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.

目前将大部分的胃肠道间质肿瘤显示为平滑肌细胞或Shwann细胞的典型特征，目前被指定为胃肠道脊髓肿瘤（GIST）。我们发现，大多数GIST在C-Kit的jextammbrane域中具有突变，而C-Kit的jxammbrane结构域则不引起C-Kkit protination c-kitectig cy-kit the c-kit cy-kiT n octectig。众所周知，C-KIT在Cajal的间质细胞中表达，Cajal是位于胃肠道基质中的起搏器细胞。我们表明，需要干细胞因子，即一种C-KIT的配体，才能使从小鼠肠分离的Cajal的间质细胞存活。我们表明，在与C-KIT基因的生殖系突变相关的熟悉的胃肠道间质肿瘤的情况下，存在Cajal的间质细胞的增生。我们建立了源自小鼠小肠的基质细胞系。用正常和突变的C-kit cDNA转染基质细胞。在用正常C-kit cDNA转染的基质细胞中，平滑肌细胞的标记分子的表达消失了，并且出现了Cajal或Gist的间质细胞的标记分子的表达。在用突变的C型cDNA转染的基质细胞中，增殖增加，凋亡减少。这些结果表明，C-KIT基因的功能收益突变对胃肠道脊髓细胞的GIST的起源起着重要作用。