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 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 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 Ras. 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.
Migliaccio
E
E
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Giorgio
M
M
Mele
S
S
Pelicci
G
G
Reboldi
P
P
Pandolfi
P P
PP
Lanfrancone
L
L
Pelicci
P G
PG
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D017209:Apoptosis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D018390:Gene Targeting; D006540:Herbicides / Q000494:pharmacology; D006579:Heterozygote; D006720:Homozygote; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008136:Longevity / Q000187:drug effects / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012641:Selection, Genetic; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006540:Herbicides; D011506:Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016159:Tumor Suppressor Protein p53; D014443:Tyrosine; D004815:Epidermal Growth Factor; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; D010269:Paraquat