Synergy between phorbol esters and retinoic acid in inducing protein kinase C activation.
All-trans retinoic acid (RA) activates brain protein kinase C (PKC) in a unique fashion. Co-factors such as Ca2+ or PtdSer are not required for histone phosphorylation. Binding experiments have provided evidence that RA does not act as a phorbol-ester-like activator. However, phorbol esters synergistically enhance this activation in a dose-dependent manner and increase the reaction rate up to five-fold when combined with 10 microM RA. Phospholipid-interacting drugs such as phenothiazines and 1-N-(6 aminohexyl) 5-chloro-1-naphthalene-sulfonamide (W7), which compete with PtdSer and inhibit phorbol ester/PtdSer-mediated activation, have potentiating effects on the RA-mediated reaction. RA elicits Ca(2+)-dependent PKC autophosphorylation. The activation resulting from the combined treatment with PtdSer and RA is more than additive in the presence of Ca2+, indicating that PtdSer- and RA-binding sites are distinct. RA shares several characteristics of activation with sodium deoxycholate and arachidonic acid. These present results suggest that the direct activation of PKC may have physiological and/or pharmacological relevance in the signaling triggered by retinoids.
Bouzinba-Segard
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INSERM U-268, Hôpital Paul-Brousse, Villejuif, France.
Fan
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Perderiset
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Castagna
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002746:Chlorpromazine / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*; D014268:Trifluoperazine / Q000494:pharmacology; D014316:Tritium
D007546:Isoquinolines; D010879:Piperazines; D013449:Sulfonamides; D014316:Tritium; D014268:Trifluoperazine; D014212:Tretinoin; C017967:W 7; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002746:Chlorpromazine