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

Enrica Migliaccio, Marco Giorgio, Simonetta Mele, Giuliana Pelicci, Paolo Reboldi, Pier Paolo Pandolfi, Luisa Lanfrancone & Pier Giuseppe Pelicci

Nature 402, 309-313 (1999).


    In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. However, some 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 (ROS). p66 is a splice variant of p52shc/p46shc, a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. It becomes tyrosine phosphorylated upon activation of growth factor receptors and forms stable complexes with Grb2, an adaptor protein for the Ras exchange factor SOS. Since long life span is highly related with oxidative stress response, so the author want to investigate the role of p66shc in stress responses. In this paper, the author develope the p66shc+/- and the p66shc-/- mice and report that targeted mutation of the mouse p66shc gene induces stress resistance and prolongs life span. The evidence include that p66shc is serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation with ultraviolet light. Ablation of p66shc enhances cellular resistance to apoptosis induced by H2O2 or ultraviolet light and p66shc-/- mice have increased resistance to paraquat and a 30% increase in life span. In addition, p53 and p21 stress response is impaired in p66shc-/- cells.


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