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PMID: 17167174 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

E2f1, E2f2, and E2f3 control E2F target expression and cellular proliferation via a p53-dependent negative feedback loop.

Molecular and cellular biology ·Vol. 27 ·No. 1 ·2007-01-00 ·Pages 65-78

Timmers C, Sharma N, Opavsky R, Maiti B, Wu L, Wu J, Orringer D, Trikha P, Saavedra HI, Leone G

Abstract

E2F-mediated control of gene expression is believed to have an essential role in the control of cellular proliferation. Using a conditional gene-targeting approach, we show that the targeted disruption of the entire E2F activator subclass composed of E2f1, E2f2, and E2f3 in mouse embryonic fibroblasts leads to the activation of p53 and the induction of p53 target genes, including p21(CIP1). Consequently, cyclin-dependent kinase activity and retinoblastoma (Rb) phosphorylation are dramatically inhibited, leading to Rb/E2F-mediated repression of E2F target gene expression and a severe block in cellular proliferation. Inactivation of p53 in E2f1-, E2f2-, and E2f3-deficient cells, either by spontaneous mutation or by conditional gene ablation, prevented the induction of p21(CIP1) and many other p53 target genes. As a result, cyclin-dependent kinase activity, Rb phosphorylation, and E2F target gene expression were restored to nearly normal levels, rendering cells responsive to normal growth signals. These findings suggest that a critical function of the E2F1, E2F2, and E2F3 activators is in the control of a p53-dependent axis that indirectly regulates E2F-mediated transcriptional repression and cellular proliferation.

MeSH Terms
Animals Cell Proliferation E2F1 Transcription Factor/physiology E2F2 Transcription Factor/physiology E2F3 Transcription Factor/physiology Fibroblasts/metabolism Gene Expression Regulation Gene Targeting Mice Mice, Knockout Mutation Phosphorylation Retinoblastoma Protein/metabolism Transcription, Genetic Tumor Suppressor Protein p53/metabolism
Chemicals
E2F1 Transcription Factor E2F2 Transcription Factor E2F3 Transcription Factor E2f3 protein, mouse Retinoblastoma Protein Tumor Suppressor Protein p53
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Timmers Cynthia
Human Cancer Genetics program, Department of Molecular Virology, Immunology and Medical Genetics, and Comprehensive Cancer Center, The Ohio State University, 410 W. 12th Avenue, Columbus, OH 43210, USA.
Sharma Nidhi
Opavsky Rene
Maiti Baidehi
Wu Lizhao
Wu Juan
Orringer Daniel
Trikha Prashant
Saavedra Harold I
Leone Gustavo
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.02147-05
Published
2007-01-00
Pages
65-78
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1800646
Subset
IM
Grants
NCI NIH HHS · R01 CA085619 · United States
NCI NIH HHS · R01 CA082259 · United States
NCI NIH HHS · K01 CA 104079 · United States
NCI NIH HHS · R01 CA 85619 · United States
NCI NIH HHS · P01 CA 097189 · United States
NCI NIH HHS · R01 CA 82259 · United States
NICHD NIH HHS · R01 HD 047470 · United States
NICHD NIH HHS · R01 HD047470 · United States
NCI NIH HHS · K01 CA104079 · United States
NCI NIH HHS · K01 CA102328 · United States
NCI NIH HHS · K01 CA 102328 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1128/MCB.02147-05 PMC Full Text View journal details
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