title: Extracellular correction of the androgen-receptor transformation defect in two families with complete androgen resistance.
abstract: We have characterized the cellular and extracellular phenotype of the mutant androgen receptor (AR) from two families who have complete androgen resistance despite a normal androgen-binding capacity (Bmax) in their genital skin fibroblasts (GSF). The cellular receptors fail to up-regulate their basal AR activity in response to prolonged incubation with 5 alpha-dihydrotestosterone (DHT), or with two synthetic androgens, methyltrienolone (MT) and mibolerone (MB), and form A-R complexes with increased equilibrium (Kd) and non-equilibrium (k) dissociation constants. In addition, they are thermolabile when recently dissociated, but not in their native state. A-R complexes made in normal or mutant cytosol at 4 degrees C elute from DEAE-Sephacel at approximately 0.25 M KCl (untransformed), with or without prior passage through Sephadex G-25; when made in cells at 37 degrees C, extracted with 0.4 M KCl in a buffer containing 10 mM Na2MoO4, and desalted by G-25, they elute at less than or equal to 0.1 M KCl. Normal KCl-extracted DHT- and MB-R complexes dissociate (37 degrees C) at the same slow, linear rate as their in-cell counterparts (transformed); the mutant ones dissociated more slowly than their rapidly-dissociating in-cell counterparts and, to a variable extent, nonlinearly-an early faster phase, a later slower (transformed). Thus, as judged by two conventional criteria of steroid-R complex transformation, the mutant A-R complexes can transform, possibly in two steps, under certain cell-free conditions. This behavior differentiates a class of structural AR mutations whose molecular definition awaits application of recombinant DNA techniques to the X-linked AR locus.
authors: Department of Biology, John Abbott College, Quebec, Canada.
authors: B
authors: B
authors: Gottlieb
authors: M
authors: M
authors: Kaufman
authors: L
authors: L
authors: Pinsky
authors: G
authors: G
authors: Leboeuf
authors: J F
authors: JF
authors: Sotos
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D002478:Cells, Cultured; D002648:Child; D012734:Disorders of Sex Development / Q000378:metabolism*; D004351:Drug Resistance; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009154:Mutation; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D012867:Skin / Q000378:metabolism*
chemical_list: D000728:Androgens; D011944:Receptors, Androgen