Analysis of p53 function in aging and tumor suppression

p53在衰老和肿瘤抑制中的功能分析

• 批准号: 6858871
• 负责人: GERARD IAN EVAN
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858871
• 关键词: DNA damage; aging; biological signal transduction; genetically modified animals; growth inhibitors; laboratory mouse; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; p53 gene /protein; protein structure function; radiation genetics; terminal nick end labeling; tumor suppressor genes; tumor suppressor proteins

p53 is best known as a critical suppressor of human neoplasia. However, emerging evidence suggests that organismal aging may be the price paid for such efficient protection from cancer. In response to DNA damage in or aberrant growth of somatic cells, p53 triggers their arrest and/or demise. However, as somatic cells accumulate damage throughout life, this same attribute of p53 can contribute to the progressive erosion of stem cell regenerative potential that characterizes aging pathologies, p53 also mediates the dramatic erosion of somatic tissues that generates the pathologies linked to acute exposure to radiation or chemotherapy and limits their use in cancer treatment. However, p53 can implement effective growth inhibition in response to a variety of persistent signals in tumor cells that do not involve overt DNA damage, including deregulated growth, aberrant chromosome complement and hypoxic stress. It is therefore possible that continuous surveillance of genotoxic injury by p53 is unnecessary for effective tumor surveillance - a relic of its evolutionary heritage as a DNA damage sensor with its role in aging and genotoxic pathologies an unfortunate consequence. We have developed a unique mouse model in which endogenous p53 can be rapidly and reversibly switched between inactive and functional states in somatic tissues in vivo. Using this model, it is possible to define the temporal requirements for p53 function in the DNA damage response, tumor suppression and organismal aging and determine whether they can be separated functionally. Using this model, we will define the timing and persistence of the p53-mediated damage response in differing somatic tissues to radiation-induced DNA damage by restoring or denying p53 function at different times before and after radiation insult (Aim 1), determine the efficacy of p53 in suppressing radiation-induced lymphomagenesis when transiently restored either during or at various times after irradiation (Aim 2) and, last, determine whether restricting p53 functionality to short repeated periods throughout life (metronomic p53) can confer both tumor resistance and protection from the vicissitudes of aging. These studies will have important implications for validation and management of future p53-based cancer therapies, for establishing the utility of inhibiting p53 function (both during and after insult) in chemo and radioprotection, and in resolving the debate over whether tumor suppression and aging are opposite sides of an evolutionary compromise borne of antagonistic pleiotropy.

P53被认为是人类肿瘤的关键抑制因子。然而，新出现的证据表明，机体老化可能是为有效预防癌症所付出的代价。作为对体细胞DNA损伤或异常生长的反应，p53触发它们的停止和/或死亡。然而，随着体细胞在整个生命过程中累积损伤，p53的这一特性可能导致干细胞再生潜力的逐渐侵蚀，这是衰老病理的特征，p53也介导体细胞组织的急剧侵蚀，产生与急性暴露于辐射或化疗有关的病理，并限制其在癌症治疗中的应用。然而，p53可以对肿瘤细胞中各种不涉及明显DNA损伤的持续信号（包括生长失控、染色体补体异常和缺氧应激）进行有效的生长抑制。因此，对p53基因毒性损伤的持续监测可能对有效的肿瘤监测是不必要的——作为DNA损伤传感器，它在衰老和基因毒性病理中的作用是一个不幸的后果。我们开发了一种独特的小鼠模型，在该模型中，内源性p53可以在体内体细胞组织中快速可逆地在无活性状态和功能状态之间切换。利用该模型，可以确定p53功能在DNA损伤应答、肿瘤抑制和机体衰老中的时间要求，并确定它们是否可以在功能上分离。使用该模型，我们将通过在辐射损伤前后的不同时间恢复或否认p53功能来确定不同体细胞组织中p53介导的损伤反应的时间和持久性（目的1），确定p53在辐射期间或照射后的不同时间短暂恢复时抑制辐射诱导的淋巴瘤发生的功效（目的2），最后，确定将p53的功能限制在生命中的短重复周期（节律性p53）是否可以同时赋予肿瘤抗性和对衰老沧桑的保护。这些研究将对未来基于p53的癌症治疗的验证和管理具有重要意义，对于确定抑制p53功能（在损伤期间和之后）在化疗和放射保护中的效用，以及解决关于肿瘤抑制和衰老是否是由拮抗多效性引起的进化妥协的对立面的争论。