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

We have examined the regulation of the c-Jun NH2-terminal kinase (JNK) subfamily of mitogen-activated protein kinases (MAPKs) in response to inhibition of DNA replication during the cell cycle of human T-lymphocytes. In this study, we demonstrate that JNK is rapidly activated following release of T-lymphocytes from G1/S-phase arrest and that this activation precedes resumption of DNA synthesis upon S-phase progression. We also show that activation of JNK correlates with dissociation of the cyclin-dependent protein kinase (CDK) inhibitor, p21WAF1, from JNK1. Since JNK1 isolated from T-lymphocytes by immunoprecipitation can be inhibited by recombinant p21WAF1 in vitro, these data suggest that JNK activation may be regulated in part by its dissociation from p21WAF1. The observation of a dynamic, physical association of native JNK1 and p21WAF1 in vivo has not previously been described and suggests a novel mechanism for JNK-mediated regulation of the cell cycle of human T-lymphocytes.
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PMID:p21WAF1 is dynamically associated with JNK in human T-lymphocytes during cell cycle progression. 966 46

The urokinase-type plasminogen activator receptor (u-PAR) has been implicated in tumor progression, and previous studies have shown that the expression of this gene is strongly up-regulated by PMA. Although the signaling mechanism by which PMA modulates u-PAR expression is not known, the effect of this phorbol ester on the expression of other genes has been ascribed to activation of the c-Raf-1-ERK signaling pathway. However, in the current study we examined an alternate possibility that the inductive effect of PMA on u-PAR expression also required a JNK1-dependent signaling cascade usually associated with stress-inducing stimuli. PMA treatment of the u-PAR-deficient OVCAR-3 ovarian cancer cells, which contain low JNK activities, resulted in a rapid (5 min) increase in JNK activity. Maximal JNK activity (12-fold induction) occurred after 30 min; this preceding the earliest detected rise in u-PAR protein (2 h). Dose-response studies with PMA also indicated that the increased JNK activity was tightly correlated with elevated u-PAR protein levels. The stimulation of u-PAR promoter activity by PMA required an intact upstream AP-1 motif (-184) and in PMA-treated cells this motif was bound with c-Jun as indicated from mobility shift assays. PMA up-regulated the c-Jun trans acting activity as indicated by the higher activity of a GAL4-regulated luciferase reporter in phorbol-ester-treated cells co-transfected with an expression vector encoding the c-Jun transactivation domain fused to the GAL4 DNA-binding domain. The ability of PMA to stimulate u-PAR promoter activity was effectively titrated out by the co-expression of either a kinase-defective JNK1 or a dominant negative MEKK1 the latter being an upstream activator of JNK1. Conversely, u-PAR promoter activity was stimulated by the co-expression of a constitutively active MEKK1 and this induction was antagonized by the inclusion of the kinase-defective JNK1 plasmid. We also determined the biological significance of the JNK1-dependent signaling cascade in regulating u-PAR promoter activity by c-Ha-ras since this oncogene is activated and/or overexpressed in a variety of tumors including ovarian cancer. Transfection of an activated c-Ha-ras into OVCAR-3 cells stimulated u-PAR promoter activity over 20-fold and this could be countered by the individual expression of dominant negative expression constructs to Rac-1, MEKK1 or JNK1. Taken together, these data suggest that the PMA- or c-Ha-Ras-dependent stimulation of u-PAR gene expression requires a JNK1-dependent signaling module and that, at least for PMA, the concurrent stimulation of a JNK1-independent signaling module is also required. Thus, caution should be exercised in invoking linear signaling modules to account for the regulation of inducible gene expression.
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PMID:Stimulation of urokinase-type plasminogen activator receptor expression by PMA requires JNK1-dependent and -independent signaling modules. 967 6

Prostaglandin receptors may be activated by their cognate ligand or by free radical catalyzed isoprostanes, products of arachidonic acid peroxidation. For example, prostaglandin F2alpha (PGF2alpha) causes hypertrophy of neonatal rat ventricular myocytes, via the PGF2alpha receptor (FP). However, the FP may also be activated by the isoprostane, 8,12-iso-iPF2alpha-III (Kunapuli, P., Lawson, J. A., Rokach, J., and FitzGerald, G. A. (1997) J. Biol. Chem. 272, 27147-27154). Both ligands induce myocyte hypertrophy with overlapping potencies. Interestingly, the hypertrophic effects of these two agonists on cardiomyocytes are additive. Furthermore, the preference of these two agonists for activation of intracellular signal transduction pathways differs in several respects. Thus, PGF2alpha and 8,12-iso-iPF2alpha-III stimulate inositol phosphate formation with EC50 values of 50 +/- 12 nM and 3.5 +/- 0.6 microM, respectively. Moreover, PGF2alpha causes a robust activation ( approximately 50-fold) of Erk2, whereas 8,12-iso-iPF2alpha-III has no effect. Similarly, PGF2alpha causes translocation of cytosolic phospholipase A2 and also results in a 7-fold increment in the formation of 6-keto-PGF1alpha, whereas 8,12-iso-iPF2alpha-III exerts no effect on this pathway. On the other hand, both agonists are equally potent in activating JNK1 and c-Jun, whereas neither activates the p38 kinase. Both PGF2alpha and 8,12-iso-iPF2alpha-III activate the p70S6 kinase (p70(S6K)), but not Akt, downstream of phosphatidylinositol-3-kinase (PI3K). However, both wortmannin, a PI3K inhibitor, and rapamycin, an inhibitor of p70(S6K) activity, inhibit 8,12-iso-iPF2alpha-III -induced myocyte hypertrophy, with IC50 values of 60 +/- 12 and 3 +/- 1.7 nM, respectively, whereas neither compound abrogates the PGF2alpha-mediated response. Thus, both PGF2alpha and 8,12-iso-iPF2alpha-III induce myocyte hypertrophy via discrete signaling pathways. Although both agonists signal via the JNK pathway to initiate changes in c-Jun-dependent gene transcription, PGF2alpha preferentially activates the MEK-Erk2- cytosolic phospholipase A2 pathway. In contrast, the PI3K-p70(S6K) pathway appears to be essential for 8,12-iso-iPF2alpha-III-induced myocyte hypertrophy.
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PMID:Prostaglandin F2alpha (PGF2alpha) and the isoprostane, 8, 12-iso-isoprostane F2alpha-III, induce cardiomyocyte hypertrophy. Differential activation of downstream signaling pathways. 971 68

Involucrin is a marker of keratinocyte terminal differentiation. Our previous studies show that involucrin mRNA levels are increased by the keratinocyte differentiating agent, 12-O-tetradecanoylphorbol-13-acetate (TPA) (Welter, J. F., Crish, J. F., Agarwal, C., and Eckert, R. L. (1995) J. Biol. Chem. 270, 12614-12622). We now study the signaling cascade responsible for this regulation. Protein kinase C and tyrosine kinase inhibitors inhibit both the TPA-dependent mRNA increase and the TPA-dependent increase in hINV promoter activity. The relevant response element is located within the promoter proximal regulatory region and includes an AP1 site, AP1-1. Co-transfection of the hINV promoter with dominant negative forms of Ras, MEKK1, MEK1, MEK7, MEK3, p38/RK, and c-Jun inhibit the TPA-dependent increase. Wild type MEKK1 enhances promoter activity and the activity can be inhibited by dominant negative MEKK1, MEK1, MEK7, MEK3, p38/RK, and c-Jun. In contrast, wild type Raf-1, ERK1, ERK2, MEK4, or JNK1 produced no change in activity and the dominant negative forms of these kinases failed to suppress TPA-dependent transcription. Treatment with an S6 kinase (S6K) inhibitor, or transfection with constitutively active S6K produced relatively minor changes in promoter activity, ruling out a regulatory role for S6K. These results suggest that activation of involucrin transcription involves a pathway that includes protein kinase C, Ras, MEKK1, MEK3, and p38/RK. Additional pathways that transfer MEKK1 activation via MEK1 and MEK7 also may function, but the downstream targets of these kinases need to be identified. AP1 transcription factors appear to be the ultimate target of this regulation.
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PMID:Regulation of human involucrin promoter activity by a protein kinase C, Ras, MEKK1, MEK3, p38/RK, AP1 signal transduction pathway. 973 28

c-Jun NH2-terminal kinases (JNKs) are protein kinases that are activated by a wide variety of extracellular signals. This study investigated the expression and regulation of JNKs in isolated gastric canine parietal cells. Western blot analysis of cell lysates from highly purified (>95%) parietal cells with an antibody recognizing JNK1 and to a lesser degree JNK2 revealed the presence of two bands of 46 and 54 kDa, respectively. JNK1 activity was quantitated by immunoprecipitation and in-gel kinase assays. Of the different agents tested, carbachol was the most potent inducer of JNK1 activity, whereas histamine and epidermal growth factor induced weaker responses. The proinflammatory cytokine tumor necrosis factor-alpha stimulated JNK1 but had no effect on extracellular signal-regulated kinase (ERK2) induction, suggesting that activation of JNK1 might represent an important event in mediation of the inflammatory response in the stomach. The action of carbachol was dose (0.1-100 microM) and time dependent, with a maximal stimulatory effect (fourfold) detected after 30 min of incubation and sustained for 2 h. Addition of the specific protein kinase C (PKC) inhibitor GF109203X did not affect the stimulatory action of carbachol. The intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid-AM inhibited carbachol induction of JNK1 activity by 60%. Thapsigargin (1 microM), an intracellular Ca2+-rising agent, induced JNK1 activity more than threefold. Carbachol activation of JNK1 resulted in induction of c-Jun (protein) transcriptional activity and in stimulation of parietal cell mRNA content of c-jun. In conclusion, our data indicate that carbachol induces JNK activity in gastric parietal cells via intracellular Ca2+-dependent, PKC-independent pathways, leading to induction of c-jun gene expression via phosphorylation and transcriptional activation of c-Jun.
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PMID:Regulation of c-Jun NH2-terminal kinases in isolated canine gastric parietal cells. 975 5

Paclitaxel (Taxol) is a novel anti-cancer drug that has shown efficacy toward several malignant tumors, particularly ovarian tumors. We reported previously that paclitaxel can induce interleukin (IL)-8 promoter activation in subgroups of ovarian cancer through the activation of both AP-1 and nuclear factor kappaB. Further analysis of paclitaxel analogs indicates that the degree of IL-8 induction by analysis correlates with the extent of cell death; however, IL-8 itself is not the cause of cell death. This suggests that pathways that lead to IL-8 and cell death may overlap, although IL-8 per se does not kill tumor cells. To decipher the upstream signals for paclitaxel-induced transcriptional activation and cell death, we studied the involvement of protein kinases that lead to the activation of AP-1, specifically the c-Jun NH2-terminal kinase (JNK1), p38, and the extracellular signal-regulated kinase 1 (ERK1). The role of IkappaB in paclitaxel-induced cell death was also analyzed. Paclitaxel activated JNK, and to a lesser degree p38, but not ERK1. Paclitaxel-induced IL-8 promoter activation was inhibited by dominant-inhibitory mutants of JNK, p38, and the super-repressor form of IkappaBalpha, but not by dominant-inhibitory forms of ERK1. Dominant-inhibitory mutants of JNK1 also greatly reduced paclitaxel-induced cell death, and the kinetics of JNK induction was closely followed by DNA fragmentation. These results indicate (i) that paclitaxel activates the JNK signaling pathway and (ii) that JNK activation is a common point of paclitaxel-induced gene induction and cell death.
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PMID:Paclitaxel (Taxol)-induced gene expression and cell death are both mediated by the activation of c-Jun NH2-terminal kinase (JNK/SAPK). 977 47

The inflammatory cytokine interleukin-1beta (IL-1beta) induces cyclooxygenase-2 (Cox-2) expression with a concomitant release of prostaglandins from glomerular mesangial cells. We reported previously that IL-1beta rapidly activates the c-Jun NH2-terminal/stress-activated protein kinases (JNK/SAPK) and p38 mitogen-activated protein kinase (MAPK) and also induces Cox-2 expression and prostaglandin E2 (PGE2) production. The current study demonstrates that overexpression of the dominant negative form of JNK1 or p54 JNK2/SAPKbeta reduces Cox-2 expression and PGE2 production stimulated by IL-1beta. Similarly, overexpression of the kinase-dead form of p38 MAPK also inhibits IL-1beta-induced Cox-2 expression and PGE2 production. These results suggest that activation of both JNK/SAPK and p38 MAPK is required for Cox-2 expression after IL-1beta activation. Furthermore, our experiments confirm that IL-1beta activates MAP kinase kinase-4 (MKK4)/SEK1, MKK3, and MKK6 in renal mesangial cells. Overexpression of the dominant negative form of MKK4/SEK1 decreases IL-1beta- induced Cox-2 expression with inhibition of both JNK/SAPK and p38 MAPK phosphorylation. Overexpression of the kinase-dead form of MKK3 or MKK6 demonstrated that either of these two mutant kinases inhibited IL-1beta-induced p38 MAPK phosphorylation and Cox-2 expression but not JNK/SAPK phosphorylation and activation. This study suggests that the activation of both JNK/SAPK and p38 MAPK signaling cascades is required for IL-1beta-induced Cox-2 expression and PGE2 synthesis.
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PMID:Interleukin-1beta-induced cyclooxygenase-2 expression requires activation of both c-Jun NH2-terminal kinase and p38 MAPK signal pathways in rat renal mesangial cells. 978 61

In previous reports we demonstrated that glucose deprivation induces metabolic oxidative stress in drug-resistant human breast carcinoma MCF-7/ADR cells (Lee, Y. J., Galoforo, S. S., Berns, c. M., Chen, J. C., Davis, B. H., Swim, J. E., Corry, P. M., and Spitz, D. R. (1998) J. Biol. Chem. 273, 5294-5299). In the study described here, we investigated intracellular responses to metabolic oxidative stress. Northern blots show an increase in the level of HSP70 and HSP28 mRNA in cells exposed to glucose-free medium for 1 h. One- and two-dimensional polyacrylamide gel analyses confirmed that glucose deprivation induced a family of HSPs, particularly an inducible HSP70. Overexpression of bcl-2 suppressed glucose deprivation-induced HSP70 gene expression, heat shock transcription factor-heat shock element binding activity, as well as c-Jun NH2-terminal kinase (JNK1) activation. Expression of a dominant-negative mutant of JNK1 also suppressed glucose deprivation-induced JNK1 activation as well as HSP70 gene expression. Taken together, the stress-activated protein kinase signal transduction pathway is involved in glucose deprivation-induced heat shock gene expression.
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PMID:Metabolic oxidative stress-induced HSP70 gene expression is mediated through SAPK pathway. Role of Bcl-2 and c-Jun NH2-terminal kinase. 979 2

Unmethylated CpG motifs in bacterial DNA, plasmid DNA and synthetic oligodeoxynucleotides (CpG ODN) activate dendritic cells (DC) and macrophages in a CD40-CD40 ligand-independent fashion. To understand the molecular mechanisms involved we focused on the cellular uptake of CpG ODN, the need for endosomal maturation and the role of the stress kinase pathway. Here we demonstrate that CpG-DNA induces phosphorylation of Jun N-terminal kinase kinase 1 (JNKK1/SEK/MKK4) and subsequent activation of the stress kinases JNK1/2 and p38 in murine macrophages and dendritic cells. This leads to activation of the transcription factor activating protein-1 (AP-1) via phosphorylation of its constituents c-Jun and ATF2. Moreover, stress kinase activation is essential for CpG-DNA-induced cytokine release of tumor necrosis factor alpha (TNFalpha) and interleukin-12 (IL-12), as inhibition of p38 results in severe impairment of this biological response. We further demonstrate that cellular uptake via endocytosis and subsequent endosomal maturation is essential for signalling, since competition by non-CpG-DNA or compounds blocking endosomal maturation such as chloroquine or bafilomycin A prevent all aspects of cellular activation. The data suggest that endosomal maturation is required for translation of intraendosomal CpG ODN sequences into signalling via the stress kinase pathway, where p38 kinase activation represents an essential step in CpG-ODN-triggered activation of antigen-presenting cells.
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PMID:CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation. 979 32

Phorone, a glutathione (GSH) depletor, induces the expression of mRNAs of heme oxygenase-1 (HO-1) and c-jun by mediating the activation of activated protein-1 (AP-1) in rat livers. We have shown that phorone activates c-Jun N-terminal kinase (JNK), thus leading to c-Jun phosphorylation, and transactivation of AP-1 and HO-1 gene expression in the rat liver in response to oxidative stress. The in-gel kinase assay showed that phorone activated JNK1 predominantly in the rat liver nuclear extract. The JNK activation by phorone was slightly observed at 1 hr after administration and gradually increased with time. Ser73-phosphorylation of c-Jun catalyzed by JNK was significantly altered by changing hepatic GSH levels based on the results observed by the combined injection of buthionine sulfoximine (BSO) or GSH isopropyl ester (GIP) with phorone. Namely, BSO, an inhibitor of GSH biosynthesis, enhanced phorone-mediated c-Jun phosphorylation as well as AP-1 binding activity. However, GSH isopropyl ester prevented GSH depletion and abolished both c-Jun phosphorylation and the activation of AP-1 binding evoked by phorone. GSH isopropyl ester also suppressed phorone-produced HO-1 and c-jun gene expressions to 25 and 30% of the induced level. Perfluorodecanoic acid (PFDA) reduced GSH S-transferase activity, prevented phorone-mediated GSH depletion and abolished either HO-1 or c-jun mRNA induction by phorone. These results indicated that oxidative stress under GSH depletion produced by phorone could activate preferentially JNK and lead to the transcriptional activation of AP-1 and consequently to HO-1 gene expression. This study suggests that JNK activation could be one of the major signaling pathways to transmit intracellular events to the nuclei during oxidative stress via GSH depletion by phorone in rat livers.
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PMID:The expression of heme oxygenase-1 gene responded to oxidative stress produced by phorone, a glutathione depletor, in the rat liver; the relevance to activation of c-jun n-terminal kinase. 980 9


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