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Molecular and Cellular Biology, June 2003, p. 3837-3846, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.3837-3846.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Inhibition of p300/CBP by Early B-Cell Factor

Fang Zhao,1,{dagger} Ruth McCarrick-Walmsley,1 Peter Åkerblad,2,{ddagger} Mikael Sigvardsson,2 and Tom Kadesch1*

Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6145,1 Department of Stem Cell Biology, University of Lund, Lund, Sweden2

Received 12 November 2002/ Returned for modification 30 December 2002/ Accepted 18 March 2003

Early B-cell factor (EBF) is a DNA binding protein required for early B-cell development. It activates transcription of several B-cell-specific genes, including the {lambda}5 gene, which encodes a protein necessary for signaling by the pre-B-cell receptor. In an effort to understand the mechanism by which EBF activates transcription, we examined its interaction with the coactivator protein p300/CBP. We found that two domains of EBF each bind the histone acetyltransferase (HAT)/CH3 domain of p300/CBP both in vitro and in vivo. Surprisingly, transcriptional activation by EBF was not sensitive to E1A, a potent p300/CBP inhibitor. In fact, overexpressed EBF mimicked E1A by severely repressing the activity of several other transcription factors, including E47, a protein that acts cooperatively with EBF to promote transcription of the {lambda}5 gene. This broad inhibitory profile correlated with EBF's ability to repress the HAT activity of p300/CBP in vivo and in vitro. However, such a repressed complex is not likely to form at the {lambda}5 promoter in vivo since (i) EBF could not bind p300/CBP and DNA simultaneously and (ii) the cooperativity imparted by E47 was sensitive to E1A. Our data reveal an intriguing inhibitory property of EBF—a property shared only by E1A, Twist, Pu.1, and the Hox family of homeodomain proteins—and suggest that E47 and EBF play distinct roles during {lambda}5 promoter activation.

* Corresponding author. Mailing address: University of Pennsylvania School of Medicine, 409 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104-6145. Phone: (215) 898-1047. Fax: (215) 898-9750. E-mail: kadesch{at}mail.med.upenn.edu.

{dagger} Present address: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.

{ddagger} Present address: AstraZeneca R&D, SE-431 83, Mölndal, Sweden.

Molecular and Cellular Biology, June 2003, p. 3837-3846, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.3837-3846.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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