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Science 295 (5564): 2450-2452

Copyright © 2002 by the American Association for the Advancement of Science

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

Shino Nemoto, Toren Finkel*

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.

Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Building 10/6N-240, 10 Center Drive, Bethesda, MD 20892-1622, USA.
*   To whom correspondence should be addressed. E-mail: finkelt{at}nih.gov

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Differential Expression of FOXO1 and FOXO3a Confers Resistance to Oxidative Cell Death upon Endometrial Decidualization.
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Phosphatidylinositol 3-Kinase-dependent Suppression of the Human Inducible Nitric-oxide Synthase Promoter Is Mediated by FKHRL1.
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Distinct Signaling Functions for Shc Isoforms in the Heart.
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Atrogin-1/MAFbx and MuRF1 Are Downregulated in Aging-Related Loss of Skeletal Muscle.
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J Gerontol A Biol Sci Med Sci 61, 663-674
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Regulation of transactivation-independent proapoptotic activity of p53 by FOXO3a.
H. You, K. Yamamoto, and T. W. Mak (2006)
PNAS 103, 9051-9056
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The Mammalian Longevity-associated Gene Product p66shc Regulates Mitochondrial Metabolism.
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Inhibition of LINE-1 expression in the heart decreases ischemic damage by activation of Akt/PKB signaling.
E. Lucchinetti, J. Feng, R. d. Silva, G. V. Tolstonog, M. C. Schaub, G. G. Schumann, and M. Zaugg (2006)
Physiol Genomics 25, 314-324
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Sos-mediated activation of rac1 by p66shc.
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p53 Mediates the Accelerated Onset of Senescence of Endothelial Progenitor Cells in Diabetes.
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Accelerated Ovarian Failure Induced by 4-Vinyl Cyclohexene Diepoxide in Nrf2 Null Mice.
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