Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors
Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors
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DOI：
10.1126/science.279.5350.577
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发表时间：
1998-01-23
期刊：
影响因子：
56.9
通讯作者：
Kitamura, Y
中科院分区：
文献类型：
--
作者：
Hirota, S;Isozaki, K;Kitamura, Y
胃肠道间质瘤(GIST)是人类消化道最常见的间叶性肿瘤，但其分子病因和细胞来源尚不清楚。从5个GIST中对编码原癌受体酪氨酸激酶(KIT)的c-kit互补DNA进行测序发现，跨膜和酪氨酸激酶结构域之间的区域发生了突变。所有相应的突变KIT蛋白在没有KIT配体干细胞因子(SCF)的情况下都被结构性激活。稳定转染突变的c-kit互补DNA可诱导BA/F3小鼠淋巴样细胞恶性转化，提示突变与肿瘤的发生有关。ICCs可能起源于Cajal间质细胞(ICCs)，因为ICCs的发育依赖于SCF-KIT的相互作用，而且像GIST一样，这些细胞同时表达KIT和CD34。
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.