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)

Previous studies have demonstrated that transient hypoxia (6 h) induces apoptotic death in cultured neurons isolated from the fetal rat forebrain. Since activation of c-Jun N-terminal kinases (JNKs) and subsequent phosphorylation of c-Jun are suspected to be involved in the apoptotic pathway in several cell types, the time course of activator protein-1 (AP-1) DNA-binding, in line with induction of the AP-1 components and JNK activation, was examined during hypoxia/reoxygenation in the same model. Gel shift analysis depicted the presence of functional AP-1 transcription factors in both control and hypoxic neurons. One hour after the onset of hypoxia, all AP-1 components were markedly overexpressed. They include c-Jun, Jun B, Jun D, c-Fos and Fos-related antigens. Whereas, only c-Jun remained elevated for up to 96 h post-reoxygenation, time at which neurons were injured, other gene products showed patterned induction/repression as hypoxia progressed and then during the post-reoxygenation period, with Fos-related antigens being finally induced at 96 h. Only JNK1 was constitutively detected in cultured neurons, and its expression was inhibited during hypoxia. Nonetheless, both JNK1 and JNK3 were markedly, but transiently, induced at 48 h post-reoxygenation, when apoptosis-related morphological features became apparent. These data support the hypothesis that transient hypoxia, independently of ischemia, may trigger apoptosis through JNK signaling pathway in developing brain neurons.
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PMID:Sequential activation of activator protein-1-related transcription factors and JNK protein kinases may contribute to apoptotic death induced by transient hypoxia in developing brain neurons. 983 68

The c-Jun NH2-terminal kinase (JNK) signaling pathway has been implicated in the immune response that is mediated by the activation and differentiation of CD4 helper T (TH) cells into TH1 and TH2 effector cells. JNK activity observed in wild-type activated TH cells was severely reduced in TH cells from Jnk1-/- mice. The Jnk1-/- T cells hyperproliferated, exhibited decreased activation-induced cell death, and preferentially differentiated to TH2 cells. The enhanced production of TH2 cytokines by Jnk1-/- cells was associated with increased nuclear accumulation of the transcription factor NFATc. Thus, the JNK1 signaling pathway plays a key role in T cell receptor-initiated TH cell proliferation, apoptosis, and differentiation.
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PMID:Defective T cell differentiation in the absence of Jnk1. 985 32

We tested the coupling of endothelin receptors to mitogen-activated protein kinases (MAPK) and nuclear factor c-Jun in intact canine pulmonary artery smooth muscle. Muscle rings denuded of endothelium were stimulated with 10(-7)M ET-1 and frozen during contraction. An <<in-gel>> kinase assay with myelin basic protein as substrate revealed protein kinase activities at 98, 75, 55, 50, 44 and 40 kDa. Erk1 and Erk2 MAPK were activated by ET-1 to 5.4+/-0.97 and 4.03+/-1. 54 times basal activity at 10 min. Using phospho-specific antibodies, we found increased threonine/tyrosine phosphorylation of p38 and JNK1 MAPK to 2.04+/-0.47 and 2.56+/-0.72 times basal. ET-1 increased the phosphorylation level of nuclear factor c-Jun with a time-course closely matching the activation of JNK1 and p38 MAPK. Therefore, endothelin receptors initiate intracellular signals leading to activation of Erk, p38 and JNK1 MAPK pathways and ultimately to nuclear targets. The activation of JNK1 MAPK seems closely related to the phosphorylation of nuclear transcription factor c-Jun.
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PMID:Endothelin-1 activates MAP kinases and c-Jun in pulmonary artery smooth muscle. 991 57

We have reported previously that native low-density lipoprotein (LDL) activates c-Jun and transcription factor AP-1 in human umbilical vein endothelial cells (HUVEC). The aim of this study was to elucidate the upstream signaling mechanisms mediating LDL activation of c-Jun/AP-1. Using a c-Jun NH2-terminal kinase (JNK) activity assay, we have detected an increase in JNK activity in LDL-exposed HUVEC, which started at 15 min and reached maximum activity after 1-2 h. This JNK activity, increased by LDL, occurred in a dose-dependent fashion starting at a concentration of 80 mg/dl of LDL and reaching maximum activation at a concentration of 160-240 mg/dl. Following cotransfection, the increase of AP-1 driven luciferase activity by LDL was attenuated 54% by a kinase-deficient JNK1. Furthermore, a specific trans-reporting system was utilized to confirm c-Jun activation by upstream signal mechanisms. The results show c-Jun activity increased by 3-fold after LDL exposure when compared with respective controls. In contrast, LDL exposure did not affect the activation of extracellular signal regulated kinase 1 and 2 (ERK1/2), even though phorbol 12-myristate 13-acetate treatment remarkably increased the activity of these kinases. Thus, this study demonstrates, for the first time, that JNK mediates LDL-induced endothelial cell activation.
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PMID:Low-density lipoprotein activates Jun N-terminal kinase (JNK) in human endothelial cells. 998 85

Activation of c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases is an early response of cells upon exposure to DNA-damaging agents. JNK-mediated phosphorylation of c-Jun is currently understood to stimulate the transactivating potency of AP-1 (e.g., c-Jun/c-Fos; c-Jun/ATF-2), thereby increasing the expression of AP-1 target genes. Here we show that stimulation of JNK1 activity is not a general early response of cells exposed to genotoxic agents. Treatment of NIH 3T3 cells with UV light (UV-C) as well as with methyl methanesulfonate (MMS) caused activation of JNK1 and an increase in c-Jun protein and AP-1 binding activity, whereas antineoplastic drugs such as mafosfamide, mitomycin C, N-hydroxyethyl-N-chloroethylnitrosourea, and treosulfan did not elicit this response. The phosphatidylinositol 3-kinase inhibitor wortmannin specifically blocked the UV-stimulated activation of JNK1 but did not affect UV-driven activation of extracellular regulated kinase 2 (ERK2). To investigate the significance of JNK1 for transactivation of c-jun, we analyzed the effect of UV irradiation on c-jun expression under conditions of wortmannin-mediated inhibition of UV-induced stimulation of JNK1. Neither the UV-induced increase in c-jun mRNA, c-Jun protein, and AP-1 binding nor the activation of the collagenase and c-jun promoters was affected by wortmannin. In contrast, the mitogen-activated protein kinase/ERK kinase inhibitor PD98056, which blocked ERK2 but not JNK1 activation by UV irradiation, impaired UV-driven c-Jun protein induction and AP-1 binding. Based on the data, we suggest that JNK1 stimulation is not essential for transactivation of c-jun after UV exposure, whereas activation of ERK2 is required for UV-induced signaling leading to elevated c-jun expression.
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PMID:Activation of c-Jun N-terminal kinase 1 by UV irradiation is inhibited by wortmannin without affecting c-iun expression. 1002 64

To understand the role of redox-sensitive mechanisms in vascular smooth muscle cell (VSMC) growth, we have studied the effect of N-acetylcysteine (NAC), a thiol antioxidant, and diphenyleneiodonium (DPI), a potent NADH/NADPH oxidase inhibitor, on serum-, platelet-derived growth factor BB-, and thrombin-induced ERK2, JNK1, and p38 mitogen-activated protein (MAP) kinase activation; c-Fos, c-Jun, and JunB expression; and DNA synthesis. Both NAC and DPI completely inhibited agonist-induced AP-1 activity and DNA synthesis in VSMC. On the contrary, these compounds had differential effects on agonist-induced ERK2, JNK1, and p38 MAP kinase activation and c-Fos, c-Jun, and JunB expression. NAC inhibited agonist-induced ERK2, JNK1, and p38 MAP kinase activation and c-Fos, c-Jun, and JunB expression except for platelet-derived growth factor BB-induced ERK2 activation. In contrast, DPI only inhibited agonist-induced p38 MAP kinase activation and c-Fos and JunB expression. Antibody supershift assays indicated the presence of c-Fos and JunB in the AP-1 complex formed in response to all three agonists. In addition, cotransfection of VSMC with expression plasmids for c-Fos and members of the Jun family along with the AP-1-dependent reporter gene revealed that AP-1 with c-Fos and JunB composition exhibited a higher transactivating activity than AP-1 with other compositions tested. All three agonists significantly stimulated reactive oxygen species production, and this effect was inhibited by both NAC and DPI. Together, these results strongly suggest a role for redox-sensitive mechanisms in agonist-induced ERK2, JNK1, and p38 MAP kinase activation; c-Fos, c-Jun, and JunB expression; AP-1 activity; and DNA synthesis in VSMC. These results also suggest a role for NADH/NADPH oxidase activity in some subset of early signaling events such as p38 MAP kinase activation and c-Fos and JunB induction, which appear to be important in agonist-induced AP-1 activity and DNA synthesis in VSMC.
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PMID:JunB forms the majority of the AP-1 complex and is a target for redox regulation by receptor tyrosine kinase and G protein-coupled receptor agonists in smooth muscle cells. 1002 27

The inflammatory mediator nitric oxide (NO*) promotes apoptotic cell death based on morphological evidence, accumulation of the tumor suppressor p53, caspase-3 activation, and DNA fragmentation in RAW 264.7 macrophages. Since nitrosothiols may actually be the predominant form of biologically active NO* in vivo, we used S-nitrosoglutathione (GSNO) to study activation of extracellular signal-regulated protein kinases1/2 (ERK1/2), c-Jun N-terminal kinases/stress-activated protein kinases (JNK1/2), and p38 kinases. Moreover, we determined the role of mitogen-activated protein kinase signaling in the apoptotic transducing ability of GSNO. ERK1/2 became activated in response to GSNO after 4 h and remained active for the next 20 h. Blocking the ERK1/2 pathway by the mitogen-activated protein kinase kinase inhibitor PD 98059 enhanced GSNO-elicited apoptosis. p38 was activated as well, but inhibition of p38 with SB 203580 left apoptosis unaltered. Activation of JNK1/2 by GSNO showed maximal kinase activities between 2 and 8 h. Attenuating JNK1/2 by antisense-depletion eliminated the pro-apoptotic action of low GSNO concentrations (250 microM), whereas apoptosis proceeded independently of JNK1/2 at higher doses of the NO donor (500 microM). Decreased apoptosis by JNK1/2 depletion prevented p53 accumulation after the addition of GSNO, which positions JNK1/2 upstream of the p53 response at low agonist concentrations. In line, JNK1/2 activation proceeded unaltered in p53-antisense transfected macrophages. However, with higher GSNO concentrations apoptotic transducing pathways, including p53 accumulation, were JNK1/2 unrelated. The regulation of mitogen-activated protein kinases by GSNO may help to define cell protective and destructive actions of reactive nitrogen species.
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PMID:Role of mitogen-activated protein kinases in S-nitrosoglutathione-induced macrophage apoptosis. 1002 20

Calcium is the principal second messenger in the control of gene expression by electrical activity in neurons. Recruitment of the coactivator CREB-binding protein, CBP, by the prototypical calcium-responsive transcription factor, CREB and stimulation of CBP activity by nuclear calcium signals is one mechanism through which calcium influx into excitable cells activates gene expression. Here we show that another CBP-interacting transcription factor, c-Jun, can mediate transcriptional activation upon activation of L-type voltage-gated calcium channels. Calcium-activated transcription mediated by c-Jun functions in the absence of stimulation of the c-Jun N-terminal protein kinase (JNK/SAPK1) signalling pathway and does not require c-Jun amino acid residues Ser63 and Ser73, the two major phosphorylation sites that regulate c-Jun activity in response to stress signals. Similar to CREB-mediated transcription, activation of c-Jun-mediated transcription by calcium signals requires calcium/ calmodulin-dependent protein kinases and is dependent on CBP function. These results identify c-Jun as a calcium-regulated transcriptional activator and suggest that control of coactivator function (i.e. recruitment of CBP and stimulation of CBP activity) is a general mechanism for gene regulation by calcium signals.
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PMID:c-Jun functions as a calcium-regulated transcriptional activator in the absence of JNK/SAPK1 activation. 1006 99

Transforming growth factor-beta (TGF-beta) exerts its effects on cell proliferation, differentiation and migration in part through its modulation of extracellular matrix components, such as fibronectin and plasminogen activator inhibitor-1 (PAI-1). Although the SMAD family of proteins recently has been shown to be a key participant in TGF-beta signaling, other signaling pathways have also been shown to be activated by TGF-beta. We report here that c-Jun N-terminal kinase (JNK), a member of the MAP kinase family, is activated in response to TGF-beta in the human fibrosarcoma HT1080-derived cell line BAHgpt. Stable expression of dominant-negative forms of JNK1 and MKK4, an upstream activator of JNK, results in loss of TGF-beta-stimulated fibronectin mRNA and protein induction, while having little effect on TGF-beta-induced levels of PAI-1. The human fibronectin promoter contains three CRE elements, one of which has been shown to bind a c-Jun-ATF-2 heterodimer. Utilizing a GAL4 fusion trans-reporting system, we demonstrate a decrease in transactivating potential of GAL4-c-Jun and GAL4-ATF-2 in dominant-negative JNK1- and MKK4-expressing cells. Finally, we show that TGF-beta-induced fibronectin synthesis is independent of Smad4. These results demonstrate that TGF-beta-mediated fibronectin induction requires activation of JNK which in turn modulates the activity of c-Jun and ATF-2 in a Smad4independent manner.
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PMID:TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. 1006

Activation of platelets results in shedding of membrane microparticles (MP) with potentially bioactive properties. Platelet MP modulate platelet, monocyte, and vascular endothelial cell function, both by direct effects of MP arachidonic acid (AA) and by its metabolism to bioactive prostanoids. We have previously reported that platelet MP induce expression of cyclooxygenase (COX)-2 and prostacyclin production in monocytes and endothelial cells. To elucidate further the molecular mechanisms that underlie MP-induced up-regulation of COX-2 expression, we investigated the response of a human monocytoid (U-937) cell line to platelet MP stimulation. In U-937 cells, MP-induced COX-2 expression and eicosanoid formation is prevented by pharmacological inhibitors of protein kinase C (PKC), PI 3-kinase, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase, and p38 kinase. Treatment with the PI 3-kinase inhibitors wortmannin and LY294002 also blocked MP-induced p42/p44 MAPK, p38, and JNK1 phosphorylation. Conversely, platelet MP stimulation of U-937 cells results in direct activation of PKC, p42/p44 MAPK, p38 kinase, and c-Jun N-terminal kinase (JNK) as well as activation of the transcription factors c-Jun and Elk-1. However, MP failed to activate the cAMP response element. Activation of U-937 cells by MP induces translocation of classical (PKCbeta), novel (PKCdelta) and atypical (PKCzeta and PKClambda) isozymes of PKC from the cytosol to the membrane, with concomitant activation of downstream MAPK. While MP-induced activation of p42/p44 MAPK and p38 kinase is transient, a sustained activation of JNK1 was observed. Although PKC activation is required for MP-induced p42/p44 MAPK, activation of the stress kinases p38 and JNK1 was PKC-independent. The fatty acid fraction of the MP accounted for these effects, which were mimicked by MP AA. Rather than acting directly via nuclear receptors, MP AA activates COX-2-dependent prostaglandin production by a PKC/p42/p44 MAPK/p38 kinase-sensitive pathway in which PI 3-kinase plays a significant role. MP AA also stimulates transcriptional activation of COX-2 as well as c-Jun and Elk-1.
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PMID:Arachidonic acid in platelet microparticles up-regulates cyclooxygenase-2-dependent prostaglandin formation via a protein kinase C/mitogen-activated protein kinase-dependent pathway. 1006 22


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