Redox Regulation of Forkhead Proteins Through a p66shc-Dependent Signaling Pathway
S Nemoto, T Finkel - Science, 2002 - science.org
S Nemoto, T Finkel
Science, 2002•science.orgGenetic 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 …
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 …
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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