P53 and Organismal Aging

描述(由申请人提供)：P53肿瘤抑制因子对各种压力作出反应，并启动细胞周期停滞、凋亡或细胞衰老程序。人类所有肿瘤中有一半存在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可以在不同的环境中调节细胞的衰老表型。此外，一些表现出异常长寿和衰老表型的小鼠模型已经改变了P53信号，这表明P53可能影响生物衰老。P53可能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，我们的实验室已经建立了一些P53突变的小鼠模型。从历史上看，p53突变小鼠对早期癌症高度敏感。然而，最近，我们开发了一种新的p53突变小鼠系，它表现出意想不到的表型。与癌症易感性不同的是，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表型，包括寿命缩短、肌肉和皮肤萎缩、骨质疏松症和应激耐力降低。目前的初步数据表明，这个特定的p53突变等位基因编码了一个截短的p53，它过度激活了野生型p53。因此，这些突变的小鼠可能具有过度活跃的P53反应。这项建议的目标是使用这个早期衰老的小鼠系和早期的P53癌症易感小鼠系来证明(1)P53确实在生物衰老中发挥重要作用，以及(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.