Androgen receptor function is modulated by the tissue-specific AR45 variant
Androgen receptor function is modulated by the tissue-specific AR45 variant
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DOI：
10.1111/j.1432-1033.2004.04395.x
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发表时间：
2005-01-01
期刊：
影响因子：
5.4
通讯作者：
Haendler, B
中科院分区：
文献类型：
--
作者：
Ahrens-Fath, I;Politz, O;Haendler, B
一种自然产生的人类雄激素受体(AR)变体被鉴定出来，名为AR45。它缺乏AR基因外显子1编码的整个区域，由AR DNA结合区、铰链区和配体结合区组成，前面有一个新的7个氨基酸的N末端延伸。一项对人体组织的研究表明，AR45主要在心脏和骨骼肌中表达。在共转染实验中，AR45抑制AR功能，这种作用需要完整的DNA和配体结合特性。AR45的过表达降低了雄激素依赖的LNCaP细胞的增殖率，这与AR45对AR促生长功能的抑制作用一致。AR45在双杂交实验中与AR N-末端结构域相互作用，表明AR抑制是由于AR-AR45异源二聚体的形成。在转录辅助激活因子TIF2或癌基因β-连环素过度表达的条件下，AR45在双氢睾酮存在的情况下刺激雄激素依赖的启动子。在外源性TIF2存在的情况下，肾上腺雄激素雄烯二酮可额外触发AR45活性。总之，这些数据表明AR45在调节AR功能中起着重要作用，并为雄激素的作用模式增加了一个新的复杂性水平。
A naturally occurring variant of the human androgen receptor (AR) named AR45 has been identified. It lacks the entire region encoded by exon 1 of the AR gene and is composed of the AR DNA-binding domain, hinge region and ligand-binding domain, preceded by a novel seven amino-acid long N-terminal extension. A survey of human tissues revealed that AR45 was expressed mainly in heart and skeletal muscle. In cotransfection experiments, AR45 inhibited AR function, an effect necessitating intact DNA- and ligand-binding properties. Overexpression of AR45 reduced the proliferation rate of the androgen-dependent LNCaP cells, in line with the repressive effects of AR45 on AR growth-promoting function. AR45 interacted with the AR N-terminal domain in two-hybrid assays, suggesting that AR inhibition was due to the formation of AR-AR45 heterodimers. Under conditions where the transcriptional coactivator TIF2 or the oncogene beta-catenin were overexpressed, AR45 stimulated androgen-dependent promoters in presence of dihydrotestosterone. AR45 activity was triggered additionally by the adrenal androgen androstenedione in presence of exogenous TIF2. Altogether, the data suggest an important role of AR45 in modulating AR function and add a novel level of complexity to the mode of action of androgens.