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PMID: 21565614 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression.

Cell ·Vol. 145 ·No. 4 ·2011-05-13 ·Pages 571-83

Brady CA, Jiang D, Mello SS, Johnson TM, Jarvis LA, Kozak MM, Kenzelmann Broz D, Basak S, Park EJ, McLaughlin ME, Karnezis AN, Attardi LD

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, p53(25,26) 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.

MeSH Terms
Animals Apoptosis Cell Cycle Cellular Senescence DNA Damage DNA Repair Gene Knock-In Techniques Humans Mice Mutation Neoplasms/metabolism Protein Structure, Tertiary Transcriptional Activation Tumor Suppressor Protein p53/chemistry,genetics,metabolism
Chemicals
Tumor Suppressor Protein p53
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Brady Colleen A
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Jiang Dadi
Mello Stephano S
Johnson Thomas M
Jarvis Lesley A
Kozak Margaret M
Kenzelmann Broz Daniela
Basak Shashwati
Park Eunice J
McLaughlin Margaret E
Karnezis Anthony N
Attardi Laura D
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2011.03.035
Published
2011-05-13
Pages
571-83
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3259909
Subset
IM
Grants
NCI NIH HHS · CA140875 · United States
NCI NIH HHS · R21 CA141087 · United States
NCI NIH HHS · R01 CA140875 · United States
NCI NIH HHS · R01 CA140875-02 · United States
NCI NIH HHS · R21 CA141087-02 · United States
Databases
GEO
GSE27901
Corrections
CommentIn
PMID: 21571212
External Links
PubMed source DOI: 10.1016/j.cell.2011.03.035 PMC Full Text View journal details
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