E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells.

TitleE2f1-3 switch from activators in progenitor cells to repressors in differentiating cells.
Publication TypeJournal Article
Year of Publication2009
AuthorsChong J-L, Wenzel PL, M Sáenz-Robles T, Nair V, Ferrey A, Hagan JP, Gomez YM, Sharma N, Chen H-Z, Ouseph M, Wang S-H, Trikha P, Culp B, Mezache L, Winton DJ, Sansom OJ, Chen D, Bremner R, Cantalupo PG, Robinson ML, Pipas JM, Leone G
JournalNature
Volume462
Issue7275
Pagination930-4
Date Published2009 Dec 17
ISSN1476-4687
KeywordsAlleles, Animals, Apoptosis, Cell Cycle, Cell Differentiation, Cell Proliferation, E2F Transcription Factors, E2F1 Transcription Factor, E2F2 Transcription Factor, E2F3 Transcription Factor, Embryo, Mammalian, Embryonic Stem Cells, Female, Gene Expression Regulation, Intestine, Small, Mice, Mice, Transgenic, Repressor Proteins, Retinoblastoma Protein
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.

DOI10.1038/nature08677
Alternate JournalNature
PubMed ID20016602
Grant ListR01CA82259 / CA / NCI NIH HHS / United States
P01CA097189 / CA / NCI NIH HHS / United States
R01HD04470 / HD / NICHD NIH HHS / United States
CA098956 / CA / NCI NIH HHS / United States
R01CA85619 / CA / NCI NIH HHS / United States
5 T32 CA106196-04 / CA / NCI NIH HHS / United States
Related Faculty: 
Madhu Ouseph, M.D., Ph.D.

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