Cellular damage invoked by reactive oxygen species plays a key role in the pathobiology of cancer and aging. Forkhead box class O (FoxO) transcription factors are involved in various cellular processes including cell cycle regulation, apoptosis and resistance to reactive oxygen species, and studies in animal models have shown that these transcription factors are of vital importance in tumor suppression, stem cell maintenance and lifespan extension. Here we report that the activity of FoxO in human cells is directly regulated by the cellular redox state through a unique mechanism in signal transduction. We show that reactive oxygen species induce the formation of cysteine-thiol disulfide–dependent complexes of FoxO and the p300/CBP acetyltransferase, and that modulation of FoxO biological activity by p300/CBP-mediated acetylation is fully dependent on the formation of this redox-dependent complex. These findings directly link cellular redox status to the activity of the longevity protein FoxO.
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We thank G.J.P.L. Kops and M.B. Toledano for critically reading the manuscript, M. Putker and I. van Zutphen for experimental support, E. Kalkhoven (University Medical Center Utrecht) for reagents and our colleagues for discussions and suggestions. This work was supported by grants from The Netherlands Science Organization (NWO, Vici), KWF (Dutch Cancer Foundation), the Center for Biomedical Genetics (CBG) and the Cancer Genomics Center (CGC).
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Dansen, T., Smits, L., van Triest, M. et al. Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nat Chem Biol 5, 664–672 (2009). https://doi.org/10.1038/nchembio.194
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