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Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress

Nature volume 419, pages 316–321 (2002)Cite this article

Abstract

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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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.

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Acknowledgements

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.

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Author notes

  1. Geert J. P. L. Kops

    Present address: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California, 92093-0670, USA

  2. René H. Medema and Boudewijn M. T. Burgering: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Physiological Chemistry, University Medical Center Utrecht and Center for Biomedical Genetics, 3584 CG, Utrecht, The Netherlands

    Geert J. P. L. Kops, Paulien E. Polderman, Ingrid Saarloos, Johannes L. Bos & Boudewijn M. T. Burgering

  2. Department of Biochemistry of Lipids, Institute of Biomembranes, Utrecht University, 3584 CH, Utrecht, The Netherlands

    Tobias B. Dansen & Karel W. A. Wirtz

  3. Department of Pulmonary Diseases, University Medical Center, 3584 CX, Utrecht, Utrecht, The Netherlands

    Paul J. Coffer

  4. Department of Pediatrics, University of California, California, 94143, San Francisco, USA

    Ting-T. Huang

  5. Division of Molecular Biology, H8, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands

    René H. Medema

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Correspondence to Boudewijn M. T. Burgering.

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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). https://doi.org/10.1038/nature01036

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