title: Cell proliferation in the absence of E2F1-3.
abstract: E2F transcription factors regulate the progression of the cell cycle by repression or transactivation of genes that encode cyclins, cyclin dependent kinases, checkpoint regulators, and replication proteins. Although some E2F functions are independent of the Retinoblastoma tumor suppressor (Rb) and related family members, p107 and p130, much of E2F-mediated repression of S phase entry is dependent upon Rb. We previously showed in cultured mouse embryonic fibroblasts that concomitant loss of three E2F activators with overlapping functions (E2F1, E2F2, and E2F3) triggered the p53-p21(Cip1) response and caused cell cycle arrest. Here we report on a dramatic difference in the requirement for E2F during development and in cultured cells by showing that cell cycle entry occurs normally in E2f1-3 triply-deficient epithelial stem cells and progenitors of the developing lens. Sixteen days after birth, however, massive apoptosis in differentiating epithelium leads to a collapse of the entire eye. Prior to this collapse, we find that expression of cell cycle-regulated genes in E2F-deficient lenses is aberrantly high. In a second set of experiments, we demonstrate that E2F3 ablation alone does not cause abnormalities in lens development but rescues phenotypic defects caused by loss of Rb, a binding partner of E2F known to recruit histone deacetylases, SWI/SNF and CtBP-polycomb complexes, methyltransferases, and other co-repressors to gene promoters. Together, these data implicate E2F1-3 in mediating transcriptional repression by Rb during cell cycle exit and point to a critical role for their repressive functions in cell survival.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Wenzel
authors.forename: Jean-Leon
authors.initials: JL
authors.lastname: Chong
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Sáenz-Robles
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: Ravi
authors.initials: R
authors.lastname: Rajmohan
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sharma
authors.forename: Hui-Zi
authors.initials: HZ
authors.lastname: Chen
authors.forename: James M
authors.initials: JM
authors.lastname: Pipas
authors.forename: Michael L
authors.initials: ML
authors.lastname: Robinson
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D050687:E2F1 Transcription Factor / Q000172:deficiency / Q000502:physiology*; D050703:E2F2 Transcription Factor / Q000172:deficiency / Q000502:physiology*; D050699:E2F3 Transcription Factor / Q000172:deficiency / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: 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; D016159:Tumor Suppressor Protein p53