The p66shc adaptor protein controls oxidative stress response and life span in mammals. Export

@article{citeulike:2630496, abstract = {Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66shc gene induces stress resistance and prolongs life span. p66shc is a splice variant of p52shc/p46shc (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66shc is serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation with ultraviolet light; (2) ablation of p66shc enhances cellular resistance to apoptosis induced by H2O2 or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66shc cannot restore the normal stress response in p66shc-/- cells; (4) the p53 and p21 stress response is impaired in p66shc-/- cells; (5) p66shc-/- mice have increased resistance to paraquat and a 30\% increase in life span. We propose that p66shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals.}, address = {Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.}, author = {Migliaccio, E. and Giorgio, M. and Mele, S. and Pelicci, G. and Reboldi, P. and Pandolfi, P. P. and Lanfrancone, L. and Pelicci, P. G.}, citeulike-article-id = {2630496}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/46311}, citeulike-linkout-1 = {http://dx.doi.org/10.1038/402309a0}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/10580504}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=10580504}, day = {18}, doi = {10.1038/46311}, issn = {0028-0836}, journal = {Nature}, keywords = {lifespan, p66, ros, yvonne}, month = {November}, number = {6759}, pages = {309--313}, posted-at = {2008-09-18 20:47:45}, priority = {2}, title = {The p66shc adaptor protein controls oxidative stress response and life span in mammals.}, url = {http://dx.doi.org/10.1038/46311}, volume = {402}, year = {1999} }

TY - JOUR ID - citeulike:2630496 L3 - citeulike-article-id:2630496 N2 - Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66shc gene induces stress resistance and prolongs life span. p66shc is a splice variant of p52shc/p46shc (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66shc is serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation with ultraviolet light; (2) ablation of p66shc enhances cellular resistance to apoptosis induced by H2O2 or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66shc cannot restore the normal stress response in p66shc-/- cells; (4) the p53 and p21 stress response is impaired in p66shc-/- cells; (5) p66shc-/- mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals. IS - 6759 JF - Nature SN - 0028-0836 AD - Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. EP - 313 TI - The p66shc adaptor protein controls oxidative stress response and life span in mammals. VL - 402 SP - 309 KW - lifespan KW - p66 KW - ros KW - yvonne AU - Migliaccio, E AU - Giorgio, M AU - Mele, S AU - Pelicci, G AU - Reboldi, P AU - Pandolfi, PP AU - Lanfrancone, L AU - Pelicci, PG PY - 1999/11/18/ UR - http://dx.doi.org/10.1038/46311 ER -