Reactive oxygen species are required for cell proliferation but can also induce apoptosis1. In proliferating cells this paradox is solved by the activation of protein kinase B (PKB; also known as c-Akt), which protects cells from apoptosis2. By contrast, it is unknown how quiescent cells that lack PKB activity are protected against cell death induced by reactive oxygen species. Here we show that the PKB-regulated Forkhead transcription factor FOXO3a (also known as FKHR-L1) protects quiescent cells from oxidative stress by directly increasing their quantities of manganese superoxide dismutase (MnSOD) messenger RNA and protein. This increase in protection from reactive oxygen species antagonizes apoptosis caused by glucose deprivation. In quiescent cells that lack the protective mechanism of PKB-mediated signalling, an alternative mechanism is induced as a consequence of PKB inactivity. This mechanism entails the activation of Forkhead transcription factors, the transcriptional activation of MnSOD and the subsequent reduction of reactive oxygen species. Increased resistance to oxidative stress is associated with longevity. The model of Forkhead involvement in regulating longevity stems from genetic analysis in Caenorhabditis elegans3,4,5,6, and we conclude that this model also extends to mammalian systems.
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Beckman, K. B. & Ames, B. N. The free radical theory of aging matures. Physiol. Rev. 78, 547–581 (1998)
Gottlob, K. et al. Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev. 15, 1406–1418 (2001)
Ogg, S. et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994–999 (1997)
Paradis, S. & Ruvkun, G. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev. 12, 2488–2498 (1998)
Honda, Y. & Honda, S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J. 13, 1385–1393 (1999)
Taub, J. et al. A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature 399, 162–166 (1999)
Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999)
Kops, G. J. et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398, 630–634 (1999)
Rena, G., Guo, S., Cichy, S. C., Unterman, T. G. & Cohen, P. Phosphorylation of the transcription factor Forkhead family member FKHR by protein kinase B. J. Biol. Chem. 274, 17179–17183 (1999)
Medema, R. H., Kops, G. J., Bos, J. L. & Burgering, B. M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782–787 (2000)
Kops, G. J. et al. Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Mol. Cell. Biol. 22, 2025–2036 (2002)
Littlewood, T. D., Hancock, D. C., Danielian, P. S., Parker, M. G. & Evan, G. I. A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins. Nucleic Acids Res. 23, 1686–1690 (1995)
Pap, E. H. et al. Ratio-fluorescence microscopy of lipid oxidation in living cells using C11-BODIPY581/591. FEBS Lett. 453, 278–282 (1999)
Nemoto, S. & Finkel, T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 295, 2450–2452 (2002)
Dijkers, P. F. et al. FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity. J. Cell Biol. 156, 531–542 (2002)
Kim, H. P., Roe, J. H., Chock, P. B. & Yim, M. B. Transcriptional activation of the human manganese superoxide dismutase gene mediated by tetradecanoylphorbol acetate. J. Biol. Chem. 274, 37455–37460 (1999)
Furuyama, T., Nakazawa, T., Nakano, I. & Mori, N. Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem. J. 349, 629–634 (2000)
Scaduto, R. C. Jr. & Grotyohann, L. W. Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys. J. 76, 469–477 (1999)
Aulwurm, U. R. & Brand, K. A. Increased formation of reactive oxygen species due to glucose depletion in primary cultures of rat thymocytes inhibits proliferation. Eur. J. Biochem. 267, 5693–5698 (2000)
Lee, Y. J. et al. Glucose deprivation-induced cytotoxicity and alterations in mitogen-activated protein kinase activation are mediated by oxidative stress in multidrug-resistant human breast carcinoma cells. J. Biol. Chem. 273, 5294–5299 (1998)
Blackburn, R. V. et al. Metabolic oxidative stress activates signal transduction and gene expression during glucose deprivation in human tumour cells. Free. Radic. Biol. Med. 26, 419–430 (1999)
Huang, T. T. et al. Superoxide-mediated cytotoxicity in superoxide dismutase-deficient fetal fibroblasts. Arch. Biochem. Biophys. 344, 424–432 (1997)
Nakamura, N. et al. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol. Cell. Biol. 20, 8969–8982 (2000)
Tran, H. et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530–534 (2002)
Kenyon, C. A conserved regulatory system for aging. Cell 105, 165–168 (2001)
Guarente, L. & Kenyon, C. Genetic pathways that regulate ageing in model organisms. Nature 408, 255–262 (2000)
Boyd, K. E., Wells, J., Gutman, J., Bartley, S. M. & Farnham, P. J. c-Myc target gene specificity is determined by a post-DNA binding mechanism. Proc. Natl Acad. Sci. USA 95, 13887–13892 (1998)
We thank P. Dijkers, M. Yim, D. Powell and J. Wispe for reagents; W. R. Sellers for discussions; M. Daniels for technical assistance; and C. Marshall for critically reading the manuscript. G.J.P.L.K. is supported by Chemical Sciences, T.T.H. is supported by the NIH.
The authors declare that they have no competing financial interests.
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Kops, G., Dansen, T., Polderman, P. et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316–321 (2002) doi:10.1038/nature01036
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