Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Docosahexaenoic acid (DHA) causes apoptosis of various cancer cells, but the mechanism of DHA-induced cell death is still unclear. We hypothesized that the early signaling of apoptosis may be important in causing cell death as well as the production of free radical metabolites. DHA caused time- and dose-dependent cell death in human HepG2 hepatoma cells transduced with CYP2E1 (E47) but not in C34 (without CYP2E1), suggesting an important role of CYP2E1 in the DHA-mediated damage. DHA increased the c-Jun N-terminal protein kinase (JNK) activity until 8 h without activating other mitogen-activated protein kinases. The contents of proapoptotic Bad and FasL at 4 h and cytochrome c and caspase 3 activity at 8 h were increased and accompanied by the JNK activation in a successive manner. In contrast, Bax and Bcl-2 were not changed. Levels of lipid peroxides (LPOs) were elevated three- and fivefold at 8 and 24 h, respectively, in DHA-induced E47 cells. However, pretreatment with chlormethiazole (CMZ), a specific inhibitor of CYP2E1, significantly reduced the levels of LPO, CYP2E1, JNK activity and the rate of cell death. In addition, pretreatment with quercetin (one as a JNK inhibitor and one as an antioxidant) significantly reduced the cell death rate and JNK and SEK-1 activities. Our results indicated that DHA-mediated apoptosis in E47 cells was induced through the activation of the JNK-related cell death pathway, which may be involved in the production of LPO or reactive oxygen species during the CYP2E1 catalytic cycle, followed by mitochondrial injury and apoptosis.
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PMID:Docosahexaenoic acid induces apoptosis in CYP2E1-containing HepG2 cells by activating the c-Jun N-terminal protein kinase related mitochondrial damage. 1696 49

Mitogen-activated protein kinase (MAPK) pathways play central roles in the transduction of extracellular stimuli into cells and the regulation of expression of numerous genes. Docosahexaenoic acid (DHA) was shown to be involved in the regulation of expression of drug metabolizing enzymes (DMEs) in rat primary hepatocytes in response to xenobiotics. Cytochrome P450 2B1 (CYP 2B1) is a DME that is dramatically induced by phenobarbital-type inducers. The constitutive androstane receptor (CAR) plays a critical role in regulating the expression of DMEs, and the phosphorylation/dephosphorylation of CAR is an important event in CYP 2B1 expression. In the present study, we determined the effect of DHA on MAPK transactivation and its role in CYP 2B1 expression induced by phenobarbital. c-Jun NH2-terminal kinase (JNK) JNK1/2 and ERK1/2 were activated by phenobarbital in a dose-dependent manner. DHA (100 muM) inhibited JNK1/2 and ERK2 activation induced by phenobarbital in a time-dependent manner. Both SP600125 (a JNK inhibitor) and SB203580 (a p38 MAPK inhibitor) inhibited CYP 2B1 protein and mRNA expression induced by phenobarbital. SB203580 significantly increased the intracellular 3'-5'-cyclic adenosine monophosphate (cAMP) concentration compared with a control group (p < 0.05). Our results suggest that inhibition of JNK activation by DHA is at least part of the mechanisms of DHA's downregulation of CYP 2B1 expression induced by phenobarbital.
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PMID:Docosahexaenoic acid downregulates phenobarbital-induced cytochrome P450 2B1 gene expression in rat primary hepatocytes via the c-Jun NH2-terminal kinase mitogen-activated protein kinase pathway. 1880 53

Docosahexaenoic acid (DHA) shows anti-inflammatory and/or anticancer effects in some cells. Activator protein-1 (AP-1) regulates cellular proliferation and apoptosis. Although recent studies demonstrate the association between gastric cancer risk and DHA, the exact molecular mechanism has not been clarified. We investigated whether AP-1 mediates DHA-induced apoptosis of gastric cancer cells. We found that DHA induced cell death and DNA fragmentation in parallel with the activation of extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK) as well as AP-1. DHA increased the protein levels of p53, cytochrome c, and Bax in gastric cancer cells. DHA-induced DNA fragmentation and protein levels of p53, cytochrome c, and Bax were inhibited in the cells transfected with c-jun dominant-negative mutant (TAM67). Because JNK and ERK are upstream signaling for AP-1 activation, we suggest that DHA-induced activation of AP-1 may mediate apoptosis of gastric cancer cells by inducing the expression of apoptotic genes in gastric cancer cells.
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PMID:Activator protein-1 mediates docosahexaenoic acid-induced apoptosis of human gastric cancer cells. 1972 51