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

American Association for the Advancement of Science (AAAS) - Tập 303 Số 5666 - Trang 2011-2015 - 2004
Anne Brunet1,2,3,4, Lora B. Sweeney1,2,3,4, James Fitzhugh Sturgill1,2,3,4, Katrin F. Chua1,2,3,4, Paul L. Greer1,2,3,4, Yingxi Lin1,2,3,4, Hien Tran1,2,3,4, Sarah E. Ross1,2,3,4, Raúl Mostoslavsky1,2,3,4, Haim Y. Cohen1,2,3,4, Linda Hu1,2,3,4, Hwei-Ling Cheng1,2,3,4, Mark P. Jedrychowski1,2,3,4, Steven P. Gygi1,2,3,4, David Sinclair1,2,3,4, Frederick W. Alt1,2,3,4, Michael E. Greenberg1,2,3,4
1Department of Cell Biology, Harvard Medical School, Boston, MA 02115 USA
2Department of Pathology, Harvard Medical School, Boston, MA 02115 USA
3Division 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.
4Howard Hughes Medical Institute, Children's Hospital, Center for Blood Research (CBR) Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.

Tóm tắt

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.

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In these experiments the PI3K inhibitor LY was included to suppress autocrine insulin-like growth factor 1 (IGF-1) signaling thereby uncoupling Akt from upstream signaling pathways. The use of LY or differences between cell lines may explain the difference between our findings and those of Nemoto and Finkel ( 23 ) regarding stress-dependent FOXO3 localization in the absence of growth factors.

Materials and methods are available as supporting material on Science Online.

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We thank J. Sage S. Paradis and E. Griffith for helpful comments on the manuscript; R. A. Weinberg H. Vaziri and S. Imai for their gifts of SIRT1 constructs; and J. Sage and T. Jacks for p53 +/+ and p53 –/– MEFs. Supported by a Senior Scholars Award from the Ellison Foundation NIH grant no. PO1 NS35138-17 and Mental Retardation Research Center grant no. NIHP30-HD18655 (M.E.G.). M.E.G. acknowledges the generous contribution of the F. M. Kirby Foundation to the Division of Neuroscience. A.B. is supported by a fellowship from the Radcliffe Institute for Advanced Studies. F.W.A. is a Howard Hughes Medical Institute investigator and is supported by an Ellison Medical Foundation Senior Scholar Award. K.C. is supported by a Pfizer postdoctoral fellowship in Rheumatology/Immunology and R.M. by a postdoctoral fellowship from the Human Frontiers Science Program.

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American Association for the Advancement of Science (AAAS)

Tập 303 Số 5666

2011-2015

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