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Letters to Nature

Nature 419, 316-321 (19 September 2002) | doi:10.1038/nature01036; Received 27 March 2002; Accepted 4 July 2002

Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress

Geert J. P. L. Kops1,2, Tobias B. Dansen3, Paulien E. Polderman1, Ingrid Saarloos1, Karel W. A. Wirtz3, Paul J. Coffer4, Ting-T. Huang5, Johannes L. Bos1, René H. Medema6,7 & Boudewijn M. T. Burgering1,7

  1. Department of Physiological Chemistry, University Medical Center Utrecht and Center for Biomedical Genetics, 3584 CG Utrecht, The Netherlands
  2. Department of Biochemistry of Lipids, Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands
  3. Department of Pulmonary Diseases, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
  4. Department of Pediatrics, University of California, San Francisco, California 94143, USA
  5. Division of Molecular Biology, H8, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
  6. These authors contributed equally to this work
  7. Present address: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California 92093-0670, USA.

Correspondence to: Boudewijn M. T. Burgering1,7 Correspondence and requests for materials should be addressed to B.M.T.B. (e-mail: Email: b.m.t.burgering@med.uu.nl).

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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.