Development of small-molecular-bioprobes and proteomic analyses of signal transduction factors.

小分子生物探针的开发和信号转导因子的蛋白质组学分析。

• 批准号: 15310156
• 负责人: OSADA Hiroyuki
• 金额: $ 8.9万
• 依托单位: RIKEN
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15310156/
• 关键词: Weel; ubiquitin; cell cycle; Cdc2; epoxytwinol; Wee1

To elucidate biological functions, there are two ways of analysis. One is the information and structure based analysis such as genome science or structural biology. The other is the chemical biology based analysis, in which proteins essential for biological process are identified using their specific inhibitors. The purposes of the present research project are to generate chemicals ("bioprobes") useful for the latter type of study, which regulate the signal transduction pathway in cells, to identify biological target molecules of the bioprobes and to mine and analyze novel molecular targets. We have conducted the project for these purposes and have obtained many important results as follows.1.Identification of molecular targets and characterization of bioprobes using proteomic analysis(1)Development of photo-crosslinked small molecule microarrays to identify specific interacting molecules for target proteins in high throughput manner. Angew.Chem.Int.Ed.(2005)(2)Elucidation of the bindi … More ng mechanism of phoslactomycin to its specific molecular target, protein phosphatase 2A.FEBS Lett.(2005)(3)Identification of a mitochondria specific heat shock protein, Hsp60 as a target molecule for epolactaene and elucidation of the mechanism to inhibit HSP60's chaperone activity. Biochem.J.(2005)2.Exploitation of novel bioprobes for the study of cellular signal transduction pathway(1)Identification of the pathway and the gene cluster in an actinomycete for the biosynthesis of PP2A specific inhibitor, phoslactomycins, and development of a method to enhance the selective production of phoslactomycins in vivo. Tetrahedron (2003),J.Biol.Chem.(2003)(2)Isolation and characterization of novel compounds, RK805 and epoxytwinol A as novel angiogenesis inhibitors. Tetrahedron (2004),Chem.Commun.(2005)3.Molecular biology on novel molecular targets(1)Elucidation of the mechanism of ubiquitin-proteasome dependent degradation of a cell cycle regulatory protein kinase, Weel. Proc.Natl.Acad.Sci.USA(2004) Less

要阐明生物功能，有两种分析方法。一种是基于信息和结构的分析，如基因组科学或结构生物学。另一种是基于化学生物学的分析，在这种分析中，对生物过程至关重要的蛋白质使用其特定的抑制物进行鉴定。本研究项目的目的是产生对后一类研究有用的化学物质(生物探针)，这些化学物质调节细胞内的信号转导途径，识别生物探针的生物靶分子，并挖掘和分析新的分子靶标。为此，我们开展了以下工作并取得了许多重要成果：1.基于蛋白质组学分析的分子靶标鉴定和生物探针的表征(1)高通量鉴定靶蛋白特异性相互作用分子的光交联型小分子芯片的研制。Angew.Chem.Int.Ed.(2005)(2)Bindi…的阐明磷乳霉素对其特异性分子靶标蛋白磷酸酶2A.FEBS Let.(2005)(3)线粒体特异性热休克蛋白HSP60的鉴定及其抑制S伴侣活性的机制。生物化学(2005)2.用于研究细胞信号转导途径的新型生物探针的开发(1)在一株放线菌中鉴定PP2A特异性抑制剂磷酸乳霉素的生物合成途径和基因簇，并开发一种提高体内磷酸乳霉素选择性生产的方法。四面体(2003)，J.Biol.Chem.(2003)(2)新化合物RK805和环氧双酚A作为新的血管生成抑制剂的分离和表征。四面体(2004)，化学共通(2005)3.新分子靶点的分子生物学(1)细胞周期调节蛋白激酶WEL依赖泛素-蛋白酶体降解机制的阐明.美国国家科学院学报(2004)少

项目成果

M-phase kinases induce phospho-depndent ubiquitination of somatic Weel by SCF^<β-TrCP>.

M 期激酶通过 SCF^<β-TrCP> 诱导体细胞 Weel 的磷酸依赖性泛素化。

• 发表时间: 2004
• 期刊: Proc.Natl.Acad.Sci., USA. 101
• 作者: N.Watanabe et al.

Synthesis of a biotin-conjugate of phosmidosine O-ethyl ester as a G1 arrest antitumor drug.

作为 G1 阻滞抗肿瘤药物的磷胺苷 O-乙酯生物素缀合物的合成。

• 发表时间: 2004
• 期刊: Bioorg.Med.Chem. 12
• 作者: 田村武志;多田勉;久国正吉;傍島邦穂;M.Sekine et al.
• 通讯作者: M.Sekine et al.

Transmembrane domain of Bcl-2 is required for inhibition of ceramide synthesis, but not cytochrome c release in the pathway of inostamysin-induced apoptosis.

Bcl-2 的跨膜结构域是抑制神经酰胺合成所必需的，但在肌壁霉素诱导的细胞凋亡途径中不需要抑制细胞色素 c 的释放。

• 发表时间: 2003
• 期刊: Exp.Cell.Res. 286
• 作者: 山本 一哉;M.Kawatani et al.
• 通讯作者: M.Kawatani et al.

ECH, an epoxycyclohexenone derivative that specifically inhibits Fas ligand^dependent apoptosis in CTL-mediated cytotoxicity

ECH，一种环氧环己烯酮衍生物，在 CTL 介导的细胞毒性中特异性抑制 Fas 配体依赖性细胞凋亡

• 发表时间: 2004
• 期刊: Journal of Immunology 172(6)
• 作者: Liwei Fu;Shujun Zhang;Na Li;Jinlan Wang;Ming Zhao;Junichi Sakai;Toshiaki Hasegawa;Tomokazu Mitsui;Takao Kataoka;Seiko Oka;Miwa Kiuchi;Katutoshi Hirose;Masayoshi Ando;Takao Kataoka;Kimiko Kadohara;Austin Dohrman;Tomokazu Mitsui;Tomokazu Mitsui
• 通讯作者: Tomokazu Mitsui

Heparanase as a molecular target of cancer chemotherapy

• DOI: 10.1111/j.1349-7006.2004.tb02485.x
• 发表时间: 2004-07
• 期刊: Cancer Science
• 影响因子: 5.7
• 作者: S. Simizu;K. Ishida;H. Osada