INVOLVEMENT OF PROTEIN-KINASE-C AND RHO-GTPASE IN THE NUCLEAR SIGNALING PATHWAY BY TRANSFORMING GROWTH-FACTOR-BETA-1 IN RAT-2 FIBROBLAST CELLS

The transforming growth factor (TGF)-beta signal-transduction cascade from the cell membrane to the nuclear target is poorly characterised. Here we report that treatment with TGF-beta 1 induces the levels of en dogenous c-fos mRNA in Rat-2 fibroblast cells. In addition, by transie nt transfection analysis, TGF-beta 1 was shown to stimulate c-fos seru m response element (SRE)-driven reporter gene activity in a dose- and time-dependent manner, suggesting that SRE is one of the nuclear targe ts of TGF-beta 1. To understand the signalling cascade by which TGF-be ta 1 mediates the transactivation of c-fos SRE, cells were either pre- treated with various inhibitors or co-transfected with expression plas mids encoding inhibitory proteins for Rho GTPase together with the SRE -luciferase reporter gene. Our results showed that an inhibition of pr otein kinase C (PKC) or RhoA selectively repressed the stimulation of c-fos SRE by TGF-beta 1, implying the possible roles of PKC and RhoA G TPase in TGF-pl-induced signalling to c-fos SRE. (C) 1998 Elsevier Sci ence Inc.