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

被引：127

作者：

Gambino, Valentina ^{[1
]}

De Michele, Giulia ^{[1
]}

Venezia, Oriella ^{[1
]}

Migliaccio, Pierluigi ^{[2
]}

Dall'Olio, Valentina ^{[1
,3
]}

Bernard, Loris ^{[1
]}

Minardi, Simone Paolo ^{[3
]}

Della Fazia, Maria Agnese ^{[4
]}

Bartoli, Daniela ^{[4
]}

Servillo, Giuseppe ^{[4
]}

Alcalay, Myriam ^{[1
,5
]}

Luzi, Lucilla ^{[1
,3
]}

Giorgio, Marco ^{[1
]}

Scrable, Heidi ^{[6
]}

Pelicci, Pier Giuseppe ^{[1
,5
]}

Migliaccio, Enrica ^{[1
]}

机构：

[1] European Inst Oncol, I-20141 Milan, Italy

[2] Univ Siena, Dipartimento Sci Biomed, Sez Anat Umana, I-53100 Siena, Italy

[3] Firc Inst Mol Oncol, I-20139 Milan, Italy

[4] Univ Perugia, Fac Med Chirurg, Dipartimento Med Clin & Sperimentale, I-06100 Perugia, Italy

[5] Univ Milan, Dipartimento Med Chirurg & Odontoiatria, I-20142 Milan, Italy

[6] Univ Massachusetts, Mayo Clin, Sch Med, Worcester, MN 55905 USA

来源：

AGING CELL | 2013年 / 12卷 / 03期

关键词：

aging genes; oxydative stress; p53; senescence; MESSENGER-RNA TRANSLATION; FATAL NEOPLASTIC DISEASES; MN SUPEROXIDE-DISMUTASE; CAUSES EARLY-ONSET; LIFE-SPAN; ANTIOXIDANT ENZYMES; DELAYED OCCURRENCE; INSULIN-RECEPTOR; MICE; OVEREXPRESSION;

D O I：

10.1111/acel.12060

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 similar to 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.

引用

页码：435 / 445

页数：11

共 44 条

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