COMPARISON OF FUNCTION OF RAS FAMILY MOLECULES
COMPARISON OF FUNCTION OF RAS FAMILY MOLECULES
批准号:
10680666
负责人:
KOIDE Hiroshi
金额:
$1.73万
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
项目状态:
已结题
起止时间:
1998 至 1999
中文摘要
RAS家族是低分子量GTP结合蛋白的一个亚家族,由RAS、R-RAS、RAL和Rap组成。为了比较两种高度同源的蛋白RAS和R-RAS的生物学作用,我们使用了依赖IL-3的造血细胞BaF3细胞和C2C12成肌细胞。R-RAS和RAS均能抑制停用IL-3后BaF3细胞的凋亡。这两个分子的不同之处在于,仅激活RAS就足以抑制细胞凋亡,而R-RAS需要IGF-1。进一步的研究。揭示了观察到的差异是由于R-RAS中缺乏ERK激活活性所致。在C2C12细胞中,RAS和R-RAS的激活导致不同的表型。R-RAS促进C2C12细胞分化,而RAS则抑制其分化。另一方面,RAS参与了成纤维细胞生长因子、肝细胞生长因子和IGF-1对C2C12细胞的趋化作用,而R-RAS不是由这三种生长因子诱导的,因此不可能参与趋化作用。因此,本研究表明RAS和R-RAS在造血细胞存活中的作用相似,但在肌肉发生中的作用不同。由于Ralgef是RAS效应因子,已有迹象表明存在RAS>;Ralgef&ral途径。为了探讨ral在RAS诱导的细胞转化中的作用,以人纤维肉瘤HT1080细胞为模型,研究了ral突变体的表达对RAS依赖的锚定非依赖性生长的影响。结果提示,RAR参与了RAS诱导的HT1080细胞的贴壁非依赖性生长,RAL可能通过调节细胞周期抑制因子p27Kip1的量来调控HT1080细胞的贴壁非依赖性生长。
英文摘要
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.
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Suzuki, J., Kaziro, Y., and Koide, H: "Synergistic action of R-Ras and IGF-1 on Bcl-xL expression and caspase-3 inhibition in BaF3 cells : R-Ras and IGF-1 control distinct anti-apoptotic kinase pathways"FEBS Lett.. 437. 112-116 (1998)
Suzuki, J.、Kaziro, Y. 和 Koide, H:“R-Ras 和 IGF-1 对 BaF3 细胞中 Bcl-xL 表达和 caspase-3 抑制的协同作用:R-Ras 和 IGF-1 控制不同的抗
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通讯作者:
鈴木 丈太郎: "Synergistic action of R-Ras and IGF-1 on Bcl-XL expression and caspase-3 inhibition in BaF3 cells"FEBS Letters. 437. 112-116 (1998)
Jotaro Suzuki:“R-Ras 和 IGF-1 对 BaF3 细胞中 Bcl-XL 表达和 caspase-3 抑制的协同作用”FEBS Letters 437. 112-116 (1998)
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鈴木丈太郎: "Synergistic action of R-Ras and IGF-1 on Bel-xL expression and caspase-3 inhibition in BaF3 cells" FEBS Letters. 437. 112-116 (1998)
Jotaro Suzuki:“R-Ras 和 IGF-1 对 BaF3 细胞中 Bel-xL 表达和 caspase-3 抑制的协同作用”FEBS Letters 437. 112-116 (1998)。
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Inoue, K., Mizutani, S., Koide, H and Kaziro, Y: "Formation of the Ras Dimer is Essential for Raf-1 Activation"J. Biol. Chem.. 275. 3737-3740 (2000)
Inoue, K.、Mizutani, S.、Koide, H 和 Kaziro, Y:“Ras 二聚体的形成对于 Raf-1 激活至关重要”J.
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通讯作者:
Suzuki, J., Kaziro, Y., and Koide, H: "Positive Regulation of Skeletal Myogenesis by R-Ras"Oncogene. (in press). (2000)
Suzuki, J.、Kaziro, Y. 和 Koide, H:“R-Ras 对骨骼肌生成的正向调节”癌基因。
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