Myc suppression of the p21Cip1 Cdk inhibitor influences the outcome of the p53 response to DNA damage

Joan Seoane, Hong- Van Le and Joan Massagué ()
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Joan Seoane: Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center
Hong- Van Le: Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center
Joan Massagué: Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center

Nature, 2002, vol. 419, issue 6908, 729-734

Abstract: 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 p21Cip1, 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 p21Cip1 promoter by the DNA-binding protein Miz-1. This interaction blocks p21Cip1 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 p21Cip1 or PUMA promoters, but selectively inhibits bound p53 from activating p21Cip1 transcription. By inhibiting p21Cip1 expression Myc favours the initiation of apoptosis, thereby influencing the outcome of a p53 response in favour of cell death.

Date: 2002
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DOI: 10.1038/nature01119

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