Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor
Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor
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DOI：
10.1093/hmg/11.17.1967
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发表时间：
2002-08-15
影响因子：
3.5
通讯作者：
Fischbeck, KH
中科院分区：
文献类型：
--
作者：
Lieberman, AP;Harmison, G;Fischbeck, KH
肯尼迪病是一种运动神经元退行性疾病，其致病突变是雄激素受体基因5‘端附近的CAG/聚谷氨酰胺束扩张。突变的蛋白质错误折叠、聚集，并与其他蛋白质异常相互作用，导致新的、有毒的功能获得和正常功能的改变。我们使用细胞培养模型来探索该突变导致雄激素受体功能改变的潜在机制。在这里，我们表明，表达野生型雄激素受体24个CAG重复的细胞通过表现出营养效应，包括在低血清中延长存活，而表达突变受体的65个CAG重复的细胞没有表现出强劲的营养反应。这种功能的部分丧失与突变蛋白水平的降低有关，这是由于泛素-蛋白酶体途径对突变蛋白的优先降解。利用寡核苷酸阵列进行的表达分析证实，突变的受体已经经历了部分功能丧失，并且无法调节其表达通常受野生型受体的配体激活影响的基因的子集。突变型受体在没有配体的情况下也经历了几次重要的翻译后修饰，包括乙酰化和磷酸化。这些修饰与突变受体在表达分析中表现出的不依赖配体的功能获得相关。我们的发现表明，多谷氨酰胺的扩张通过促进雄激素受体的降解和改变其作为转录因子的活性来改变雄激素受体的功能。
Kennedy's disease is a degenerative disease of motor neurons in which the causative mutation is expansion of a CAG/polyglutamine tract near the 5' end of the androgen receptor gene. The mutant protein misfolds, aggregates, and interacts abnormally with other proteins, leading to a novel, toxic gain of function and an alteration of normal function. We used a cell culture model to explore the mechanisms underlying the alterations in androgen receptor function conferred by the mutation. Here we show that cells expressing the wild-type androgen receptor with 24 CAG repeats respond to ligand by showing trophic effects including prolonged survival in low serum, whereas cells expressing the mutant receptor with 65 CAG repeats do not show a robust trophic response. This partial loss of function correlates with decreased levels of the mutant protein due to its preferential degradation by the ubiquitin-proteasome pathway. Expression analysis using oligonucleotide arrays confirms that the mutant receptor has undergone a partial loss of function, and fails to regulate a subset of genes whose expression is normally affected by ligand activation of the wild-type receptor. The mutant receptor has also undergone several functionally important post-translational modifications in the absence of ligand that the wild-type receptor undergoes in the presence of ligand, including acetylation and phosphorylation. These modifications correlate with a ligand-independent gain of function exhibited by the mutant receptor in expression analysis. Our findings suggest that polyglutamine expansion alters androgen receptor function by promoting its degradation and by modifying its activity as a transcription factor.