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Effect of gain-of-function mutation of c-kit on apoptosis in gastrointestinal mesenchymal cells

c-kit功能获得性突变对胃肠道间充质细胞凋亡的影响

基本信息

批准号：
12670483
负责人：
SHINOMURA Yasuhisa
金额：
$ 2.43万
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：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670483/
关键词：
gastrointestinal stromal tumor leimyoma leiomyosarcoma c-kit mutation apoptosis

项目摘要

A large proportion of gastrointestinal mesenchymal tumors, which do not show typical features of smooth muscle cells or Shwann cells, are presently designated as gastrointestinal stromal tumor (GIST).We have found that most of GISTs have mutations in the juxtamembrane domain of c-kit, which cause constitutive activation of c-kit protein without the c-kit ligands. It is known that c-kit is expressed in interstitial cells of Cajal, which are pacemaker cells located in gastrointestinal stroma. We showed that stem cell factor, a ligand of c-kit, was needed for the survival of interstitial cells of Cajal isolated from the mouse intestine. We showed that hyperplasia of interstitial cells of Cajal was present in a case of familiar gastrointestinal stromal tumors associated with germ line mutation of c-kit gene. We established stromal cell lines originating from the small intestine of the mouse. The stromal cells were transfected with normal and mutated c-kit cDNA. In the stromal cells transfected with normal c-kit cDNA, the expression of marker molecules of smooth muscle cells disappeared and the expression of marker molecules of interstitial cells of Cajal or GISTs appeared. In the stromal cells transfected with mutated c-kit cDNA, proliferation increased and apoptosis decreased. These results suggest that gain-of-function mutations of c-kit gene play an important role for the genesis of GISTs from gastrointestinal stromal cells.

胃肠道间充质瘤目前被称为胃肠道间质瘤(GIST)，它没有表现出典型的平滑肌细胞或Shwann细胞的特征。我们发现，大多数GIST在c-kit的膜旁区域发生突变，导致c-kit蛋白在没有c-kit配体的情况下被结构性激活。已知c-kit在Cajal间质细胞中表达，Cajal间质细胞是位于胃肠道间质的起搏细胞。我们发现干细胞因子是c-kit的配体，是从小鼠肠道分离的Cajal间质细胞生存所必需的。我们发现1例常见的胃肠道间质瘤伴发c-kit基因胚系突变，表现为Cajal间质细胞增生。我们建立了来源于小鼠小肠的基质细胞系。将正常和突变的c-kit基因分别导入基质细胞。在正常c-kit基因转染的基质细胞中，平滑肌细胞标记分子的表达消失，Cajal间质细胞或GIST间质细胞标记分子的表达出现。C-kit基因突变后的基质细胞增殖增加，细胞凋亡率降低。这些结果提示c-kit基因的功能获得突变在胃肠道基质细胞GIST的发生中起重要作用。