The E2F1-3 transcription factors are essential for cellular proliferation.
The retinoblastoma tumour suppressor (Rb) pathway is believed to have a critical role in the control of cellular proliferation by regulating E2F activities. E2F1, E2F2 and E2F3 belong to a subclass of E2F factors thought to act as transcriptional activators important for progression through the G1/S transition. Here we show, by taking a conditional gene targeting approach, that the combined loss of these three E2F factors severely affects E2F target expression and completely abolishes the ability of mouse embryonic fibroblasts to enter S phase, progress through mitosis and proliferate. Loss of E2F function results in an elevation of p21Cip1 protein, leading to a decrease in cyclin-dependent kinase activity and Rb phosphorylation. These findings suggest a function for this subclass of E2F transcriptional activators in a positive feedback loop, through down-modulation of p21Cip1, that leads to the inactivation of Rb-dependent repression and S phase entry. By targeting the entire subclass of E2F transcriptional activators we provide direct genetic evidence for their essential role in cell cycle progression, proliferation and development.
Wu
L
L
Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, and Department of Molecular Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
Timmers
C
C
Maiti
B
B
Saavedra
H I
HI
Sang
L
L
Chong
G T
GT
Nuckolls
F
F
Giangrande
P
P
Wright
F A
FA
Field
S J
SJ
Greenberg
M E
ME
Orkin
S
S
Nevins
J R
JR
Robinson
M L
ML
Leone
G
G
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D005347:Fibroblasts / Q000166:cytology; D018390:Gene Targeting; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; C493754:E2f1 protein, mouse; C490840:E2f3 protein, mouse; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases