A role for protein kinase C alpha in stimulation of prostaglandin G/H synthase-2 transcription by 14,15-epoxyeicosatrienoic acid.
Arachidonic acid, but not eicosapentaenoic acid, increased prostaglandin G/H endoperoxide synthase-2 transcription in cultured intestinal epithelial cells. This stimulatory effect on PGHS-2 synthesis was prevented by an AA utilization inhibitor, eicosatetraynoic acid. Specific inhibitors of the cyclooxygenase or the lipoxygenase pathways of AA metabolism did not prevent AA-mediated induction of PGHS-2 synthesis; however, the involvement of cytochrome P450 monoxygenases (CYP450) was indicated as several CYP450 blockers, ketoconazole, miconazole, and metyrapone, inhibited the induction of PGHS-2 mRNA synthesis by AA. This blockade by CYP450 inhibitors could be overcome by the addition of the AA epoxygenase metabolite 14,15-epoxyeicosatrienoic acid (14,15-EET); other EET regio-isomers were unable to elevate PGHS-2 mRNA level. Blockade of protein kinase C with a specific inhibitor, bisindolyl maleimide-1, or translational inhibition of protein kinase C alpha by antisense oligonucleotides reduced PGHS-2 transcription, suggesting the involvement of protein kinase C alpha in the signal transduction pathway.
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Research Center, Ste. Justine Hospital, Catherine, Montreal, Canada.
Almazan
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Varma
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Chemtob
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D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D051546:Cyclooxygenase 2; D004008:Diclofenac / Q000494:pharmacology; D004847:Epithelial Cells; D007413:Intestinal Mucosa; D007527:Isoenzymes / Q000235:genetics* / Q000502:physiology*; D007654:Ketoconazole / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D008825:Miconazole / Q000494:pharmacology; D010544:Peroxidases / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D051571:Protein Kinase C-alpha; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D007527:Isoenzymes; D011461:Prostaglandins F, Synthetic; D012333:RNA, Messenger; D004008:Diclofenac; D005576:Colforsin; D008825:Miconazole; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D010544:Peroxidases; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D015126:8,11,14-Eicosatrienoic Acid; D015064:16,16-Dimethylprostaglandin E2; D013755:Tetradecanoylphorbol Acetate; D007654:Ketoconazole; C039153:fenprostalene; D008797:Metyrapone