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The Androgen Receptor (AR) Amino-Terminus Imposes Androgen-Specific Regulation of AR Gene Expression via an Exonic Enhancer¹

Department of Molecular & Cellular Pharmacology (J.M.G., L.S.L., K.L.B.), University of Miami School of Medicine, Miami, Florida 33101; Geriatric Research, Education and Clinical Center (K.L.B.), Miami VA Medical Center, Miami, Florida 33125; Department of Human Genetics (D.M.R.), University of Michigan School of Medicine, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Kerry L. Burnstein, Ph.D., Department of Molecular & Cellular Pharmacology (R-189), P.O. Box 016189, Miami, Florida 33101. E-mail: kburnste{at}miami.edu

Androgen and glucocorticoid receptor (AR, GR), two closely related members of the nuclear receptor superfamily, can recognize a similar cis-acting DNA sequence, or hormone response element (HRE). Despite this apparent commonality, these receptors regulate distinct target genes in vivo. The AR gene itself is regulated by AR but not GR in a variety of cell types, including osteoblast-like cells, as shown here. To understand this specificity, we first identified the DNA sequences responsible for androgen-mediated up-regulation of AR messenger RNA. A 6.5-kb region encompassing exon D, intron 4, and exon E of the AR gene contains four exonic HREs and exhibits cell type-specific, AR-mediated transcriptional enhancement when placed upstream of a heterologous promoter and reporter gene. A 350-bp fragment consisting of just exons D and E exhibits the same cell- and androgen-specificity as the 6.5-kb region, as well as the native AR gene. Consistent with a role for the exonic HREs, androgen regulation via this intragenic enhancer requires the HREs as well as a functional receptor DNA binding domain. A panel of AR/GR chimeric receptors was used to test which AR domains (amino-terminal, DNA binding or ligand binding) confer androgen-specific regulation of the 350-bp enhancer. Only chimeric receptors containing the amino-terminus of AR induced reporter gene activity from the AR gene enhancer. Further, a constitutively active AR consisting of only the AR amino-terminus and DNA binding domain (AA) retained the capacity to activate the internal responsive region, unlike a constitutively active chimera harboring the GR amino-terminus and AR DNA binding domain (GA). Thus, the AR amino terminus is the sole determinant for androgen-specific regulation of the AR gene internal enhancer. These findings support a model in which the amino termini of ARs bound to HREs within the AR gene interact with an exclusive auxiliary factor(s) to elicit androgen-specific regulation of AR messenger RNA. This is the first example of androgen-specific response in which the necessary and sufficient distinguishing capacity resides within the AR amino terminus.

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