Distinguishing Androgen Receptor Agonists and Antagonists: Distinct Mechanisms of Activation by Medroxyprogesterone Acetate and Dihydrotestosterone
| Autor: | Kelce Wr, Kathy Bobseine, Elizabeth Langley, Choi iok Wong, Elizabeth M. Wilson, Jon A. Kemppainen |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
medicine.medical_specialty
Transcription Genetic medicine.medical_treatment Medroxyprogesterone Acetate Biology Transfection Mice chemistry.chemical_compound Endocrinology Internal medicine Nitriles Androgen Receptor Antagonists medicine Animals Nandrolone Mibolerone Medroxyprogesterone acetate Luciferases Testosterone Congeners Molecular Biology Dose-Response Relationship Drug Progesterone Congeners Imidazoles Cyproterone acetate Androgen Antagonists Dihydrotestosterone DNA General Medicine Metribolone Peptide Fragments Recombinant Proteins Androgen receptor Mammary Tumor Virus Mouse chemistry Receptors Androgen COS Cells Androgens Fluoxymesterone Hydroxyflutamide Dimerization medicine.drug |
| Zdroj: | Molecular Endocrinology. 13:440-454 |
| ISSN: | 1944-9917 0888-8809 |
| DOI: | 10.1210/mend.13.3.0255 |
| Popis: | Natural and pharmacological androgen receptor (AR) ligands were tested for their ability to induce the AR NH2-terminal and carboxyl-terminal (N/C) interaction in a two-hybrid protein assay to determine whether N/C complex formation distinguishes in vivo AR agonists from antagonists. High-affinity agonists such as dihydrotestosterone, mibolerone, testosterone, and methyltrienolone at concentrations between 0.1 and 1 nM induce the N/C interaction more than 40-fold. The lower affinity anabolic steroids, oxandrolone and fluoxymesterone, require concentrations of 10-100 nM for up to 23-fold induction of the N/C interaction. However no N/C interaction was detected in the presence of the antagonists, hydroxyflutamide, cyproterone acetate, or RU56187, at concentrations up to 1 microM, or with 1 microM estradiol, progesterone, or medroxyprogesterone acetate; each of these steroids at 1-500 nM inhibited the dihydrotestosterone-induced N/C interaction, with medroxyprogesterone acetate being the most effective. In transient and stable cotransfection assays using the mouse mammary tumor virus reporter vector, all ligands displayed concentration-dependent AR agonist activity that paralleled induction of the N/C interaction, with antagonists and weaker agonists failing to induce the N/C interaction. AR dimerization and DNA binding in mobility shift assays and AR stabilization reflected, but were not dependent on, the N/C interaction. The results indicate that the N/C interaction facilitates agonist potency at low physiological ligand concentrations as detected in transcription, dimerization/DNA binding, and stabilization assays. However the N/C interaction is not required for agonist activity at sufficiently high ligand concentrations, nor does its inhibition imply antagonist activity. |
| Databáze: | OpenAIRE |
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