Journal Article10.1126/SCIENCE.1069004
Redox Regulation of Forkhead Proteins Through a p66shc-Dependent Signaling Pathway
Shino Nemoto,Toren Finkel +1 more
TL;DR: It is demonstrated that p66shc regulates intracellular oxidant levels in mammalian cells and that hydrogen peroxide can negatively regulate forkhead activity, and that expression of FKHRL1 results in an increase in both hydrogenperoxide scavenging and oxidative stress resistance.
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Abstract: Genetic determinants of longevity include the forkhead-related transcription factor DAF-16 in the worm Caenorhabditis elegans and the p66shc locus in mice. We demonstrate that p66shc regulates intracellular oxidant levels in mammalian cells and that hydrogen peroxide can negatively regulate forkhead activity. In p66shc-/- cells, the activity of the mammalian forkhead homolog FKHRL1 is increased and redox-dependent forkhead inactivation is reduced. In addition, expression of FKHRL1 results in an increase in both hydrogen peroxide scavenging and oxidative stress resistance. These results demonstrate an important functional relation between three distinct elements linked to aging: forkhead proteins, p66shc, and intracellular oxidants.
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References
Oxidants, oxidative stress and the biology of ageing.
Toren Finkel,Nikki J. Holbrook +1 more
TL;DR: Evidence that the appropriate and inappropriate production of oxidants, together with the ability of organisms to respond to oxidative stress, is intricately connected to ageing and life span is reviewed.
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Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor
Anne Brunet,Azad Bonni,Michael J. Zigmond,Michael Z. Lin,Peter Juo,Linda Hu,Michael J. Anderson,Karen C. Arden,John Blenis,Michael E. Greenberg +9 more
TL;DR: It is demonstrated that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors, which triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.
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The p66shc adaptor protein controls oxidative stress response and life span in mammals
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TL;DR: It is proposed that p66shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals.
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AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.
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Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1.
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