, a D2/D3 receptor agonist has been reported to have neuroprotective effects. We showed that ropinirole can prevent rotenone-induced apoptosis in dopaminergic cell line SH-SY5Y through D3 receptor. We found that ropinirole can block the rotenone-induced phosphorylation of JNK, P38 and p-c-Jun, but promote the phosphorylation of ERK1/2. Furthermore, we demonstrated that ropinirole can reduce the rotenone-induced cleavages of caspase 9, caspase 3 and PARP and elevate the expression of anti-apoptotic proteins of p-Akt and bcl-2. These results provide a basis for neuroprotection by this drug for the treatment of Parkinson disease.
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PMID:D2/D3 receptor agonist ropinirole protects dopaminergic cell line against rotenone-induced apoptosis through inhibition of caspase- and JNK-dependent pathways. 1824 71

Recent studies have shown that the mevalonate pathway plays an important role in skeletal metabolism. Statins stimulate bone morphogenetic proteins-2 (BMP-2) production in osteoblasts, implicating a possible beneficial role for statins in promoting anabolic effects on bone. Here, we investigated the effects of a lipophilic simvastatin on osteoblast differentiation using mouse myoblast C2C12 cells, in the presence of tumor necrosis factor-alpha (TNF-alpha), an inflammatory cytokine that inhibits osteogenesis. The addition of TNF-alpha to C2C12 cells suppressed the BMP-2-induced expression of key osteoblastic markers including Runx2 and alkaline phosphatase (ALP) activity. Simvastatin had no independent effects on Runx2 and alkaline phosphatase activity; however, it reversed the suppressive effects of TNF-alpha. The ability of simvastatin to reverse TNF-alpha inhibition of BMP-induced Smad1,5,8 phosphorylation and Id-1 promoter activity suggests the involvement of Smad signaling pathway in simvastatin action. In addition, cDNA array analysis revealed that simvastatin increased expression levels of Smads in C2C12 cells exposed to TNF-alpha that also activated mitogen-activated protein kinase (MAPK) signaling pathways, including extracellular signal-regulated kinase 1/2 (ERK1/2), P38, and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). Simvastatin potently suppressed TNF-alpha-induced phosphorylation of ERK1/2 and SAPK/JNK by inhibiting TNF-alpha-induced membrane localization of Ras and RhoA. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) reversed the simvastatin effects on TNF-alpha-induced activation of Ras/Rho/MAPK pathways. FPP and GGPP also restored the simvastatin effects on TNF-alpha-induced suppression of Runx2 and ALP activity. In addition, simvastatin decreased the expression levels of TNF type-1 and -2 receptor mRNAs. Collectively, simvastatin supports BMP-induced osteoblast differentiation through antagonizing TNF-alpha-to-Ras/Rho/MAPK pathway and augmenting BMP-Smad signaling, suggesting a potential usage of statins to ameliorate inflammatory bone damage.
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PMID:Simvastatin antagonizes tumor necrosis factor-alpha inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway. 1831 Apr 56

TNFalpha exerts apoptosis throughout an intracellular transduction pathway that involves the kinase proteins TRAF-2 (integration point of apoptotic and survival signals), ASK1 (pro-apoptotic protein), MEK-4 (p38 activator and metastasis suppressor gene), JNK (stress mitogen activated protein kinase) and the transcription factor AP-1. TNFalpha also exerts proliferation by p38 activation, or when TRAF-2 simultaneously induces the transcription factor NF-kappaB by NIK. NIK and p38 may also be activated by IL-1. P38 activated several transcription factors such as Elk-1, ATF-2 and NF-kappaB. NIK also may activate NF-kappaB. The aim of the present article was to evaluate the different components of this TNFalpha/IL-1 transduction pathway in human prostate carcinoma (PC) in comparison with normal human prostate. In prostate cancer, pro-apoptotic TNFalpha/AP-1 pathway is probably inactivated by different factors such as p21 (at ASK-1 level) and bcl-2 (at JNK level), or diverted towards p38 or NIK activation. IL-1alpha enhances proliferation through IL-1RI that activates either NIK or p38 transduction pathway. P38 and NIK activate different transcription factors related with cell proliferation and survival such as ATF-2, Elk-1 or NF-kappaB. In order to search a possible target to cancer prostate treatment we proposed that inhibition of several proinflamatory cytokines such as IL-1 and TNFalpha might be a possible target for PC treatment, because decrease the activity of all transduction pathway members that activate transcription factors as NF-kappaB, Elk-1 or ATF-2.
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PMID:TNF-alpha/IL-1/NF-kappaB transduction pathway in human cancer prostate. 1871 80

Overexpression of epidermal growth factor (EGF) and urokinase plasminogen activator receptor (uPAR) have been observed in human gastric cancers. However, the interaction between EGF and uPAR in gastric cancer has not been well elucidated. In this study, we investigated the effect of EGF on uPAR expression and the underlying signal pathways in human gastric cancer AGS cells. EGF induced uPAR mRNA expression in a time- and concentration-dependent manner. EGF also induced uPAR promoter activity. In addition, EGF induced the activation of extracellular signal regulated kinase-1/2 (ERK-1/2) and P38 mitogen-activated protein kinase (MAPK) but not the activation of c-Jun amino terminal kinase. A specific inhibitor of MEK-1 (an upstream effector of ERK-1/2) and a dominant negative MEK-1 were able to suppress the EGF-induced uPAR promoter activity. Site-directed mutagenesis and electrophoretic mobility shift assays demonstrated that the binding sites of transcription factors, activator protein-1 (AP-1) and nuclear factor (NF)-kappaB, are involved in the EGF-induced uPAR transcription. Suppression of the EGF-induced uPAR promoter activity by the AP-1 decoy oligonuclotide, as well as expression vectors encoding mutated-type NF-kappaB-inducting kinase and I-kappaB, confirmed that the activation of AP-1 and NF-kappaB are essential for the EGF-induced uPAR upregulation. The AGS cells pretreated with EGF showed a remarkably enhanced invasiveness and this effect was partially abrogated by uPAR neutralizing antibodies and by the inhibitors of ERK-1/2, AP-1, and NF-kappaB. The above results suggest that EGF induces uPAR expression via ERK-1/2, AP-1, and NF-kappaB signaling pathways and, in turn, stimulates cell invasiveness in human gastric cancer AGS cells.
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PMID:EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells. 1902 Jul 43

The classical concept of linear pathways is being increasingly challenged by network representations, which emphasize the importance of interactions between components of a biological system, and motivates for adopting a system-level approach in biology. We have developed a dynamical system that integrates quantitative, dynamic and topological representation of network of ERK5 (Extracellular signal-regulated kinases 5), JNK(c-Jun N-terminal kinases) and P38 kinase cascades. We have observered that, the transient activation of ERK5, JNK1 and P38beta kinase, and the persistent activation of JNK2, JNK3 and P38 delta kinase does not get affected due to the cross-talks between ERK5, JNK and P38 kinase cascades. But it is due to the cross - talks, the transiently activated P38alpha kinase become inactivated, and the transiently activated P38gamma kinase become persistently activated. The impacts of one-way cross-talks between the cascades are insignificant and differ from the impact of two-way cross-talks. We generate a hypothesis that, signaling pathways should be studied as a system by considering the cross-talks between the two adjacent cascades.
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PMID:Analysis of the impact of ERK5, JNK, and P38 kinase cascades on each other: a systems approach. 1925 43

Signal transduction is a complex protein signaling process with a rich network of multifunctional interactions that occur in a non-linear fashion. Mitogen-activated protein kinase (MAPK) signal transduction pathways regulate diverse cellular processes ranging from proliferation and differentiation to apoptosis. In mammals, out of five, there are three well characterized subfamilies of MAPKs - ERKs (Extracellular signal-regulated kinases), JNKs (c-Jun N-terminal kinases), and P38 kinases, and their activators, are implicated in human diseases and are targets for drug development. Kinase cascades in MAPK pathways mediate the sensing and processing of stimuli. To understand how cells makes decisions, the dynamic interactions of components of signaling cascades are important rather than just creating static maps. Based on enzyme kinetic reactions, we have developed a mathematical model to analyze the impact of the cross-talks between JNK and P38 kinase cascades. Cross-talks between JNK and P38 kinase cascades influence the activities of P38 kinases. Responses of the signals should be studied for network of kinase cascades by considering cross-talks.
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PMID:Computational prediction and analysis of impact of the cross-talks between JNK and P38 kinase cascades. 1925 44

It has been reported that icariin protects neurons against ischemia/reperfusion injury. In this study, we found that icariin could enhance neuronal viability and suppress neuronal death after oxygen and glucose deprivation (OGD). Further study showed that neuroprotection by icariin was through the induction of Sirtuin type 1 (SIRT1), an effect that was reversed by SIRT1 inhibitor III and P38 inhibitor SB203580. SIRT1 is an endogenous gene of longevity, which increased neuronal viability and could be activated by stimulating the mitogen-activated protein kinase (MAPK) pathway. However, this study found that icariin activated the MAPK/P38 pathway, not the extracellular signal-regulated kinase (MAPK/ERK) or c-Jun N-terminal protein kinase (MAPK/JNK) to regulate SIRT1 expression. The results suggest that icariin may be developed into a neuroprotectant for ischemia-related brain injury.
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PMID:Icariin enhances neuronal survival after oxygen and glucose deprivation by increasing SIRT1. 1930 70

Vascular endothelial growth factor (VEGF) has been implicated in breast tumor angiogenesis. And tumor necrosis factor-alpha (TNF-alpha) is a positive regulator of VEGF. This study was aimed to identify the signalling pathway of TNF-alpha in VEGF expression regulation in breast cancer cell line MCF7. Using luciferase reporter assays, we demonstrated that TNF-alpha significantly increased activator protein-1 (AP-1) transcriptional activity in the MCF7 cells. The expression of the AP-1 family members c-Jun, c-Fos and JunB and phosphorylation levels of c-Jun were upregulated by TNF-alpha, whereas other AP-1 family members Fra-1, Fra-2, and JunD were unaffected. The activation of AP-1 was associated with the formation of p-c-Jun-c-Jun and p-c-Jun-JunB homodimers. Furthermore, the phosphorylation levels of c-Jun N-terminal kinase (JNK) but not P38 and ERK were elevated by TNF-alpha in MCF7 cells. TNF-alpha potently upregulated the mRNA and protein levels of VEGF, which were significantly reversed by JNK inhibitor SP600125. Finally using chromatin immunoprecipitation (CHIP) assays, we found that p-c-Jun bound to the VEGF promoter and regulated VEGF transcription directly. These data suggest that the pro-inflammatory cytokine TNF-alpha is a critical regulator of VEGF expression in breast cancer cells, at least partially via a JNK and AP-1 dependent pathway.
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PMID:JNK/AP-1 pathway is involved in tumor necrosis factor-alpha induced expression of vascular endothelial growth factor in MCF7 cells. 1955 68

ABSTRACT Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the silica-induced pulmonary fibrosis. The effect of silica on the expression of PAI-1 was investigated in human lung epithelial cells (A549). Silica induced PAI-1 expression in a concentration-(50-200 mug/mL) and time-(4-24 h) dependent manner in A549 cells. Furthermore, the roles of mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling pathways in silica-induced PAI-1 expression were examined. We found that silica (200 mug/mL) treatment for 4 to 24 h resulted in AP-1 activation in A549 cells. Cells were pretreated with the AP-1 inhibitor curcumin (10, 25, 50 muM), and silica-induced PAI-1 expression was reduced by 20%, 63%, and 65%, respectively. In addition, dominant-negative mutant c-Jun (TAM67) down-regulated silica-induced PAI-1 expression by 59%. P38 kinase inhibitor SB203580 (20 muM) and Erk inhibitor PD98059 (50 muM) suppressed silica-induced PAI-1 expression by 35% and 51%, respectively. Additionally, PD98059 but not SB203580 inhibited the AP-1 DNA binding activity induced by silica. The results suggest that the PAI-1 expression induced by silica may be involved in the activation of MAPKs/AP-1 signaling pathways in human lung epithelial cells.
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PMID:Silica Induces Plasminogen Activator Inhibitor-1 Expression through a MAPKs/AP-1-Dependent Mechanism in Human Lung Epithelial Cells. 2002 Aug 54


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