Myc suppression of the p21Cip1 Cdk inhibitor influences the outcome of the p53 response to DNA damage Journal Article
| Authors: | Seoane, J.; Le, H. V.; Massagué, J. |
| Article Title: | Myc suppression of the p21Cip1 Cdk inhibitor influences the outcome of the p53 response to DNA damage |
| Abstract: | 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 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 clear. 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. |
| Keywords: | dna binding protein; gene deletion; dna-binding proteins; flow cytometry; proteins; animals; cell cycle proteins; cell death; dna damage; cell cycle; apoptosis; transforming growth factor beta; protein binding; colonic neoplasms; tumor cells, cultured; cos cells; protein p53; transcription factors; nuclear proteins; gene expression regulation, neoplastic; dna; tumors; colon cancer; cancer cell; tumor suppressor protein p53; cyclin-dependent kinase inhibitor p21; cyclins; cyclin dependent kinase inhibitor; proto-oncogene proteins c-myc; protein p21; transcriptional activation; oncogene myc; cytostasis; cells; dna footprinting; promoter regions (genetics); helminth proteins; cancer; humans; priority journal; article |
| Journal Title: | Nature |
| Volume: | 419 |
| Issue: | 6908 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2002-10-17 |
| Start Page: | 729 |
| End Page: | 734 |
| Language: | English |
| DOI: | 10.1038/nature01119 |
| PUBMED: | 12384701 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
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