Overexpression of c-Myc inhibits p21WAF1/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 transformation. We previously found (M. V. Blagosklonny, et al., Cancer Res., 57: 320-325, 1997) that exposure of human SkBr3 breast cancer and LNCaP prostate cancer cells to 12-O-tetradecanoylphorbol-13-acetate (TPA) led to a growth arrest associated with the up-regulation of the cyclin-dependent kinase inhibitor p21(WAF1/cIP1) and the inhibition of c-Myc expression. We show here that exogenous c-Myc inhibits p21 expression in SkBr3 and LNCaP cells induced to enter into S-phase. p27 expression was not increased from basal levels in TPA-treated growth-arrested cells. A time course after infection of TPA-arrested cells using a c-Myc-expressing adenovirus revealed that the inhibition 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 endogenous p21 mRNA, and transfection of c-Myc repressed p21-promoter luciferase-reporter gene expression. The results suggest that the down-regulation of p21 expression may contribute to c-Myc-dependent entry into S-phase, possibly in situations in which growth arrest is associated with increased p21 expression.
D000256:Adenoviridae; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured