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Cell Growth & Differentiation Vol. 10, 223-230, April 1999
© 1999 American Association for Cancer Research

Overexpression of c-Myc Inhibits p21WAF1/CIP1 Expression and Induces S-Phase Entry in 12-O-Tetradecanoylphorbol-13-acetate (TPA)-sensitive Human Cancer Cells1

Kyran O. Mitchell and Wafik S. El-Deiry2

Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Department of Medicine, Genetics, Cancer Center, and Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

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 p21WAF1/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.




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Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1999 by the American Association of Cancer Research.