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Mechanism of Action of Hic-5/Androgen Receptor Activator 55, a LIM Domain-Containing Nuclear Receptor Coactivator

Department of Cell Biology and Physiology (M.D.H.) and Department of Pharmacology (D.B.D.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: D. B. DeFranco, Department of Pharmacology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, Pennsylvania 15261. E-mail: dod1{at}pitt.edu.

Hic-5/androgen receptor (AR) coactivator 55 (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 because 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 mouse mammary tumor virus, 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 transcriptional intermediary factor 2, receptor-associated coactivator 3, cAMP response element binding protein-binding protein, and p300 within Hic-5/ARA55 complexes on the mouse mammary tumor virus promoter in hormone-treated cells. Ablation of Hic-5/ARA55 expression resulted in reduction of both transcriptional intermediary factor 2 and p300 recruitment to glucocorticoid-responsive promoters. Hic-5/ARA55 is also associated with the corepressor, nuclear receptor corepressor, 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Coregulators:   ARA55  |  TRIP6  |  CBP  |  p300  |  FHL2  |  SRC-1  |  GRIP1  |  AIB1  |  NCOR

Ligands:   Dexamethasone

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