Regulation of by protein degradation and transport.

通过蛋白质降解和运输进行调节。

基本信息

批准号：
13043039
负责人：
SEKIGUCHI Takeshi
金额：
$ 29.89万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2005
项目状态：
已结题

项目摘要

Sekiguchi has studied mechanisms of nuclear-cytoplasmic transport of macromolecuar complex, mainly on GTP binding protein Ran related proteins, RCC1, RRAG A/GTR1, DDX3. RCC1 is a chromatin binding protein and a Ran Guanine exchange factor. In this study, we found that Gtrlp interacts to Ran-binding protein, Yrb2p, ribosome biogenesis proteins, Rpcl9p and Nop8p. We also found that RRAG A interacts to GTP binding proteins, RRAG C and RRAG D, and a novel nucleolar protein, NOP132. We isolated hamster temperature-sensitive mutant of DDX3, an RNA DEAD-box helicase playing roles in ribosome biogenesis and translation. DDX3 turned out to play a role in cyclin A expression in hamster cells. Nakayama investigates mammalian Skp2 and Fbw7, which are F-box protein components of an SCF-type ubiquitin ligase. Fbw7 targets c-Myc, Notch, c-Jun, and cyclin E, all of which function to promote cell cycle, for ubiquitin-dependent proteolysis. Clinical evidence suggests that loss of Fbw7 function results i … More n cancer development. We generated mice deficient in Fbw7 and found that the embryos died in utero, manifesting marked abnormalities in vascular development. To investigate the role of Fbw7 in cell-cycle control during cellular differentiation, we have generated mice in which Fbw7 is ablated only in T-cell lineage (Fbw7 conditional knockout mice: CKO). We used two promoters for Cre-expressing transgenic lines, Lck-promoter and CD4-promoter. In both cases, thymic hyperplasia was observed in Fbw7 CKO with specific expansion of CD4+CD8+ population. In normal mice, T cells are mainly proliferated at CD4-CD8-stage, and cell cycle ceases at CD4+CD8+ stage, whereas cell cycle remained activated at CD4+CD8+ stage in Fbw7 CKO. In CD4+CD8+ stage of Fbw7 CKO, c-Myc and Notch highly accumulated, whereas cyclin E levels were unaffected. Fbw7 CKO mice are predisposed to lymphomas. These data suggest that Fbw7 is indispensable for the cell cycle arrest at CD4+CD8+ stage, and loss of Fbw7 results in lymphomatogenesis. Less

Sekiguchi研究了大分子复合物的核-胞质转运机制，主要研究GTP结合蛋白Ran相关蛋白，RCC1、RRAG A/GTR1，DDX3是染色质结合蛋白和Ran鸟嘌呤交换因子。 Gtrlp 与 Ran 结合蛋白、Yrb2p、核糖体生物发生蛋白、Rpcl9p 和 Nop8p 相互作用。 RRAG A 与 GTP 结合蛋白 RRAG C 和 RRAG D 以及一种新型核仁蛋白 NOP132 相互作用，我们分离出 DDX3 的仓鼠温度敏感突变体，这是一种在核糖体生物发生和翻译中发挥作用的 RNA DEAD-box 解旋酶。 Nakayama 研究了哺乳动物 Skp2 和 Fbw7，它们是细胞周期蛋白 A 的组成部分。 SCF 型泛素连接酶以 c-Myc、Notch、c-Jun 和细胞周期蛋白 E 为靶点，所有这些酶都具有促进细胞周期的作用，可进行泛素依赖性蛋白水解。我们培育了缺乏 Fbw7 的小鼠，发现胚胎在子宫内死亡，表现出血管发育的明显异常。在细胞分化过程中的细胞周期控制中，我们产生了仅在 T 细胞谱系中 Fbw7 被消除的小鼠（Fbw7 条件敲除小鼠：CKO），我们使用了表达 Cre 的转基因系的两个启动子：Lck 启动子和 CD4- 启动子。在这两种情况下，在 Fbw7 CKO 中观察到胸腺增生，并伴有 CD4+CD8+ 群体的特异性扩增。在正常小鼠中，T 细胞主要在CD4-CD8-阶段，细胞周期在CD4+CD8+阶段停止，而Fbw7 CKO的细胞周期在CD4+CD8+阶段保持激活。在Fbw7 CKO的CD4+CD8+阶段，c-Myc和Notch高度积累，而细胞周期蛋白E。 Fbw7 CKO 小鼠易患淋巴瘤。这些数据表明 Fbw7 对于细胞周期停滞是必不可少的。 CD4+CD8+ 阶段和 Fbw7 缺失导致淋巴瘤发生较少。