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)

We have previously reported that hydrogen peroxide, an active oxygen species and a cellular oxidant, induces c-Fos and c-Jun mRNA expression and DNA synthesis in vascular smooth muscle cells and that these events require arachidonic acid release and metabolism through the lipoxygenase pathway. Here we have identified the eicosanoids that mediate the hydrogen peroxide-induced growth-related events in these cells. Hydrogen peroxide stimulated the production of 12- and 15-hydroperoxyeicosatetraenoic acids in vascular smooth muscle cells. Both 12- and 15-hydroperoxyeicosatetraenoic acids induced the expression of c-Fos and c-Jun protein and increased activating protein 1 (AP-1) activity, as measured by AP-1-DNA binding and AP-1-dependent human collagenase promoter-driven chloramphenicol acetyltransferase reporter gene transcription. Hydrogen peroxide and arachidonic acid also induced the expression of c-Fos and c-Jun protein and AP-1 activity. Nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway, significantly inhibited both hydrogen peroxide and arachidonic acid-stimulated c-Fos and c-Jun protein expression and AP-1 activity. Together, these findings suggest that hydrogen peroxide induces the production of eicosanoids and that the eicosanoids are potential mediators of the oxidative stress-stimulated growth-related events in vascular smooth muscle cells.
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PMID:Role of hydroperoxyeicosatetraenoic acids in oxidative stress-induced activating protein 1 (AP-1) activity. 891 Mar 70

It was found that Syk protein-tyrosine kinase is rapidly activated in B cells after H2O2 treatment (oxidative stress) or increased extracellular NaCl concentration (osmotic stress) as well as in response to B cell receptor activation. In this study we examined the involvement of Syk in responses elicited by these types of extracellular stress, particularly Ca2+ responses and c-Jun amino-terminal kinase (JNK) activation, using a chicken B cell line, DT40, as well as the DT40-derived mutant DT40/Syk(-), which does not express Syk. Osmotic stress evokes increases in [Ca2+]i by stimulating an extracellular Ca2+ influx in both DT40 and DT40/Syk(-) cells. In comparison, oxidative stress elicits an increase in [Ca2+]i by stimulating both an extracellular Ca2+ influx and Ca2+ release from internal stores in DT40 cells, but this Ca2+ response is partially abolished in DT40/Syk(-) cells, indicating that the oxidative stress-induced Ca2+ response is at least partly dependent on Syk. Interestingly, the depletion of Ca2+ results in a significantly decreased level of Syk activation in DT40 cells stimulated by oxidative but not osmotic stress. Furthermore, JNK is activated to different extents by these two types of stress. The extent of JNK activation in DT40/Syk(-) cells in response to osmotic stress is comparable to that observed in DT40 cells. Intriguingly, oxidative stress-induced JNK activation is significantly compromised in DT40/Syk(-) cells. Collectively, these results indicate that both the Ca2+ response and JNK activity induced by oxidative stress are partly dependent on Syk, whereas those induced by osmotic stress are independent of Syk.
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PMID:Syk-dependent and -independent signaling cascades in B cells elicited by osmotic and oxidative stress. 899 8

Bioflavonoid quercetin is known as an anti-cancer agent that induces apoptosis of tumor cells. Currently, however, little is understood about the effect of this drug on the function of normal cells. In this report, we address an unexpected, novel action of quercetin against apoptosis. Pretreatment with quercetin protected mesangial cells from hydrogen peroxide (H2O2)-induced apoptosis. A similar effect was observed in other cell types including LLC-PK1 epithelial cells and NRK49F fibroblasts. To explore the molecular mechanisms involved, we tested the effect of quercetin on c-Jun/activator protein-1 AP-1), the crucial mediator for H2O2-initiated apoptosis. Northern blot analysis revealed that quercetin suppressed the c-jun expression by H2O2. This was correlated with blunted activation of 12-O-tetradecanoylphorbol 13-acetate response element (TRE) in response to H2O2. These results suggested that quercetin inhibited apoptosis via intervention in the c-Jun/AP-1 pathway. To further investigate the action of quercetin, its effect on tyrosine kinases was studied. Immunoblot analysis revealed that H2O2 induced tyrosine phosphorylation. Quercetin inhibited this process in a dose-dependent manner. Inactivation of tyrosine kinases was an event upstream of c-Jun/AP-1, because tyrosine kinase inhibitors suppressed both activation of c-Jun/AP-1 and induction of apoptosis by H2O2. These findings elucidated the novel action of quercetin as an apoptosis inhibitor. This cytoprotective effect was found to be via suppression of the tyrosine kinase-c-Jun/AP-1 pathway triggered by oxidant stress.
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PMID:Unexpected protection of glomerular mesangial cells from oxidant-triggered apoptosis by bioflavonoid quercetin. 927 81

To determine whether intracellular signaling events involved in apoptosis may also mediate necrosis, the role of the transcription factor AP-1 was investigated in a hepatoma cell model of cellular necrosis induced by oxidant stress. Treatment of the human hepatoma cell line HuH-7 with H2O2 caused dose-dependent necrosis as determined by light microscopy, fluorescent staining, and an absence of DNA fragmentation. H2O2 treatment led to increases in c-fos and c-jun mRNA levels, Jun nuclear kinase activity, and AP-1 DNA binding. AP-1 transcriptional activity measured with an AP-1-driven luciferase reporter gene was also increased. To determine whether this AP-1 activation contributed to H2O2-induced cell necrosis, HuH-7 cells were stably transfected with an antisense c-jun expression vector. Cells expressing antisense c-jun had decreased levels of AP-1 activation and significantly increased survival after H2O2 exposure. These data indicate that AP-1 activation occurs during oxidant-induced cell necrosis and contributes to cell death. Necrosis is therefore not always a passive process but may involve the activation of intracellular signaling pathways similar to those that mediate apoptosis.
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PMID:Hydrogen peroxide-induced liver cell necrosis is dependent on AP-1 activation. 935 20

Oxidant stress is a trigger of cell death in various cell types. Hydrogen peroxide (H2O2) induced mesangial cell death with nuclear condensation and DNA fragmentation typical of apoptosis. To explore molecular mechanisms involved in this process, redox-sensitive transacting molecules, activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappa B), have been brought into focus. Northern blot analysis and transient transfection assays using reporter plasmids showed that H2O2 activated both AP-1 and NF-kappa B. Downregulation of c-Jun/AP-1 using a transdominant negative mutant of c-jun, an antisense c-jun, or a pharmacologic inhibitor curcumin inhibited the H2O2-initiated apoptosis. In contrast, inhibition of the NF-kappa B activation using a transdominant negative mutant of the p50 NF-kappa B subunit did not affect the H2O2-triggered cellular death. These data elucidated that c-Jun/AP-1, but not NF-kappa B, is involved in the oxidant-initiated cell death program in glomerular mesangial cells.
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PMID:c-Jun/AP-1, but not NF-kappa B, is a mediator for oxidant-initiated apoptosis in glomerular mesangial cells. 938 8

The effect of ultraviolet (UV) B irradiation on pi class glutathione transferase (GST-P) gene expression was examined in cultured rat keratinocytes. Immunoblotting demonstrated GST-P to be the major GST form in the cells, and it was significantly decreased following irradiation. Northern blot analysis revealed that the mRNA decreased to 10-25% of the initial value 24 h after irradiation at a dose of 40 mJ/cm2. No remarkable changes were observed at earlier time points. Hydrogen peroxide treatment enhanced GST-P mRNA expression, with a 70% increase at 250 microM concentration. Alterations in possible trans-acting factors were examined to clarify the mechanism of repression by UV irradiation. c-Jun mRNA was induced 3.5-fold at 4 h after irradiation, but by 24 h fell to a lower level than that observed initially. c-Fos mRNA was increased 10-fold at 1 h but was completely suppressed at 12 and 24 h. Thus, the changes of c-Jun and c-Fos mRNA differed from that of GST-P mRNA. The level of mRNA for silencer factor-B was decreased to less than 10% at 12 h. UV irradiation of cells transfected with the chloramphenicol acetyltransferase (CAT) reporter gene containing enhancer (GPE I) or silencer regions of the GST-P gene did not suppress CAT activity. Although basal expression of the GST-P gene was mainly dependent on GPE I, altered expression of c-jun, c-fos and other genes coding for factors possibly trans-acting on GPE I did not appear to be responsible for the decreased GST-P mRNA levels.
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PMID:Decrease in class pi glutathione transferase mRNA levels by ultraviolet irradiation of cultured rat keratinocytes. 943 81

"Stress-regulated" mitogen-activated protein kinases (SR-MAPKs) comprise the stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) and the p38-MAPKs. In the perfused heart, ischemia/reperfusion activates SR-MAPKs. Although the agent(s) directly responsible is unclear, reactive oxygen species are generated during ischemia/reperfusion. We have assessed the ability of oxidative stress (as exemplified by H2O2) to activate SR-MAPKs in the perfused heart and compared it with the effect of ischemia/reperfusion. H2O2 activated both SAPKs/JNKs and p38-MAPK. Maximal activation by H2O2 in both cases was observed at 0.5 mM. Whereas activation of p38-MAPK by H2O2 was comparable to that of ischemia and ischemia/reperfusion, activation of the SAPKs/JNKs was less than that of ischemia/reperfusion. As with ischemia/reperfusion, there was minimal activation of the ERK MAPK subfamily by H2O2. MAPK-activated protein kinase 2 (MAPKAPK2), a downstream substrate of p38-MAPKs, was activated by H2O2 to a similar extent as with ischemia or ischemia/reperfusion. In all instances, activation of MAPKAPK2 in perfused hearts was inhibited by SB203580, an inhibitor of p38-MAPKs. Perfusion of hearts at high aortic pressure (20 kilopascals) also activated the SR-MAPKs and MAPKAPK2. Free radical trapping agents (dimethyl sulfoxide and N-t-butyl-alpha-phenyl nitrone) inhibited the activation of SR-MAPKs and MAPKAPK2 by ischemia/reperfusion. These data are consistent with a role for reactive oxygen species in the activation of SR-MAPKs during ischemia/reperfusion.
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PMID:Stimulation of "stress-regulated" mitogen-activated protein kinases (stress-activated protein kinases/c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses. 951 15

Several recently identified intracellular proteins associate with the tumor necrosis factor (TNF) receptor and activate nuclear transcription factor (NF)-kappaB, c-Jun kinase, and apoptosis. However, the mechanism is not understood. In the present report, we investigated the role of reactive oxygen intermediates in TNF-induced signaling. Overexpression of manganese superoxide dismutase (Mn-SOD) in human breast cancer MCF-7 cells completely abolished TNF-mediated NF-kappaB activation, IkappaB alpha degradation, p65 nuclear translocation, and NF-kappaB-dependent reporter gene expression. Besides TNF, phorbol ester-, okadaic acid-, ceramide-, and lipopolysaccharide-induced activation of NF-kappaB was blocked by Mn-SOD, indicating a common pathway of activation. H2O2-induced NF-kappaB activation, however, was potentiated. In addition, Mn-SOD blocked the TNF-mediated activation of activated protein-1, stress-activated c-Jun protein kinase, and mitogen-activated protein kinase kinase. TNF-induced antiproliferative effects and caspase-3 activation, indicators of apoptosis, were also completely suppressed by transfection of cells with Mn-SOD. Suppression of apoptosis induced by okadaic acid, H2O2, and taxol was also inhibited by Mn-SOD but not that induced by vincristine, vinblastine, or daunomycin. Overall, these results demonstrate that, in addition to several recently identified signaling molecules, reactive oxygen intermediates play a critical role in activation of NF-kappaB, activated protein-1, c-Jun kinase, and apoptosis induced by TNF and other agents.
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PMID:Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappaB and activated protein-1. 958 69

We investigated the activation of three subfamilies of mitogen-activated protein kinases (MAPKs), namely the stress-activated protein kinases/c-Jun N-terminal kinases (SAPKs/JNKs), the extracellularly responsive kinases (ERKs) and p38-MAPK, by oxidative stress as exemplified by H2O2 in primary cultures of neonatal rat ventricular myocytes. The 46 and 54 kDa species of SAPKs/JNKs were activated 5- and 10-fold, respectively, by 0.1 mM H2O2 (the maximally effective concentration). Maximal activation occurred at 15-30 min, but was still detectable after 2 h. Both ERK1 and ERK2 were activated 16-fold by 0.1 mM H2O2 with a similar time course to the SAPKs/JNKs, and this was comparable with their activation by 1 microM PMA, the most powerful activator of ERKs that we have so far identified in these cells. The activation of ERKs by H2O2 was inhibited by PD98059, which inhibits the activation of MAPK (or ERK) kinases, and by the protein kinase C (PKC) inhibitor, GF109203X. ERK activation was also inhibited by down-regulation of PMA-sensitive PKC isoforms. p38-MAPK was activated by 0.1 mM H2O2 as shown by an increase in its phosphorylation. However, maximal phosphorylation (activation) was more rapid (<5 min) than for the SAPKs/JNKs or the ERKs. We studied the downstream consequences of p38-MAPK activation by examining activation of MAPK-activated protein kinase 2 (MAPKAPK2) and phosphorylation of the MAPKAPK2 substrate, the small heat shock protein HSP25/27. As with p38-MAPK, MAPKAPK2 was rapidly activated (maximal within 5 min) by 0.1 mM H2O2. This activation was abolished by 10 microM SB203580, a selective inhibitor of certain p38-MAPK isoforms. The phosphorylation of HSP25/27 rapidly followed activation of MAPKAPK2 and was also inhibited by SB203580. Phosphorylation of HSP25/27 was associated with a decrease in its aggregation state. These data indicate that oxidative stress is a powerful activator of all three MAPK subfamilies in neonatal rat ventricular myocytes. Activation of all three MAPKs has been associated with the development of the hypertrophic phenotype. However, stimulation of p38-MAPK and the consequent phosphorylation of HSP25/27 may also be important in cardioprotection.
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PMID:Stimulation of multiple mitogen-activated protein kinase sub-families by oxidative stress and phosphorylation of the small heat shock protein, HSP25/27, in neonatal ventricular myocytes. 967 16

Reactive oxygen species generated by treatment of smooth muscle cells (SMCs) with either phorbol 12-myristate 13-acetate or with the combination of H2O2 and vanadate strongly induce expression of the class A scavenger receptor (SR-A) gene. In the current studies, cis-acting elements in the proximal 245 bp of the SR-A promoter were shown to direct luciferase reporter expression in response to oxidative stress in both SMCs and macrophages. A composite activating protein-1 (AP-1)/ets binding element located between -67 and -50 bp relative to the transcriptional start site is critical for macrophage SR-A activity. Mutation of either the AP-1 or the ets component of this site also prevented promoter activity in SMCs. Mutation of a second site located between -44 and -21 bp, which we have identified as a CCAAT/enhancer binding protein (C/EBP) element, reduced the inducible activity of the promoter in SMCs by 50%, suggesting that combinatorial interactions between these sites are necessary for optimal gene induction. Interactions between SMC nuclear extracts and the SR-A promoter were analyzed by electrophoretic mobility shift assay. c-Jun/AP-1 binding activity, specific for the -67- to -50-bp site, was induced in SMCs by the same conditions that increased SR-A expression. Moreover, phorbol 12-myristate 13-acetate, H2O2, or the combination of H2O2 and sodium orthovanadate (vanadate) activated c-Jun-activating kinase. The binding activity within SMC extracts specific for the C/EBP site was shown to be C/EBPbeta in SMCs. Taken together, these findings demonstrate that reactive oxygen species regulate the interactions between c-Jun/AP-1 and C/EBPbeta in the SR-A promoter. Furthermore, induction of oxidative stress in THP-1 cells, with a combination of 10 micromol/L vanadate and 100 micromol/L H2O2, induced macrophage differentiation, adhesion, and SR activity. These data suggest that vascular oxidative stress may contribute to the induction of SR-A expression and thereby promote the uptake of oxidatively modified low density lipoprotein by both macrophage and SMCs to produce foam cells in atherosclerotic lesions.
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PMID:Transcriptional activation of scavenger receptor expression in human smooth muscle cells requires AP-1/c-Jun and C/EBPbeta: both AP-1 binding and JNK activation are induced by phorbol esters and oxidative stress. 974 33


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