Ligand-specific thermal misbehavior of synthetic androgen-receptor complexes in genital skin fibroblasts of subjects with familial ligand-sensitive androgen resistance.
We have used 5 alpha-dihydrotestosterone (DHT) and two synthetic, non-metabolizable androgens, methyltrienolone (MT) and mibolerone (MB), to study intact genital skin fibroblasts from four subjects with familial incomplete androgen resistance. In each, the free androgen receptor has normal binding capacity at 37 degrees C and normal half-lives at 37-43 degrees C. In three the mutant receptor misbehaves in a pattern that is ligand-specific and temperature-dependent. At 37 degrees C the equilibrium (Kd) and non-equilibrium (k) dissociation constants, and the ability to augment binding activity during prolonged exposure to androgen, are impaired with DHT, but not with MT; with MB, only the k is abnormal. Mutant MT-receptor complexes dissociate normally even at 42 degrees C; yet, in cells post-incubated at 42 degrees C with cycloheximide and a saturating concentration of ligand, their pool size decays in the rank order, MT greater than MB greater than normal. This measure of lability is nonlinear as a semilogarithmic function of time; it varies directly with temperature and the concentration of cycloheximide, but inversely with that of ligand. Thus, MT and MB evoke distinct forms of thermal dysfunction from the androgen receptor in ligand-sensitive androgen resistance. This observation will help to elucidate the combinatorial properties of normal androgen-receptor complexes that enable them to regulate gene transcription differentially in various androgen target tissues.
D000728:Androgens / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000378:metabolism; D012734:Disorders of Sex Development / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance; D004963:Estrenes / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005837:Genitalia, Male / Q000166:cytology*; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D015741:Metribolone; D009154:Mutation; D009277:Nandrolone / Q000031:analogs & derivatives / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000166:cytology*; D013696:Temperature
D000728:Androgens; D004963:Estrenes; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D015741:Metribolone; D009277:Nandrolone; D003513:Cycloheximide; C100075:mibolerone