title: E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells.
abstract: In the established model of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells from entering S phase by binding and sequestering E2f activators (E2f1, E2f2 and E2f3), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase. Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles we examined the effects of E2f1, E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryos and small intestines. We show that in normal dividing progenitor cells E2f1-3 function as transcriptional activators, but contrary to the current view, are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1-3 function in a complex with Rb as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1-3 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions. Loss of E2f1-3 completely suppressed these phenotypes caused by Rb deficiency. This work contextualizes the activator versus repressor functions of E2f1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Jean-Leon
authors.initials: JL
authors.lastname: Chong
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Wenzel
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Sáenz-Robles
authors.forename: Vivek
authors.initials: V
authors.lastname: Nair
authors.forename: Antoney
authors.initials: A
authors.lastname: Ferrey
authors.forename: John P
authors.initials: JP
authors.lastname: Hagan
authors.forename: Yorman M
authors.initials: YM
authors.lastname: Gomez
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sharma
authors.forename: Hui-Zi
authors.initials: HZ
authors.lastname: Chen
authors.forename: Madhu
authors.initials: M
authors.lastname: Ouseph
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Wang
authors.forename: Prashant
authors.initials: P
authors.lastname: Trikha
authors.forename: Brian
authors.initials: B
authors.lastname: Culp
authors.forename: Louise
authors.initials: L
authors.lastname: Mezache
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Winton
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Danian
authors.initials: D
authors.lastname: Chen
authors.forename: Rod
authors.initials: R
authors.lastname: Bremner
authors.forename: Paul G
authors.initials: PG
authors.lastname: Cantalupo
authors.forename: Michael L
authors.initials: ML
authors.lastname: Robinson
authors.forename: James M
authors.initials: JM
authors.lastname: Pipas
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation; D049109:Cell Proliferation; D050684:E2F Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050703:E2F2 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000378:metabolism
chemical_list: D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; C493754:E2f1 protein, mouse; C484940:E2f2 protein, mouse; C490840:E2f3 protein, mouse; D012097:Repressor Proteins; D016160:Retinoblastoma Protein