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

24 Citations (Scopus)


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
Issue number3
Publication statusPublished - Mar 2016


  • Anaphase-Promoting Complex-Cyclosome
  • Animals
  • Cdh1 Proteins
  • Cells, Cultured
  • Cyclins
  • E2F Transcription Factors
  • Feedback, Physiological
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Journal Article
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding
  • Research Support, Non-U.S. Gov't
  • S Phase

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