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Science 296 (5567): 530-534

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

DNA Repair Pathway Stimulated by the Forkhead Transcription Factor FOXO3a Through the Gadd45 Protein

Hien Tran,1* Anne Brunet,1* Jill M. Grenier,2 Sandeep R. Datta,1 Albert J. Fornace Jr.,3 Peter S. DiStefano,2 Lillian W. Chiang,2 Michael E. Greenberg1dagger

The signaling pathway from phosphoinositide 3-kinase to the protein kinase Akt controls organismal life-span in invertebrates and cell survival and proliferation in mammals by inhibiting the activity of members of the FOXO family of transcription factors. We show that mammalian FOXO3a also functions at the G2 to M checkpoint in the cell cycle and triggers the repair of damaged DNA. By gene array analysis, FOXO3a was found to modulate the expression of several genes that regulate the cellular response to stress at the G2-M checkpoint. The growth arrest and DNA damage response gene Gadd45a appeared to be a direct target of FOXO3a that mediates part of FOXO3a's effects on DNA repair. These findings indicate that in mammals FOXO3a regulates the resistance of cells to stress by inducing DNA repair and thereby may also affect organismal life-span.

1 Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
2 Millennium Pharmaceuticals, Inc., 640 Memorial Drive, Cambridge, MA 02139, USA.
3 Building 37, Room 6144, NCI, National Institutes of Health, 37 Convent Drive MSC 4255, Bethesda, MD 20892, USA.
*   These authors contributed equally to this work.

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

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Nucleic Acids Res. 34, 485-495
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Forkhead Transcription Factors Inhibit Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia.
Md. R. Abid, K. Yano, S. Guo, V. I. Patel, G. Shrikhande, K. C. Spokes, C. Ferran, and W. C. Aird (2005)
J. Biol. Chem. 280, 29864-29873
   Abstract »    Full Text »    PDF »
LY294002 and LY303511 Sensitize Tumor Cells to Drug-Induced Apoptosis via Intracellular Hydrogen Peroxide Production Independent of the Phosphoinositide 3-Kinase-Akt Pathway.
T. W. Poh and S. Pervaiz (2005)
Cancer Res. 65, 6264-6274
   Abstract »    Full Text »    PDF »
Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress.
A. B. Salmon, S. Murakami, A. Bartke, J. Kopchick, K. Yasumura, and R. A. Miller (2005)
Am J Physiol Endocrinol Metab 289, E23-E29
   Abstract »    Full Text »    PDF »
Glucose-dependent Insulinotropic Polypeptide (GIP) Stimulation of Pancreatic {beta}-Cell Survival Is Dependent upon Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (PKB) Signaling, Inactivation of the Forkhead Transcription Factor Foxo1, and Down-regulation of bax Expression.
S.-J. Kim, K. Winter, C. Nian, M. Tsuneoka, Y. Koda, and C. H. S. McIntosh (2005)
J. Biol. Chem. 280, 22297-22307
   Abstract »    Full Text »    PDF »
Phosphorylation of p66Shc and forkhead proteins mediates A{beta} toxicity.
W. W. Smith, D. D. Norton, M. Gorospe, H. Jiang, S. Nemoto, N. J. Holbrook, T. Finkel, and J. W. Kusiak (2005)
J. Cell Biol. 169, 331-339
   Abstract »    Full Text »    PDF »
Genes Affecting the Cell Cycle, Growth, Maintenance, and Drug Sensitivity Are Preferentially Regulated by Anti-HER2 Antibody through Phosphatidylinositol 3-Kinase-AKT Signaling.
X.-F. Le, A. Lammayot, D. Gold, Y. Lu, W. Mao, T. Chang, A. Patel, G. B. Mills, and R. C. Bast Jr. (2005)
J. Biol. Chem. 280, 2092-2104
   Abstract »    Full Text »    PDF »
Disruption of Yeast Forkhead-associated Cell Cycle Transcription by Oxidative Stress.
M. Shapira, E. Segal, and D. Botstein (2004)
Mol. Biol. Cell 15, 5659-5669
   Abstract »    Full Text »    PDF »
MUC1 Oncoprotein Activates the FOXO3a Transcription Factor in a Survival Response to Oxidative Stress.
L. Yin, L. Huang, and D. Kufe (2004)
J. Biol. Chem. 279, 45721-45727
   Abstract »    Full Text »    PDF »
p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1.
H. You, Y. Jang, A. I. You-Ten, H. Okada, J. Liepa, A. Wakeham, K. Zaugg, and T. W. Mak (2004)
PNAS 101, 14057-14062
   Abstract »    Full Text »    PDF »
Skeletal Muscle FOXO1 (FKHR) Transgenic Mice Have Less Skeletal Muscle Mass, Down-regulated Type I (Slow Twitch/Red Muscle) Fiber Genes, and Impaired Glycemic Control.
Y. Kamei, S. Miura, M. Suzuki, Y. Kai, J. Mizukami, T. Taniguchi, K. Mochida, T. Hata, J. Matsuda, H. Aburatani, et al. (2004)
J. Biol. Chem. 279, 41114-41123
   Abstract »    Full Text »    PDF »
Abnormal Angiogenesis in Foxo1 (Fkhr)-deficient Mice.
T. Furuyama, K. Kitayama, Y. Shimoda, M. Ogawa, K. Sone, K. Yoshida-Araki, H. Hisatsune, S.-i. Nishikawa, K. Nakayama, K. Nakayama, et al. (2004)
J. Biol. Chem. 279, 34741-34749
   Abstract »    Full Text »    PDF »
Insulin and IGF-I as determinants of low 'Western' cancer rates in the rural third world.
M. F McCarty (2004)
Int. J. Epidemiol. 33, 908-910
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Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins.
C. Bouchard, J. Marquardt, A. Bras, R. H. Medema, and M. Eilers (2004)
EMBO J. 23, 2830-2840
   Abstract »    Full Text »    PDF »

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