Analysis on interaction between triplet repeat disease gene products and neuron-specific transcription-related factors

三联体重复疾病基因产物与神经元特异性转录相关因子的相互作用分析

• 批准号: 10670574
• 负责人: OKAZAWA Hitoshi
• 金额: $ 2.11万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670574/
• 关键词: triplet repeat diseases; polyglutamine; transcription factor; neuronal death; 神経特異的転写因子; 転写補助因子

We have cloned binding proteins to the polyglutamine tract by screening human embryonic cDNA library with yeast two-hybrid method. We obtained more than 6 clones and all of them encoded polar amino acid-rich sequences. Therefore, we suspected that polar amino acid-rich sequences can bind to the polyglutamine tract via hydrogen bond. Next, we analyzed one of the clone encoding a new gene designated as PQBP-1. This protein contains WWP domain which is participated in protein-protein interaction and polar amino acid-rich sequences composed of hepta- and di-amino acid repeats. The latter region was considered to be the binding domain to the polyglutamine tract. We showed that PQBP-1 binds to the polyglutamine of both triplet repeat disease gene products and transcription-related factors. PQBP-1 acts as a negative transcriptional regulator. It is located mainly in the nucleus. Among tissues, its expression was highest in the cortex of the cerebellum. From these observations, we are investigating the role of PQBP-1 in the pathogenesis of triplet repeat disorders.We have also used this support for the research on the role of presenilin-1 and found that presenilin-1 modulates c-Jun homodimer function. With this grant, we also found that AP-2 beta suppresses D1A dopamine receptor gene expression.

我们用酵母双杂交方法筛选人胚胎cDNA文库，克隆了与多聚谷氨酰胺束结合的蛋白。我们获得了6个以上的克隆，它们都编码了富含氨基酸的极性序列。因此，我们怀疑富含氨基酸的极性序列可以通过氢键与聚谷氨酰胺束结合。接下来，我们分析了其中一个编码新基因PQBP-1的克隆。该蛋白含有参与蛋白质相互作用的WWP结构域，以及由七个和二个氨基酸重复组成的富含极性氨基酸的序列。后一个区域被认为是聚谷氨酰胺束的结合域。我们发现PQBP-1与三联体重复病基因产物和转录相关因子的聚谷氨酰胺结合。PQBP-1是一种负转录调控因子。它主要位于细胞核内。在组织中，它在小脑皮质中的表达最高。通过这些观察，我们正在研究PQBP-1在三联体重复障碍发病机制中的作用。我们也利用这一支持来研究早老素-1的作用，发现早老素-1调节c-jun同源二聚体的功能。有了这项授权，我们还发现AP-2β抑制了D1A多巴胺受体基因的表达。

项目成果

Takeuchi S. et al: "AP-2β represses D1A dopamine receptor gene transcription in Neuro 2a Cells."Molecular Brain Research. 74. 208-216 (1999)

Takeuchi S. 等人：“AP-2β 抑制 Neuro 2a 细胞中的 D1A 多巴胺受体基因转录。”《分子脑研究》74. 208-216 (1999)

Takeuchi S. et al.: "AP-2β represses D1A dopamine receptor gene transcription in Neuro 2a cells"Molecular Brain Research. 74. 208-216 (1999)

Takeuchi S. 等人：“AP-2β 抑制 Neuro 2a 细胞中的 D1A 多巴胺受体基因转录”《分子脑研究》74. 208-216 (1999)。

Skala H., et al.: "Upstream elements involved in vivo in activation of the brain specific rat aldolase C gene"The Journal of Biological Chemistry. 273・48. 31806-31814 (1998)

Skala H.等人：“大脑特异性大鼠醛缩酶C基因激活中涉及的上游元件”《生物化学杂志》273·48（1998）。

Skala H. et al: "Upstream elements involved in vivo Inactivation of the brain specific rat aldolase C gene."The Journal of Biological Chemistry. 273-48. 31806-31814 (1998)

Skala H. 等人：“上游元素参与大脑特异性大鼠醛缩酶 C 基因的体内失活。”《生物化学杂志》。

Imafuku I., et al.: "Polar amino acid-rich sequences bind to polyglutamine tracts"Biochem. Biophys. Res. Commun.. 253. 16-20 (1998)

Imafuku I. 等人：“富含极性氨基酸的序列与聚谷氨酰胺束结合”Biochem。