Analysis of p53 function in aging and tumor suppression

最广为人知的是，p53是人类肿瘤的关键抑制因子。然而，新出现的证据表明，机体衰老可能是为了有效地预防癌症而付出的代价。作为对体细胞DNA损伤或异常生长的反应，P53触发体细胞的停滞和/或死亡。然而，随着体细胞在整个生命过程中积累损伤，P53的这一相同属性可以促进干细胞再生潜力的进行性侵蚀，这是衰老病理的特征，P53也介导了体细胞组织的急剧侵蚀，从而产生了与急性放射或化疗相关的病理，并限制了它们在癌症治疗中的应用。然而，P53可以有效地抑制肿瘤细胞中的各种持续信号，这些信号不涉及明显的DNA损伤，包括失调的生长、异常的染色体互补和低氧应激。因此，对于有效的肿瘤监测来说，持续监测P53的基因毒性损伤是可能的--这是其作为DNA损伤传感器的进化遗产的遗迹，其在衰老和基因毒性病理中的作用是一个不幸的后果。我们已经建立了一种独特的小鼠模型，在体内，内源性P53可以在身体组织中快速且可逆地在非活动状态和功能状态之间切换。利用这个模型，可以定义在DNA损伤反应、肿瘤抑制和组织衰老中对P53功能的时间要求，并确定它们是否可以从功能上分离。利用这个模型，我们将通过在辐射损伤前和辐射后的不同时间恢复或拒绝P53功能来定义不同身体组织中P53介导的损伤反应的时序和持久性(目标1)，确定在辐射期间或之后的不同时间瞬时恢复时P53在抑制辐射诱导的淋巴肿大中的有效性(目标2)，以及最后确定是否将P53的功能限制在生命的短重复周期(节律P53)是否可以提供肿瘤抵抗和保护免受衰老变迁的影响。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(包括在损伤期间和之后)在化疗和放射防护中的效用，以及在解决关于肿瘤抑制和衰老是否是由拮抗多效性所导致的进化妥协的对立面的争论中，将具有重要意义。

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.