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)

Protein kinase Cepsilon (PKCepsilon) plays a pivotal role in cardioprotection during cardiac ischemia and reperfusion injury. Recent studies demonstrated that prenatal cocaine exposure caused a decrease in PKCepsilon expression and increased heart susceptibility to ischemic injury in adult offspring, suggesting an in utero programming of PKCepsilon gene expression pattern in the heart. The present investigation aimed to elucidate whether an epigenetic mechanism, DNA methylation, accounts for cocaine-mediated repression of the PKCepsilon gene in the heart. Pregnant rats were administered either saline or cocaine intraperitoneally (15 mg/kg) twice daily from days 15 to 20 of gestational age, and term fetal hearts were studied. Cocaine treatment significantly decreased PKCepsilon mRNA and protein levels in the heart. CpG dinucleotides found in cAMP response element-binding protein (CREB), CREB/c-Jun1, and CREB/c-Jun2 binding sites at the proximal promoter region of the PKCepsilon gene were densely methylated and were not affected by cocaine. In contrast, methylation of CpGs in the activator protein 1 (AP-1) binding sites was low but was significantly increased by cocaine. Reporter gene assays showed that the AP-1 binding site played a strong stimulatory role of PKCepsilon gene transcription. Methylation of the AP-1 binding sites significantly decreased AP-1 binding to the PKCepsilon promoter. Supershift analyses implicated c-Jun homodimers binding to the AP-1 binding sites. Cocaine did not affect nuclear c-Jun levels or the binding of c-Jun to the unmethylated AP-1 binding sites. The results indicate a role for DNA methylation in cocaine-mediated PKCepsilon gene repression in the developing heart and suggest an epigenetic mechanism affecting this gene linked with vulnerability of ischemic injury in the heart of adult offspring.
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PMID:Maternal cocaine administration causes an epigenetic modification of protein kinase Cepsilon gene expression in fetal rat heart. 1730 99

Cocaine exposure results in aberrant outgrowth and decreased survival for locus coeruleus (LC), a noradrenergic population of neurons that putatively regulates attentional function; however, the underlying mechanisms for these events are not known. We previously showed that cocaine exposure in vitro activates pro-apoptotic Bax, caspase-9, and caspase-3 in LC neurons dissected from embryonic day 14 rats, implicating that apoptosis may be orchestrated via signal transduction events. In the current study in vitro, we examined upstream events to determine the role of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), on LC signal transduction, because cocaine exposure to LC neurons triggered TNF-alpha expression at 30 min as measured by ELISA. Exposure of LC neurons to recombinant-TNF-alpha resulted in decreased metabolic activity, an indicator of reduced neuron viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay], and increased apoptosis (terminal deoxynucleotidyl transferase-mediated DNA nick end labeling assay). Pro-apoptotic caspase-3 was induced by cocaine starting at 30 min. Recombinant-TNF-alpha induced caspase-3 activity earlier than cocaine (15 and 20 min). The caspase-3 levels were significantly reduced when cocaine and TNF-alpha were combined with neutralizing-TNF-alpha (nTNF-alpha), respectively. Further, cocaine alone elevated phospho-p38-mitogen-activated protein kinases that persisted when combined with nTNF-alpha. However, both cocaine and TNF-alpha independently increased phospho-c-Jun NH(2)-terminal kinase and Bax levels at concurrent time periods (30 min and 1 h), and this elevation was attenuated in the presence of nTNF-alpha. These simultaneous molecular events triggered by cocaine and TNF-alpha implicate a potential apoptotic signal transduction pathway via induction of phospho-c-Jun NH(2)-terminal kinase and Bax that may lead to caspase-3 activation and apoptosis in cocaine-exposed fetal LC neurons.
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PMID:Cocaine exposure in vitro induces apoptosis in fetal locus coeruleus neurons through TNF-alpha-mediated induction of Bax and phosphorylated c-Jun NH(2)-terminal kinase. 1763 74

Chronic cocaine exposure is associated with severe cardiac complications, but the mechanisms of cocaine cardiotoxicity remain unclear, and current therapies are unsatisfactory. We investigated the hypothesis of oxidative stress-mediated cardiotoxicity and the role of NADPH oxidase in this process in a mouse model of chronic escalating "binge" cocaine administration (milligrams per kilogram): days 1 to 4 at 3 x 15 mg, days 5 to 8 at 3 x 20 mg, days 9 to 12 at 3 x 25 mg, and days 13 to 14 at 3 x 30 mg. Compared with vehicle controls, chronic binge cocaine administration significantly increased the cardiac NADPH-dependent O(2)(.) production (1.96- +/- 0.4-fold) as detected by tiron (an O(2)(.) scavenger)-inhibitable lucigenin chemiluminescence and dihydroethidium fluorescence. Cocaine-induced reactive oxygen species (ROS) production was associated with significant increases ( approximately 2-fold) in the protein expressions of Nox2 (an isoform of NADPH oxidase) and its regulatory subunits: p22(phox), p67(phox), p47(phox), p40(phox), and Rac1, and in p47(phox) phosphorylation as detected by immunoblotting (all p < 0.03). Increased Nox2 activity was accompanied by the activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase (MAPK), and c-Jun NH(2)-terminal kinase, notably in the cardiomyocytes. Cell culture experiments revealed that cocaine-induced ROS production was primarily a direct action of cocaine on cardiac myocytes, which caused severe oxidative damage to myocytes and cell death as detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. These could be inhibited by inhibitors to protein kinase C (bisindolymaleimide) or by depletion of Nox2 using small interfering RNA. In conclusion, chronic cocaine administration directly causes severe myocardial oxidative stress through the activation of Nox2 oxidase. Increased ROS production contributes to MAPK activation and the subsequent myocyte damage. Inhibitors to NADPH oxidase or antioxidants may have therapeutic potential in the treatment of cocaine cardiotoxicity.
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PMID:Chronic cocaine-induced cardiac oxidative stress and mitogen-activated protein kinase activation: the role of Nox2 oxidase. 1895 86