The p66(shc) adaptor protein controls oxidative stress response and life span in mammals Journal Article
| Authors: | Migliaccio, E.; Giogio, M.; Mele, S.; Pelicci, G.; Reboldi, P.; Pandolfi, P. P.; Lanfrancone, L.; Pelicci, P. G. |
| Article Title: | The p66(shc) adaptor protein controls oxidative stress response and life span in mammals |
| 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 p66(shc) gene induces stress resistance and prolongs life span. p66(shc) is a splice variant of p52(shc)/p46(shc) (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66(shc) is serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation with ultraviolet light; (2) ablation of p66(shc) enhances cellular resistance to apoptosis induced by H2O2 or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66(shc) cannot restore the normal stress response in p66 (shc-/-) cells; (4) the p53 and p21 stress response is impaired in p66(shc-/-) cells; (5) p66(shc-/-) mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66(shc) is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals. |
| Keywords: | signal transduction; epidermal growth factor; controlled study; protein phosphorylation; gene mutation; genetics; nonhuman; ultraviolet radiation; proteins; animal cell; mouse; animal; metabolism; animals; mice; gene targeting; apoptosis; embryo; animal experiment; protein; drug effect; protein serine threonine kinase; tyrosine; phosphorylation; heterozygote; protein p53; radiation exposure; physiology; selection (genetics); protein-serine-threonine kinases; mammal; homozygote; reactive oxygen metabolite; adaptor proteins, signal transducing; tumor suppressor protein p53; gene control; longevity; ras protein; upregulation; hydrogen peroxide; oxidative stress; cdkn1a protein, mouse; cyclin dependent kinase inhibitor 1a; cyclin-dependent kinase inhibitor p21; cycline; up-regulation; ultraviolet rays; cyclins; protein p21; signal transducing adaptor protein; herbicides; lifespan; genetic selection; vesicular transport adaptor protein; adaptor proteins, vesicular transport; adaptor protein; herbicide; male; priority journal; article; paraquat; src homology 2 domain containing, transforming protein 1; src homology 2 domain-containing, transforming protein 1 |
| Journal Title: | Nature |
| Volume: | 402 |
| Issue: | 6759 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 1999-11-18 |
| Start Page: | 309 |
| End Page: | 313 |
| Language: | English |
| DOI: | 10.1038/46311 |
| PUBMED: | 10580504 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 16 August 2016 -- Source: Scopus |
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