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Submitted on January 27, 2005
Accepted on August 22, 2005
Department of Cell Biology and Physiology, Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
* To whom correspondence should be addressed. E-mail: dod1+{at}pitt.edu.
Hic-5/ARA55 is a group III LIM domain protein that functions as a nuclear receptor coactivator. In the present study, we examined the mechanism by which Hic-5/ARA55 potentiates glucocorticoid receptor (GR) transactivation in the A1-2 derivative of T47D breast cancer cells. Hic-5/ARA55 is an important component of GR-coactivator complexes in A1-2 cells since ablation of Hic-5/ARA55 expression by RNA interference-mediated silencing reduced GR transactivation. As shown by chromatin immunoprecipitation (ChIP) assays, Hic-5/ARA55 is recruited to glucocorticoid-responsive promoters of the MMTV, c-fos, and p21 genes in response to glucocorticoid treatment. Results from sequential ChIPs established that Hic-5/ARA55 associates with GR-containing complexes at these promoters. We also used sequential ChIPs to examine Hic-5/ARA55 interactions with other well characterized nuclear receptor coactivators and detected TIF-2, RAC3, CBP, and p300 within Hic-5/ARA55 complexes on the MMTV promoter in hormone treated cells. Ablation of Hic-5/ARA55 expression resulted in reduction of both TIF-2 and p300 recruitment to glucocorticoid-responsive promoters. Hic-5/ARA55 is also associated with the corepressor, NCoR, on glucocorticoid responsive promoters in cells not exposed to glucocorticoids. These results suggest that Hic-5/ARA55 is required for optimal GR-mediated gene expression possibly by providing a scaffold that organizes or stabilizes coactivator complexes at some hormone-responsive promoters.
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