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Thyroid Receptor Activator Molecule, TRAM-1, Is an Androgen Receptor Coactivator¹

The Laboratories for Reproductive Biology and the Departments of Pediatrics and Cell Biology and Anatomy (P.P.), University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7500

Address all correspondence and requests for reprints to: Frank S. French, Laboratories for Reproductive Biology, CB 7500, 382 Medical Sciences Research Building, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7500. E-mail: fsfrench{at}med.unc.edu

An androgen receptor (AR) interacting protein was isolated from a HeLa cell complementary DNA library by two-hybrid screening in yeast using the AR DNA and ligand binding domains [amino acids (aa) 481–919] as bait. AR binding of the protein in yeast was dependent on the presence of testosterone or dihydrotestosterone (DHT). The isolated protein is identical to thyroid receptor activator molecule TRAM-1 but lacking aa 1–458. TRAM-1 is a steroid receptor coactivator-3 (SRC-3) subtype. In affinity matrix assays, ³⁵S-labeled TRAM-1 bound the GST-AR ligand binding domain (aa 624–919) and GST-AR N-terminal and DNA binding domains (aa 1–660), but not the GST-AR DNA binding domain (aa 544–634) alone. Coexpression of TRAM-1 increased DHT-dependent AR transactivation 5-fold and constitutive activity of AR (aa 1–660) N-terminal and DNA-binding domains increased 9-fold. Full-length TRAM-1 (aa 1–1424) and the partial (aa 459-1424) were AR and GR coactivators as was SRC-1. In human testis, immunostaining of SRC-3 colocalized with AR in nuclei of Sertoli cells and peritubular myoid cells, indicating it could function as an AR coactivator in these cells. SRC-3 was also present in nuclei of spermatogenic cells where AR was not expressed, suggesting it might also be a coactivator with other nuclear receptors that regulate spermatogenesis.

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