Cell proliferation in the absence of E2F1-3. Dev Biol 2011 Mar 01;351(1):35-45
Date
12/28/2010Pubmed ID
21185283Pubmed Central ID
PMC3868453DOI
10.1016/j.ydbio.2010.12.025Scopus ID
2-s2.0-79551681885 (requires institutional sign-in at Scopus site) 56 CitationsAbstract
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.
Author List
Wenzel PL, Chong JL, Sáenz-Robles MT, Ferrey A, Hagan JP, Gomez YM, Rajmohan R, Sharma N, Chen HZ, Pipas JM, Robinson ML, Leone GAuthors
Hui-Zi Chen MD, PhD Assistant Professor in the Medicine department at Medical College of WisconsinGustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Cell Proliferation
Cell Survival
DNA Breaks, Double-Stranded
E2F1 Transcription Factor
E2F2 Transcription Factor
E2F3 Transcription Factor
Epithelial Cells
Mice
Mice, Inbred C57BL
Mice, Knockout
Repressor Proteins
Retinoblastoma Protein
Tumor Suppressor Protein p53
