Cytochrome c oxidase subunit Vb interacts with human androgen receptor:: A potential mechanism for neurotoxicity in spinobulbar muscular atrophy
Cytochrome c oxidase subunit Vb interacts with human androgen receptor:: A potential mechanism for neurotoxicity in spinobulbar muscular atrophy
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DOI：
10.1016/s0361-9230(01)00583-4
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发表时间：
2001-10-01
影响因子：
3.8
通讯作者：
Trifiro, MA
中科院分区：
文献类型：
--
作者：
Beauchemin, AMJ;Gottlieb, B;Trifiro, MA
脊髓延髓肌萎缩症（SBMA）是一种由人雄激素受体（hAR）中多聚谷氨酰胺（polyGln）序列扩增引起的神经退行性疾病。多聚谷氨酰胺扩增的蛋白质被认为导致神经毒性的一种机制是通过与关键细胞蛋白质的异常相互作用以及可能的隔离。我们的目标是确认并进一步描述hAR与细胞色素c氧化酶亚基Vb（COXVb）之间的相互作用，COXVb是一种核编码的线粒体蛋白质。我们最初在酵母双杂交筛选中分离出COXVb作为一种与AR相互作用的蛋白质，以鉴定与正常及多聚谷氨酰胺扩增的AR相互作用的候选蛋白质。利用哺乳动物双杂交系统，我们确认COXVb与正常及突变的AR相互作用，并证明热休克蛋白70刺激COXVb与正常AR的相互作用。此外，在雄激素处理的细胞中，蓝色荧光蛋白标记的AR与绿色荧光蛋白标记的多聚谷氨酰胺扩增的AR形成的细胞质聚集体特异性共定位。在多聚谷氨酰胺扩增的疾病中，线粒体功能障碍可能先于神经病理学发现，因此可能代表神经毒性中的一个早期事件。COXVb与hAR的相互作用以及随后COXVb的隔离，可能为SBMA中假定的线粒体功能障碍提供一种机制。（C）2001年爱思唯尔科学公司
Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of the polyglutamine (polyGln) tract in the human androgen receptor (hAR). One mechanism by which polyGin-expanded proteins are believed to cause neuronotoxicity is through aberrant interaction(s) with, and possible sequestration of, critical cellular protein(s). Our goal was to confirm and further characterize the interaction between hAR and cytochrome c oxidase subunit Vb (COXVb), a nuclear-encoded mitochondrial protein. We initially isolated COXVb as an AR-interacting protein in a yeast two-hybrid screen to identify candidate proteins that interacted with normal and polyGin-expanded AR. Using the mammalian two-hybrid system, we confirm that COXVb interacts with normal and mutant AR and demonstrated that the COXVb-normal AR interaction is stimulated by heat shock protein 70. In addition, blue fluorescent protein-tagged AR specifically co-localized with cytoplasmic aggregates formed by green fluorescent protein-labeled polyGin-expanded AR in androgen-treated cells. Mitochondrial dysfunction may precede neuropathological findings in polyGin-expanded disorders and may thus represent an early event in neuronotoxicity. Interaction of COXVb and hAR, with subsequent sequestration of COXVb, may provide a mechanism for putative mitochondrial dysfunction in SBMA. (C) 2001 Elsevier Science Inc.