Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations
Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations
复制标题
DOI：
10.1073/pnas.0708043104
复制
发表时间：
2007-10-16
影响因子：
11.1
通讯作者：
Levine, Arnold J.
中科院分区：
文献类型：
--
作者：
Feng, Zhaohui;Hu, Wenwei;Levine, Arnold J.
癌症是一种衰老的疾病。个体细胞一生中突变的积累被认为是原因。在这项工作中，我们探索了一个额外的假设：p53功能是否会随着年龄的增长而下降，这将有助于在衰老过程中增强突变频率和肿瘤发生？在几个近交系的衰老小鼠的各种组织中，发现p53对γ-辐射的反应的效率显著下降，包括较低的p53转录活性和p53依赖性细胞凋亡。这种下降是由于应激后p53蛋白的稳定性降低所致。共济失调-毛细血管扩张突变（ATM）激酶的功能随着年龄的增长而显著下降，这可能是p53对辐射反应下降的原因。在来自衰老小鼠的培养脾细胞中也观察到对其他应激的p53应答下降。有趣的是，这种p53反应降低的开始时间与小鼠的寿命相关;寿命更长的小鼠随着时间的推移延迟了p53活性降低的开始。这些结果表明，由于p53介导的细胞凋亡或衰老在应激反应中的保真度下降，老年人中突变的固定增强，并且它们为肿瘤发生和衰老过程之间的相关性提出了合理的解释。
Cancer is a disease of aging. The accumulation of mutations in individual cells over a lifetime is thought to be the reason. In this work, we explored an additional hypothesis: could p53 function decline with age, which would contribute to an enhanced mutation frequency and tumorigenesis in the aging process? The efficiency of the p53 response to gamma-irradiation was found to decline significantly in various tissues of aging mice from several inbred strains, including lower p53 transcriptional activity and p53-dependent apoptosis. This decline resulted from a decreased stabilization of the p53 protein after stress. The function of the Ataxia-telangiectasia mutated (ATM) kinase declined significantly with age, which may then be responsible for the decline of the p53 response to radiation. Declining p53 responses to other stresses were also observed in the cultured splenocytes from aging mice. Interestingly, the time of onset of this decreased p53 response correlated with the life span of mice; mice that live longer delay their onset of decreased p53 activity with time. These results suggest an enhanced fixation of mutations in older individuals because of the declining fidelity of p53-mediated apoptosis or senescence in response to stress, and they suggest a plausible explanation for the correlation between tumorigenesis and the aging process.