Phorbol ester inhibits 13-cis-retinoic acid-induced hydrolysis of phosphatidylinositol 4,5-bisphosphate in cultured murine keratinocytes: a possible negative feedback via protein kinase C-activation.
The incubation of double-labelled [( 14C]-glycerol and [3H]-myoinositol) keratinocytes with 13-cis retinoic acid induced the transient and simultaneous release of [3H]-inositol trisphosphate ([3H]-InsP3) and [14C]-diacylglycerol ([14C]-DAG) indicating that a possible mode of action of this retinoid on murine keratinocytes may be at least in part the early transient release of the two putative messengers (InsP3 and DAG) from phosphatidylinositol-4,5 bisphosphate (PtdIns4, 5P2). In contrast, the preincubation of the keratinocytes with 12-O-tetradecanoylphorbol-13-acetate (TPA) prior to incubation with 13-cis-RA suppressed the 13-cis-RA-induced release of [3H]-InsP3 and [14C]-DAG. The specificity of the TPA effect was established by the lack of effect of the biologically inactive 4 alpha-phorbol 12, 13-didecanoate. Furthermore, the incubation of the TPA-primed keratinocytes with 13-cis-RA caused a delayed and sustained accumulation of [14C]-DAG. An exploration of the source of this late release of [14C]-DAG revealed that this [14C]-DAG was released from non-inositol containing phospholipids, particularly, phosphatidylcholine. This latter DAG released in the TPA-primed cells correlated with the translocation of the cytoplasmic protein kinase C (PKC) activity to the membrane associated PKC activity. Taken together, these results suggest that alteration of PKC activity, presumably induced by DAG released from non-inositol phospholipids, may play a major role in the TPA-induced negative feedback inhibition of 13-cis RA-induced hydrolysis of keratinocyte PtdIns4, 5P2.
Tang
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Department of Dermatology, University of California, Davis 95616.
Ziboh
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D000818:Animals; D000831:Animals, Newborn; D004075:Diglycerides / Q000378:metabolism; D004789:Enzyme Activation; D015474:Isotretinoin / Q000494:pharmacology*; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010703:Phorbol Esters / Q000494:pharmacology; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D004075:Diglycerides; D010703:Phorbol Esters; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; C008876:phorbol-12,13-didecanoate; D011493:Protein Kinase C; D015474:Isotretinoin; D013755:Tetradecanoylphorbol Acetate