COMPARISON OF FUNCTION OF RAS FAMILY MOLECULES

RAS家族分子的功能比较

基本信息

批准号：
10680666
负责人：
KOIDE Hiroshi
金额：
$ 1.73万
依托单位：
Tokyo Institute of Technology
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-10680666/
关键词：
Oncogene Protein Molecular Biology biochemistry Signal Transduction GTP-binding protein

项目摘要

Ras family is a subfamily of low molecular weight GTP-binding protein and consists of Ras, R-Ras, Ral and Rap. To compare the biological roles of two highly homologous proteins, Ras and R-Ras, IL-3-dependent hematopoietic BaF3 cells and C2C12 myoblasts were utilized. R-Ras, as well as Ras, was found to suppress apoptosis of BaF3 cells upon IL-3 withdrawal. The difference between the two molecules was that activation of Ras alone was enough to inhibit apoptosis, while R-Ras required IGF-1. Further studies. revealed that the observed difference was due to the lack of ERK-activating activity in R-Ras. In the case of C2C12 cells, activation of Ras and R-Ras resulted in different phenotypes. R-Ras promoted differentiation of C2C12 cells, whereas Ras inhibited it. On the other hand, Ras was found to be involved in chemotaxis of C2C12 cells by FGF, HGF and IGF-1, while involvement of R-Ras in the chemotaxis was unlikely since activation of R-Ras was not induced by the three growth factors. Thus, the present study show that Ras and R-Ras play a similar role in survival of hematopoietic cells, but distinct roles in myogenesis.The relation between Ras and Ral was also examined. Since RalGEF is a Ras effector, existence of the Ras > RalGEF > Ral pathway has been indicated. To examine a role of Ral in Ras-induced cellular transformation, effect of expression of Ral mutants on Ras-dependent anchorage-independent growth was investigated using human fibrosarcoma HT1080 cells. As a result, it was suggested that Ral is involved in Ras-induced anchorage-independent growth of HT1080 cells and that Ral may modulate the anchorage-independent growth through regulation of the amount of a cell cycle inhibitor, p27Kip1.

RAS家族是低分子量GTP结合蛋白的亚家族，由RAS，R-RAS，RAL和RAP组成。为了比较两种高度同源蛋白RAS和R-RAS的生物学作用，使用IL-3依赖性造血BAF3细胞和C2C12肌细胞。发现R-RAS和RAS在戒断IL-3时抑制BAF3细胞的凋亡。两个分子之间的差异是，单独的RAS激活足以抑制凋亡，而R-RAS则需要IGF-1。进一步的研究。发现观察到的差异是由于R-RAS缺乏ERK激活活性。在C2C12细胞的情况下，RAS和R-RAS的激活导致不同的表型。 R-RAS促进了C2C12细胞的分化，而RAS抑制了C2C12细胞。另一方面，发现RAS通过FGF，HGF和IGF-1参与C2C12细胞的趋化性，而R-RAS参与趋化性是不可能的，因为这三个生长因素未诱导R-RAS的激活。因此，本研究表明，RAS和R-RAS在造血细胞的存活中起着相似的作用，但在肌发生中的作用不同。还检查了RAS与RAL之间的关系。由于Ralgef是RAS效应子，因此已经指出了RAS> RALGEF> RAL途径的存在。为了检验RAL在RAS诱导的细胞转化中的作用，使用人纤维肉瘤HT1080细胞研究了RAL突变体对RAS依赖性锚定依赖性生长的影响。结果，有人提出RAL参与了HT1080细胞的RAS诱导的非依赖性生长，并且RAL可以通过调节细胞周期抑制剂P27KIP1的量来调节非锚固依赖性的生长。