Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging.
Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging.
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DOI：
10.1111/acel.12060
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发表时间：
2013-06
期刊：
影响因子：
7.8
通讯作者：
Migliaccio E
中科院分区：
文献类型：
--
作者：
Gambino V;De Michele G;Venezia O;Migliaccio P;Dall'Olio V;Bernard L;Minardi SP;Della Fazia MA;Bartoli D;Servillo G;Alcalay M;Luzi L;Giorgio M;Scrable H;Pelicci PG;Migliaccio E
氧化应激是细胞衰老和老化的一个决定性因素，也是肿瘤抑制因子p53的一种强效诱导物。在哺乳动物中，对氧化应激的抵抗与衰老延迟相关，且不会加速肿瘤发生，这表明某些p53下游通路失活。我们研究了p66缺失小鼠中p53的调控情况，p66缺失这种突变会延缓衰老，并赋予细胞和机体对氧化应激的抵抗力。我们确定了一个约200个基因的转录网络，这些基因受p53抑制，编码有丝分裂进程的决定因素或衰老抑制因子。在氧化应激后，它们在培养的成纤维细胞中选择性下调，在体内，在增殖组织中和生理老化过程中也是如此。这种选择性是由p66的表达以及p44/p53（也称为Δ40p53）的激活所决定的，p44/p53是一种p53异构体，它会加速衰老，并在蛋白质损伤后阻止有丝分裂。p66缺失会延缓衰老，并延长p44/p53转基因小鼠的寿命。因此，氧化应激激活了一种由p44/p53和p66介导的特定p53转录反应，这种反应调节细胞衰老和老化。
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.
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影响因子：
64.5
作者：
Giorgio, M;Migliaccio, E;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
--
作者：
Feng, Zhaohui;Lin, Meihua;Wu, Rui
通讯作者：
Wu, Rui
影响因子：
8
作者：
Candeias, M. M.;Powell, D. J.;Fahraeus, R.
通讯作者：
Fahraeus, R.
影响因子：
4.8
作者：
Desaint, S;Luriau, S;Toledano, MB
通讯作者：
Toledano, MB
影响因子：
10.5
作者：
Maier, B;Gluba, W;Scrable, H
通讯作者：
Scrable, H