Regulation of cyclin-dependent kinases

我们研究了Cdk-cyclin复合物及其调节因子在体内的调节和功能。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。每个信号通路均由Akt/PKB-cyclin B-Cdc2第一次减数分裂时的Plkl， MAPK- Plkl-cyclin B-Cdc2第二次减数分裂时的MAPK- Plkl-cyclin B-Cdc2和胚胎有丝分裂时的cyclin A-Cdc2-Plkl-cyclin B-Cdc2组成。在所有这些途径中，Plkl的主要靶点不是Cdc25，而是Mytl。这些发现表明Akt/PKB具有m期触发激酶的新作用，Plkl具有新的上游和下游途径。调控机制已经研究了周期蛋白B-Cdc2在爪蟾卵母细胞中期ii期阻滞（CSF，细胞抑制因子，阻滞）中如何维持在较高水平的活性。与P. Jackson小组的报告表明Emil是脑脊液的重要组成部分相反，我们已经证明，在中期ii期卵母细胞阻滞中，Emil是不可检测的，APC/C甚至具有功能，从而为脑脊液骤停的研究提供了新的观点。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通过结合CRM1和p27促进核输出和Cdk抑制剂p27的破坏；(2) Jabl在髓细胞白血病、胰腺癌和肺癌中过度表达和激活，并伴有p27异常破坏和恶性肿瘤加速；(3) jabl基因敲除小鼠具有胚胎致死性，伴随细胞周期蛋白E、p53、p27过表达，可能抑制细胞增殖，激活细胞凋亡；(4) Jabl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。

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.