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Molecular and Cellular Biology, September 2005, p. 7423-7431, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7423-7431.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

p53-Dependent Transcriptional Repression of c-myc Is Required for G1 Cell Cycle Arrest

Jenny S. L. Ho, Weili Ma, Daniel Y. L. Mao, and Samuel Benchimol*

Ontario Cancer Institute, Princess Margaret Hospital, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2M9

Received 30 October 2004/ Returned for modification 10 December 2004/ Accepted 2 June 2005

The ability of p53 to promote apoptosis and cell cycle arrest is believed to be important for its tumor suppression function. Besides activating the expression of cell cycle arrest and proapoptotic genes, p53 also represses a number of genes. Previous studies have shown an association between p53 activation and down-regulation of c-myc expression. However, the mechanism and physiological significance of p53-mediated c-myc repression remain unclear. Here, we show that c-myc is repressed in a p53-dependent manner in various mouse and human cell lines and mouse tissues. Furthermore, c-myc repression is not dependent on the expression of p21WAF1. Abrogating the repression of c-myc by ectopic c-myc expression interferes with the ability of p53 to induce G1 cell cycle arrest and differentiation but enhances the ability of p53 to promote apoptosis. We propose that p53-dependent cell cycle arrest is dependent not only on the transactivation of cell cycle arrest genes but also on the transrepression of c-myc. Chromatin immunoprecipitation assays indicate that p53 is bound to the c-myc promoter in vivo. We report that trichostatin A, an inhibitor of histone deacetylases, abrogates the ability of p53 to repress c-myc transcription. We also show that p53-mediated transcriptional repression of c-myc is accompanied by a decrease in the level of acetylated histone H4 at the c-myc promoter and by recruitment of the corepressor mSin3a. These data suggest that p53 represses c-myc transcription through a mechanism that involves histone deacetylation.

* Corresponding author. Mailing address: Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: (416) 946-2955. Fax: (416) 946-2840. E-mail: benchimo{at}uhnres.utoronto.ca.

Molecular and Cellular Biology, September 2005, p. 7423-7431, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7423-7431.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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