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Differential Roles for the E2A Activation Domains in B Lymphocytes and Macrophages¹

Savita Bhalla^*, Christina Spaulding^*, Rachel L. Brumbaugh^*, Derek E. Zagort^*, Mark E. Massari, Cornelis Murre and Barbara L. Kee^2,*,

^* Department of Pathology and Committees on Immunology, Cancer Biology and Developmental Biology, University of Chicago, Chicago, IL 60637; and Department of Biology, University of California at San Diego, La Jolla, CA 92190

The E2A gene encodes two E protein/class I basic helix-loop-helix transcription factors, E12 and E47, that are essential for B lymphopoiesis. In addition to the DNA-binding and protein dimerization domain, the E proteins share two highly conserved transcription activation domains. In this study, we show that both activation domains are required for optimal E2A-dependent transcription. Surprisingly, however, neither activation domain is required for E2A to rescue B lymphopoiesis from E2A^–/– hemopoietic progenitors, although the N terminus of E2A, which harbors some transcription capacity, is required. Therefore, the E protein activation domains function redundantly in promoting B cell development. In contrast, the N-terminal activation domain, AD1, is required for a newly described ability of E2A to suppress macrophage development in vitro. Our findings demonstrate distinct functionalities for the E protein activation domains in B lymphocytes and macrophages.

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.

¹ This work was supported by the National Institutes of Health (R01 CA099978, to B.L.K.).

² Address correspondence and reprint requests to Dr. Barbara L. Kee, Department of Pathology, University of Chicago, 5841 South Maryland Avenue, MC1089, Chicago, IL 60637. E-mail address: bkee{at}bsd.uchicago.edu

³ Abbreviations used in this paper: EBF, early B cell factor; bHLH, basic helix-loop-helix; FL MPP, fetal liver multipotent progenitor; AD, activation domain; LH, loop helix; IRES, internal ribosomal entry site; QPCR, quantitative real-time PCR; WT, wild type; FSC, forward scatter; SSC, side scatter; MFI, mean fluorescence intensity.