title: Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression.
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.
authors.affiliation: Division of Cell Biology I (B5), The Netherlands Cancer Institute (NKI-AvL), Amsterdam, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Boekhout
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Ruixue
authors.initials: R
authors.lastname: Yuan
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Annelotte P
authors.initials: AP
authors.lastname: Wondergem
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Hendrika A
authors.initials: HA
authors.lastname: Segeren
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Elsbeth A
authors.initials: EA
authors.lastname: van Liere
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Nesibu
authors.initials: N
authors.lastname: Awol
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Imke
authors.initials: I
authors.lastname: Jansen
authors.affiliation: Division of Cell Biology I (B5), The Netherlands Cancer Institute (NKI-AvL), Amsterdam, The Netherlands.
authors.forename: Rob M F
authors.initials: RM
authors.lastname: Wolthuis
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands Department of Pediatrics, Division of Molecular Genetics, University Medical Center Groningen University of Groningen, Groningen, The Netherlands a.debruin@uu.nl b.westendorp@uu.nl.
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands a.debruin@uu.nl b.westendorp@uu.nl.
authors.forename: Bart
authors.initials: B
authors.lastname: Westendorp
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000818:Animals; D064200:Cdh1 Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016213:Cyclins / Q000378:metabolism; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D016196:S Phase
chemical_list: D064200:Cdh1 Proteins; D016213:Cyclins; D050684:E2F Transcription Factors; D064173:Anaphase-Promoting Complex-Cyclosome
keywords: CDH1; DNA replication; E2F; anaphase‐promoting complex; cell cycle