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 death. 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 clear. 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.
Seoane
Joan
J
Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Le
Hong-Van
HV
Massagué
Joan
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D019556:COS Cells; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D018797:Cell Cycle Proteins; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D018983:DNA Footprinting; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015801:Helminth Proteins; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D015801:Helminth Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; C112738:PUMA1 protein, Parascaris univalens; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C107961:ZBTB17 protein, human; D004247:DNA