Nature Cell Biology：p53诱导成体干细胞消亡关键因子
来源：生物谷
加利福尼亚大学圣地亚哥分校的生物学家们发现一个在细胞程序性死亡中起关键作用的基因Puma是导致成体干细胞消亡的重要因子。这一发现将有助于改善患者在癌症治疗过程中的健康状况。研究论文在线发表于Nature Cell Biology杂志上。
“放疗或是化疗都是通过诱导细胞基因组的DNA损伤而杀伤癌细胞。其中一个最主要的副作用就是会造成癌症患者自身成体干细胞毒害，尤其是与造血和胃肠道相关的细胞，因此导致患者出现贫血、食欲丧失及体重剧降，”加利福尼亚大学生物系教授、该研究小组的负责人Yang Xu说道：“如果我们能够阻止癌症治疗过程中干细胞的消亡，将有利于患者的健康。”
在癌症治疗过程中当正常细胞累积大量的DNA损伤时，肿瘤抑制因子p53被激活可导致细胞停止分裂，进入休眠状态并最终发生细胞程序性死亡。Puma基因在p53启动的DNA损伤细胞死亡中起关键作用。
使用遗传修饰小鼠持续激活p53，Xu和他的同事们发现p53一旦被激活就可导致各种成体干细胞包括与造血和肠细胞相关的干细胞发生消亡。他们还证实Puma在p53依赖的各种成体干细胞消亡过程中发挥关键作用。
“因为p53是一个关键的肿瘤抑制子，你不能通过抑制p53来阻止成体干细胞消亡因为它会诱导癌症产生，”Xu说：“但是你可以通过靶向Puma来阻止p53调控的成体干细胞消亡，因为Puma缺陷不会促进癌症的发展，这给了我们一个新靶点阻止DNA损伤所致p53依赖的成体干细胞消亡。如果能够抑制Puma基因功能，就能够挽救在癌症治疗中由于DNA损伤积累导致的成体干细胞丧失。”
生物谷推荐英文摘要：
Nature Cell Biology doi:10.1038/ncb2100
Puma is required for p53-induced depletion of adult stem cells
Dongping Liu,Linda Ou,Gregory D. Clemenson Jr,Connie Chao,Marshall Eli Lutske,Gerard P. Zambetti,Fred H. Gage& Yang Xu
Mammalian ageing is accompanied by accumulation of genomic DNA damage and progressive decline in the ability of tissues to regenerate1. 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 2, 3, 4, 5). 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 damage6, 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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