Redox Regulation of Forkhead Proteins Through a p66shc-Dependent Signaling Pathway

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Science  29 Mar 2002:
Vol. 295, Issue 5564, pp. 2450-2452
DOI: 10.1126/science.1069004

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Genetic determinants of longevity include the forkhead-related transcription factor DAF-16 in the worm Caenorhabditis elegansand the p66shc locus in mice. We demonstrate thatp66shc 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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