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Science 303 (5666): 2011-2015

Copyright © 2004 by the American Association for the Advancement of Science

Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase

Anne Brunet,1* Lora B. Sweeney,1 J. Fitzhugh Sturgill,1 Katrin F. Chua,2 Paul L. Greer,1 Yingxi Lin,1 Hien Tran,1 Sarah E. Ross,1 Raul Mostoslavsky,2 Haim Y. Cohen,3 Linda S. Hu,1 Hwei-Ling Cheng,2 Mark P. Jedrychowski,4 Steven P. Gygi,4 David A. Sinclair,3 Frederick W. Alt,2 Michael E. Greenberg1{dagger}

Abstract: The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.

1 Division of Neuroscience, Children's Hospital, and Department of Neurobiology, Center for Blood Research (CBR) Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.
2 Howard Hughes Medical Institute, Children's Hospital, Center for Blood Research (CBR) Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.
3 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
4 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

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* Present address: Department of Genetics, Stanford University, Stanford, CA 94305, USA.

{dagger} To whom correspondence should be addressed. E-mail: michael.greenberg{at}childrens.harvard.edu

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SIRT1 Acts as a Modulator of Neointima Formation Following Vascular Injury in Mice.
L. Li, H.-N. Zhang, H.-Z. Chen, P. Gao, L.-H. Zhu, H.-L. Li, X. Lv, Q.-J. Zhang, R. Zhang, Z. Wang, et al. (2011)
Circ. Res. 108, 1180-1189
   Abstract »    Full Text »    PDF »
Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase.
B. A. Benayoun, A. B. Georges, D. L'Hote, N. Andersson, A. Dipietromaria, A.-L. Todeschini, S. Caburet, C. Bazin, M. Anttonen, and R. A. Veitia (2011)
Hum. Mol. Genet. 20, 1673-1686
   Abstract »    Full Text »    PDF »
Hypoxia Increases Sirtuin 1 Expression in a Hypoxia-inducible Factor-dependent Manner.
R. Chen, E. M. Dioum, R. T. Hogg, R. D. Gerard, and J. A. Garcia (2011)
J. Biol. Chem. 286, 13869-13878
   Abstract »    Full Text »    PDF »
Hepatic FoxOs Regulate Lipid Metabolism via Modulation of Expression of the Nicotinamide Phosphoribosyltransferase Gene.
R. Tao, D. Wei, H. Gao, Y. Liu, R. A. DePinho, and X. C. Dong (2011)
J. Biol. Chem. 286, 14681-14690
   Abstract »    Full Text »    PDF »
Review: NAD + : A modulator of immune functions.
A. Grahnert, A. Grahnert, C. Klein, E. Schilling, J. Wehrhahn, and S. Hauschildt (2011)
Innate Immunity 17, 212-233
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Involvement of Oxygen-regulated Protein 150 in AMP-activated Protein Kinase-mediated Alleviation of Lipid-induced Endoplasmic Reticulum Stress.
Y. Wang, Z. Wu, D. Li, D. Wang, X. Wang, X. Feng, and M. Xia (2011)
J. Biol. Chem. 286, 11119-11131
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Salicylate Treatment Improves Age-Associated Vascular Endothelial Dysfunction: Potential Role of Nuclear Factor {kappa}B and Forkhead Box O Phosphorylation.
L. A. Lesniewski, J. R. Durrant, M. L. Connell, B. J. Folian, A. J. Donato, and D. R. Seals (2011)
J Gerontol A Biol Sci Med Sci 66A, 409-418
   Abstract »    Full Text »    PDF »
Sirtuins at a glance.
T. Nakagawa and L. Guarente (2011)
J. Cell Sci. 124, 833-838
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FoxO1 and SIRT1 Regulate {beta}-Cell Responses to Nitric Oxide.
K. J. Hughes, G. P. Meares, P. A. Hansen, and J. A. Corbett (2011)
J. Biol. Chem. 286, 8338-8348
   Abstract »    Full Text »    PDF »
FoxO1 Mediates an Autofeedback Loop Regulating SIRT1 Expression.
S. Xiong, G. Salazar, N. Patrushev, and R. W. Alexander (2011)
J. Biol. Chem. 286, 5289-5299
   Abstract »    Full Text »    PDF »

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