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J. Biol. Chem., Vol. 279, Issue 25, 26126-26133, June 18, 2004

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Heregulin Regulates the Ability of the ErbB3-binding Protein Ebp1 to Bind E2F Promoter Elements and Repress E2F-mediated Transcription^*

Yuexing Zhang and Anne W. Hamburger¶

From the Greenebaum Cancer Center and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201

The ErbB3/4 ligand heregulin (HRG) profoundly affects cell growth and differentiation, but its mechanism of action is poorly understood. Ebp1, a protein isolated by its binding to ErbB3, inhibits cell growth and represses transcription of E2F-regulated cell cycle genes. Since Ebp1 shares 38% identity with a Schizosaccharomyces pombe DNA-binding protein, we postulated that Ebp1 could bind E2F consensus elements in an HRG-inducible manner, leading to transcriptional repression. We show here that GST-Ebp1 bound to the DNA sequence bound by the S. pombe protein. Whereas GST-Ebp1 alone failed to bind E2F1 promoter elements, Ebp1 contained in nuclear lysates associated with E2F1 consensus sequences in the E2F1 promoter. Endogenous Ebp1 was recruited to the E2F1 promoter in vivo as demonstrated by chromatin immunoprecipitation assays. Ebp1 bound E2F consensus oligonucleotides in association with E2F1, retinoblastoma protein, and HDAC2. HRG regulated the association of Ebp1 with E2F promoter sequences and enhanced the ability of Ebp1 to repress transcription. Our findings suggest that Ebp1, by linking HRG activation of membrane receptors to E2F gene activity, may be a downstream modulator of the effects of HRG on cell cycle progression.

Received for publication, December 30, 2003 , and in revised form, March 31, 2004.

^* This work was supported in part by National Institutes of Health Grants R01 CA76047 and R21 088882-01 (to A. W. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Greenebaum Cancer Center, University of Maryland at Baltimore, BRB 9-047, 655 W. Baltimore St., Baltimore, MD 21201. Tel.: 410-328-3911; Fax: 410-328-6559; E-mail: ahamburg{at}som.umaryland.edu.

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