Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress

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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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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) doi:10.1038/nature01036

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