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

Aging Cell

Valentina Gambino¹  Giulia De Michele¹  Oriella Venezia¹  Pierluigi Migliaccio³  Valentina Dall'Olio¹  Loris Bernard¹  Simone Paolo Minardi⁴  Maria Agnese Della Fazia⁶  Daniela Bartoli⁶  Giuseppe Servillo⁶  Myriam Alcalay¹  Lucilla Luzi¹  Marco Giorgio¹  Heidi Scrable⁵  Pier Giuseppe Pelicci² 

[1] European Institute of Oncology, Milan, Italy;Dipartimento di Medicina, Chirurgia e Odontoiatria, University of Milan, Milan, Italy;Dipartimento di Scienze Biomediche - Sez. di Anatomia Umana, University of Siena, Siena, Italy;Firc Institute for Molecular Oncology, Milan, Italy;Mayo Clinic, University of Massachusetts Medical School, Worcester, MN, USA;Dipartimento di Medicina Clinica e Sperimentale, Facoltà di Medicina e Chirurgia, University of Perugia, Perugia, Italy

关键词: aging genes;    oxydative stress;    p53;    senescence;   

DOI  :  10.1111/acel.12060

来源: Wiley

【 摘 要 】

Summary

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.

【 授权许可】

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