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Molecular and Cellular Biology, December 2002, p. 8539-8551, Vol. 22, No. 24
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.24.8539-8551.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Early B-Cell Factor, E2A, and Pax-5 Cooperate To Activate the Early B Cell-Specific mb-1 Promoter

Mikael Sigvardsson,1 Dawn R. Clark,2,3 Daniel Fitzsimmons,2,3 Michelle Doyle,2,3 Peter Åkerblad,1 Thomas Breslin,4 Sven Bilke,4 Ronggui Li,2,3 Carmen Yeamans,2,3 Gongyi Zhang,2,3 and James Hagman2,3*

Department for Stem Cell Biology,1 Division of Complex Systems, SE-22184 Lund, Sweden,1 Integrated Department of Immunology, National Jewish Medical and Research Center,2 University of Colorado Health Sciences Center, Denver, Colorado 802623

Received 5 June 2002/ Returned for modification 8 August 2002/ Accepted 19 September 2002

Previous studies have suggested that the early-B-cell-specific mb-1(Ig{alpha}) promoter is regulated by EBF and Pax-5. Here, we used in vivo footprinting assays to detect occupation of binding sites in endogenous mb-1 promoters at various stages of B-cell differentiation. In addition to EBF and Pax-5 binding sites, we detected occupancy of a consensus binding site for E2A proteins (E box) in pre-B cells. EBF and E box sites are crucial for promoter function in transfected pre-B cells, and EBF and E2A proteins synergistically activated the promoter in transfected HeLa cells. Other data suggest that EBF and E box sites are less important for promoter function at later stages of differentiation, whereas binding sites for Pax-5 (and its Ets ternary complex partners) are required for promoter function in all mb-1-expressing cells. Using DNA microarrays, we found that expression of endogenous mb-1 transcripts correlates most closely with EBF expression and negatively with Id1, an inhibitor of E2A protein function, further linking regulation of the mb-1 gene with EBF and E2A. Together, our studies demonstrate the complexity of factors regulating tissue-specific transcription and support the concept that EBF, E2A, and Pax-5 cooperate to activate target genes in early B-cell development.

* Corresponding author. Mailing address: Integrated Department of Immunology, National Jewish Medical and Research Center, 1400 Jackson St., K516B, Denver, CO 80206. Phone: (303) 398-1398. Fax: (303) 398-1396. E-mail: hagmanj{at}njc.org.

Molecular and Cellular Biology, December 2002, p. 8539-8551, Vol. 22, No. 24
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.24.8539-8551.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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