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 indicate that activation of c-Jun kinase (JNK) is necessary for apoptosis of trophic factor-deprived PC12 cells and that death in this system is suppressed by multiple agents, including BCL2, inhibitors of the interleukin-1-converting enzyme (ICE) family of proteases, blockers of transcription, and a variety of small molecules with differing modes of action. Here, we determine the order in which these agents block apoptosis relative to JNK activation. Overexpression of BCL2 promotes PC12 cell survival and blocks JNK activation caused by trophic factor withdrawal. Similarly, the survival-promoting agents aurintricarboxylic acid, N-acetylcysteine, the nitric oxide generator diethylenetriamine nitric oxide, 8-bromo-cGMP, and 8-(4-chlorophenylthio)-cAMP act upstream to inhibit JNK activation. In contrast, zVAD-fluoromethylketone (a permeant ICE family inhibitor), actinomycin D, and the G1/S cell cycle inhibitor deferoxamine, all promote survival after trophic factor withdrawal, but do not affect JNK activation. These findings are consistent with the presence of an ordered cell death pathway triggered by trophic factor deprivation in which 1) BCL2 and a number of survival-promoting agents act upstream of JNK, 2) ICE family protease actions, regulated genes required for cell death, and certain cell cycle blockers lie either downstream of JNK or on independent pathways required for apoptotic death.
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PMID:Ordering the cell death pathway. Differential effects of BCL2, an interleukin-1-converting enzyme family protease inhibitor, and other survival agents on JNK activation in serum/nerve growth factor-deprived PC12 cells. 870 92

Exposure of rat glomerular mesangial cells and primary cultures of bovine glomerular endothelial cells to compounds releasing nitric oxide (NO), including MAHMA-NONOate, S-nitrosoglutathione, and spermine-NO, results in a time- and concentration-dependent activation of stress-activated protein kinases (SAPK) as measured by the phosphorylation of c-Jun in a solid phase kinase assay. Dibutyryl cGMP had no effect on SAPK activity. Pretreatment of the cells with the tyrosine kinase inhibitor genistein strongly attenuated NO-induced c-Jun phosphorylation. Furthermore, N-acetylcysteine markedly reduced the activation of SAPK in response to NO. These studies identify SAPK as a target for NO which may be critical for the NO-induced apoptosis of glomerular mesangial and endothelial cells.
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PMID:Nitric oxide stimulates stress-activated protein kinases in glomerular endothelial and mesangial cells. 890 68

Atrial natriuretic peptide (ANP) has been shown to counteract various actions of endothelin-1 (ET-1) in mesangial cells. We have reported that both extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) are activated by ET-1 and ET-1-induced activation of ERK is inhibited by ANP. To further clarify the action of ANP, we examined the effect of ANP on ET-1-induced activation of JNK. ANP inhibited ET-1-induced activation of JNK in a dose-dependent manner. This inhibitory effect of ANP was reversed by HS-142-1, an antagonist for biological receptors of ANP, while C-ANP, an analog specific to clearance receptors of ANP, failed to inhibit ET-1-induced activation of JNK. 8-Bromo-cGMP and sodium nitroprusside were also able to inhibit ET-1-induced activation of JNK, suggesting cGMP-dependent action of ANP. In contrast, ANP failed to inhibit interleukin-1 beta (IL-1 beta)-induced activation of JNK. Since an increase in intracellular calcium ([Ca2+]i) was shown to be necessary for ET-1-induced activation of JNK in mesangial cells, we measured [Ca2+]i using fura-2. ANP attenuated the ET-1-induced increase in [Ca2+]i in concentrations enough to inhibit ET-1-induced activation of JNK. Finally, ANP was able to inhibit ET-1-, but not IL-1 beta-induced increase in DNA-binding activity of AP-1 by gel shift assay. These results indicate that ANP is able to inhibit ET-1-induced activation of AP-1 by inhibiting both ERK and JNK, suggesting that ANP might be able to counteract the expression of AP-1-dependent genes induced by ET-1.
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PMID:Atrial natriuretic peptide inhibits endothelin-1-induced activation of JNK in glomerular mesangial cells. 957 27

1. Protein phosphorylation is involved in the induction of nitric oxide synthase II (NOS II, iNOS) in several types of animal cells. Here we have investigated the possible involvement of major protein kinases in the induction of NOS II expression in human DLD-1 cells. 2. In DLD-1 cells, interferon--gamma alone induced a submaximal NOS II expression; a cytokine mixture consisting of interferon-gamma, tumour necrosis factor-alpha and interleukin-1beta produced maximal NOS II induction. 3. Activators of protein kinase A (forskolin, 8-dibutyryl-cyclic AMP), of protein kinase C (tetradecanoylphorbol-13-acetate), and of protein kinase G (8-bromo cyclic GMP) did not induce NOS II mRNA by themselves, nor did they alter NOS II mRNA induction in response to cytokines. 4. Inhibitors of protein kinase A (compound H89), of protein kinase C (bisindolylmaleimide, chelerythrine or staurosporine), of phosphatidylinositol 3-kinase (wortmannin), of p38 mitogen-activated protein kinase (compound SB 203580) and of extracellular signal-regulated kinase (compound PD 98059) also had no influence on basal or cytokine-induced NOS II mRNA expression. 5. Immunoprecipitation kinase assays showed no activation of extracellular signal-regulated kinase or p38 mitogen-activated protein kinase in cytokine-incubated DLD-1 cells. The c-Jun NH2-terminal kinase was activated by cytokines, but the most efficacious cytokine was tumour necrosis factor-alpha which did not induce NOS II by itself. 6. In contrast, the protein tyrosine kinase inhibitor tyrphostin B42 (a specific inhibitor of interferon-gamma-activated janus kinase 2) and the protein tyrosine kinase inhibitor tyrphostin A25 both reduced CM-induced NOS II mRNA expression in a concentration-dependent manner. 7. These results suggest that activation of NOS II expression in DLD-1 cells is independent of the activities of protein kinases A, C and G, phosphatidylinositol 3-kinase, extracellular signal regulated kinase and p38 mitogen-activated protein kinase, but seems to require protein tyrosine kinase activity, especially the interferon-gamma-activated janus kinase 2.
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PMID:Involvement of protein kinases in the induction of NO synthase II in human DLD-1 cells. 960 80

The atrial natriuretic peptide (ANP) is suggested to regulate inflammatory response by alteration of macrophage functions. The aim of this study was to investigate whether ANP influences production of TNF-alpha. TNF-alpha production in murine bone marrow-derived macrophages was induced by LPS, and TNF-alpha secretion (+/-ANP) was determined by L929 bioassay. ANP dose dependently (10-8-10-6 M) inhibited TNF-alpha release by up to 95%. The effect was mediated via the guanylate cyclase-coupled A receptor, as was shown by employing dibutyryl-cGMP, the cGMP-inhibitory compound Ly-83583, and the A receptor antagonist HS-142-1. A specific ligand of the natriuretic peptide "clearance" receptor inhibited TNF-alpha production only at 10-7 and 10-8 M, but not at 10-6 M. The B receptor ligand C-type natriuretic peptide showed no TNF-alpha-inhibitory effect. To investigate the underlying mechanism of ANP-mediated TNF-alpha inhibition, Northern blot was performed. ANP-treated macrophages displayed decreased TNF-alpha-mRNA levels. Besides the known inhibition of NF-kappaB activation, in this study we demonstrated that ANP also attenuates the activation of the proinflammatory transcription factor AP-1 (gel shift assay). ANP did not alter subunit composition of AP-1 complexes, as was shown by supershift assays applying anti-c-jun and anti-c-fos Abs. To get information on the ANP effect for human inflammatory processes, we investigated cytokine production in human LPS-activated blood. ANP significantly attenuated production of TNF-alpha and IL-1beta without affecting production of IL-10 and IL-1ra. In summary, ANP was shown to attenuate TNF-alpha production of LPS-activated macrophages via cGMP. The inhibition is suggested to involve transcriptional processes that are the result of reduced activation of responsible transcription factors.
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PMID:cGMP-mediated inhibition of TNF-alpha production by the atrial natriuretic peptide in murine macrophages. 1086 Oct 50

Sulindac sulfone (Exisulind) induces apoptosis and exhibits cancer chemopreventive activity, but in contrast to sulindac, it does not inhibit cyclooxygenases 1 or 2. We found that sulindac sulfone and two potent derivatives, CP248 and CP461, inhibited the cyclic GMP (cGMP) phosphodiesterases (PDE) 2 and 5 in human colon cells, and these compounds caused rapid and sustained activation of the c-Jun NH2-terminal kinase 1 (JNK1). Rapid activation of stress-activated protein/ERK kinase 1 (SEK1) and mitogen-activated protein kinase kinase kinase (MEKK1), which are upstream of JNK1, was also observed. Other compounds that increase cellular levels of cGMP also activated JNK1, and an inhibitor of protein kinase G (PKG), Rp-8-pCPT-cGMPS, inhibited JNK1 activation by the sulindac sulfone derivatives. Expression of a dominant-negative JNK1 protein inhibited CP248-induced cleavage of poly(ADP-ribose) polymerase, a marker of apoptosis. Thus, it appears that sulindac sulfone and related compounds induce apoptosis, at least in part, through activation of PKG, which then activates the MEKK1-SEK1-JNK1 cascade. These studies also indicate a role for cGMP and PKG in the JNK pathway.
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PMID:Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1. 1105 Dec 67

In axotomised adult rat dorsal root ganglion (DRG), many neurons show a marked increase in expression of neuronal nitric oxide synthase (nNOS). It has been established that NO functions as a neuron-glial signalling molecule by generating cGMP in glia cells that surround the neuron in DRG. Furthermore, in cultures of dissociated DRG deprived of nerve growth factor, many neurons expressed nNOS and cGMP and subsequently died if either enzyme's activity was inhibited suggesting that NO-cGMP pathway could be neuroprotective in stressed DRG neurons. This has now been tested in vivo. It was found, 10 days after sciatic axotomy that nNOS was expressed in 36% of DRG neurons in the L5 and L6 ganglia giving rise to the damaged nerve, compared with 6% in contralateral ganglia. Almost all nNOS neurons and 24% of non-nNOS neurons expressed c-Jun in their nuclei. Ten days following axotomy, treatment with the relatively selective nNOS-blocker, 1-(2-trifluoromethylphenyl) imidazole (TRIM), caused morphology changes in approximately 50% of neurons that consisted of vacuolations, blebbing and highly irregular cell boundaries. Sham operated, TRIM treated, nerve-sectioned, vehicle treated, and controls did not show these changes. These observations further support the view that NO could be neuroprotective in some injured/stressed primary sensory neurons.
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PMID:Inhibition of neuronal nitric oxide synthase results in neurodegenerative changes in the axotomised dorsal root ganglion neurons: evidence for a neuroprotective role of nitric oxide in vivo. 1131 3

The functional role of p53 in nitric oxide (NO)-mediated vascular smooth muscle cell (VSMC) apoptosis remains unknown. In this study, VSMC from p53-/- and p53+/+ murine aortas were exposed to exogenous or endogenous sources of NO. Unexpectedly, p53-/- VSMC were much more sensitive to the proapoptotic effects of NO than were p53+/+ VSMC. Furthermore, this paradox appeared to be specific to NO, because other proapoptotic agents did not demonstrate this differential effect on p53-/- cells. NO-induced apoptosis in p53-/- VSMC occurred independently of cGMP generation. However, mitogen-activated protein kinase (MAPK) pathways appeared to play a significant role. Treatment of the p53-/- VSMC with S-nitroso-N-acetylpenicillamine resulted in a marked activation of p38 MAPK and, to a lesser extent, of c-Jun NH(2)-terminal kinase, mitogen-activated protein kinase kinase (MEK) 1/2, and p42/44 (extracellular signal-regulated kinase, ERK). Furthermore, basal activity of the MEK-p42/44 (ERK) pathway was increased in the p53+/+ VSMC. Inhibition of p38 MAPK with SB-203580 or of MEK1/2 with PD-98059 blocked NO-induced apoptosis. Therefore, p53 may protect VSMC against NO-mediated apoptosis, in part, through differential regulation of MAPK pathways.
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PMID:Potentiation of nitric oxide-induced apoptosis in p53-/- vascular smooth muscle cells. 1183 48

The production of matrix metalloproteinases (MMP) by UV-irradiated skin fibroblasts and the degradation of the extracellular matrix by these enzymes is known as one of the main causes of photoaging. Recently, the Fisher group showed that MMP expression is mainly regulated by members of the mitogen-activated protein kinase family such as extracellular signal-regulated kinase, c-Jun amino-terminal kinase, and p38, each of which forms a signaling pathway. In this work, we initially examined the effect of nitric oxide (NO) and nitric oxide synthase (NOS) inhibitors on the production of MMP-1 and MMP-2 by human dermal fibroblasts (HDF). NO is a multifunctional messenger molecule generated from L-arginine and can activate guanylate cyclase to increase cGMP. We found that treatment of HDF with an NO donor, sodium nitroprusside (50 microM), enhanced the expression of MMP-1 and -2 by 153% and 243%, respectively, and treatment by 8-Br-cGMP enhanced MMP-1 and -2 expression by 137% and 254%, respectively. When UV-irradiated HDF was treated with NOS inhibitors such as aminoguanidine (AG) and baicalein (BAC), there resulted a decrease in MMP production. When 20 microM of BAC was added in the culture media of UV-irradiated HDF, only 40% of MMP-1 and 42% of MMP-2 was produced, compared to the case without BAC. Taken together, we concluded that the production of MMP-1 and -2 by UV-irradiated HDF is regulated through the signaling pathway involving NO and that it can be downregulated using NOS inhibitors.
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PMID:Inhibition of matrix metalloproteinase-1 and -2 expression using nitric oxide synthase inhibitors in UV-irradiated human dermal fibroblasts. 1285 22

The transcription factor NFAT (nuclear factor of activated T-cells) is implicated in cardiac hypertrophy and vasculogenesis. NFAT activation, reflecting dephosphorylation by the calcium-dependent phosphatase, calcineurin, and subsequent nuclear localization, is generally thought to require a sustained increase in intracellular calcium. However, in smooth muscle we have found that elevation of calcium by membrane depolarization fails to induce an increase in nuclear localization of the NFATc3 isoform. Here, we demonstrate that physiological intravascular pressure (100 mm Hg) induces an increase in NFATc3 nuclear localization in mouse cerebral arteries. Pressure-induced NFATc3 nuclear accumulation is abrogated by endothelial denudation and by nitric-oxide synthase, cGMP-dependent kinase (PKG), and voltage-dependent calcium channels inhibition. We further show that exogenous nitric oxide, in combination with an elevation in calcium, is an effective stimulus for NFATc3 nuclear accumulation. c-Jun terminal kinase 2 (JNK) activity, which has been shown to regulate NFATc3 nuclear export, is also reduced by pressure, an effect that is prevented by pretreatment with a PKG inhibitor. Consistent with this, pressure-induced NFATc3 nuclear accumulation is independent of PKG in arteries from JNK2(-/-) mice. Collectively, our results indicate that both activation of the NO/PKG pathway and elevation of smooth muscle calcium are required for NFATc3 nuclear accumulation and that PKG inhibits JNK2 to decrease NFAT nuclear export. Our findings suggest that at physiological intravascular pressures NFATc3 is localized to the nucleus in smooth muscle cells of intact arteries and indicate a novel and unexpected role for nitric oxide/PKG in NFAT activation.
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PMID:Intraluminal pressure is a stimulus for NFATc3 nuclear accumulation: role of calcium, endothelium-derived nitric oxide, and cGMP-dependent protein kinase. 1468 53


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