P21WAF1 is component of a positive feedback loop that maintains the p53 transcriptional program

Lisa Y. Pang, Mary Scott, Richard L. Hayward, Hisham Mohammed, C. Bruce A. Whitelaw, Graeme C.M. Smith, Ted R. Hupp

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The regulation of p53 activity through the MDM2 negative feedback loop is driven in part by an extrinsic ATM-pulse that maintains p53 oscillations in response to DNA damage. We report here that the p53 pathway has evolved an intrinsic positive feedback loop that is maintained by the p53-inducible gene product p21WAF1. p21-null cancer cells have defects in p53 protein turnover, reductions in MDM2-mediated degradation of p53, and reduced DNA damage-induced ubiquitination of p53. TLR3-IRF1 or ATM-dependent signaling to p53 is defective in p21-null cells and complementation of the p21 gene in p21-null cancer cells restores the p53 transcriptional response. The mechanism of p53 inactivity in p21-null cells is linked to a p53 protein equilibrium shift from chromatin into cytosolic fractions and complementation of the p21 gene into p21-null cells restores the nuclear localization of p53. A loss of p53 transcriptional function in murine B-cells heterozygous or homozygous null for p21 highlights a p21-gene dosage effect that maintains the full p53 transcriptional response. ATM inhibition results in nuclear exclusion of p53 highlighting a positive genetic interaction between ATM and p21. p21 protein oscillates in undamaged proliferating cells, and reductions of p21 protein using siRNA eliminate the DNA damage-induced p53 pulse. The p53 transcription program has evolved a negative feedback loop maintained by MDM2 that is counteracted by a positive feedback loop maintained by ATM-p21 the balance of which controls the specific activity of p53 as a transcription factor.

Original languageEnglish (US)
Pages (from-to)932-950
Number of pages19
JournalCell Cycle
Volume10
Issue number6
DOIs
StatePublished - Mar 15 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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