The state transitions of normal and mutant androgen-receptor complexes in human genital skin fibroblasts.
We have incubated cells from controls and subjects with receptor-defective androgen resistance with 3H-labelled testosterone (T), methyltrienolone (MT), dihydrotestosterone (DHT) or mibolerone (MB) and studied the temperature dependence of the dissociation rate constants of these various androgen-receptor (A-R) complexes both within cells and after they were extracted from them. In control cells, Arrhenius plots for T-, MT-, DHT- and MB-R complexes were linear and formed a hierarchy of dissociation states with energies of state IV greater than III greater than II, greater than I, respectively. Relative to this hierarchy, the dissociation states of the MB-, DHT- and MT-R complexes in mutant cells were displaced to higher, androgen-inappropriate energies in a mutant-distinctive pattern. When extracted from cells control or mutant T- or MT-R complexes, and mutant (but not control) DHT- or MB-R complexes lowered their respective dissociation rates by undergoing state transitions in conformity with the hierarchy. Hence we propose that different A-R complexes reach different dissociative states by undergoing sequential transitions along a common pathway, and that these transitions are co-regulated both by the chemical characteristics of the bound androgen and by other cellular non-receptor factors.
Kaufman
M
M
Lady Davis Institute for Medical Research, Department of Pediatrics, McGill University, Montreal, Canada.
Pinsky
L
L
Gottlieb
B
B
Trifiro
M
M
D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D004735:Energy Transfer; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D005836:Genitalia, Female; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D008954:Models, Biological; D009154:Mutation; D009277:Nandrolone / Q000031:analogs & derivatives / Q000494:pharmacology; D011944:Receptors, Androgen / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D012611:Scrotum; D012867:Skin / Q000737:chemistry / Q000187:drug effects*; D013696:Temperature; D013739:Testosterone / Q000494:pharmacology
D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D015741:Metribolone; D013739:Testosterone; D009277:Nandrolone; C100075:mibolerone