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


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.


  1. Martin,G. M., Austad,S. N. & Johnson,T. E. Genetic analysis of aging: role of oxidative damage and environmental stresses. Nature Genet. 13, 25–34 (1996).

    Article  CAS  Google Scholar 

  2. Migliaccio,E. et al. Opposite effects of the p52shc/p46shc splicing isoforms on the EGF receptor-MAP kinase-fos signaling pathway. EMBO J. 16, 706–716 (1997).

    Article  CAS  Google Scholar 

  3. Pelicci,G et al. A novel transforming protein (SHC) with a SH2 domain is implicated in mitogenic signal transduction. Cell 70, 93–104 (1992).

    Article  CAS  Google Scholar 

  4. Bonfini,L., Migliaccio,E., Pelicci,G., Lanfrancone,L. & Pelicci,P. G. Not all Shc's roads lead to Ras. Trends Biochem. Sci. 21, 257–261 (1996).

    Article  CAS  Google Scholar 

  5. Rozakis-Adcock,M. et al. Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinase. Nature 360, 689–692 (1992).

    Article  ADS  CAS  Google Scholar 

  6. Sen,C. & Packer,L. Antioxidant and redox regulation of gene transcription. FASEB J. 10, 709–720 (1996).

    Article  CAS  Google Scholar 

  7. Renzing,J., Hansen,S. & Lane,D. P. Oxidative stress is involved in the UV activation of p53. J. Cell Sci. 109, 1105–1112 (1996).

    CAS  PubMed  Google Scholar 

  8. Stevenson,M. A., Pollock,S. S., Coleman,C. N. & Calderwood,S. K. X-irradiation, phorbol esters, and H2O2 stimulate mitogen-activated protein kinase activity in NiH-3T3 cells through the formation of reactive oxygen intermediates. Cancer Res. 54, 12–15 (1994).

    CAS  PubMed  Google Scholar 

  9. Lu,X. & Lane,D. P. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes? Cell 75, 765–778 (1993).

    Article  CAS  Google Scholar 

  10. Deng,C., Zhang,P., Harper,J. W., Elledge,S. J. & Leder,P. Mice lacking p21CIP/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82, 675–684 (1995).

    Article  CAS  Google Scholar 

  11. Russo,T. et al. A p53-independent pathway for activation of WAF1/C1P1 expression following oxidative stress. J. Biol. Chem. 270, 29386–29391 (1995).

    Article  CAS  Google Scholar 

  12. Macleod,K. F. et al. p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes Dev. 9, 935–944 (1995).

    Article  CAS  Google Scholar 

  13. Yin,Y., Solomon,G., Deng,C. & Barrett,J. C. Differential regulation of p21 by p53 and Rb in cellular response to oxidative stress. Mol. Carcin. 24, 15–24 (1999).

    Article  CAS  Google Scholar 

  14. Yin,Y. et al. Involvement of p85 in p53-dependent apoptotic response to oxidative stress. Nature 391, 707–710 (1998).

    Article  ADS  CAS  Google Scholar 

  15. De Haan j.,B. et al. Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide. J. Biol. Chem. 273, 22528–22536 (1998).

    Article  Google Scholar 

  16. Sun,J., Childress,A. M., Pinswasdl,C. & Jazwinski,S. Divergent roles of RAS1 and RAS2 in yeast longevity. J. Biol. Chem. 269, 18638–18645 (1994).

    CAS  PubMed  Google Scholar 

  17. Kennedy,B. K., Austriaco,N. R., Zhang,J. & Guarente,L. Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell 80, 485–496 (1995).

    Article  CAS  Google Scholar 

  18. Murakami,S. & Johnson,T. E. A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics 143, 1207–1218 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Larsen,P. L., Albert,P. S. & Riddle,D. L. Genes that regulate both development and longevity in C. elegans. Genetics 139, 1576–1583 (1995).

    Google Scholar 

  20. Service,P. M., Hutchinson,E. W., MacKinley,M. D. & Rose,M. R. Resistance to environmental stress in Drosophila melanogaster selected for postponed senescence. Physiol. Zool. 58, 380–389 (1985).

    Article  Google Scholar 

  21. Lin,Y. J., Seroude,L. & Benzer,S. Extended life-span and stress resistance in the Drosophila mutant methuselah. Science 282, 943–946 (1998).

    Article  ADS  CAS  Google Scholar 

  22. Ishi,N. et al. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 394, 694–697 (1998).

    Article  ADS  Google Scholar 

  23. Orr,W. C. & Sohal,R. S. Extension of life-span by overexpression of superoxide dismutase and catalase in D. melanoganster. Science 263, 1128–1130 (1994).

    Article  ADS  CAS  Google Scholar 

  24. Marubini,E. & Valsecchi,M. G. Analysing Survival Data from Clinical Trials and Observational Studies (Wiley, New York, 1995).

    MATH  Google Scholar 

  25. Weindruch,R., Walford,R. L., Fligiel,S. & Guthetrie,D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J. Nutr. 116, 641–654 (1986).

    Article  CAS  Google Scholar 

  26. Weindruch,R. & Walford,R. L. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science 215, 1415–1417 (1982).

    Article  ADS  CAS  Google Scholar 

  27. Medawar,P. B. Old age and natural death. Modern Quarterly 1, 30–56 (1946).

    Google Scholar 

  28. Lithgow,G. J. & Kirkwood,T. B. L. Mechanisms and evolution of aging. Science 273, 80 (1996).

    Article  ADS  CAS  Google Scholar 

  29. Taub,J. et al. A cytosolic catalase is needed to extend adult life span in C. elegans daf-C and clk-1 mutants. Nature 399, 162–166 (1999).

    Article  ADS  CAS  Google Scholar 

  30. Sohal,R. S. & Weindruch,R. Oxidative stress, caloric restriction, and aging. Science 273, 59–63 (1996).

    Article  ADS  CAS  Google Scholar 

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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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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).

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