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Molecular and Cellular Biology, November 1999, p. 7447-7460, Vol. 19, No. 11
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

Sheng Wang, Niharika Nath, Gina Fusaro, and Srikumar Chellappan*

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.

* 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.

Molecular and Cellular Biology, November 1999, p. 7447-7460, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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