Interaction of Huntington disease protein with transcriptional activator Sp1
Interaction of Huntington disease protein with transcriptional activator Sp1
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亨廷顿病蛋白与转录激活因子 Sp1 的相互作用
DOI：
10.1128/mcb.22.5.1277-1287.2002
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发表时间：
2002-03-01
影响因子：
5.3
通讯作者：
Li, XJ
中科院分区：
文献类型：
--
作者：
Li, SH;Cheng, AL;Li, XJ
聚谷氨酰胺的膨胀会导致亨廷顿病(HD)和至少其他七种神经退行性疾病。在HD中，带有扩张的谷氨酰胺束的亨廷顿蛋白的N末端片段能够在细胞核内聚集和积聚。虽然核内亨廷顿蛋白影响许多基因的表达，但这种核效应的机制尚不清楚。在这里，我们报道了亨廷顿蛋白与Sp1相互作用，Sp1是一种转录因子，它与某些启动子中富含GC的元件结合，并激活相应基因的转录。体外结合和免疫沉淀分析表明，聚谷氨酰胺扩张增强了N端亨廷顿蛋白与Sp1的相互作用。在HD转基因小鼠(R6/2)中，表达N端突变的亨廷顿蛋白，Sp1与突变的亨廷顿蛋白的可溶性形式结合，但不与聚集的亨廷顿蛋白结合。突变的Huntingtin在培养细胞中抑制核Sp1与神经生长因子受体启动子的结合并抑制其转录活性。Sp1的过表达可减少核内突变型亨廷顿蛋白引起的细胞毒性和神经延伸缺陷。这些发现表明，核中可溶形式的突变亨廷顿蛋白可能通过与Sp1结合而导致细胞功能障碍，从而减少Sp1调控基因的表达。
Polyglutamine expansion causes Huntington disease (HD) and at least seven other neurodegenerative diseases. In HD, N-terminal fragments of huntingtin with an expanded glutamine tract are able to aggregate and accumulate in the nucleus. Although intranuclear huntingtin affects the expression of numerous genes, the mechanism of this nuclear effect is unknown. Here we report that huntingtin interacts with Sp1, a transcription factor that binds to GC-rich elements in certain promoters and activates transcription of the corresponding genes. In vitro binding and immunoprecipitation assays show that polyglutamine expansion enhances the interaction of N-terminal huntingtin with Sp1. In HD transgenic mice (R6/2) that express N-terminal-mutant huntingtin, Sp1 binds to the soluble form of mutant huntingtin but not to aggregated huntingtin. Mutant huntingtin inhibits the binding of nuclear Sp1 to the promoter of nerve growth factor receptor and suppresses its transcriptional activity in cultured cells. Overexpression of Sp1 reduces the cellular toxicity and neuritic extension defects caused by intranuclear mutant huntingtin. These findings suggest that the soluble form of mutant huntingtin in the nucleus may cause cellular dysfunction by binding to Sp1 and thus reducing the expression of Sp1-regulated genes.