Puma is required for p53-induced depletion of adult stem cells.
Puma is required for p53-induced depletion of adult stem cells.
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DOI：
10.1038/ncb2100
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发表时间：
2010-10
影响因子：
21.3
通讯作者：
Xu, Yang
中科院分区：
文献类型：
--
作者：
Liu, Dongping;Ou, Linda;Clemenson, Gregory D., Jr.;Chao, Connie;Lutske, Marshall Eli;Zambetti, Gerard P.;Gage, Fred H.;Xu, Yang
哺乳动物衰老伴随着基因组DNA损伤的积累和组织再生能力的逐渐下降。DNA损伤激活肿瘤抑制因子p53，导致细胞周期停滞、衰老或凋亡。p53的稳定性和活性由DNA损伤通过翻译后修饰如Thr 21和Ser 23的磷酸化诱导（参考文献）。为了研究DNA损伤和p53在组织再生能力中的作用，将两个磷酸化位点突变（T21D和S23D）引入小鼠内源性p53基因，使得合成的蛋白质模拟磷酸化的p53。敲入小鼠表现出组成性p53激活和节段性早衰，这与包括骨髓、脑和睾丸在内的多种组织中成体干细胞的耗竭相关。此外，DNA损伤后p53依赖性凋亡所需的Puma的缺乏拯救了节段性早衰症并防止了成体干细胞的耗尽。这些发现表明，p53依赖性细胞凋亡在DNA损伤积累后耗尽成体干细胞中起关键作用，这导致组织再生减少。
Mammalian ageing is accompanied by accumulation of genomic DNA damage and progressive decline in the ability of tissues to regenerate. DNA damage activates the tumour suppressor p53, which leads to cell-cycle arrest, senescence or apoptosis. The stability and activity of p53 are induced by DNA damage through posttranslational modifications such as phosphorylation of Thr 21 and Ser 23 (refs). To investigate the roles of DNA damage and p53 in tissue-regenerative capability, two phosphorylation-site mutations (T21D and S23D) were introduced into the endogenous p53 gene in mice, so that the synthesized protein mimics phosphorylated p53. The knock-in mice exhibit constitutive p53 activation and segmental progeria that is correlated with the depletion of adult stem cells in multiple tissues, including bone marrow, brain and testes. Furthermore, a deficiency of Puma, which is required for p53-dependent apoptosis after DNA damage, rescues segmental progeria and prevents the depletion of adult stem cells. These findings suggest a key role of p53-dependent apoptosis in depleting adult stem cells after the accumulation of DNA damage, which leads to a decrease in tissue regeneration.
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