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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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J. Chintapalli, S. Yang, D. Opawumi, S. R. Goyal, N. Shamsuddin, A. Malhotra, K. Reiss, and L. G. Meggs (2007)
Am J Physiol Renal Physiol 292, F523-F530
   Abstract »    Full Text »    PDF »
Critical Role for FoxO3a-Dependent Regulation of p21CIP1/WAF1 in Response to Statin Signaling in Cardiac Myocytes.
L. Hauck, C. Harms, D. Grothe, J. An, K. Gertz, G. Kronenberg, R. Dietz, M. Endres, and R. von Harsdorf (2007)
Circ. Res. 100, 50-60
   Abstract »    Full Text »    PDF »
An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations.
K. C. Kregel and H. J. Zhang (2007)
Am J Physiol Regulatory Integrative Comp Physiol 292, R18-R36
   Abstract »    Full Text »    PDF »
A Novel Class of Vascular Endothelial Growth Factor-responsive Genes That Require Forkhead Activity for Expression.
Md. R. Abid, S.-C. Shih, H. H. Otu, K. C. Spokes, Y. Okada, D. T. Curiel, T. Minami, and W. C. Aird (2006)
J. Biol. Chem. 281, 35544-35553
   Abstract »    Full Text »    PDF »
Oxidant-mediated Akt Activation in Human RPE Cells..
P. Yang, J. J. Peairs, R. Tano, and G. J. Jaffe (2006)
Invest. Ophthalmol. Vis. Sci. 47, 4598-4606
   Abstract »    Full Text »    PDF »
Phosphatidylinositol 3-Kinase-dependent Suppression of the Human Inducible Nitric-oxide Synthase Promoter Is Mediated by FKHRL1.
A. S. Kristof, J. Fielhaber, A. Triantafillopoulos, S. Nemoto, and J. Moss (2006)
J. Biol. Chem. 281, 23958-23968
   Abstract »    Full Text »    PDF »
Distinct Signaling Functions for Shc Isoforms in the Heart.
M. Obreztchikova, H. Elouardighi, M. Ho, B. A. Wilson, Z. Gertsberg, and S. F. Steinberg (2006)
J. Biol. Chem. 281, 20197-20204
   Abstract »    Full Text »    PDF »
Atrogin-1/MAFbx and MuRF1 Are Downregulated in Aging-Related Loss of Skeletal Muscle.
E. Edstrom, M. Altun, M. Hagglund, and B. Ulfhake (2006)
J Gerontol A Biol Sci Med Sci 61, 663-674
   Abstract »    Full Text »    PDF »
Regulation of transactivation-independent proapoptotic activity of p53 by FOXO3a.
H. You, K. Yamamoto, and T. W. Mak (2006)
PNAS 103, 9051-9056
   Abstract »    Full Text »    PDF »
The Mammalian Longevity-associated Gene Product p66shc Regulates Mitochondrial Metabolism.
S. Nemoto, C. A. Combs, S. French, B.-H. Ahn, M. M. Fergusson, R. S. Balaban, and T. Finkel (2006)
J. Biol. Chem. 281, 10555-10560
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »

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