Analysis of p53 function in aging and tumor suppression

点击翻译按钮获取中文摘要

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.