1. Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA

Correspondence to: Joan Massagué Correspondence and requests for materials should be addressed to J.M. (e-mail: Email: j-massague@ski.mskcc.org).

Abstract

Activation of the tumour suppressor p53 by DNA damage induces either cell cycle arrest or apoptotic cell death¹. The cytostatic effect of p53 is mediated by transcriptional activation of the cyclin-dependent kinase (CDK) inhibitor p21^Cip1, whereas the apoptotic effect is mediated by transcriptional activation of mediators including PUMA and PIG3 (ref. 2). What determines the choice between cytostasis and apoptosis is not clear³. Here we show that the transcription factor Myc is a principal determinant of this choice. Myc is directly recruited to the p21^Cip1 promoter by the DNA-binding protein Miz-1. This interaction blocks p21^Cip1 induction by p53 and other activators. As a result Myc switches, from cytostatic to apoptotic, the p53-dependent response of colon cancer cells to DNA damage. Myc does not modify the ability of p53 to bind to the p21^Cip1 or PUMA promoters, but selectively inhibits bound p53 from activating p21^Cip1 transcription. By inhibiting p21^Cip1 expression Myc favours the initiation of apoptosis, thereby influencing the outcome of a p53 response in favour of cell death.