Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations Export

@article{citeulike:1908257, abstract = {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. 10.1073/pnas.0708043104}, author = {Feng, Zhaohui and Hu, Wenwei and Teresky, Angelika K. and Hernando, Eva and Cordon-Cardo, Carlos and Levine, Arnold J.}, citeulike-article-id = {1908257}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0708043104}, citeulike-linkout-1 = {http://www.pnas.org/cgi/content/abstract/104/42/16633}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/17921246}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=17921246}, comment = {Very exciting paper where it is shown that p53 function (transcritional activation of apoptotic response and senescence genes) decreases with age. The mechanisms by which this happens are not clear. p53 protein accumulation upon irradiation decreased with age. ATM kinase activity (and levels) also decreased with age. I am not sure why they did not measure p53 mRNA accumulation.}, day = {16}, doi = {10.1073/pnas.0708043104}, journal = {Proceedings of the National Academy of Sciences}, keywords = {aging, cancer, p53}, month = {October}, number = {42}, pages = {16633--16638}, posted-at = {2007-11-13 18:19:18}, priority = {0}, title = {Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations}, url = {http://dx.doi.org/10.1073/pnas.0708043104}, volume = {104}, year = {2007} }

TY - JOUR ID - citeulike:1908257 L3 - citeulike-article-id:1908257 N2 - 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. 10.1073/pnas.0708043104 IS - 42 JF - Proceedings of the National Academy of Sciences EP - 16638 TI - Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations VL - 104 SP - 16633 KW - aging KW - cancer KW - p53 N1 - Very exciting paper where it is shown that p53 function (transcritional activation of apoptotic response and senescence genes) decreases with age. The mechanisms by which this happens are not clear. p53 protein accumulation upon irradiation decreased with age. ATM kinase activity (and levels) also decreased with age. I am not sure why they did not measure p53 mRNA accumulation. AU - Feng, Zhaohui AU - Hu, Wenwei AU - Teresky, Angelika AU - Hernando, Eva AU - Cordon-Cardo, Carlos AU - Levine, Arnold PY - 2007/10/16/ UR - http://dx.doi.org/10.1073/pnas.0708043104 ER -