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

Previous studies have shown that structurally diverse tumor promoters can modulate protein kinases involved in signal transduction. In this study, we show that palytoxin, a potent non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin tumor promoter, induces a signaling pathway leading to the activation of the stress-activated protein kinases/c-Jun N-terminal kinases (JNK) in Swiss 3T3 fibroblasts. Treatment of cells with doses as low as 0.1 mN palytoxin results in significant activation of JNK. In contrast to epidermal growth factor, which induces a transient activation of JNK in Swiss 3T3 cells, palytoxin causes prolonged enzyme activation. Since stimulation of ion flux appears to play an important role in the mechanism of action of palytoxin in other systems, we investigated the role of sodium and calcium in the activation of JNK: (a) our results show that incubation of Swiss 3T3 cells in a sodium-free medium dramatically reduced the magnitude of JNK activation by palytoxin; and (b) we found that the sodium ionophore gramicidin activates JNK. Together, these results suggest that sodium influx, which is a hallmark of palytoxin action, may play a key role in the activation of JNK by palytoxin. Our results indicate that calcium influx is not necessary or sufficient for palytoxin-induced activation of JNK. In contrast to palytoxin, the TPA-type tumor promoter phorbol 12,13-dibutyrate and the non-TPA-type tumor promoters thapsigargin and okadaic acid do not appear to activate JNK in this system. In contrast to phorbol 12,13-dibutyrate, palytoxin does not activate the p42/p44 mitogen-activated protein kinases. Our results demonstrate that Swiss 3T3 fibroblasts, palytoxin can activate a protein kinase signaling pathway that is distinct from that activated by the prototypical phorbol ester tumor promoters and other potent skin tumor promoters.
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PMID:Activation of stress-activator protein kinase/c-Jun N-terminal kinase by the non-TPA-type tumor promoter palytoxin. 856 84

Certain small GTP-binding proteins control the enzymatic activity of a family of closely related serine-threonine kinases known as mitogen-activated protein kinases (MAPKs). In turn, these MAPKs, such as p44(mapk) and p42(mapk), referred to herein as MAPKs, and stress-activated protein kinases, also termed c-Jun N-terminal kinases (JNKs), phosphorylate and regulate the activity of key molecules that ultimately control the expression of genes essential for many cellular processes. Whereas Ras controls the activation of MAPK, we and others have recently observed that two members of the Rho family of small GTP-binding proteins, Rac1 and Cdc42, regulate the activity of JNKs. The identity of molecules communicating Rac1 and Cdc42 to JNK is still poorly understood. It has been suggested that Pak1 is the most upstream kinase connecting these GTPases to JNK; however, we have observed that coexpression of Pak1 with activated forms of Cdc42 or Rac1 diminishes rather than enhances JNK activation. This prompted us to explore the possibility that kinases other than Pak might participate in signaling from GTP-binding proteins to JNK. In this regard, a computer-assisted search for proteins containing areas of homology to that in Pak1 that is involved in binding to Rac1 and Cdc42 led to the identification of mixed lineage kinase 3 (MLK3), also known as protein-tyrosine kinase 1, as a potential candidate for this function. In this study, we found that MLK3 overexpression is sufficient to activate JNK potently without affecting the phosphorylating activity of MAPK or p38. Furthermore, we present evidence that MLK3 binds the GTP-binding proteins Cdc42 and Rac1 in vivo and that MLK3 mediates activation of MEKK-SEK-JNK kinase cascade by Rac1 and Cdc42. Taken together, these findings strongly suggest that members of the novel MLK family of highly related kinases link small GTP-binding proteins to the JNK signaling pathway.
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PMID:Signaling from the small GTP-binding proteins Rac1 and Cdc42 to the c-Jun N-terminal kinase/stress-activated protein kinase pathway. A role for mixed lineage kinase 3/protein-tyrosine kinase 1, a novel member of the mixed lineage kinase family. 891 Feb 92

Stimulation of HEL 299 cells with tumor necrosis factor alpha (TNF-alpha) or interleukin 1beta (IL-1beta) had no effect on M2 muscarinic receptor expression. However, the combination of these two cytokines markedly down-regulated muscarinic M2 receptor protein and mRNA expression and uncoupled M2 receptors from adenylyl cyclase. There was no effect of TNF-alpha and IL-1beta on the m2 muscarinic receptor mRNA stability, and nuclear run-on assays showed reduced m2 receptor gene transcription. Sequential cytokine addition suggests that the synergy involves postreceptor events. Although the cAMP-dependent protein kinase inhibitor H8 provided a significant protection against receptor down-regulation, the protein kinase C inhibitor GF109203X had no effect. The ceramide analog C2-ceramide (N-acetylsphingosine) was without effect on m2 receptor expression. However, a strong synergistic effect was demonstrated when cells were treated with the combination of C2-ceramide and TNF-alpha or IL-1beta. TNF-alpha and/or IL-1beta combination also activated the 46- and 55-kDa c-Jun NH2-terminal protein kinases and to a lesser extent p42 and p44 mitogen-activated protein kinase isoforms. Cycloheximide abolished the TNF-alpha and IL-1beta effect, suggesting that de novo protein synthesis is required for receptor down-regulation. These results suggest that the TNF-alpha and IL-1beta synergize to induce transcriptional down-regulation of the M2 muscarinic receptor, which seems to be mediated through activation of both ceramide and cAMP-dependent protein kinase pathways. Furthermore, these results suggest that M2 receptor expression is under the control of a cytokine network.
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PMID:Synergy between tumor necrosis factor alpha and interleukin 1beta in inducing transcriptional down-regulation of muscarinic M2 receptor gene expression. Involvement of protein kinase A and ceramide pathways. 895 85

Endothelin-1 (ET-1) is known to induce the contraction and proliferation of glomerular mesangial cells. ET-1 has been shown to activate p42 and p44 mitogen-activated protein kinases (MAPKs), also known as extracellular signal regulated kinases (ERKs), through both protein kinase C (PKC) and protein tyrosine kinase (PTK)-dependent pathways. However, an involvement of c-Jun NH2-terminal kinase (JNK), one of members of the MAPK family, in ET-1 signaling in mesangial cells has not yet been elucidated. To clarify this point, we examined whether ET-1 could activate JNK and the mechanism of activation in cultured mesangial cells. ET-1 enhanced the activities of JNK in a dose-dependent (10(-8) M maximum) and time-dependent manner, with a peak at 15 minutes. ET-1-induced activation of JNK was blocked by BQ-123, an antagonist for the ETA receptor. The depletion of PKC by prolonged treatment with phorbol 12,13 dibutyrate or the inhibition of PKC by GF 109203X failed to inhibit ET-1-induced activation of JNK. In contrast, ET-1-induced activation of JNK was significantly reduced by calcium chelation (with BAPTA/AM and EGTA). In addition, ionomycin, a calcium ionophore, and thapsigargin, an intracellular calcium-rising agent, were able to induce the activation of JNK. ET-1-induced activation of JNK was also inhibited by PTK inhibitors (herbimycin A and genistein). Furthermore, ET-1 increased the DNA-binding activity of AP-1 containing c-Jun and c-Fos proteins. These results indicate that ET-1 is able to activate JNK in glomerular mesangial cells through PKC-independent and PTK-dependent pathways and intracellular calcium is necessary to the activation of JNK.
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PMID:Endothelin-1 activates c-Jun NH2-terminal kinase in mesangial cells. 906 93

Heparin-binding epidermal growth factor (HB-EGF) gene transcription is rapidly activated in NIH 3T3 cells transformed by oncogenic Ras and Raf and mediates the autocrine activation of the c-Jun N-terminal kinases (JNKs) observed in these cells. A 1.7-kb fragment of the promoter of the murine HB-EGF gene linked to a luciferase reporter was strongly induced following activation of deltaRaf-1:ER, a conditionally active form of oncogenic human Raf-1. Promoter activation by deltaRaf-1:ER required a composite AP-1/Ets transcription factor binding site located between bp -974 and -988 upstream of the translation initiation site. In vivo genomic footprinting indicated that the basal level of occupancy of this composite AP-1/Ets element increased following deltaRaf-1:ER activation. Cotransfection of Ets-2 and p44 mitogen-activated protein (MAP) kinase expression vectors strongly potentiated HB-EGF promoter activation in response to deltaRaf-1:ER. Potentiated activation required both p44 MAP kinase catalytic activity and threonine 72 in the Pointed domain of Ets-2. Biochemical assays demonstrated the ability of the p42 and p44 MAP kinases to phosphorylate Ets-2 on threonine 72. Importantly, in intact cells, the kinetics of phosphorylation of Ets-2 on this residue closely mirror the activation of the p42 and p44 MAP kinases and the observed onset of HB-EGF gene transcription following deltaRaf-1:ER activation. These data firmly establish Ets-2 as a direct target of the Raf-MEK-MAP kinase signaling pathway and strongly implicate Ets-2 in the regulation of HB-EGF gene expression.
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PMID:Rapid phosphorylation of Ets-2 accompanies mitogen-activated protein kinase activation and the induction of heparin-binding epidermal growth factor gene expression by oncogenic Raf-1. 911 9

We characterized participation of the stress-activated protein kinase (SAPK) cascade in the lethal actions of the cytotoxic lipid messengers ceramide and sphingosine in U937 human monoblastic leukemia cells. Acute exposure of U937 cells to either lipid resulted in loss of proliferative capacity, degradation of genomic DNA, and manifestation of apoptotic cytoarchitecture. Ceramide robustly stimulated p46-JNK1/p54-JNK2 activity and increased expression of c-jun mRNA and c-Jun protein; in contrast, sphingosine moderately stimulated p46-JNK1/p54-JNK2 and failed to modify c-jun/c-Jun expression. Dominant-negative blockade of normal c-Jun activity by transfection with the TAM-67 c-Jun NH2-terminal deletion mutant abolished the lethal actions of ceramide but was without effect on those of sphingosine, indicating that ceramide-related apoptosis is directly dependent on activation of c-Jun, whereas sphingosine-induced cell death proceeds via an unrelated downstream mechanism. Characterization of the mitogen-activated protein kinase (MAPK) cascade in these responses revealed a further functional disparity between the two lipids: basal p42-ERK1/ p44-ERK2 activity was gradually reduced by ceramide but immediately and completely suppressed by sphingosine. Moreover, blockade of the MAPK cascade by the aminomethoxyflavone MEK1 inhibitor PD-98059 unexpectedly activated p46-JNK1/p54-JNK2 and induced apoptosis in a manner qualitatively resembling that of sphingosine. Both lipids sharply increased p38-RK activity; selective pharmacological inhibition of p38-RK by the pyridinyl imidazole SB-203580 failed to mitigate the cytotoxicity associated with either ceramide or sphingosine, suggesting that p38-RK is not essential for lipid-induced apoptosis. These findings demonstrate that reciprocal alterations in the SAPK and MAPK cascades are associated with the apoptotic influence of either lipid inasmuch as (i) ceramide-mediated lethality is primarily associated with strong stimulation of SAPK and weak inhibition of MAPK, whereas (ii) sphingosine-mediated lethality is primarily associated with weak stimulation of SAPK and strong inhibition of MAPK. We therefore propose that leukemic cell survival depends on the maintenance of an imbalance of the outputs from the MAPK and SAPK systems such that the dominant basal influence of the MAPK cascade allows sustained proliferation, whereas acute redirection of this balance toward the SAPK cascade initiates apoptotic cell death.
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PMID:Coordinate regulation of stress- and mitogen-activated protein kinases in the apoptotic actions of ceramide and sphingosine. 941 3

The in vivo signal transduction pathway, responsible for hypertension-induced glomerular injury, remains to be clarified. In this study, the effect of angiotensin II (Ang II)-induced hypertension was examined on glomerular mitogen activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK), and on glomerular transcription factors activator protein-1 (AP-1) and Sp 1. MAPK activities were determined by in-gel kinase assay. DNA binding activity of AP-1 and Sp 1 was determined by gel mobility shift assay. Continuous infusion of Ang II (1000 ng/kg per min, intravenously) to conscious rats rapidly increased BP, followed by the rapid and transient activation of glomerular p42 and p44 ERK and p46 and p55 JNK with the peak at 15 to 180 min. Glomerular AP-1 binding activity was increased 2.6-fold (P < 0.01) at 24 h after the start of Ang II infusion. Supershift analysis showed that the activated AP-1 complexes contained c-Fos and c-Jun proteins. On the other hand, glomerular Sp 1 DNA binding activity was not changed throughout 7 d of Ang II infusion. These results provided the first in vivo evidence that Ang II-induced hypertension causes the activation of glomerular ERK and JNK, leading to the activation of AP-1. Thus, ERK and JNK signaling cascades, via the activation of AP-1, may be implicated in the development of hypertension-induced glomerular injury.
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PMID:Activation of glomerular mitogen-activated protein kinases in angiotensin II-mediated hypertension. 951 99

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine that elicits a large number of biological effects. However, the intracellular signaling mechanisms that are responsible for the TNF-alpha effects remain largely unknown. We have previously demonstrated that cultured mouse Sertoli cells, after TNF-alpha treatment, increase the surface expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and interleukin-6 (IL-6) production (Riccioli, A., Filippini, A., De Cesaris, P., Barbacci, E., Stefanini, M., Starace, G., and Ziparo, E. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 5808-5812). Here, we show that, in cultured Sertoli cells, TNF-alpha activates the mitogen-activated protein kinase pathway (p38, c-Jun N-terminal protein kinase/stress-activated protein kinase, and the p42/p44 mitogen-activated protein kinases) as revealed by an increased phosphorylation of p38, activating transcription factor-2, c-Jun, and Elk-1. Furthermore, our data indicate that the biological effects induced by TNF-alpha in Sertoli cells (enhancement of ICAM-1, VCAM-1, and IL-6 expression) depend on the activation of different signaling pathways. SB203580, a highly specific p38 inhibitor, does not affect ICAM-1 and VCAM-1 expression, but strongly inhibits IL-6 production. Moreover, interferon-gamma, which up-regulates adhesion molecule expression and reduces IL-6 production, does not induce phosphorylation of p38. Our data strongly support the hypothesis that, in response to TNF-alpha, activation of p38 leads to IL-6 production, whereas ICAM-1 and VCAM-1 expression could be induced by activation of the c-Jun N-terminal protein kinase/stress-activated protein kinase pathway.
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PMID:Tumor necrosis factor-alpha induces interleukin-6 production and integrin ligand expression by distinct transduction pathways. 951 59

After treatment with TCDD, the activities of cytosolic AhR-associated c-Src kinase, microsomal protein kinase C (nPKC epsilon), microsomal c-Src kinase, nuclear p44/42 MAPK, c-Jun N terminus kinase, and the amount of microsomal pan-Ras protein were different in males and females. TCDD did not decrease body or adipose tissue weights in transgenic src-deficient male mice as compared to their wild-type littermates, and the activity of AhR-associated c-Src kinase was not increased by TCDD in src-deficient male mice. Similar results were obtained when TCDD was given to male guinea pigs treated with the Src-kinase inhibitor, geldanamycin. Treatment with estradiol protected male guinea pigs from TCDD-induced wasting. TCDD induced similar changes in protein tyrosine kinase activity in adipose tissues of castrated male and intact female guinea pigs. The gender-specific mechanisms of TCDD-induced toxicity appear to involve c-Src kinase, nPKC epsilon, and pan-Ras, as well as overlap in the cytosolic signal transduction pathways of TCDD and sex steroids.
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PMID:Mechanisms of gender-specific TCDD-induced toxicity in guinea pig adipose tissue. 962 58

The alpha-chemokine stromal cell-derived factor (SDF)-1alpha binds to the seven transmembrane G-protein-coupled CXCR-4 receptor and acts to modulate cell migration and proliferation. The signaling pathways that mediate the effects of SDF-1alpha are not well characterized. We studied events following SDF-1alpha binding to CXCR-4 in a model murine pre-B cell line transfected with human CXCR-4. There was enhanced tyrosine phosphorylation and association of components of focal adhesion complexes such as the related adhesion focal tyrosine kinase, paxillin, and Crk. We also observed activation of phosphatidylinositol 3-kinase. Wortmannin, a selective inhibitor of phosphatidylinositol 3-kinase, partially inhibited the SDF-1alpha-induced migration and tyrosine phosphorylation of paxillin. SDF-1alpha treatment selectively activated p44/42 mitogen-activated protein kinase (Erk 1 and Erk 2) and its upstream kinase mitogen-activated protein kinase kinase but not p38 mitogen-activated protein kinase, c-Jun amino-terminal kinase or mitogen activated protein kinase kinase. We also observed that SDF-1alpha treatment increased NF-kappaB activity in nuclear extracts from the CXCR-4 transfectants. Taken together, these studies revealed that SDF-1alpha activates distinct signaling pathways that may mediate cell growth, migration, and transcriptional activation.
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PMID:The alpha-chemokine, stromal cell-derived factor-1alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. 972 46


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