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Mutant and Wild-Type Androgen Receptors Exhibit Cross-Talk on Androgen-, Glucocorticoid-, and Progesterone-Mediated Transcription

Division of Genetics (P.M.Y., Y.L., J.W., W.W.C.) Department of Medicine Brigham and Women’s Hospital and Harvard Medical School Boston, Massachusetts 02115
Divisions of Genetics and Endocrinology (M.T., L.P.) Department of Medicine Sir Mortimer B. Davis-Jewish General Hospital Lady Davis Research Institute for Medical Research McGill University, Montreal, Quebec H3T 12E2 Canada
Institute of Biomedicine (J.J.P, O.A.J.) Department of Physiology University of Helsinki FIN-00014, Helsinki, Finland

Androgen, glucocorticoid, and progesterone receptors (ARs, GRs, and PRs) often can regulate transcription via composite hormone response elements in target genes. We have used artificial and natural mutant ARs from patients with androgen resistance to study their effects on dominant negative activity on wild type AR, GR, and PR function on mouse mammary tumor virus (MMTV) and tyrosine aminotransferase (TAT) promoters. Artificial ARs that contained internal deletions within the amino-terminal region had minimal transcriptional activity but blocked ligand-mediated transcription by wild type AR. Mutants containing deletions of the DNA-binding and ligand-binding domains had minimal or weak dominant negative activity. We then tested the ability of wild type and mutant ARs to modulate GR- and PR-mediated transcriptional activity. The amino-terminal deletion mutants exerted dominant negative effects on GR- and PR-mediated activity, both in the absence and presence of testosterone. Surprisingly, wild type AR, which had approximately 20% of the maximal transcriptional activity of GR on the MMTV promoter, also had dominant negative activity on dexamethasone-regulated transcription mediated by GR. This dominant negative activity likely involves DNA binding because a point mutation in the DNA-binding domain abrogated such activity of an amino-terminal deletion mutant. Additionally, natural human AR mutants from patients with androgen resistance, which do not bind either DNA or ligand, did not block dexamethasone-mediated transcription. In summary, these studies suggest that mutant and wild type ARs can display dominant negative activity on other steroid hormone receptors that bind to a composite hormone response element. This cross-regulation may be important in regulating maximal transcriptional activity in tissues where these receptors are coexpressed and may contribute to the phenotype of patients with steroid hormone resistance.

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