The E2F1–3 transcription factors are essential for cellular proliferation

Lizhao Wu, Cynthia Timmers, Baidehi Maiti, Harold I. Saavedra, Ling Sang, Gabriel T. Chong, Faison Nuckolls, Paloma Giangrande, Fred A. Wright, Seth J. Field, Michael E. Greenberg, Stuart Orkin, Joseph R. Nevins, Michael L. Robinson and Gustavo Leone ()
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Lizhao Wu: Immunology and Medical Genetics, The Ohio State University
Cynthia Timmers: Immunology and Medical Genetics, The Ohio State University
Baidehi Maiti: Immunology and Medical Genetics, The Ohio State University
Harold I. Saavedra: Immunology and Medical Genetics, The Ohio State University
Ling Sang: Immunology and Medical Genetics, The Ohio State University
Gabriel T. Chong: Immunology and Medical Genetics, The Ohio State University
Faison Nuckolls: Howard Hughes Medical Institute, Duke University Medical Center
Paloma Giangrande: Howard Hughes Medical Institute, Duke University Medical Center
Fred A. Wright: Immunology and Medical Genetics, The Ohio State University
Seth J. Field: Harvard Medical School
Michael E. Greenberg: Harvard Medical School
Stuart Orkin: Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School
Joseph R. Nevins: Howard Hughes Medical Institute, Duke University Medical Center
Michael L. Robinson: Children's Research Institute, The Ohio State University
Gustavo Leone: Immunology and Medical Genetics, The Ohio State University

Nature, 2001, vol. 414, issue 6862, 457-462

Abstract: Abstract The retinoblastoma tumour suppressor (Rb) pathway is believed to have a critical role in the control of cellular proliferation by regulating E2F activities1,2. E2F1, E2F2 and E2F3 belong to a subclass of E2F factors thought to act as transcriptional activators important for progression through the G1/S transition3. 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.

Date: 2001
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DOI: 10.1038/35106593

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