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Molecular and Cellular Biology, April 2006, p. 3060-3070, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.3060-3070.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

GA-Binding Protein and p300 Are Essential Components of a Retinoic Acid-Induced Enhanceosome in Myeloid Cells

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island,¹ Department of Medicine, Division of Hematology, Brown Medical School, Providence, Rhode Island,² Rhode Island Hospital, Providence, Rhode Island³

Received 6 September 2005/ Returned for modification 9 November 2005/ Accepted 24 January 2006

Expression of CD18, the ß chain of the leukocyte integrins, is transcriptionally regulated by retinoic acid (RA) in myeloid cells. Full RA responsiveness of the CD18 gene requires its proximal promoter, which lacks a retinoic acid response element (RARE). Rather, RA responsiveness of the CD18 proximal promoter requires ets sites that are bound by GA-binding protein (GABP). The transcriptional coactivator, p300, further increases CD18 RA responsiveness. We demonstrate that GABP, the ets DNA-binding subunit of GABP, physically interacts with p300 in myeloid cells. This interaction involves the GABP pointed domain (PNT) and identifies p300 as the first known interaction partner of GABP PNT. Expression of the PNT domain, alone, disrupts the GABP-p300 interaction and decreases the RA responsiveness of the CD18 proximal promoter. Chromatin immunoprecipitation and chromosome conformation capture demonstrate that, in the presence of RA, GABP and p300 at the proximal promoter recruit retinoic acid receptor/retinoid X receptor from a distal RARE to form an enhanceosome. A dominant negative p300 construct disrupts enhanceosome formation and reduces the RA responsiveness of CD18. Thus, proteins on the CD18 proximal promoter recruit the distal RARE in the presence of RA. This is the first description of an RA-induced enhanceosome and demonstrates that GABP and p300 are essential components of CD18 RA responsiveness in myeloid cells.

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