E2f1, E2f2, and E2f3 control E2F target expression and cellular proliferation via a p53-dependent negative feedback loop.
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.
Timmers
Cynthia
C
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
N
Opavsky
Rene
R
Maiti
Baidehi
B
Wu
Lizhao
L
Wu
Juan
J
Orringer
Daniel
D
Trikha
Prashant
P
Saavedra
Harold I
HI
Leone
Gustavo
G
D000818:Animals; D049109:Cell Proliferation; D050687:E2F1 Transcription Factor / Q000502:physiology*; D050703:E2F2 Transcription Factor / Q000502:physiology*; D050699:E2F3 Transcription Factor / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D018390:Gene Targeting; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; C490840:E2f3 protein, mouse; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53