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Aging Cell. 2013 Jun;12(3):435-45. doi: 10.1111/acel.12060. Epub 2013 Mar 27.

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

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  • 1European Institute of Oncology, Via Ripamonti 435, Milan, 20141, Italy.

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.

© 2013 John Wiley & Sons Ltd and the Anatomical Society.

PMID:
23448364
[PubMed - indexed for MEDLINE]
PMCID:
PMC3709138
Free PMC Article
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