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Sci. Aging Knowl. Environ., 13 March 2002 OTHER RESOURCESRedox Regulation of Forkhead Proteins Through a p66shc-Dependent Signaling PathwayShino Nemoto, and Toren Finkel http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/10/or3Abstract: Science 7 March 2002 (10.1126/science.1069004) (Science Express Reports) 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 in mammalian cells, p66shc regulates intracellular oxidant levels and that hydrogen peroxide can negatively regulate forkhead activity. In p66shc-/- cells, the activity of the mammalian forkhead homologue 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 relationship between three distinct elements linked to aging, forkhead proteins, p66shc, and intracellular oxidants.
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