Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging

Valentina Gambino, Giulia De Michele, Oriella Venezia, Pierluigi Migliaccio, Valentina Dall'Olio, Loris Bernard, Simone Paolo Minardi, Maria Agnese Della Fazia, Daniela Bartoli, Giuseppe Servillo, Myriam Alcalay, Lucilla Luzi, Marco Giorgio, Heidi Scrable, Pier Giuseppe Pelicci, Enrica Migliaccio

Research output: Contribution to journalArticle

Abstract

Oxidative stress is a determining factor of cellular senescence and aging and a potent inducer of the tumour-suppressor p53. Resistance to oxidative stress correlates with delayed aging in mammals, in the absence of accelerated tumorigenesis, suggesting inactivation of selected p53-downstream pathways. We investigated p53 regulation in mice carrying deletion of p66, a mutation that retards aging and confers cellular resistance and systemic resistance to oxidative stress. We identified a transcriptional network of ~200 genes that are repressed by p53 and encode for determinants of progression through mitosis or suppression of senescence. They are selectively down-regulated in cultured fibroblasts after oxidative stress, and, in vivo, in proliferating tissues and during physiological aging. Selectivity is imposed by p66 expression and activation of p44/p53 (also named Delta40p53), a p53 isoform that accelerates aging and prevents mitosis after protein damage. p66 deletion retards aging and increases longevity of p44/p53 transgenic mice. Thus, oxidative stress activates a specific p53 transcriptional response, mediated by p44/p53 and p66, which regulates cellular senescence and aging.

Original languageEnglish (US)
Pages (from-to)435-445
Number of pages11
JournalAging Cell
Volume12
Issue number3
DOIs
StatePublished - Jun 2013

Keywords

  • Aging genes
  • Oxydative stress
  • P53
  • Senescence

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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