Early Gene Responses to Transforming Growth Factor-β in Cells Lacking Growth-Suppressive RB Function

Abstract

The growth-suppressive function of the retinoblastoma susceptibility gene product, RB, has been implicated in the mediation of growth inhibition and negative regulation of certain proliferation related genes by transforming growth factor-β1(TGF-β1. Early gene responses to TGF-β1were examined in order to determine their dependence on the cell cycle and on the growth-suppressive function of RB. TGF-β1 which rapidly elevates the steady-state level of junB and PAI-1 mRNAs and decreases that of c-myc mRNA, induces these responses in S-phase populations of Mv1Lu lung epithelial cells containing RB in a phosphorylated state. Since in this state RB is presumed to lack growth-suppressive activity, the response to TGF-β1 was also examined in DU145 human prostate carcinoma cells whose mutant RB product lacks growth-suppressive function. In these cells, TGF-β1 also decreases c-myc expression at the transcription initiation level. These results suggests that the c-myc, junB, and PAI-1 responses to TGF-β1 are not restricted to the G₁ phase of the cell cycle and that down-regulation of c-myc expression by TGF-β1 can occur through a mechanism independent from the growth-suppressive function of RB.