p63 deficiency activates a program of cellular senescence and leads to accelerated aging
p63 deficiency activates a program of cellular senescence and leads to accelerated aging
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DOI：
10.1101/gad.342305
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发表时间：
2005-09-01
影响因子：
10.5
通讯作者：
Mills, AA
中科院分区：
文献类型：
--
作者：
Keyes, WM;Wu, Y;Mills, AA
p53肿瘤抑制因子在机体衰老中起关键作用。一种被认为驱动衰老过程的细胞机制是细胞衰老，部分由p53介导。尽管衰老细胞在老年人体内积累，但大多数研究都依赖于体外衰老测定与体内衰老表型的相关性。在这里，我们使用两种不同的小鼠模型，其中p53相关蛋白p63受损，我们证明细胞衰老和机体衰老密切相关，这些过程是由p63损失介导的。我们发现p63（+/-）小鼠寿命缩短，衰老加速。种系和体细胞诱导的p63缺乏都激活了广泛的细胞衰老，衰老标志物SA-P-gal、PML和p16 （INK4a）的表达增强。利用可诱导的组织特异性p63条件模型，我们进一步证明p63缺乏诱导细胞衰老并导致成人加速衰老表型。因此，我们的研究结果表明细胞衰老与体内衰老之间存在因果关系，并证明p63缺乏加速了这一过程。
The p53 tumor suppressor plays a key role in organismal aging. A cellular mechanism postulated to drive the aging process is cellular senescence, mediated in part by p53. Although senescent cells accumulate in elderly individuals, most studies have relied on correlating in vitro senescence assays with in vivo phenotypes of aging. Here, using two different mouse models in which the p53-related protein p63 is compromised, we demonstrate that cellular senescence and organismal aging are intimately linked and that these processes are mediated by p63 loss. We found that p63(+/-) mice have a shortened life span and display features of accelerated aging. Both germline and somatically induced p63 deficiency activates widespread cellular senescence with enhanced expression of senescent markers SA-P-gal, PML, and p16 (INK4a). Using an inducible tissue-specific p63 conditional model, we further show that p63 deficiency induces cellular senescence and causes accelerated aging phenotypes in the adult. Our results thus suggest a causative link between cellular senescence and aging in vivo, and demonstrate that p63 deficiency accelerates this process.