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/苏氨酸蛋白激酶相关，最初因其与酿酒酵母 IpI1p 和果蝇 aurora 的密切同源性而被识别，而这两种蛋白是有丝分裂事件协调的关键调节因子。 Aurora-A 的蛋白质水平、有丝分裂期间的峰值激酶活性及其激活均归因于磷酸化。在这里，我们证明该酶是一种精氨酸导向的激酶，并定义了其底物特异性。我们还发现，激活环内的 Thr288 是体外激活磷酸化事件的关键残基，并且它在体内时空限制于复制中心体和靠近两极的纺锤体微管上有丝分裂时的短暂窗口。免疫耗竭分析表明，除了自磷酸化之外，哺乳动物细胞中可能还存在 Aurora-A 的上游激酶。此外，人类激活的 Aurora-A 与在 Thr320 上被负磷酸化的负调节蛋白丝氨酸/苏氨酸磷酸酶 1 (PP1) 形成复合物。有趣的是，磷酸化特异性 Aurora-A 单克隆抗体在体外抑制 Aurora-A 激酶活性，提供了进一步探索的治疗途径。

项目成果

Mechanism of Aurora-B degradation and its dependency on intact KEN and A-boxes : identification of an aneuploidy-promoting preperty.

Aurora-B 降解机制及其对完整 KEN 和 A-box 的依赖性：非整倍体促进特性的鉴定。

• 发表时间: 2005
• 期刊: Mol. Cell Biol. 25
• 作者: Hayashi;K.;et al.;Nguyen HG. et al.
• 通讯作者: Nguyen HG. et al.

Epigenetic inactivation of class II transactivator (CIITA) is associated with the absence of interferon-g-induced HLA-DR expression in colorectal and gastric cancer cells.

II 类反式激活因子 (CIITA) 的表观遗传失活与结直肠癌细胞和胃癌细胞中干扰素 g 诱导的 HLA-DR 表达缺失有关。

• 发表时间: 2004
• 期刊: Oncogene 23・55
• 作者: Ueda;G.;Satoh A
• 通讯作者: Satoh A

Ganglioside GD3 promotes cell growth and invasion through p180Cas and paxillin in malignant melanoma cells

神经节苷脂GD3通过p180Cas和桩蛋白促进恶性黑色素瘤细胞的细胞生长和侵袭

• 发表时间: 2005
• 期刊: Proc. Natl. Acad. Sci. U S A. 102
• 作者: Iwamoto;T.;Hamamara K. et al.
• 通讯作者: Hamamara K. et al.

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