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

Nature volume 402, pages 309–313 (1999)Cite this article

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.

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Figure 1: Serine phosphorylation of p66shc by oxidative damage.
Figure 2: Targeted mutation of p66shc induces cellular resistance to oxidative damage.
Figure 3: shc-/- MEFs after H2O2, UV and X-rays.
Figure 4: Mapping of p66shc serine-phosphorylation sites.
Figure 5: Effects of p21 expression on the oxidative stress response of wild-type and p66shc-/- cells.
Figure 6: Increased resistance to oxidative stress and prolonged life span of p66shc-/- mice.

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Acknowledgements

We thank V. Soares, P. P. DiFiore, K. Helin, L. Bonfini, I. Nicoletti and G. Della Porta for discussions; C. Matteucci, C. Casciari, M. Scanarini and G. Pelliccia for technical help; A. Ventura and A. Cicalese for contributions; and A. Ariesi for secretarial work. We also acknowledge continuous technical and intellectual support from L. Pozzi in conducting animal experiments. E.M. is the recipient of a fellowship from FIRC. This work was supported by A.I.R.C.

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Author notes

  1. Enrica Migliaccio and Marco Giorgio: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Experimental Oncology, European Institute of Oncology, Milan, 20141, Italy

    Enrica Migliaccio, Marco Giorgio, Giuliana Pelicci, Luisa Lanfrancone & Pier Giuseppe Pelicci

  2. Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, Molecular Biology and Cell Biology Programs, Sloan-Kettering Institute, New York, 1021, New York, USA

    Pier Paolo Pandolfi

  3. Istituto di Patologia Medica, Perugia University, Perugia, 06100, Italy

    Paolo Reboldi

  4. Istituto di Medicina Interna e Scienze Oncologiche, Perugia University, Perugia, 06100, Italy

    Simonetta Mele & Pier Giuseppe Pelicci

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  1. Enrica Migliaccio
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Correspondence to Pier Giuseppe Pelicci.

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Migliaccio, E., Giorgio, M., Mele, S. et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309–313 (1999). https://doi.org/10.1038/46311

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