Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression

Michiel Boekhout, Ruixue Yuan, Annelotte P Wondergem, Hendrika A Segeren, Elsbeth A van Liere, Nesibu Awol, Imke Jansen, Rob M F Wolthuis, Alain de Bruin, Bart Westendorp

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

E2F transcription factors control the oscillating expression pattern of multiple target genes during the cell cycle. Activator E2Fs, E2F1-3, induce an upswing of E2F targets, which is essential for the G1-to-S phase transition, whereas atypical E2Fs, E2F7 and E2F8, mediate a downswing of the same targets during late S, G2, and M phases. Expression of atypical E2Fs is induced by E2F1-3, but it is unknown how atypical E2Fs are inactivated in a timely manner. Here, we demonstrate that E2F7 and E2F8 are substrates of the anaphase-promoting complex/cyclosome (APC/C). Removal of CDH1, or mutating the CDH1-interacting KEN boxes, stabilized E2F7/8 from anaphase onwards and during G1. Expressing KEN mutant E2F7 during G1 impairs S phase entry and eventually results in cell death. Furthermore, we show that E2F8, but not E2F7, interacts also with APC/C(C) (dc20). Importantly, atypical E2Fs can activate APC/C(C) (dh1) by repressing its inhibitors cyclin A, cyclin E, and Emi1. In conclusion, we discovered a feedback loop between atypical E2Fs and APC/C(C) (dh1), which ensures balanced expression of cell cycle genes and normal cell cycle progression.

Original languageEnglish
Pages (from-to)414-27
Number of pages14
JournalEMBO Reports
Volume17
Issue number3
DOIs
Publication statusPublished - Mar 2016

Cite this

Boekhout, M., Yuan, R., Wondergem, A. P., Segeren, H. A., van Liere, E. A., Awol, N., ... Westendorp, B. (2016). Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression. EMBO Reports, 17(3), 414-27. https://doi.org/10.15252/embr.201540984
Boekhout, Michiel ; Yuan, Ruixue ; Wondergem, Annelotte P ; Segeren, Hendrika A ; van Liere, Elsbeth A ; Awol, Nesibu ; Jansen, Imke ; Wolthuis, Rob M F ; de Bruin, Alain ; Westendorp, Bart. / Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression. In: EMBO Reports. 2016 ; Vol. 17, No. 3. pp. 414-27.
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Boekhout, M, Yuan, R, Wondergem, AP, Segeren, HA, van Liere, EA, Awol, N, Jansen, I, Wolthuis, RMF, de Bruin, A & Westendorp, B 2016, 'Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression' EMBO Reports, vol. 17, no. 3, pp. 414-27. https://doi.org/10.15252/embr.201540984

Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression. / Boekhout, Michiel; Yuan, Ruixue; Wondergem, Annelotte P; Segeren, Hendrika A; van Liere, Elsbeth A; Awol, Nesibu; Jansen, Imke; Wolthuis, Rob M F; de Bruin, Alain; Westendorp, Bart.

In: EMBO Reports, Vol. 17, No. 3, 03.2016, p. 414-27.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression

AU - Boekhout, Michiel

AU - Yuan, Ruixue

AU - Wondergem, Annelotte P

AU - Segeren, Hendrika A

AU - van Liere, Elsbeth A

AU - Awol, Nesibu

AU - Jansen, Imke

AU - Wolthuis, Rob M F

AU - de Bruin, Alain

AU - Westendorp, Bart

N1 - © 2016 The Authors.

PY - 2016/3

Y1 - 2016/3

N2 - E2F transcription factors control the oscillating expression pattern of multiple target genes during the cell cycle. Activator E2Fs, E2F1-3, induce an upswing of E2F targets, which is essential for the G1-to-S phase transition, whereas atypical E2Fs, E2F7 and E2F8, mediate a downswing of the same targets during late S, G2, and M phases. Expression of atypical E2Fs is induced by E2F1-3, but it is unknown how atypical E2Fs are inactivated in a timely manner. Here, we demonstrate that E2F7 and E2F8 are substrates of the anaphase-promoting complex/cyclosome (APC/C). Removal of CDH1, or mutating the CDH1-interacting KEN boxes, stabilized E2F7/8 from anaphase onwards and during G1. Expressing KEN mutant E2F7 during G1 impairs S phase entry and eventually results in cell death. Furthermore, we show that E2F8, but not E2F7, interacts also with APC/C(C) (dc20). Importantly, atypical E2Fs can activate APC/C(C) (dh1) by repressing its inhibitors cyclin A, cyclin E, and Emi1. In conclusion, we discovered a feedback loop between atypical E2Fs and APC/C(C) (dh1), which ensures balanced expression of cell cycle genes and normal cell cycle progression.

AB - E2F transcription factors control the oscillating expression pattern of multiple target genes during the cell cycle. Activator E2Fs, E2F1-3, induce an upswing of E2F targets, which is essential for the G1-to-S phase transition, whereas atypical E2Fs, E2F7 and E2F8, mediate a downswing of the same targets during late S, G2, and M phases. Expression of atypical E2Fs is induced by E2F1-3, but it is unknown how atypical E2Fs are inactivated in a timely manner. Here, we demonstrate that E2F7 and E2F8 are substrates of the anaphase-promoting complex/cyclosome (APC/C). Removal of CDH1, or mutating the CDH1-interacting KEN boxes, stabilized E2F7/8 from anaphase onwards and during G1. Expressing KEN mutant E2F7 during G1 impairs S phase entry and eventually results in cell death. Furthermore, we show that E2F8, but not E2F7, interacts also with APC/C(C) (dc20). Importantly, atypical E2Fs can activate APC/C(C) (dh1) by repressing its inhibitors cyclin A, cyclin E, and Emi1. In conclusion, we discovered a feedback loop between atypical E2Fs and APC/C(C) (dh1), which ensures balanced expression of cell cycle genes and normal cell cycle progression.

KW - Anaphase-Promoting Complex-Cyclosome

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KW - E2F Transcription Factors

KW - Feedback, Physiological

KW - HEK293 Cells

KW - HeLa Cells

KW - Humans

KW - Mice

KW - Mice, Inbred C57BL

KW - Protein Binding

KW - S Phase

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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SN - 1469-221X

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Boekhout M, Yuan R, Wondergem AP, Segeren HA, van Liere EA, Awol N et al. Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression. EMBO Reports. 2016 Mar;17(3):414-27. https://doi.org/10.15252/embr.201540984