P53 and Organismal Aging

描述（由申请人提供）：p53肿瘤抑制因子响应各种应激并启动细胞周期阻滞、细胞凋亡或细胞衰老程序。一半的人类肿瘤存在p53基因突变，超过80%的肿瘤存在p53信号缺陷。许多体外研究表明，p53可以在各种情况下介导细胞衰老表型。此外，一些表现出异常长寿和衰老表型的小鼠模型改变了p53信号，表明p53可能影响机体衰老。p53影响衰老过程的机制尚不清楚。为了更好地了解p53在肿瘤抑制中的作用，我们实验室建立了多个p53突变小鼠模型。从历史上看，p53突变小鼠对早期癌症非常敏感。然而，最近，我们开发了一种新的p53突变小鼠，显示出意想不到的表型。与癌症易感性不同，这种突变小鼠对自发癌症表现出了抵抗力。此外，这些小鼠表现出许多与衰老相关的早期表型，包括寿命缩短、肌肉和皮肤萎缩、骨质疏松症和应激耐受性降低。目前的初步数据表明，这个特定的p53突变等位基因编码一个截断的p53，该基因会过度激活p53的野生型。因此，这些突变小鼠可能有过度活跃的p53反应。本研究的目的是利用这一早期衰老小鼠系和早期p53癌症易感小鼠系来证明(1)p53确实在机体衰老中发挥重要作用，(2)确定p53可能影响衰老过程的一些分子和生物学机制。

DESCRIPTION (provided by applicant): The p53 tumor suppressor responds to a variety of stresses and initiates cell cycle arrest, apoptosis, or cellular senescence programs. One half of all human tumors have mutations in the p53 gene and more than 80% of tumors have defects in p53 signaling. A number of in vitro studies have shown that p53 can mediate a cellular senescence phenotype in various contexts. Moreover, some mouse models that exhibit abnormal longevity and aging phenotypes have altered p53 signaling, suggesting that p53 may affect organismal aging. The mechanisms through which p53 might affect the aging process remain unclear. To better understand the role of p53 in cancer suppression, our laboratory has generated a number of p53 mutant mouse models. Historically, p53 mutant mice have been highly susceptible to early cancers. Recently, however, we developed a new line of p53 mutant mice that showed unexpected phenotypes. Instead of cancer susceptibility, this line of mutant mice showed resistance to spontaneous cancers. In addition, these mice exhibited early appearance of a number of aging-associated phenotypes, including reduced longevity, muscle and skin atrophy, osteoporosis, and reduced stress tolerance. Current preliminary data indicates that this particular mutant allele of p53 encodes a truncated p53 that hyperactivates the wild type form of p53. Thus, these mutant mice may have a hyperactive p53 response. The goals of this proposal are to use this early aging mouse line and earlier p53 cancer susceptible mouse lines to show that (1) p53 does play an important role in organismal aging, and (2) determine some of the molecular and biological mechanisms through which p53 may influence the aging process.