Ser46 phosphorylation regulates p53-dependent apoptosis and replicative senescence
Ser46 phosphorylation regulates p53-dependent apoptosis and replicative senescence
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DOI：
10.4161/cc.5.23.3526
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发表时间：
2006-12-01
期刊：
影响因子：
4.3
通讯作者：
Xu, Yang
中科院分区：
文献类型：
--
作者：
Feng, Lijin;Hollstein, Monica;Xu, Yang
翻译后修饰如p53的磷酸化在激活p53对各种细胞和遗传毒性应激的反应中起重要作用。细胞系研究表明Ser 46的磷酸化与p53凋亡活性的激活相关。为了解决Ser 46磷酸化的生理作用，我们采用同源重组和LoxP/Cre介导的缺失将Ser 46至Ala错义突变引入小鼠中的人p53敲入（HUPKI）等位基因（p53 hki（S46 A））。在p53 hki（S46 A）胚胎干（ES）细胞、小鼠胚胎成纤维细胞（MEF）和胸腺细胞中，响应于各种类型的DNA损伤的p53稳定性适度降低。此外，在DNA损伤后，p53 hki（S46 A）胸腺细胞和表达E1 A/Ras的小鼠胚胎成纤维细胞（MEFs）中p53依赖性凋亡部分受损。与这一发现相一致的是，DNA损伤后，p53靶向凋亡基因的转录优先受到S46 A突变的影响。p53 hki（S46 A）MEFs正常增殖并达到衰老，但比野生型MEFs更容易自发永生化。此外，p53 hki（S46 A）MEFs更容易逃避Ras诱导的衰老。因此，Ser 46磷酸化激活由DNA损伤诱导的p53依赖性凋亡和由致癌应激诱导的细胞衰老。
Posttranslational modification such as phosphorylation of p53 plays important roles in activating p53 responses to various cellular and genotoxic stresses. Cell line studies have shown that phosphorylation of Ser46 is correlated with the activation of p53 apoptotic activity. To address the physiological roles of Ser46 phosphorylation, we employed homologous recombination and LoxP/Cre-mediated deletion to introduce Ser46 to Ala missense mutation into the human p53 knock-in (HUPKI) allele in mice (p53hki(S46A)). p53 stabilization in response to various types of DNA damage is modestly reduced in p53hki(S46A) embryonic stem (ES) cells, mouse embryonic fibroblasts (MEFs) and thymocytes. In addition, p53-dependent apoptosis is partially impaired in p53hki(S46A) thymocytes and E1A/Ras-expressing mouse embryonic fibroblasts (MEFs) after DNA damage. Consistent with this finding, transcription of p53 target apoptotic genes is preferentially affected by S46A mutation after DNA damage. p53hki(S46A) MEFs proliferate and reach senescence normally but can be spontaneously immortalized more easily than wild type MEFs. In addition, p53hki(S46A) MEFs more readily escapes from Ras-induced senescence. Therefore, Ser46 phosphorylation activates p53-dependent apoptosis induced by DNA damage and cellular senescence induced by oncogenic stress.