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Functional Activities of the A and B Forms of the Human Androgen Receptor in Response to Androgen Receptor Agonists and Antagonists

Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75235

The androgen receptor (AR) is present in many cells in two forms. The B form migrates with an apparent mass of 110 kDa and constitutes more than 80% of the immunoreactive receptor in most cell types. The A form of the AR migrates with an apparent mass of 87 kDa, appears to derive from internal translation initiation at methionine-188 in the AR open-reading frame, and usually constitutes 20% or less of the immunoreactive AR present. Previous experiments designed to examine the functional capacity of the A and B forms of the AR have been hampered by marked differences in the expression levels of the two isoforms, as the nucleotide sequence surrounding the codon encoding methionine-188 causes it to be used inefficiently as a translation initiation site. To circumvent this, we altered the nucleotide sequence surrounding methionine-188 to render it more similar to that surrounding the codon encoding methionine-1. Transfection of a cDNA containing these changes resulted in similar levels of expression of A and B forms of the AR as assessed by immunoblot assays using antibodies directed at an epitope preserved in both. Functional activities of these cDNAs were assessed using cotransfection assays that employed two model androgen-responsive genes (MMTV-luciferase and PRE₂-tk-luciferase) in response to mibolerone, a potent androgen agonist, in three different cell lines. These studies demonstrated subtle differences in the activities of the A and B isoforms, which depended on the promoter and cell context. Additional studies failed to reveal any major differences in the responses of the AR-A and AR-B isoforms to a variety of androgen agonists and antagonists, suggesting that the previously reported functional defect of the AR-A is due principally to its level of expression. When assays of AR function are performed under conditions in which levels of expression of the two isoforms are equivalent, the AR-A and AR-B possess similar functional activities.

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