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Role of gain-of-function mutations of c-kit gene on tumor development in gastrointestinal stromal tumor.

c-kit基因功能获得性突变对胃肠道间质瘤肿瘤发生发展的作用。

基本信息

批准号：
10670471
负责人：
SHINOMURA Yasuhisa
金额：
$ 2.05万
依托单位：
Osaka University
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-10670471/
关键词：
GIST c-kit stromal tumor mutation 消化管間葉腫瘍

项目摘要

The c-kit proto-oncogene encodes a receptor tyrosine kinase (KIT), the ligand of which is stem cell factor (SCF). KIT consists of an extracellular domain, a transmembrane domain, a juxtamembrane domain and a tyrosine kinase domain. Gain-of-function mutations of the c-kit gene have been found in several tumor mast cell lines of rodents and humans and in mast cell tumors of humans. The constitutive activation of KIT in these cell lines and tumors was the result of a point mutation in the tyrosine kinase domain of the c-kit gene.A large proportion of mesenchymal tumors, which do not show typical features of smooth muscle cells or Schwann cells, are presently designated as gastrointestinal stromal tumor (GIST). We found that most of GISTs expressed KIT. Sequencing of c-kit complementary DNA from GISTs revealed a variety of mutations in the region between the transmembrane and tyrosine kinase domains. Most of mutations in GISTs were located with in the 11 amino acids (Lys-550 to Val-560) in the juxtamembrane domain. The corresponding mutant KIT proteins were constitutively dimerized and activated without the KIT ligands. Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells. Most of all GISTs which developed during a short periods showed mutations of c-kit, while half of mutations of c-kit contribute to tumor development in GIST.

c-kit原癌基因编码受体酪氨酸激酶（KIT），其配体是干细胞因子（SCF）。KIT由胞外结构域、跨膜结构域、跨膜结构域和酪氨酸激酶结构域组成。c-kit基因的功能获得性突变已在啮齿动物和人类的几种肿瘤肥大细胞系以及人类的肥大细胞肿瘤中发现。这些细胞系和肿瘤中KIT的组成性激活是c-kit基因酪氨酸激酶结构域点突变的结果。大部分间充质肿瘤不具有平滑肌细胞或雪旺细胞的典型特征，目前被称为胃肠道间质瘤（GIST）。我们发现大多数GIST表达KIT。从GIST的c-kit互补DNA的测序揭示了跨膜和酪氨酸激酶结构域之间的区域中的各种突变。GIST的突变主要发生在质膜结构域的11个氨基酸（Lys-550 ~瓦尔-560）。相应的突变KIT蛋白组成型二聚化和激活没有KIT配体。稳定转染突变型c-kit互补DNA诱导Ba/F3小鼠淋巴细胞恶性转化。大多数发生于短时间内的GIST都存在c-kit突变，而在GIST中有一半的c-kit突变与肿瘤的发生有关。