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 and Pier Giuseppe Pelicci ()
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Enrica Migliaccio: European Institute of Oncology
Marco Giorgio: European Institute of Oncology
Simonetta Mele: Istituto di Medicina Interna e Scienze Oncologiche, Perugia University
Giuliana Pelicci: European Institute of Oncology
Paolo Reboldi: Istituto di Patologia Medica, Perugia University
Pier Paolo Pandolfi: Memorial Sloan-Kettering Cancer Center, Molecular Biology and Cell Biology Programs, Sloan-Kettering Institute
Luisa Lanfrancone: European Institute of Oncology
Pier Giuseppe Pelicci: European Institute of Oncology

Nature, 1999, vol. 402, issue 6759, 309-313

Abstract: 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 species1. 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 Ras3. 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.

Date: 1999
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DOI: 10.1038/46311

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