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J. Biol. Chem., Vol. 279, Issue 53, 55362-55371, December 31, 2004

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E2A-PBX1 Interacts Directly with the KIX Domain of CBP/p300 in the Induction of Proliferation in Primary Hematopoietic Cells^*

Richard Bayly, Luan Chuen, Richard A. Currie, Brandy D. Hyndman, Richard Casselman, Gerd A. Blobel¶, and David P. LeBrun||

From the Queen's University Cancer Research Institute, Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, K7L 3N6, Canada and the ^¶Division of Hematology, The Children's Hospital, Philadelphia, Pennsylvania 19104

The E2A gene encodes DNA-binding transcription factors, called E12 and E47, involved in cell specification and maturation. E2A is also involved in a chromosomal translocation that leads to the expression of an oncogenic transcription factor called E2A-PBX1 in cases of acute leukemia. In the work described here, we elucidate the interaction between E2A-PBX1 and transcriptional co-activators. We confirm that the E2A portion can interact with CBP and PCAF and map required elements on E2A and CBP. On CBP, the interaction involves the KIX domain, a well characterized domain that mediates interactions with several other oncogenic transcription factors. On E2A, the interaction with CBP requires conserved -helical domains that reside within activation domains 1 and 2 (AD1 and AD2, respectively). Using purified, recombinant proteins, we show that the E2A-CBP interaction is direct. Notwithstanding the previously demonstrated ability of AD1 and AD2 to function independently, some of our findings suggest functional cooperativity between these two domains. Finally, we show that the CBP/p300-interactive helical domains of E2A are important in the induction of proliferation in cultured primary bone marrow cells retrovirally transduced with E2A-PBX1. Our findings suggest that some aspects of E2A-PBX1 oncogenesis involve a direct interaction with the KIX domain of CBP/p300.

Received for publication, July 29, 2004 , and in revised form, October 26, 2004.

^* This work was supported in part by research grants (to D. P. L.) from the Canadian Institutes of Health Research and the National Cancer Institute of Canada. 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.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1.

Recipients of Leukemia Research Fund of Canada Studentships.

^|| To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, Richardson Laboratory, Queen's University, Kingston, Ontario K7L 3N6, Canada. Tel.: 613-533-3209; Fax: 613-533-6830; E-mail: lebrun{at}cliff.path.queensu.ca.

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