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Molecular and Cellular Biology, April 2003, p. 2749-2761, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2749-2761.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

NF-B-Dependent Assembly of an Enhanceosome-Like Complex on the Promoter Region of Apoptosis Inhibitor Bfl-1/A1

Leonard C. Edelstein,^1,2,3, Lynn Lagos,^1,3 Matthew Simmons,^1,3 Hemamalini Tirumalai,⁴ and Céline Gélinas^1,5*

Center for Advanced Biotechnology and Medicine,¹ Graduate Program in Biotechnology,² Graduate Program in Biochemistry and Molecular Biology,³ Graduate Program in Molecular Biosciences,⁴ Department of Biochemistry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854⁵

Received 29 July 2002/ Returned for modification 7 October 2002/ Accepted 23 January 2003

Expression of the prosurvival Bcl-2 homologue Bfl-1/A1 is induced by NF-B-activating stimuli, while B and T cells from c-rel knockout mice show an absolute defect in bfl-1/a1 gene activation. Here, we demonstrate NF-B-dependent assembly of an enhanceosome-like complex on the promoter region of bfl-1. Binding of NF-B subunit c-Rel to DNA nucleated the concerted binding of transcription factors AP-1 and C/EBPß to the 5'-regulatory region of bfl-1. Optimal stability of the complex was dependent on proper orientation and phasing of the NF-B site. Chromatin immunoprecipitation analyses demonstrated that T-cell activation triggers in vivo binding of endogenous c-Rel, c-Jun, C/EBPß, and HMG-IC to the bfl-1 regulatory region, coincident with selective recruitment of coactivators TAFII250 and p300, SWI/SNF chromatin remodeling factor component BRG-1, and basal transcription factors TATA-binding protein (TBP) and TFIIB, as well as hyperacetylation of histones H3 and H4. These results highlight a critical role for NF-B in bfl-1 transcription and point to the need for a complex and precise regulatory network to control bfl-1 expression. To our knowledge, this is the first demonstration of enhanceosome-mediated regulation of a cell death inhibitor.

Present address: Department of Pathology, Children's Hospital, Harvard Medical School, Boston, MA 02115.

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