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 expression of the c-jun proto-oncogene is rapidly induced in response to mitogens acting on a large variety of cell surface receptors. The resulting functional activity of c-Jun proteins appears to be critical for cell proliferation. Recently, we have shown that a large family of G protein-coupled receptors (GPCRs), represented by the m1 muscarinic receptor, can initiate intracellular signaling cascades that result in the activation of mitogen-activated protein kinases (MAPK) and c-Jun NH2-terminal kinases (JNK) and that the activation of JNK but not of MAPK correlated with a remarkable increase in the expression of c-jun mRNA. Subsequently, however, we obtained evidence that GPCRs can potently stimulate the activity of the c-jun promoter through MEF2 transcription factors, which do not act downstream from JNK. In view of these observations, we set out to investigate further the nature of the signaling pathway linking GPCRs to the c-jun promoter. Utilizing NIH 3T3 cells, we found that GPCRs can activate the c-jun promoter in a JNK-independent manner. Additionally, we demonstrated that these GPCRs can elevate the activity of novel members of the MAPK family, including ERK5, p38alpha, p38gamma, and p38delta, and that the activation of certain kinases acting downstream from MEK5 (ERK5) and MKK6 (p38alpha and p38gamma) is necessary to fully activate the c-jun promoter. Moreover, in addition to JNK, ERK5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. Taken together, these results suggest that the pathway linking GPCRs to the c-jun promoter involves the integration of numerous signals transduced by a highly complex network of MAPK, rather than resulting from the stimulation of a single linear protein kinase cascade. Furthermore, our findings suggest that each signaling pathway affects one or more regulatory elements on the c-jun promoter and that the transcriptional response most likely results from the temporal integration of each of these biochemical routes.
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PMID:A network of mitogen-activated protein kinases links G protein-coupled receptors to the c-jun promoter: a role for c-Jun NH2-terminal kinase, p38s, and extracellular signal-regulated kinase 5. 1033 Jan 70

Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase kinase 3 (MEKK3) activates the c-Jun NH2-terminal kinase (JNK) pathway, although no substrates for MEKK3 have been identified. We have examined the regulation by MEKK3 of MAPK kinase 7 (MKK7) and MKK6, two novel MAPK kinases specific for JNK and p38, respectively. Coexpression of MKK7 with MEKK3 in COS-7 cells enhanced MKK7 autophosphorylation and its ability to activate recombinant JNK1 in vitro. MKK6 autophosphorylation and in vitro activation of p38alpha were also observed following coexpression of MKK6 with MEKK3. MEKK2, a closely related homologue of MEKK3, also activated MKK7 and MKK6 in COS-7 cells. Importantly, immunoprecipitates of either MEKK3 or MEKK2 directly activated recombinant MKK7 and MKK6 in vitro. These data identify MEKK3 as a MAPK kinase kinase specific for MKK7 and MKK6 in the JNK and p38 pathways. We have also examined whether MEKK3 or MEKK2 activates p38 in intact cells using MAPK-activated protein kinase-2 (MAPKAPK2) as an affinity ligand and substrate. Anisomycin, sorbitol, or the expression of MEKK3 in HEK293 cells enhanced MAPKAPK2 phosphorylation, whereas MEKK2 was less effective. Furthermore, MAPKAPK2 phosphorylation induced by MEKK3 or cellular stress was abolished by the p38 inhibitor SB-203580, suggesting that MEKK3 is coupled to p38 activation in intact cells.
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PMID:MEK kinase 3 directly activates MKK6 and MKK7, specific activators of the p38 and c-Jun NH2-terminal kinases. 1034 27

Electroconvulsive shock (ECS), an effective treatment for psychiatric diseases, has been reported to induce immediate-early genes (IEGs) and to activate p42 and p44 MAPKs (ERK-1 and ERK-2) in rat brain. In this study, we examined the activation of the other members of MAPK family, c-Jun N-terminal protein kinase (JNK/SAPK) and p38. Following ECS, the phosphorylation of p38 was substantially increased in both hippocampus and cerebellum, but the increase of JNK phosphorylation was observed only in hippocampus. We also investigated the phosphorylation of their upstream kinases, SEK-1, MKK6 and MKK3. In both hippocampus and cerebellum, the phosphorylation of MKK6 showed closer correlation with p38 phosphorylation than that of MKK3. However, SEK-1, known as upstream kinase of JNK and p38 in vitro, corresponded with none of MAPKs. These results, with previous reports on the activation of ERK, indicate that ECS activates three MAPKs differentially in rat hippocampus and cerebellum, and suggest the possibility that unknown MAPKK may be involved in the activation of JNK in rat brain after ECS.
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PMID:Differential activation of c-Jun N-terminal protein kinase and p38 in rat hippocampus and cerebellum after electroconvulsive shock. 1047 12

Palytoxin is a potent non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin tumor promoter. We used COS7 and HeLa cells to investigate the protein kinase cascades by which palytoxin activates the mitogen-activated protein kinase (MAPK) p38. Three p38 kinases have been identified: stress-activated protein kinase/extracellular signal-regulated kinase kinase-1 (SEK1), MAPK kinase 3 (MKK3), and MKK6. SEK1 phosphorylates and activates both p38 and c-Jun NH(2)-terminal kinase (JNK), whereas MKK3 and MKK6 selectively phosphorylate and activate p38. Although transiently overexpressed SEK1 activates p38 in cells, the importance of endogenous SEK1 for the activation of p38 by specific types of stimuli is unclear because some agents, such as sorbitol, can activate p38 in cells derived from SEK1 knockout mice. Because we previously showed that palytoxin activates JNK through an SEK1-dependent pathway, we investigated whether SEK1 also mediates the activation of p38 by palytoxin. The results presented here demonstrate that endogenous SEK1 does play an important role in the activation of p38 by palytoxin in specific cell types. In COS7 cells, palytoxin stimulated the phosphorylation of SEK1 and MKK6, and expression of dominant negative mutants of either SEK1 or MKK6 inhibited palytoxin-stimulated p38 activation. In HeLa cells, palytoxin stimulated the phosphorylation of MKK3 in addition to SEK1 and MKK6. In contrast to COS7 cells, in HeLa cells expression of a dominant negative mutant of SEK1 did not inhibit palytoxin-stimulated activation of p38, although expression of dominant negative mutants of either MKK3 or MKK6 did inhibit palytoxin-stimulated p38 activation in this cell type. These studies indicate that the importance of SEK1 in the activation of p38 by palytoxin depends on the ability of palytoxin to activate MKK3 and MKK6.
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PMID:Cell-type-specific activation of p38 protein kinase cascades by the novel tumor promoter palytoxin. 1052 9

Interleukin 1beta (IL-1beta) induces expression of the inducible nitric-oxide synthase (iNOS) with concomitant release of nitric oxide (NO) from glomerular mesangial cells. These events are preceded by activation of the c-Jun NH(2)-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38(MAPK). Our current study demonstrates that overexpression of the dominant negative form of JNK1 or p54 SAPKbeta/JNK2 significantly reduces the iNOS protein expression and NO production induced by IL-1beta. Similarly, overexpression of the kinase-dead mutant form of p38alpha(MAPK) also inhibits IL-1beta-induced iNOS expression and NO production. In previous studies we demonstrated that IL-1beta can activate MKK4/SEK1, MKK3, and MKK6 in renal mesangial cells; therefore, we examined the role of these MAPK kinases in the modulation of iNOS induced by IL-1beta. Overexpression of the dominant negative form of MKK4/SEK1 decreases IL-1beta-induced iNOS expression and NO production with inhibition of both SAPK/JNK and p38(MAPK) phosphorylation. Overexpression of the kinase-dead mutant form of MKK3 or MKK6 demonstrated that either of these two mutant kinase inhibited IL-1beta-induced p38(MAPK) (but not JNK/SAPK) phosphorylation and iNOS expression. Interestingly overexpression of wild type MKK3/6 was associated with phosphorylation of p38(MAPK); however, in the absence of IL-1beta, iNOS expression was not enhanced. This study suggests that the activation of both SAPK/JNK and p38alpha(MAPK) signaling cascades are necessary for the IL-1beta-induced expression of iNOS and production of NO in renal mesangial cells.
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PMID:Both p38alpha(MAPK) and JNK/SAPK pathways are important for induction of nitric-oxide synthase by interleukin-1beta in rat glomerular mesangial cells. 1059 6

The serine/threonine kinase Cot is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family implicated in cellular transformation. Enhanced expression of this protein has been shown to activate both the MAPK and the c-Jun N-terminal kinase (JNK) pathways and to stimulate the nuclear factor of activated T cells and NF-kappaB-dependent transcription. However, the nature of the normal functions of the Cot protein and the molecular mechanisms responsible for its oncogenic potential are still largely unknown. Here, we show that overexpression of the cot proto-oncogene is sufficient to stimulate the expression of c-jun and that, in turn, the activity of c-Jun is required for Cot-induced transformation. These observations prompted us to explore the molecular events by which Cot regulates c-jun expression. We found that Cot potently stimulates the activity of the c-jun promoter utilizing JNK-dependent and -independent pathways, the latter involving two novel members of the MAPK family, p38gamma (ERK6) and ERK5. Molecularly, this activity was found to be dependent on the ability of Cot to activate, in vivo, members of each class of the MAPK kinase superfamily, including MEK, SEK, MKK6, and MEK5. Furthermore, the use of dominant interfering molecules revealed that Cot requires JNK, p38s, and ERK5 to stimulate the c-jun promoter fully and to induce neoplastic transformation. These findings indicate that Cot represents the first example of a serine/threonine kinase acting simultaneously on all known MAPK cascades. Moreover, these observations strongly suggest that the transforming ability of Cot results from the coordinated activation of these pathways, which ultimately converge on the regulation of the expression and activity of the product of the c-jun proto-oncogene.
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PMID:Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation. 1066 51

Clostridium difficile toxin A causes acute neutrophil infiltration and intestinal mucosal injury. In cultured cells, toxin A inactivates Rho proteins by monoglucosylation. In monocytes, toxin A induces IL-8 production and necrosis by unknown mechanisms. We investigated the role of mitogen-activated protein (MAP) kinases in these events. In THP-1 monocytic cells, toxin A activated the 3 main MAP kinase cascades within 1 to 2 minutes. Activation of p38 was sustained, whereas stimulation of extracellular signal-regulated kinases and c-Jun NH(2)-terminal kinase was transient. Rho glucosylation became evident after 15 minutes. IL-8 gene expression was reduced by 70% by the MEK inhibitor PD98059 and abrogated by the p38 inhibitor SB203580 or by overexpression of dominant-negative mutants of the p38-activating kinases MKK3 and MKK6. SB203580 also blocked monocyte necrosis and IL-1beta release caused by toxin A but not by other toxins. Finally, in mouse ileum, SB203580 prevented toxin A-induced neutrophil recruitment by 92% and villous destruction by 90%. Thus, in monocytes exposed to toxin A, MAP kinase activation appears to precede Rho glucosylation and is required for IL-8 transcription and cell necrosis. p38 MAP kinase also mediates intestinal inflammation and mucosal damage induced by toxin A.
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PMID:p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. 1077 60

The transcriptional induction of SPRR1B by phorbol 12-myristate 13-acetate (PMA) is mainly mediated by the first -152-base pair 5'-flanking region containing two functional AP-1 sites. In this study, we have analyzed the signaling pathways that mediate the induction in tracheobronchial epithelial cells. PKC inhibitor ablated PMA-stimulated expression of endogenous SPRR1B and reporter gene expression driven by SPRR1B promoter. PKC activator promoted the transcription. The dominant negative protein kinase Cdelta (dn-PKCdelta) and rottlerin (PKCdelta inhibitor) completely suppressed PMA-stimulated promoter activity. dn-Ras or dn-MEKK1 inhibited PMA-stimulated promoter activity, while their corresponding constitutively active mutants augmented it. dn-c-Raf-1 did not have any effect on reporter gene expression. Since MEKK1 activates multiple parallel pathways, we examined involvement of JNK/SAPK, p38, and MKK1 in promoter regulation. Co-expression of the dominant negative forms of MKK4, MKK7, JNK/SAPK, MKK3, MKK6, or p38alpha did not suppress PMA-stimulated reporter gene expression. However, MKK1 inhibitors UO126 and PD98095 suppressed gene expression. Consistent with this, expression of dn-MKK1 strongly suppressed PMA-stimulated promoter activity, while the constitutively active MKK1 augmented it. However, MKK1-mediated induction of SPRR1B probably does not depend on extracellular signal-regulated kinases 1 and 2, suggesting the requirement of another kinase(s). dn-c-Jun mutants abolished PMA-stimulated expression supporting an important role for AP-1 proteins in SPRR1B expression. Together, these results suggest that a PKCdelta/Ras/MEKK1/MKK1-dependent/AP-1 pathway regulates the PMA-inducible expression of the SPRR1B in tracheobronchial epithelial cells.
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PMID:Phorbol ester-induced expression of airway squamous cell differentiation marker, SPRR1B, is regulated by protein kinase Cdelta /Ras/MEKK1/MKK1-dependent/AP-1 signal transduction pathway. 1091 63

We examined the pattern of activation and deactivation of the stress-activated protein kinase signalling molecules c-Jun NH2-terminal kinase (JNK) and p38 kinase in skeletal muscle in response to prolonged strenuous running exercise in human subjects. Male subjects (n = 14; age 32 +/- 2 years; VO2,max 60 +/- 2 ml kg-1 min-1) completed a 42.2 km marathon (mean race time 3 h 35 min). Muscle biopsies were obtained 10 days prior to the marathon, immediately following the race, and 1, 3 and 5 days after the race. The activation of JNK and p38, including both p38alpha and p38gamma, was measured with immune complex assays. The phosphorylation state of p38 (alpha and gamma) and the upstream regulators of JNK and p38, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 6 (MKK6), were assessed using phosphospecific antibodies. JNK activity increased 7-fold over basal level immediately post-exercise, but decreased back to basal levels 1, 3 and 5 days after the exercise. p38gamma phosphorylation (4-fold) and activity (1.5-fold) increased immediately post-exercise and returned to basal levels at 1, 3 and 5 days following exercise. In contrast, p38alpha phosphorylation and activity did not change over the time course studied. MKK4 and MKK6 phosphorylation increased and decreased in a trend similar to that observed with JNK activity and p38gamma phosphorylation. Prolonged running exercise did not affect JNK, p38alpha, or p38gamma protein expression in the days following the race. This study demonstrates that both JNK and p38 intracellular signalling cascades are robustly, yet transiently increased following prolonged running exercise. The differential activation of the p38 isoforms with exercise in human skeletal muscle indicates that these proteins may have distinct functions in vivo.
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PMID:Marathon running transiently increases c-Jun NH2-terminal kinase and p38 activities in human skeletal muscle. 1092 16

Protein phosphatase 2C (PP2C) is implicated in the negative regulation of stress-activated protein kinase cascades in yeast and mammalian cells. In this study, we determined the role of PP2Cbeta-1, a major isoform of mammalian PP2C, in the TAK1 signaling pathway, a stress-activated protein kinase cascade that is activated by interleukin-1, transforming growth factor-beta, or stress. Ectopic expression of PP2Cbeta-1 inhibited the TAK1-mediated mitogen-activated protein kinase kinase 4-c-Jun amino-terminal kinase and mitogen-activated protein kinase kinase 6-p38 signaling pathways. In vitro, PP2Cbeta-1 dephosphorylated and inactivated TAK1. Coimmunoprecipitation experiments indicated that PP2Cbeta-1 associates with the central region of TAK1. A phosphatase-negative mutant of PP2Cbeta-1, PP2Cbeta-1 (R/G), acted as a dominant negative mutant, inhibiting dephosphorylation of TAK1 by wild-type PP2Cbeta-1 in vitro. In addition, ectopic expression of PP2Cbeta-1(R/G) enhanced interleukin-1-induced activation of an AP-1 reporter gene. Collectively, these results indicate that PP2Cbeta negatively regulates the TAK1 signaling pathway by direct dephosphorylation of TAK1.
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PMID:Regulation of the TAK1 signaling pathway by protein phosphatase 2C. 1110 63


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