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

Colleen A. Brady, Dadi Jiang, Stephano S. Mello, Thomas M. Johnson, Lesley A. Jarvis, Margaret M. Kozak, Daniela Kenzelmann Broz, Shashwati Basak, Eunice J. Park, Margaret E. McLaughlin, Anthony Karnezis, Laura D. Attardi

Research output: Contribution to journalArticle

284 Citations (Scopus)

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, p5325,26, is severely compromised for transactivation of most p53 target genes, and, moreover, p5325,26 cannot induce G1-arrest or apoptosis in response to acute DNA damage. Surprisingly, p5325,26 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 p5325,26,53,54 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.

Original languageEnglish (US)
Pages (from-to)571-583
Number of pages13
JournalCell
Volume145
Issue number4
DOIs
StatePublished - May 13 2011
Externally publishedYes

Fingerprint

DNA Damage
Tumors
Transcriptional Activation
DNA
Neoplasms
p53 Genes
Genes
Chemotherapy
Microarray Analysis
Microarrays
Carcinogenesis
Chemical activation
Association reactions
Apoptosis
Drug Therapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Brady, C. A., Jiang, D., Mello, S. S., Johnson, T. M., Jarvis, L. A., Kozak, M. M., ... Attardi, L. D. (2011). Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell, 145(4), 571-583. https://doi.org/10.1016/j.cell.2011.03.035

Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. / Brady, Colleen A.; Jiang, Dadi; Mello, Stephano S.; Johnson, Thomas M.; Jarvis, Lesley A.; Kozak, Margaret M.; Broz, Daniela Kenzelmann; Basak, Shashwati; Park, Eunice J.; McLaughlin, Margaret E.; Karnezis, Anthony; Attardi, Laura D.

In: Cell, Vol. 145, No. 4, 13.05.2011, p. 571-583.

Research output: Contribution to journalArticle

Brady, CA, Jiang, D, Mello, SS, Johnson, TM, Jarvis, LA, Kozak, MM, Broz, DK, Basak, S, Park, EJ, McLaughlin, ME, Karnezis, A & Attardi, LD 2011, 'Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression', Cell, vol. 145, no. 4, pp. 571-583. https://doi.org/10.1016/j.cell.2011.03.035
Brady CA, Jiang D, Mello SS, Johnson TM, Jarvis LA, Kozak MM et al. Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell. 2011 May 13;145(4):571-583. https://doi.org/10.1016/j.cell.2011.03.035
Brady, Colleen A. ; Jiang, Dadi ; Mello, Stephano S. ; Johnson, Thomas M. ; Jarvis, Lesley A. ; Kozak, Margaret M. ; Broz, Daniela Kenzelmann ; Basak, Shashwati ; Park, Eunice J. ; McLaughlin, Margaret E. ; Karnezis, Anthony ; Attardi, Laura D. / Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. In: Cell. 2011 ; Vol. 145, No. 4. pp. 571-583.
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