Overexpression of c-Myc inhibits p(21WAF1/CIP1) expression and induces S-phase entry in 12-O-tetradecanoylphorbol-13-acetate (TPA)-sensitive human cancer cells

The c-Myc oncoprotein is a transcription factor involved in cellular transf ormation. We previously found (M. V. Blagosklonny, et al., Cancer Res., 57: 320-325, 1997) that exposure of human SkBr3 breast cancer and LNCaP prosta te cancer cells to 12-O-tetradecanoylphorbol-13-acetate (TPA) led to a grow th arrest associated with the up-regulation of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and the inhibition of c-Myc expression. We show he re that exogenous c-Myo inhibits p21 expression in SkBr3 and LNCaP cells in duced to enter into S-phase. p27 expression was not increased from basal le vels in TPA-treated growth-arrested cells. A time course after infection of TPA-arrested cells using a c-Myc-expressing adenovirus revealed that the i nhibition of p21 expression preceded entry into S-phase, In contrast, after infection by E2F-1-expressing adenovirus, p21 expression was reduced after the cells entered S-phase. Overexpression of c-Myc reduced the levels of e ndogenous p21 mRNA, and transfection of c-Myc repressed p21-promoter lucife rase-reporter gene expression. The results suggest that the downregulation of p21 expression may contribute to c-Myc-dependent entry into S-phase, pos sibly in situations in which growth arrest is associated with increased p21 expression.