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Type: Journal article
Title: A novel androgen receptor mutant, A748T, exhibits hormone concentration-dependent defects in nuclear accumulation and activity despite normal hormone-binding affinity
Author: James, A.
Agoulnik, I.
Harris, J.
Buchanan, G.
Tilley, W.
Marcelli, M.
Lamb, D.
Weigel, N.
Citation: Molecular Endocrinology, 2002; 16(12):2692-2705
Publisher: Endocrine Soc
Issue Date: 2002
ISSN: 0888-8809
Statement of
Alaina J. James, Irina U. Agoulnik, Jonathan M. Harris, Grant Buchanan, Wayne D. Tilley, Marco Marcelli, Dolores J. Lamb, and Nancy L. Weigel
Abstract: Functional analysis of androgen receptor (AR) gene mutations isolated from prostate cancer has led to the identification of residues that play important roles in the structure and function of the receptor. Here we report the characteristics of a novel AR mutation A748T located in helix 5 of the ligand-binding domain, which was identified in metastatic prostate cancer. Despite a normal hormone-binding affinity, A748T causes hormone concentration-dependent defects in nuclear accumulation and transcriptional activation. Moreover, when equivalent amounts of DNA are transfected, the mutant is expressed at much lower levels than the wild-type AR (ARWT). Treatment with geldanamycin to disrupt receptor-heat shock protein complexes rapidly decreases the levels of ARWT but not A748T, suggesting that the lower expression and rapid degradation rate of A748T is due to weaker interactions with heat shock proteins. Further analysis revealed that hormone dissociates from A748T five times faster than from ARWT. Loss of the ability to form stable amino/carboxyl-terminal interactions causes accelerated dissociation rates in some AR mutants. However, A748T exhibits normal amino/carboxyl-terminal interactions at high hormone concentrations, suggesting that the mutation alters interactions with ligand. Consistent with this conclusion, our structural model predicts that A748T disrupts crucial contact points with ligand, thereby altering the conformation of the ligand-binding domain.
Keywords: COS Cells
Cell Nucleus
Prostatic Neoplasms
Heat-Shock Proteins
Receptors, Androgen
Drug Stability
Gene Expression
Transcription, Genetic
Binding Sites
Protein Conformation
Structure-Activity Relationship
Biological Transport
Dose-Response Relationship, Drug
Models, Molecular
Description: © 2002 by The Endocrine Society
DOI: 10.1210/me.2001-0281
Appears in Collections:Aurora harvest
Medicine publications

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