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. |
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Authors: | W Tang V A Ziboh |
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Institution: | Department of Dermatology, University of California, Davis 95616. |
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Abstract: | 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. |
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Keywords: | PtdIns phosphatidylinositol PtdIns4P phosphatidylinositol 4-phosphate PtdInS4 5P2 phosphatidylinositol 4 5-bisphosphate InsP Inostiol phosphate InsP2 inositol bisphosphate InsP3 inositol trisphosphate TPA 12-0-tetradecanoylphorbol-13-acetate |
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