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The study of the intracellular signal transduction pathway for cell proliferation and differentiation - Modulation by gangliosides.

细胞增殖和分化的细胞内信号转导途径的研究——神经节苷脂的调节。

基本信息

批准号：
03670415
负责人：
MUTOH Tatsuro
金额：
$ 1.34万
依托单位：
Fukui Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1993
项目状态：
已结题

项目摘要

[Objective]To elucidate the role of endogenous gangliosides (Gg) on the process of cell differentiation and proliferation, we analyzed the effect of Gg on the activity of intracellular signal transduction pathways for cell differentiation and proliferation.[Method]As for cell proliferation, we examined the activity of intracellular signal transduction pathway of epidermal growth factor (EGF) in skin fibroblasts from patients with GM1 gangliosidosis and normal controls. We previously reported that GM1 ganglioside is accumulated in fibroblasts from GM1 gangliosidosis when compared with that of normal controls. As for cell differentiation, we examined the effect of B subunit cholera toxin (CTB)-pretreatment, which specifically binds to GM1 and causes the re-distribution of GM1 on the plane of the plasma membrances, on NGF-signaling pathway in PC12 cells.[Results and Discussion]GM1 was found to be the negative regulator of EGF receptor function by reducing EGF-binding and by inhibiting EGF receptor associated tyrosine kinase (TK) activity. On the other hand, CTB augmented the intracellular NGF-signaling pathway. Moreover, in Trk A-immune complex kinase assay, GM1 was found to be a potent activator of Trk A-associated TK activity that is senseitve to NGF.Thus, GM1 seems to be an endogenous stimulator for cell differentiation.

【目的】分析内源性神经节苷脂（Gg）对细胞分化和增殖信号转导通路活性的影响，阐明Gg在细胞分化和增殖过程中的作用。[方法]在细胞增殖方面，检测了GM1神经节苷脂沉积症患者和正常人皮肤成纤维细胞表皮生长因子（EGF）胞内信号转导通路的活性。我们以前报道过，与正常对照相比，GM1神经节苷脂在GM1神经节苷脂沉积症的成纤维细胞中积累。至于细胞分化，我们研究了B亚单位霍乱毒素（CT B）预处理对PC 12细胞中NGF信号通路的影响，该毒素特异性结合GM 1并导致GM 1在质膜平面上的重新分布。[结果与讨论]GM1通过减少EGF结合和抑制EGF受体相关酪氨酸激酶（TK）活性，成为EGF受体功能的负调节因子。另一方面，CTB增强了细胞内的NGF信号通路。此外，在Trk A免疫复合物激酶试验中，发现GM 1是一种对NGF敏感的Trk A相关TK活性的有效激活剂，因此GM 1可能是一种内源性细胞分化刺激因子。