Genetic analysis of p53 stability and activity

描述（申请人提供）：p53是人类癌症中最常见的突变肿瘤抑制因子，在细胞周期阻滞、细胞凋亡、分化和DNA修复等方面发挥着关键作用。虽然最近的研究也将p53与衰老联系起来，但p53在衰老中的确切作用仍不清楚，因为只在一些而不是所有p53活性增加的小鼠模型中观察到过早衰老。在各种应激反应中，p53蛋白水平上调，其转录活性被激活。p53的翻译后修饰，包括磷酸化和乙酰化，被认为在调节p53对基因毒性和致癌应激的反应中起重要作用。为了解决p53翻译后修饰在调节其稳定性和活性中的生理作用，我们采用小鼠敲入技术在胚胎干细胞和小鼠的内源性p53基因的磷酸化或乙酰化位点引入错义突变。这些基因研究为p53的复杂调控提供了重要的，有时甚至是令人惊讶的见解。有了这些初步的成功，我建议继续利用小鼠遗传学来研究各种磷酸化和乙酰化事件在调节p53活性中的作用，更重要的是，在p53依赖性肿瘤抑制和体内衰老中的作用。

DESCRIPTION (provided by applicant): p53 is the most commonly mutated tumor suppressor in human cancers and plays critical roles in cell cycle arrest, apoptosis, differentiation and DNA repair. While recent studies also link p53 to aging, the exact roles of p53 in aging remains unclear because premature aging is only observed in some but not all mouse models that have increased p53 activities. In responses to various stresses, p53 protein levels are upregulated and its transcription activities activated. Posttranslational modifications of p53, including phosphorylation and acetylation, are thought to play important roles in regulating p53 responses to genotoxic and oncogenic stresses. To address the physiological roles of p53 posttranslational modifications in regulating its stability and activity, we have employed mouse knock-in technology to introduce missense mutations into the phosphorylation or acetylation sites of the endogenous p53 gene in embryonic stem (ES) cells and mice. These genetic studies have provided important and sometimes surprising insights into the complex regulation of p53. With these initial successes, I propose to continue to employ mouse genetics to investigate the roles of various phosphorylation and acetylation events in regulating p53 activity, and more importantly, in p53-dependent tumor suppression and aging in vivo.