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Molecular and Cellular Biology, November 1999, p. 7447-7460, Vol. 19, No. 11
Department of Pathology, College of
Physicians and Surgeons, Columbia University, New York, New York
10032
Received 19 January 1999/Returned for modification 22 March
1999/Accepted 2 August 1999
E2F transcription factor is subject to stringent regulation by a
variety of molecules. We recently observed that prohibitin, a potential
tumor suppressor protein, binds to the retinoblastoma (Rb) protein and
represses E2F transcriptional activity. Here we demonstrate that
prohibitin requires the marked box region of E2F for repression;
further, prohibitin can effectively inhibit colony formation induced by
overexpression of E2F1 in T47D cells. Prohibitin was also found to
interact with the signaling kinase c-Raf-1, and Raf-1 could effectively
reverse prohibitin-mediated repression of E2F activity. Agents such as
E1A, p38 kinase, and cyclins D and E had no effect on
prohibitin-mediated repression of E2F1, but all of these molecules
could reverse Rb function. Similarly, stimulation of the immunoglobulin
M signaling pathway in Ramos cells could inactivate prohibitin, but
this had no effect on Rb function. Serum stimulation of quiescent Ramos
cells inactivated Rb and prohibitin with different kinetics; further,
while the serum-dependent inactivation of Rb was dependent on
cyclin-dependent kinase activity, the inactivation of prohibitin was
not. We believe that prohibitin is a novel regulator of E2F function
which channels specific signaling cascades to the cell cycle regulatory machinery.
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Rb and Prohibitin Target Distinct Regions of E2F1 for Repression
and Respond to Different Upstream Signals
*
Corresponding author. Mailing address: Department of
Pathology, College of Physicians and Surgeons, Columbia University,
630W 168th St., New York, NY 10032. Phone: (212) 305-3736. Fax: (212) 305-5498. E-mail: spc10{at}columbia.edu.
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