FORMATION AND MAINTENANCE OF BONE AND TOOTH - APPROACH THROUGH THE ANALYSTS OF HYPOPHOSPHATASIA

骨骼和牙齿的形成和维护 - 通过低磷酸盐分析师的方法

• 批准号: 11470388
• 负责人: ODA Kimimitsu
• 金额: $ 9.28万
• 依托单位: NIIGATA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470388/
• 关键词: Hvpophosphatasia; Mineralization; Alkaline phosphaiase; cis-Golgi; Proteasome; ER quality control system; 組織非特異型アルカリホスファターゼ; 細胞内輸送; プロテアゾーム; グリコシルホスファチジルイノシトール; バキュロウイルス

As a first step to understand the molecular mechanism by. which mutations in the tissue-nonspecific alkaline phosphatase gene (TNSALP) cause hypophosphatasia, we have analyzed the effects of severafmissense mutations on.the properties of TNSALP Analyzed mutants are as follows: TNSALP (R54C), TNSALP (D277A) and TNSALP [N153D] reported in the patients diagnosed with sever form of hypophsophatasia. When being expressed in COS- 1 cells, these mutated form of TNSALP were found to fail to assume proper folding and correct assembly, resulting in the formation of a high-molecular mass aggregate. These aberrant proteins tend to accumulate in the endoplasmic reticulum (TNSALP [R54C]) and cis-Golgi (TNSALP [N153D] en route to the cell surface, followed by degradation in proteasome.

作为了解分子机制的第一步。组织非特异性碱性磷酸酶基因 (TNSALP) 中的哪些突变会导致低磷酸酯酶症，我们分析了严重错义突变的影响。TNSALP 分析突变体的特性如下：在诊断为严重的患者中报告的 TNSALP (R54C)、TNSALP (D277A) 和 TNSALP [N153D] 磷酸酯酶减退症的形式。当在 COS-1 细胞中表达时，发现这些突变形式的 TNSALP 无法进行正确的折叠和正确的组装，从而导致形成高分子聚集体。这些异常蛋白倾向于在内质网 (TNSALP [R54C]) 和顺式高尔基体 (TNSALP [N153D]) 中积累，并在到达细胞表面的途中，随后在蛋白酶体中降解。

项目成果

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Amizuka,N. et al.: "The bipartite action of parathyroid hormone (PTH) - related peptide (PTHrP) mediating by binding……"Recent.Res.Devel.Endocrinol.. 1. 233-245 (2000)

Amizuka, N. 等人：“甲状旁腺激素 (PTH) 相关肽 (PTHrP) 通过结合介导的双向作用”Recent.Res.Devel.Endocrinol.. 1. 233-245 (2000)

Orimo.H: "Mutationai analysis and functional correiation with phenotype in german patients with childhood-type hypophosphatasia"Journal of Bone and Mineral Research. 16. 2313-2319 (2001)

Orimo.H：“德国儿童型低磷酸酯酶症患者的突变分析及其与表型的功能相关性”骨与矿物质研究杂志。

Ito, M: "Retentlon at the cis-Golgi and delayed degraclation of tisseu-nonspecific aikaline phosphatase with an Asnl53-Asp"Blochemical journal. 361. 473-480 (2002)

Ito, M：“顺式高尔基体的保留和 Asnl53-Asp 延迟组织非特异性碱性磷酸酶的降解”Blochemical 杂志。

Oda, K., Amaya, Y. et al.: "A general method for rapid purification of soluble versions of glycosylphosphatidylinositol-anchored proteins ---"Journal of Biochemistry. 126. 694-699 (1999)

Oda, K.、Amaya, Y. 等人：“快速纯化可溶性糖基磷脂酰肌醇锚定蛋白的通用方法 ---”《生物化学杂志》。