@article{9483375f5072419cb31077cfcb858530,
title = "Chk1 and 14-3-3 proteins inhibit atypical E2Fs to prevent a permanent cell cycle arrest",
abstract = "The atypical E2Fs, E2F7 and E2F8, act as potent transcriptional repressors of DNA replication genes providing them with the ability to induce a permanent S-phase arrest and suppress tumorigenesis. Surprisingly in human cancer, transcript levels of atypical E2Fs are frequently elevated in proliferating cancer cells, suggesting that the tumor suppressor functions of atypical E2Fs might be inhibited through unknown post-translational mechanisms. Here, we show that atypical E2Fs can be directly phosphorylated by checkpoint kinase 1 (Chk1) to prevent a permanent cell cycle arrest. We found that 14-3-3 protein isoforms interact with both E2Fs in a Chk1-dependent manner. Strikingly, Chk1 phosphorylation and 14-3-3-binding did not relocate or degrade atypical E2Fs, but instead, 14-3-3 is recruited to E2F7/8 target gene promoters to possibly interfere with transcription. We observed that high levels of 14-3-3 strongly correlate with upregulated transcription of atypical E2F target genes in human cancer. Thus, we reveal that Chk1 and 14-3-3 proteins cooperate to inactivate the transcriptional repressor functions of atypical E2Fs. This mechanism might be of particular importance to cancer cells, since they are exposed frequently to DNA-damaging therapeutic reagents.",
keywords = "14-3-3 proteins, atypical E2Fs, cell cycle, checkpoint kinase 1, DNA damage",
author = "Ruixue Yuan and Vos, {Harmjan R.} and {van Es}, {Robert M.} and Jing Chen and Burgering, {Boudewijn M.T.} and Bart Westendorp and {de Bruin}, Alain",
note = "Funding Information: We thank Ger Arkesteijn (Faculty of Veterinary Medicine, Utrecht University, NL) for providing professional assistance with the FACS sorting. Richard Wubbolts and Esther van?t Veld in the Center for Cellular Imaging (Faculty of Veterinary Medicine, Utrecht University, NL) provided technical support with the stripe assays and live cell imaging. We thank Rachel Thomas for her contribution to manuscript revision. This work is financially supported by the China Scholarship Council (CSC) (File No. 201306380101), ?Proteins at Work? program of The Netherlands Organization for Scientific Research (NWO) (project number 184.032.201), a Dutch Cancer Society funding (KWF: UU2013-5777) to Bart Westendorp and Alain de Bruin, a ZonMW grant 91116011, and by the Netherlands Organization for Scientific Research (NWO: ALW-IN11-28) to Alain de Bruin. Funding Information: We thank Ger Arkesteijn (Faculty of Veterinary Medicine, Utrecht University, NL) for providing professional assistance with the FACS sorting. Richard Wubbolts and Esther van{\textquoteleft}t Veld in the Center for Cellular Imaging (Faculty of Veterinary Medicine, Utrecht University, NL) provided technical support with the stripe assays and live cell imaging. We thank Rachel Thomas for her contribution to manuscript revision. This work is financially supported by the China Scholarship Council (CSC) (File No. 201306380101), “Proteins at Work” program of The Netherlands Organization for Scientific Research (NWO) (project number 184.032.201), a Dutch Cancer Society funding (KWF: UU2013-5777) to Bart Westendorp and Alain de Bruin, a ZonMW grant 91116011, and by the Netherlands Organization for Scientific Research (NWO: ALW-IN11-28) to Alain de Bruin. Publisher Copyright: {\textcopyright} 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license",
year = "2018",
month = mar,
day = "1",
doi = "10.15252/embj.201797877",
language = "English",
volume = "37",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Springer Science and Business Media Deutschland GmbH",
number = "5",
}