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Published Online February 19, 2004
Science DOI: 10.1126/science.1094637

Reports

Submitted on December 12, 2003
Accepted on January 11, 2004

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

Anne Brunet 1, Lora B. Sweeney 2, J. Fitzhugh Sturgill 2, Katrin F. Chua 3, Paul L. Greer 2, Yingxi Lin 2, Hien Tran 2, Sarah E. Ross 2, Raul Mostoslavsky 4, Haim Y. Cohen 5, Linda S. Hu 2, Hwei-Ling Cheng 3, Mark P. Jedrychowski 6, Steven P. Gygi 6, David A. Sinclair 5, Frederick W. Alt 3, Michael E. Greenberg 2*

1 Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Present address: Department of Genetics, Stanford University, Stanford, CA 94305, USA.
2 Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
3 Division of Genetics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4 Division of Genetics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
5 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
6 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

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

The Sir2 deacetylase modulates organismal lifespan in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homologue SIRT1 appears to control the cellular response to stress by regulating FOXO 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.


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   Abstract »    Full Text »    PDF »
SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase.
I. Mattagajasingh, C.-S. Kim, A. Naqvi, T. Yamamori, T. A. Hoffman, S.-B. Jung, J. DeRicco, K. Kasuno, and K. Irani (2007)
PNAS 104, 14855-14860
   Abstract »    Full Text »    PDF »
Elevation of Cellular NAD Levels by Nicotinic Acid and Involvement of Nicotinic Acid Phosphoribosyltransferase in Human Cells.
N. Hara, K. Yamada, T. Shibata, H. Osago, T. Hashimoto, and M. Tsuchiya (2007)
J. Biol. Chem. 282, 24574-24582
   Abstract »    Full Text »    PDF »
Oxidative Stress Modulates Complement Factor H Expression in Retinal Pigmented Epithelial Cells by Acetylation of FOXO3.
Z. Wu, T. W. Lauer, A. Sick, S. F. Hackett, and P. A. Campochiaro (2007)
J. Biol. Chem. 282, 22414-22425
   Abstract »    Full Text »    PDF »
Dynamic FoxO transcription factors.
H. Huang and D. J. Tindall (2007)
J. Cell Sci. 120, 2479-2487
   Abstract »    Full Text »    PDF »
Sirtuin Functions in Health and Disease.
H. Yamamoto, K. Schoonjans, and J. Auwerx (2007)
Mol. Endocrinol. 21, 1745-1755
   Abstract »    Full Text »    PDF »
Sirtuin 1 Is Required for Antagonist-Induced Transcriptional Repression of Androgen-Responsive Genes by the Androgen Receptor.
Y. Dai, D. Ngo, L. W. Forman, D. C. Qin, J. Jacob, and D. V. Faller (2007)
Mol. Endocrinol. 21, 1807-1821
   Abstract »    Full Text »    PDF »
SIRT1 Is Significantly Elevated in Mouse and Human Prostate Cancer.
D. M. Huffman, W. E. Grizzle, M. M. Bamman, J.-s. Kim, I. A. Eltoum, A. Elgavish, and T. R. Nagy (2007)
Cancer Res. 67, 6612-6618
   Abstract »    Full Text »    PDF »
Incorporation of an Internal Ribosome Entry Site-Dependent Mechanism in Arsenic-Induced GADD45{alpha} Expression.
Q. Chang, D. Bhatia, Y. Zhang, T. Meighan, V. Castranova, X. Shi, and F. Chen (2007)
Cancer Res. 67, 6146-6154
   Abstract »    Full Text »    PDF »
Induction of Mxi1-SR{alpha} by FOXO3a Contributes to Repression of Myc-Dependent Gene Expression.
O. Delpuech, B. Griffiths, P. East, A. Essafi, E. W.-F. Lam, B. Burgering, J. Downward, and A. Schulze (2007)
Mol. Cell. Biol. 27, 4917-4930
   Abstract »    Full Text »    PDF »
Role of FoxO1 in FFA-induced oxidative stress in adipocytes.
A. R. Subauste and C. F. Burant (2007)
Am J Physiol Endocrinol Metab 293, E159-E164
   Abstract »    Full Text »    PDF »
Reactive Oxygen Species as a Signal in Glucose-Stimulated Insulin Secretion.
J. Pi, Y. Bai, Q. Zhang, V. Wong, L. M. Floering, K. Daniel, J. M. Reece, J. T. Deeney, M. E. Andersen, B. E. Corkey, et al. (2007)
Diabetes 56, 1783-1791
   Abstract »    Full Text »    PDF »
FOXO Transcription Factors in the Regulatory Networks of Longevity.
H. Daitoku and A. Fukamizu (2007)
J. Biochem. 141, 769-774
   Abstract »    Full Text »    PDF »
Do We Age on Sirt1 Expression?.
D. Sedding and J. Haendeler (2007)
Circ. Res. 100, 1396-1398
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Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart.
R. R. Alcendor, S. Gao, P. Zhai, D. Zablocki, E. Holle, X. Yu, B. Tian, T. Wagner, S. F. Vatner, and J. Sadoshima (2007)
Circ. Res. 100, 1512-1521
   Abstract »    Full Text »    PDF »
Differential Regulation of Foxo3a Target Genes in Erythropoiesis.
W. J. Bakker, T. B. van Dijk, M. Parren-van Amelsvoort, A. Kolbus, K. Yamamoto, P. Steinlein, R. G. W. Verhaak, T. W. Mak, H. Beug, B. Lowenberg, et al. (2007)
Mol. Cell. Biol. 27, 3839-3854
   Abstract »    Full Text »    PDF »
Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma.
R. K. Lindemann, A. Newbold, K. F. Whitecross, L. A. Cluse, A. J. Frew, L. Ellis, S. Williams, A. P. Wiegmans, A. E. Dear, C. L. Scott, et al. (2007)
PNAS 104, 8071-8076
   Abstract »    Full Text »    PDF »
The emerging role of FOXO transcription factors in pancreatic {beta} cells.
D. A Glauser and W. Schlegel (2007)
J. Endocrinol. 193, 195-207
   Abstract »    Full Text »    PDF »


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