Amino acid substitutions in the hormone-binding domain of the human androgen receptor alter the stability of the hormone receptor complex.
Amino acid substitutions in the hormone-binding domain of the human androgen receptor alter the stability of the hormone receptor complex.
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人雄激素受体激素结合域中的氨基酸取代改变了激素受体复合物的稳定性。
DOI：
10.1172/jci117507
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
McPhaul,MJ
中科院分区：
文献类型：
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作者：
Marcelli,M;Zoppi,S;Wilson,CM;Griffin,JE;McPhaul,MJ
我们研究了7个完全睾丸女性化或赖芬斯坦综合征患者雄激素抵抗的基础，这些患者是由雄激素受体结合区的单个氨基酸取代引起的。培养的生殖器皮肤成纤维细胞的单层结合试验表明缺乏配体结合，雄激素结合的定性异常，或定性正常受体的量减少。这些突变的后果进行了检查，通过引入突变的雄激素受体cDNA序列的定点诱变和表达突变的cDNA在哺乳动物细胞。研究了氨基酸取代对不同雄激素结合和配体结合受体激活报告基因的能力的影响。突变雄激素受体与睾酮、5 α-二氢睾酮和米勃龙孵育的反应存在显著差异。在几种情况下，增加激素剂量或增加向孵育培养基中添加激素的频率导致表达突变雄激素受体的细胞正常或接近正常地激活报告基因。这些研究表明，激素受体复合物的稳定性是体内受体功能的主要决定因素。图片
We have investigated the basis of androgen resistance in seven unrelated individuals with complete testicular feminization or Reifenstein syndrome caused by single amino acid substitutions in the hormone-binding domain of the androgen receptor. Monolayer-binding assays of cultured genital skin fibroblasts demonstrated absent ligand binding, qualitative abnormalities of androgen binding, or a decreased amount of qualitatively normal receptor. The consequences of these mutations were examined by introducing the mutations by site-directed mutagenesis into the androgen receptor cDNA sequence and expressing the mutant cDNAs in mammalian cells. The effects of the amino acid substitutions on the binding of different androgens and on the capacity of the ligand-bound receptors to activate a reporter gene were investigated. Substantial differences were found in the responses of the mutant androgen receptors to incubation with testosterone, 5 alpha-dihydrotestosterone, and mibolerone. In several instances, increased doses of hormone or increased frequency of hormone addition to the incubation medium resulted in normal or near normal activation of a reporter gene by cells expressing the mutant androgen receptors. These studies suggest that the stability of the hormone receptor complex is a major determinant of receptor function in vivo.Images