Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function
Mutations at the boundary of the hinge and ligand binding domain of the androgen receptor confer increased transactivation function
复制标题
DOI：
10.1210/me.15.1.46
复制
发表时间：
2001-01-01
影响因子：
--
通讯作者：
Tilley, WD
中科院分区：
文献类型：
--
作者：
Buchanan, G;Yang, MO;Tilley, WD
雄激素受体（AR）是核转录因子类固醇受体超家族的成员，在多种靶组织中介导雄激素信号传导。在这里，我们报告了在人前列腺癌和小鼠前列腺模型的原位转基因腺癌中鉴定的AR基因突变，其共定位于铰链和配体结合结构域边界处的残基（668）QPIF（671），导致与野生型AR相比，在对双氢睾酮、雌二醇、孕酮、肾上腺雄激素、和AR拮抗剂羟基芴醇，对受体水平、配体结合动力学或DNA结合没有明显影响。这些或类似变体的表达可以解释一部分患者中激素难治性疾病的出现。同源性建模表明氨基酸残基（668）QPIF（671）形成一个脊，该脊与潜在的蛋白质-蛋白质相互作用表面接壤。本研究中报告的天然存在的AR基因突变导致该表面的疏水性降低，表明受体-蛋白质相互作用的改变介导了AR变体的早熟活性。
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 wildtype 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.