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Type: Journal article
Title: Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function
Author: Buchanan, G.
Yang, M.
Harris, J.
Nahm, H.
Han, G.
Moore, N.
Bentel, J.
Matusik, R.
Horsfall, D.
Marshall, V.
Greenberg, N.
Tilley, W.
Citation: Molecular Endocrinology, 2001; 15(1):45-56
Publisher: Endocrine Soc
Issue Date: 2001
ISSN: 0888-8809
Statement of
Grant Buchanan, Miao Yang, Jonathan M. Harris, Hyun S. Nahm, Guangzhou Han, Nicole Moore, Jacqueline M. Bentel, Robert J. Matusik, David J. Horsfall, Villis R. Marshall, Norman M. Greenberg, and Wayne D. Tilley
Abstract: The androgen receptor (AR), a member of the steroid receptor superfamily of nuclear transcription factors, mediates androgen signaling in diverse target tissues. Here we report AR gene mutations identified in human prostate cancer and the autochthonous transgenic adenocarcinoma of the mouse prostate model that colocate to residues 668QPIF671 at the boundary of the hinge and ligand-binding domain, resulting in receptors that exhibit 2- to 4-fold increased activity compared with wild-type AR in response to dihydrotestosterone, estradiol, progesterone, adrenal androgens, and the AR antagonist, hydroxyflutamide, without an apparent effect on receptor levels, ligand binding kinetics, or DNA binding. The expression of these or similar variants could explain the emergence of hormone refractory disease in a subset of patients. Homology modeling indicates that amino acid residues 668QPIF671 form a ridge bordering a potential protein-protein interaction surface. The naturally occurring AR gene mutations reported in this study result in decreased hydrophobicity of this surface, suggesting that altered receptor-protein interaction mediates the precocious activity of the AR variants.
Keywords: Cell Line; COS Cells; Animals; Mice, Transgenic; Humans; Mice; Adenocarcinoma; Prostatic Neoplasms; Flutamide; Dihydrotestosterone; Estradiol; Progesterone; Androgen Antagonists; Receptors, Androgen; DNA; Androgens; Transfection; Mutagenesis; Binding Sites; Protein Structure, Secondary; Structure-Activity Relationship; Mutation; Models, Molecular; Male; Transcriptional Activation
Rights: © 2001 by The Endocrine Society
RMID: 0020065957
DOI: 10.1210/mend.15.1.0581
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Appears in Collections:Medicine publications

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