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Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity

Nature Chemical Biology volume 5, pages 664–672 (2009)Cite this article

Abstract

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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Figure 1: Peroxide-induced lysine acetylation is dependent on cysteine residues in FoxO4.
Figure 2: FoxO4 and p300 form a peroxide-induced, disulfide-mediated heterodimer.
Figure 3: Hydrogen peroxide induces the redox-dependent FoxO4-p300 complex in a concentration-dependent manner.
Figure 4: Thioredoxin activity determines the duration of the stress-induced FoxO4-p300 interaction.
Figure 5: p300 represses FoxO4 transcriptional activity and FoxO4-induced cell cycle arrest in a redox-dependent manner.
Figure 6: p300 enhances FoxO4-induced cell death in a redox-dependent manner.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Physiological Chemistry, University Medical Center Utrecht, Utrecht, The Netherlands

    Tobias B Dansen, Lydia M M Smits, Miranda H van Triest, Peter L J de Keizer, Dik van Leenen, Marian Groot Koerkamp, Anna Szypowska, Amanda Meppelink, Arjan B Brenkman, Frank C P Holstege & Boudewijn M T Burgering

  2. Cancer Genomics Center, University Medical Center Utrecht, Utrecht, The Netherlands

    Arjan B Brenkman

  3. Institute for Virus Research, Kyoto University 53, Kawahara-cho, Shogoin, Sakyo, Kyoto, Japan

    Junji Yodoi

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Contributions

T.B.D. and B.M.T.B. designed most experiments. T.B.D., L.M.M.S., M.H.v.T., P.L.J.d.K., D.v.L., M.G.K., A.S., A.M. and B.M.T.B. performed the experiments and analyzed the data. A.B.B., F.C.P.H. and J.Y. provided essential reagents. T.B.D. and B.M.T.B. wrote the paper.

Corresponding authors

Correspondence to Tobias B Dansen or Boudewijn M T Burgering.

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Supplementary Figures 1–12, Supplementary Table 1 and Supplementary Methods (PDF 5730 kb)

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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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