Distinct pathways mediate transcriptional regulation of platelet-derived growth factor B/c-sis expression.
The biochemical mechanisms responsible for regulating cellular platelet-derived growth factor expression are incompletely understood. Our previous studies have shown that platelet-derived growth factor B/c-sis mRNA levels are induced in human renal microvascular endothelial cells by either thrombin or transforming growth factor (TGF-beta), while exposure to agents which elevate cAMP levels blocks the induction responses. The current studies use combined transcription run-off and message decay rate experiments to show greater than 3-fold increases in rate of transcription after stimulation with either thrombin or TGF-beta. c-sis message has a 70-90-min half-life under basal conditions that is effectively unaltered by thrombin or TGF-beta. Forskolin does not decrease the stability of c-sis mRNA, although it attenuates transcription increases seen with inducing agents. TGF-beta induction of c-sis transcription is mediated independent of the protein kinase C (Ca2+- and phospholipid-dependent enzyme)-mediated responses to phorbol ester, as it remains intact following down-regulation of protein kinase C response; TGF-beta and phorbol elicit additive induction. Inhibitory effects of cAMP upon transcription act distal to early thrombin-receptor-coupled increases in phosphatidylinositol turnover and are capable of turning off TGF-beta-activated transcription after activation has been established. Both inducing and suppressing agents alter endothelial platelet-derived growth factor B/c-sis mRNA expression dominantly through effects upon rates of transcription, cAMP suppression of transcription is dominant, and TGF-beta and phorbol esters mediate induction of transcription through distinct pathways.
Daniel
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Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232.
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D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D005786:Gene Expression Regulation; D005796:Genes; D006801:Humans; D007672:Kidney Cortex / Q000098:blood supply; D007700:Kinetics; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D015291:Transforming Growth Factors / Q000494:pharmacology
D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D015291:Transforming Growth Factors; D013917:Thrombin; D013755:Tetradecanoylphorbol Acetate