COMPARISON OF FUNCTION OF RAS FAMILY MOLECULES

RAS家族分子的功能比较

• 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

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结合蛋白的一个亚家族，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，利用IL-3依赖性造血BaF 3细胞和C2 C12成肌细胞。发现R-Ras以及Ras在IL-3撤除后抑制BaF 3细胞的凋亡。这两种分子之间的区别在于，单独激活Ras就足以抑制细胞凋亡，而R-Ras需要IGF-1。进一步研究。揭示了所观察到的差异是由于R-Ras中缺乏ERK激活活性。在C2 C12细胞的情况下，Ras和R-Ras的激活导致不同的表型。R-Ras能促进C2 C12细胞的分化，而Ras能抑制C2 C12细胞的分化; R-Ras还参与了FGF、HGF和IGF-1对C2 C12细胞的趋化作用，但R-Ras不参与C2 C12细胞的趋化作用，因为这三种生长因子均不能激活R-Ras。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，但在肌肉发生中起着不同的作用，并探讨了Ras和Ral之间的关系。由于RalGEF是Ras效应子，因此已经表明存在Ras > RalGEF > Ral途径。为了研究Ral在Ras诱导的细胞转化中的作用，使用人纤维肉瘤HT 1080细胞研究了Ral突变体的表达对Ras依赖性锚定非依赖性生长的影响。结果表明，Ral参与Ras诱导的HT 1080细胞的锚定非依赖性生长，并且Ral可以通过调节细胞周期抑制剂p27 Kip 1的量来调节锚定非依赖性生长。

项目成果

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

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)

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)。

井上薫: "Formation of the Ras dimer is essential for Raf-1 activation"The Journal of Biological Chemistry. 275. 3737-3740 (2000)

Kaoru Inoue：“Ras 二聚体的形成对于 Raf-1 的激活至关重要”《生物化学杂志》275. 3737-3740 (2000)。

鈴木丈太郎: "Positive regulation of skeletal myogenesis by R-Ras"Oncogene. (印刷中). (2000)

Jotaro Suzuki：“R-Ras 对骨骼肌发生的积极调节”Oncogene（出版中）。