Regulation of cyclin-dependent kinases

细胞周期蛋白依赖性激酶的调节

基本信息

批准号：
13043015
负责人：
KISHIMOTO Takeo
金额：
$ 65.66万
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 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

We have investigated in vivo regulation and function of Cdk-cyclin complexes and their regulators.1. Signalling pathways that lead to activation of cyclin B-Cdc2 have been studied at entry into various M- phases during meiotic and early embryonic cell cycles in starfish oocytes and eggs. Each signalling pathway is found to be composed of Akt/PKB-cyclin B-Cdc2 Plkl at the first meiosis, MAPK--Plkl-- cyclin B-Cdc2 at the second meiosis, and cyclin A-Cdc2-Plkl-cyclin B-Cdc2 at embryonic mitosis. In all of these pathways, a major target of Plkl is not Cdc25 but Mytl. These findings identify Akt/PKB with a novel role for a trigger kinase of M-phase, and also Plkl with novel upstream and downstream pathways.2. Regulatory mechanisms have been studied how the activity of cyclin B-Cdc2 is maintained at elevated levels in metaphase-II arrest (CSF, cytostatic factor, arrest) of Xenopus oocytes. In contrast to the report by P. Jackson's group indicating that Emil is an essential component of CSF, we have demonstrated that in oocytes arresting at metaphase-II, Emil is undetectable and the APC/C is even functional, thus providing the study of CSF arrest with novel viewpoints.3. Roles of Jabl for cell proliferation control have been studied in mammalian somatic cells. We have demonstrated : (1) Jabl promotes nuclear export and the resulting destruction of the Cdk inhibitor, p27, through binding to both CRM1 and p27 ; (2) Jabl is over expressed and activated in myelocytic leukemia, pancreatic cancer and lung cancer, accompanied with unusal destruction of p27 and accerelation of malignancy ; (3) Jabl-knockout mice are embryonic lethal, accompanied with over expression of cyclin E, p53, and p27 which might cause inhibition of cell proliferation and activation of apoptosis ; (4) Jabl transgenic mice suffer leukemia, possibly due to perturbed expression and intracellular localization of p27 andp16.

我们研究了Cdk-cyclin复合物及其调节因子的体内调控和功能。1．在海星卵母细胞和卵子的减数分裂和早期胚胎细胞周期进入各个 M 期时，已经研究了导致细胞周期蛋白 B-Cdc2 激活的信号通路。发现每条信号通路均由第一次减数分裂时的 Akt/PKB-cyclin B-Cdc2 Plkl、第二次减数分裂时的 MAPK--Plkl--cyclin B-Cdc2 和 cyclin A-Cdc2-Plkl-cyclin B-Cdc2 组成。在胚胎有丝分裂时。在所有这些途径中，Plkl 的主要靶标不是 Cdc25，而是 Mytl。这些发现确定了Akt/PKB对于M期触发激酶具有新的作用，并且Plkl也具有新的上游和下游通路。2．人们已经研究了细胞周期蛋白 B-Cdc2 的活性如何在非洲爪蟾卵母细胞中期 II 停滞（CSF、细胞生长抑制因子、停滞）中维持在升高水平的调节机制。与P. Jackson小组的报告表明Emil是CSF的重要组成部分相反，我们已经证明在停滞于中期II的卵母细胞中，Emil是检测不到的，并且APC/C甚至是有功能的，从而为CSF的研究提供了基础。以新颖的观点被捕。3。 Jabl 在细胞增殖控制中的作用已在哺乳动物体细胞中进行了研究。我们已经证明：(1) Jabl 通过与 CRM1 和 p27 结合，促进核输出并由此破坏 Cdk 抑制剂 p27； (2) Jabl在粒细胞白血病、胰腺癌和肺癌中过度表达和激活，并伴有p27的异常破坏和恶性肿瘤的加速； (3) Jabl基因敲除小鼠胚胎致死，伴有cyclin E、p53、p27过度表达，可能导致细胞增殖抑制和细胞凋亡激活； (4) Jabl 转基因小鼠患有白血病，可能是由于 p27 和 p16 的表达和细胞内定位受到干扰。