Phosphatidic acid modulates DNA synthesis, phospholipase C, and platelet-derived growth factor mRNAs in cultured mesangial cells. Role of protein kinase C.
Increases in cell phosphatidic acid content occur in response to a wide variety of agonists, many of which have growth promoting properties. These changes have correlated with calcium flux, enzyme activation, gene induction, or cell proliferation. In the current studies we show that exogenous phosphatidic acid (PA) and phosphatidylserine stimulate phosphoinositide hydrolysis and DNA synthesis in cultured human renal mesangial cells. These phospholipids also induce mRNAs for platelet-derived growth factor (PDGF). The activation of phospholipase C by PA appears to be desensitized via protein kinase C as brief preincubation with phorbol ester abrogates the effect. PA-induced DNA synthesis is only partly mediated via protein kinase C as co-incubation with the inhibitor staurosporine blunts DNA synthesis by only one-third. In contrast, induction of PDGF A-chain mRNA is almost totally inhibited by staurosporine. We propose that changes in endogenous phospholipids such as PA or phosphatidylserine may serve as common signaling pathway for a variety of growth factors. Induction of PDGF proto-oncogenes via protein kinase C may represent one mechanism by which this cell activation occurs.
Knauss
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TC
Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
Jaffer
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Abboud
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HE
D000470:Alkaloids / Q000494:pharmacology; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects*; D004789:Enzyme Activation; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D010712:Phosphatidic Acids / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D010718:Phosphatidylserines / Q000494:pharmacology*; D010743:Phospholipids / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism*
D000470:Alkaloids; D007295:Inositol Phosphates; D010712:Phosphatidic Acids; D010716:Phosphatidylinositols; D010718:Phosphatidylserines; D010743:Phospholipids; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011493:Protein Kinase C; D010738:Type C Phospholipases; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate