Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Forkhead transcription factors increase cellular protection against ROS.
Figure 2: FOXO3a directly regulates the MnSOD promoter through an inverse DBE.
Figure 3: A Forkhead-mediated increase in MnSOD is required for the survival of arrested cells.

Similar content being viewed by others


  1. Beckman, K. B. & Ames, B. N. The free radical theory of aging matures. Physiol. Rev. 78, 547–581 (1998)

    Article  CAS  Google Scholar 

  2. 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)

    Article  CAS  Google Scholar 

  3. 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)

    Article  ADS  CAS  Google Scholar 

  4. 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)

    Article  CAS  Google Scholar 

  5. 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)

    Article  CAS  Google Scholar 

  6. 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)

    Article  ADS  CAS  Google Scholar 

  7. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999)

    Article  CAS  Google Scholar 

  8. Kops, G. J. et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398, 630–634 (1999)

    Article  ADS  CAS  Google Scholar 

  9. 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)

    Article  CAS  Google Scholar 

  10. 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)

    Article  ADS  CAS  Google Scholar 

  11. 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)

    Article  CAS  Google Scholar 

  12. 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)

    Article  CAS  Google Scholar 

  13. Pap, E. H. et al. Ratio-fluorescence microscopy of lipid oxidation in living cells using C11-BODIPY581/591. FEBS Lett. 453, 278–282 (1999)

    Article  CAS  Google Scholar 

  14. Nemoto, S. & Finkel, T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 295, 2450–2452 (2002)

    Article  ADS  CAS  Google Scholar 

  15. 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)

    Article  CAS  Google Scholar 

  16. 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)

    Article  CAS  Google Scholar 

  17. 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)

    Article  CAS  Google Scholar 

  18. Scaduto, R. C. Jr. & Grotyohann, L. W. Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys. J. 76, 469–477 (1999)

    Article  CAS  Google Scholar 

  19. 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)

    Article  CAS  Google Scholar 

  20. 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)

    Article  CAS  Google Scholar 

  21. 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)

    Article  CAS  Google Scholar 

  22. Huang, T. T. et al. Superoxide-mediated cytotoxicity in superoxide dismutase-deficient fetal fibroblasts. Arch. Biochem. Biophys. 344, 424–432 (1997)

    Article  CAS  Google Scholar 

  23. 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)

    Article  CAS  Google Scholar 

  24. Tran, H. et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530–534 (2002)

    Article  ADS  CAS  Google Scholar 

  25. Kenyon, C. A conserved regulatory system for aging. Cell 105, 165–168 (2001)

    Article  CAS  Google Scholar 

  26. Guarente, L. & Kenyon, C. Genetic pathways that regulate ageing in model organisms. Nature 408, 255–262 (2000)

    Article  ADS  CAS  Google Scholar 

  27. 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)

    Article  ADS  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Boudewijn M. T. Burgering.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kops, G., Dansen, T., Polderman, P. et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316–321 (2002).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing