Molecular basis of Cancer-specific cell cycle

癌症特异性细胞周期的分子基础

• 批准号: 16590222
• 负责人: URANO Takeshi
• 金额: $ 2.3万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590222/
• 关键词: Cell cycle; Aurora; mitotic kinase; calmodulin; calcium; オーロラキナーゼ; 染色体分離; 細胞周期; Aurora; プロテインキナーゼ; ヒストンH3リン酸化; ヒストンH3メチル化; 修飾特異的モノクローナル抗体; 染色体パッセンジャータンパク質

Mammalian Aurora-A is related to a serine/threonine protein kinase that was originally identified by its close homology with Saccharomyces cerevisiae IpI1p and Drosophila melanogaster aurora that are key regulators in the orchestration of mitotic events. The protein level of Aurora-A, its peak kinase activity during mitosis and its activation have been attributed to phosphorylation. Here we show that this enzyme is an arginine-directed kinase and define its substrate specificity. We also found that Thr288 within the activation loop is a critical residue for activating phosphorylation events in vitro and that it is spatiotemporally restricted to a brief window at mitosis on duplicated centrosomes and on spindle microtubules proximal to the poles in vivo. Immunodepletion assays indicated that an upstream kinase(s) of Aurora-A might exist in mammalian cells in addition to autophosphorylation. Furthermore, human activated Aurora-A forms complexes with the negative regulator protein serine/threonine phosphatase type 1 (PP1) that was negatively phosphorylated on Thr320. Interestingly, phospho-specific Aurora-A monoclonal antibodies restrain Aurora-A kinase activity in vitro, providing further therapeutic avenues to explore.

哺乳动物Aurora-A与丝氨酸/苏氨酸蛋白激酶有关，该蛋白激酶最初通过其与酿酒酵母IpI 1 p和果蝇Aurora的密切同源性而被鉴定，这两种蛋白激酶是有丝分裂事件协调中的关键调节因子。Aurora-A的蛋白质水平、有丝分裂期间其峰值激酶活性及其活化已归因于磷酸化。在这里，我们表明，这种酶是一种丝氨酸定向激酶，并定义其底物特异性。我们还发现，Thr 288内的激活环是一个关键的残基激活磷酸化事件在体外，它是时空限制在一个简短的窗口，在有丝分裂复制中心体和纺锤体微管近端的两极在体内。免疫耗竭分析表明，Aurora-A的上游激酶可能存在于哺乳动物细胞中除了自磷酸化。此外，人激活的Aurora-A与在Thr 320上负磷酸化的负调节蛋白丝氨酸/苏氨酸磷酸酶1型（PP 1）形成复合物。有趣的是，磷酸特异性Aurora-A单克隆抗体在体外抑制Aurora-A激酶活性，提供了进一步的治疗途径。

项目成果

RNA polymerase II is required for RNAi-dependent heterochromatin assembly

• DOI: 10.1126/science.1114955
• 发表时间: 2005-07-15
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Kato, H;Goto, DB;Murakami, Y
• 通讯作者: Murakami, Y

Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modefications and lack of its antisense transcript Air.

Igf2r 印记的神经元特异性松弛与神经元特异性组蛋白修饰和其反义转录物 Air 的缺乏有关。

• 发表时间: 2005
• 期刊: Hum. Mol. Genet. 14
• 作者: Iwamoto;T.;Yamasaki Y. et al.
• 通讯作者: Yamasaki Y. et al.

オーロラAタンパク質の活性調節剤及びその利用

Aurora A蛋白活性调节剂及其用途

• 发表时间: 2005

Autophosphorylation of a newly identified site of Aurora-B is indispensable for cytokinesis

• DOI: 10.1074/jbc.m311128200
• 发表时间: 2004-03-26
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Yasui, Y;Urano, T;Inagaki, M
• 通讯作者: Inagaki, M

Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air

• DOI: 10.1093/hmg/ddi255
• 发表时间: 2005-09-01
• 期刊: HUMAN MOLECULAR GENETICS
• 影响因子: 3.5
• 作者: Yamasaki, Y;Kayashima, T;Kishino, T
• 通讯作者: Kishino, T