Nature Cell Biology：p53誘導(dǎo)成體干細(xì)胞消亡關(guān)鍵因子
來源：生物谷
加利福尼亞大學(xué)圣地亞哥分校的生物學(xué)家們發(fā)現(xiàn)一個(gè)在細(xì)胞程序性死亡中起關(guān)鍵作用的基因Puma是導(dǎo)致成體干細(xì)胞消亡的重要因子。這一發(fā)現(xiàn)將有助于改善患者在癌癥治療過程中的健康狀況。研究論文在線發(fā)表于Nature Cell Biology雜志上。
“放療或是化療都是通過誘導(dǎo)細(xì)胞基因組的DNA損傷而殺傷癌細(xì)胞。其中一個(gè)最主要的副作用就是會(huì)造成癌癥患者自身成體干細(xì)胞毒害，尤其是與造血和胃腸道相關(guān)的細(xì)胞，因此導(dǎo)致患者出現(xiàn)貧血、食欲喪失及體重劇降，”加利福尼亞大學(xué)生物系教授、該研究小組的負(fù)責(zé)人Yang Xu說道：“如果我們能夠阻止癌癥治療過程中干細(xì)胞的消亡，將有利于患者的健康。”
在癌癥治療過程中當(dāng)正常細(xì)胞累積大量的DNA損傷時(shí)，腫瘤抑制因子p53被激活可導(dǎo)致細(xì)胞停止分裂，進(jìn)入休眠狀態(tài)并最終發(fā)生細(xì)胞程序性死亡。Puma基因在p53啟動(dòng)的DNA損傷細(xì)胞死亡中起關(guān)鍵作用。
使用遺傳修飾小鼠持續(xù)激活p53，Xu和他的同事們發(fā)現(xiàn)p53一旦被激活就可導(dǎo)致各種成體干細(xì)胞包括與造血和腸細(xì)胞相關(guān)的干細(xì)胞發(fā)生消亡。他們還證實(shí)Puma在p53依賴的各種成體干細(xì)胞消亡過程中發(fā)揮關(guān)鍵作用。
“因?yàn)閜53是一個(gè)關(guān)鍵的腫瘤抑制子，你不能通過抑制p53來阻止成體干細(xì)胞消亡因?yàn)樗鼤?huì)誘導(dǎo)癌癥產(chǎn)生，”Xu說：“但是你可以通過靶向Puma來阻止p53調(diào)控的成體干細(xì)胞消亡，因?yàn)镻uma缺陷不會(huì)促進(jìn)癌癥的發(fā)展，這給了我們一個(gè)新靶點(diǎn)阻止DNA損傷所致p53依賴的成體干細(xì)胞消亡。如果能夠抑制Puma基因功能，就能夠挽救在癌癥治療中由于DNA損傷積累導(dǎo)致的成體干細(xì)胞喪失。”
生物谷推薦英文摘要：
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.
