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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-细胞周期蛋白复合体及其调控因子的体内调控和功能。在海星卵母细胞和卵的减数分裂和早期胚胎细胞周期中，导致细胞周期蛋白B-CDC2激活的信号通路已经被研究到进入不同的M期。每个信号通路在第一次减数分裂时由Akt/PKB-Cyclin B-CDc2 Plk1组成，在第二次减数分裂时由MAPK-Plk1-Cyclin B-CDc2组成，在胚胎有丝分裂时由Cyclin A-CDc2-Plk1-Cyclin B-CDc2组成。在所有这些途径中，Plk1的主要靶点不是CDC25，而是Myt1。这些发现证实Akt/PKB具有M期触发蛋白激酶的新作用，并且Plk1具有新的上下游通路。在非洲爪哇卵母细胞中期-II停滞(脑脊液、细胞抑制因子、停滞)过程中，细胞周期蛋白B-CDc2的活性如何维持在较高水平的调控机制已有研究。与P.Jackson等人的报告指出EmIL是脑脊液的重要成分不同，我们证明了在卵母细胞中期II停滞时，EmIL是检测不到的，APC/C甚至具有功能，从而为脑脊液停止的研究提供了新的视角。已经在哺乳动物体细胞中研究了JABL在细胞增殖控制中的作用。我们已经证明：(1)JABL基因敲除小鼠通过与CRM1和p27结合，促进了核输出和CDK抑制物p27的破坏；(2)JAPL基因在粒细胞白血病、胰腺癌和肺癌中过表达和激活，并伴随着p27的非选择性破坏和恶性肿瘤的加速；(3)JABL基因敲除小鼠是胚胎致死的，伴随着细胞周期蛋白E、p53和p27的过度表达，这可能导致细胞增殖抑制和细胞凋亡激活；(4)JAPL转基因小鼠患白血病，可能是由于p27和p16的表达和细胞内定位受到干扰。