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A mutation that causes lability of the androgen receptor under conditions that normally promote transformation to the DNA-binding state.
J Clin Invest. 1984 Apr; 73(4):1095-104.JCI

Abstract

Dihydrotestosterone-receptor complexes formed in human fibroblast cytosol prepared at 0 degrees C in the presence of sodium molybdate can be readily transformed to the DNA-binding state by heating at 25 degrees C. Under these conditions 50-70% of dihydrotestosterone-receptor complexes bind to DNA. We describe here studies of the transformation process in cytosols derived from normal cells and from fibroblasts propagated from subjects with syndromes of androgen resistance. In contrast to the situation with dihydrotestosterone, normal testosterone-receptor complexes are unstable under in vitro transforming conditions. Although equal amounts of hormone-receptor complex are formed at 0 degrees C, only 15% of testosterone-receptor complexes remain stable and acquire DNA-binding capacity after warming. This instability is not reversible upon lowering the temperature and is corrected by low concentrations (0.25 microM) of the protease inhibitor leupeptin. We have also identified two cousins with androgen resistance whose androgen-receptor complexes exhibit similar in vitro transformation lability with both dihydrotestosterone and testosterone. Phenotypic evidence in these subjects indicates that dihydrotestosterone-mediated processes are more completely impaired than are testosterone-mediated events. These findings suggest that dihydrotestosterone may amplify the androgenic signal at its targets not only by its higher affinity for the receptor but also by its more efficient conversion to the DNA-binding state and that such amplification may be less critical in target tissues in which testosterone suffices for androgenic effect. This offers one possible explanation of how a mutation that affects a single receptor protein may differentially impair the actions of two binding ligands of the receptor.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

6323534

Citation

Kovacs, W J., et al. "A Mutation That Causes Lability of the Androgen Receptor Under Conditions That Normally Promote Transformation to the DNA-binding State." The Journal of Clinical Investigation, vol. 73, no. 4, 1984, pp. 1095-104.
Kovacs WJ, Griffin JE, Weaver DD, et al. A mutation that causes lability of the androgen receptor under conditions that normally promote transformation to the DNA-binding state. J Clin Invest. 1984;73(4):1095-104.
Kovacs, W. J., Griffin, J. E., Weaver, D. D., Carlson, B. R., & Wilson, J. D. (1984). A mutation that causes lability of the androgen receptor under conditions that normally promote transformation to the DNA-binding state. The Journal of Clinical Investigation, 73(4), 1095-104.
Kovacs WJ, et al. A Mutation That Causes Lability of the Androgen Receptor Under Conditions That Normally Promote Transformation to the DNA-binding State. J Clin Invest. 1984;73(4):1095-104. PubMed PMID: 6323534.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A mutation that causes lability of the androgen receptor under conditions that normally promote transformation to the DNA-binding state. AU - Kovacs,W J, AU - Griffin,J E, AU - Weaver,D D, AU - Carlson,B R, AU - Wilson,J D, PY - 1984/4/1/pubmed PY - 1984/4/1/medline PY - 1984/4/1/entrez SP - 1095 EP - 104 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 73 IS - 4 N2 - Dihydrotestosterone-receptor complexes formed in human fibroblast cytosol prepared at 0 degrees C in the presence of sodium molybdate can be readily transformed to the DNA-binding state by heating at 25 degrees C. Under these conditions 50-70% of dihydrotestosterone-receptor complexes bind to DNA. We describe here studies of the transformation process in cytosols derived from normal cells and from fibroblasts propagated from subjects with syndromes of androgen resistance. In contrast to the situation with dihydrotestosterone, normal testosterone-receptor complexes are unstable under in vitro transforming conditions. Although equal amounts of hormone-receptor complex are formed at 0 degrees C, only 15% of testosterone-receptor complexes remain stable and acquire DNA-binding capacity after warming. This instability is not reversible upon lowering the temperature and is corrected by low concentrations (0.25 microM) of the protease inhibitor leupeptin. We have also identified two cousins with androgen resistance whose androgen-receptor complexes exhibit similar in vitro transformation lability with both dihydrotestosterone and testosterone. Phenotypic evidence in these subjects indicates that dihydrotestosterone-mediated processes are more completely impaired than are testosterone-mediated events. These findings suggest that dihydrotestosterone may amplify the androgenic signal at its targets not only by its higher affinity for the receptor but also by its more efficient conversion to the DNA-binding state and that such amplification may be less critical in target tissues in which testosterone suffices for androgenic effect. This offers one possible explanation of how a mutation that affects a single receptor protein may differentially impair the actions of two binding ligands of the receptor. SN - 0021-9738 UR - https://www.unboundmedicine.com/medline/citation/6323534/A_mutation_that_causes_lability_of_the_androgen_receptor_under_conditions_that_normally_promote_transformation_to_the_DNA_binding_state_ L2 - https://doi.org/10.1172/JCI111295 DB - PRIME DP - Unbound Medicine ER -