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: 7007682
• 负责人: GERARD IAN EVAN
• 金额: $ 14.79万
• 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/7007682
• 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最为人所知的是作为人类肿瘤形成的关键抑制因子。然而，新出现的证据表明，生物体衰老可能是这种有效预防癌症的代价。为了响应体细胞中的DNA损伤或异常生长，p53触发它们的停滞和/或死亡。然而，随着体细胞在整个生命过程中积累损伤，p53的这种相同属性可以有助于干细胞再生潜力的进行性侵蚀，这是衰老病理学的特征，p53还介导体组织的急剧侵蚀，这产生与急性暴露于辐射或化学疗法相关的病理学，并限制它们在癌症治疗中的使用。然而，p53可以响应于肿瘤细胞中不涉及明显DNA损伤的各种持续信号而实施有效的生长抑制，所述持续信号包括失调生长、异常染色体补体和缺氧应激。因此，有可能持续监测p53的遗传毒性损伤对于有效的肿瘤监测是不必要的-其作为DNA损伤传感器的进化遗产的遗迹，其在衰老和遗传毒性病理学中的作用是一个不幸的后果。我们已经开发了一种独特的小鼠模型，其中内源性p53可以在体内体细胞组织中在非活性和功能状态之间快速可逆地切换。使用该模型，可以定义p53在DNA损伤反应、肿瘤抑制和生物体衰老中的功能的时间要求，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之前和之后的不同时间恢复或拒绝p53功能来定义不同体组织中p53介导的损伤反应对辐射诱导的DNA损伤的时间和持续性（目的1），确定当在辐射期间或辐射之后的不同时间短暂恢复时p53在抑制辐射诱导的淋巴瘤发生中的功效（目的2），最后，确定是否限制p53功能在整个生命中短暂重复的时期（节拍式p53）可以赋予肿瘤抵抗力和保护免受衰老的影响。这些研究将有重要的意义，验证和管理未来的p53为基础的癌症治疗，建立效用抑制p53功能（包括期间和之后的侮辱）在化疗和放射防护，并在解决的争论是否肿瘤抑制和老化的对立双方的进化妥协承担的拮抗多效性。