TGF-β and phorbol esters inhibit mitogenesis utilizing parallel protein kinase C-dependent pathways

Robert H Weiss, A. P. Yabes, R. Sinaee

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Transforming growth factor (TGF-β)-β mediates matrix production in both mesangial and vascular smooth muscle cells. Both TGF-β and phorbol-12-myristate-13-acetate (PMA) exert both positive and negative effects on mitogenesis in these as well as other cell types. Phorbol esters act through stimulation of protein kinase C (PKC) and are among the most potent tumor promoters known. The present study was conducted to determine if the growth inhibitory effect of TGF-β parallels that of the phorbol esters and whether this effect of TGF-β is dependent on activation of PKC. We show that, in vascular smooth muscle cells stimulated to divide by the addition of the serum component basic fibroblast growth factor bFGF), TGF-β1 inhibits mitogenesis in a dose-dependent manner, by a maximum of 79% when applied at a concentration of 1 ng/ml. Furthermore, the inhibitory effect on mitogenesis of either TGF-β1 or PMA, when added four hours after bFGF, are 71% and 84%, respectively. Both TGF-β1 and PMA cause translocation of cellular PKC with similar time courses, while neither PKC-α nor PKC-βII are increased in quantity in response to TGF-β1. In addition, down-regulation of PKC by 24 hours incubation with PMA abolishes TGF-β's inhibitory effect in bFGF-stimulated cells. We conclude that (i) the signaling pathway utilized by TGF-β resulting in inhibition of mitogenesis parallels that of PMA, and (ii) the inhibitory effect of TGF-β1 on bFGF-induced mitogenesis is partially due to activation of PKC. These data suggest that TGF-β may be an endogenous activator of the growth-inhibitory pathway of PKC, and, since cellular differentiated functions generally occur when the cells are proliferation-inhibited, PKC may be a modulator of extracellular matrix deposition.

Original languageEnglish (US)
Pages (from-to)738-744
Number of pages7
JournalKidney International
Volume48
Issue number3
StatePublished - 1995

ASJC Scopus subject areas

  • Nephrology

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