Myc suppression of the p21^Cip1 Cdk inhibitor influences the outcome of the p53 response to DNA damage

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) inhibitorp21^Cip1, whereas the apoptotic effect is mediated by transcriptional activation of mediators includingPUMAandPIG3(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 thep21^Cip1promoter by the DNA-binding protein Miz-1. This interaction blocksp21^Cip1induction 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 thep21^Cip1orPUMApromoters, but selectively inhibits bound p53 from activatingp21^Cip1transcription. By inhibitingp21^Cip1expression Myc favours the initiation of apoptosis, thereby influencing the outcome of a p53 response in favour of cell death.