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

CA Brady, D Jiang, SS Mello, TM Johnson, LA Jarvis… - Cell, 2011 - cell.com
CA Brady, D Jiang, SS Mello, TM Johnson, LA Jarvis, MM Kozak, DK Broz, S Basak, EJ Park…
Cell, 2011cell.com
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 …
Summary
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.
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