Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function.

Buchanan G, Yang M, Harris JM, Nahm HS, Han G, Moore N, Bentel JM, Matusik RJ, Horsfall DJ, Marshall VR, Greenberg NM, Tilley WD
Mol Endocrinol. 2001 15 (1): 46-56

PMID: 11145738 · DOI:10.1210/mend.15.1.0581

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 (668)QPIF(671) 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 (668)QPIF(671) 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.

MeSH Terms (25)

Adenocarcinoma Androgen Antagonists Androgens Animals Binding Sites Cell Line COS Cells Dihydrotestosterone DNA Estradiol Flutamide Humans Male Mice Mice, Transgenic Models, Molecular Mutagenesis Mutation Progesterone Prostatic Neoplasms Protein Structure, Secondary Receptors, Androgen Structure-Activity Relationship Transcriptional Activation Transfection

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