CREB-binding protein sequestration by expanded polyglutamine
CREB-binding protein sequestration by expanded polyglutamine
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DOI：
10.1093/hmg/9.14.2197
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发表时间：
2000-09-01
影响因子：
3.5
通讯作者：
Fischbeck, KH
中科院分区：
文献类型：
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作者：
McCampbell, A;Taylor, JP;Fischbeck, KH
脊髓和球性肌萎缩症（SBMA）是已知由CAG重复扩增引起的八种遗传性神经退行性疾病之一。这种扩张导致聚谷氨酰胺束的扩张，这可能赋予受影响的蛋白质一种新的毒性功能。细胞培养和转基因小鼠研究表明，细胞核是发病的一个部位，表明一个关键的核因子或过程被聚谷氨酰胺扩增破坏。在本报告中，我们提出证据表明，creb结合蛋白（CBP）是一种转录共激活因子，可协调细胞核对各种细胞信号级联反应，在培养细胞中被纳入由含聚谷氨酰胺的蛋白形成的核内含物中。转基因小鼠和SBMA患者的组织。我们还在另一种多聚谷氨酰胺疾病脊髓小脑性共济失调3型细胞培养模型中发现了CBP与核内含物的结合。我们发现，尽管CBP mRNA水平升高，但在表达扩增型多聚谷氨酰胺的细胞中，CBP的可溶性水平降低。最后，我们证明，在神经细胞培养中，CBP的过表达可以拯救细胞免受多聚谷氨酰胺介导的毒性，这些数据支持多聚谷氨酰胺扩增病的CBP隔离模型。
Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion results in an expanded polyglutamine tract, which likely confers a novel, toxic function to the affected protein. Cell culture and transgenic mouse studies have implicated the nucleus as a site for pathogenesis, suggesting that a critical nuclear factor or process is disrupted by the polyglutamine expansion, In this report we present evidence that CREB-binding protein (CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA. We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another polyglutamine disease, spinocerebellar ataxia type 3, We present evidence that soluble levels of CBP are reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA, Finally, we demonstrate that over-expression of CBP rescues cells from polyglutamine-mediated toxicity in neuronal cell culture, These data support a CBP-sequestration model of polyglutamine expansion disease.