Journal article
Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
Cell, Vol.145(4), pp.571-583
05/13/2011
DOI: 10.1016/j.cell.2011.03.035
PMCID: PMC3259909
PMID: 21565614
Abstract
The molecular basis for p53-mediated tumor suppression remains unclear. Here, to elucidate mechanisms of p53 tumor suppression, we use knockin mice expressing an allelic series of p53 transcriptional activation mutants. Microarray analysis reveals that one mutant, p53(25,26), is severely compromised for transactivation of most p53 target genes, and, moreover, p53(25,26) cannot induce G(1)-arrest or apoptosis in response to acute DNA damage. Surprisingly, p(5325,26) retains robust activity in senescence and tumor suppression, indicating that efficient transactivation of the majority of known p53 targets is dispensable for these pathways. In contrast, the transactivation-dead p53(25,26,53,54) mutant cannot induce senescence or inhibit tumorigenesis, like p53 nullizygosity. Thus, p53 transactivation is essential for tumor suppression but, intriguingly, in association with a small set of novel p53 target genes. Together, our studies distinguish the p53 transcriptional programs involved in acute DNA-damage responses and tumor suppression-a critical goal for designing therapeutics that block p53-dependent side effects of chemotherapy without compromising p53 tumor suppression.
Details
- Title: Subtitle
- Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
- Creators
- Colleen A. Brady - Stanford UniversityDadi Jiang - Stanford UniversityStephano S. Mello - Stanford UniversityThomas M. Johnson - Stanford UniversityLesley A. Jarvis - Stanford UniversityMargaret M. Kozak - Stanford UniversityDaniela Kenzelmann Broz - Stanford UniversityShashwati Basak - Stanford UniversityEunice J. Park - Stanford UniversityMargaret E. McLaughlin - Massachusetts Institute of TechnologyAnthony N. Karnezis - UCSF Helen Diller Family Comprehensive Cancer CenterLaura D. Attardi - Stanford University
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.145(4), pp.571-583
- DOI
- 10.1016/j.cell.2011.03.035
- PMID
- 21565614
- PMCID
- PMC3259909
- NLM abbreviation
- Cell
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Publisher
- Elsevier
- Number of pages
- 13
- Grant note
- Swiss National Science Foundation; Swiss National Science Foundation (SNSF); European Commission Leukemia and Lymphoma Society C.A.P.E.S; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) National Science Foundation; National Science Foundation (NSF) Gerald Lieberman Dissertation Fellowship CA140875 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01CA140875 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Smith Stanford Graduate Fellowship Lucille P. Markey Biomedical Research Stanford Graduate Fellowship American Cancer Society
- Language
- English
- Date published
- 05/13/2011
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984313085802771
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