Mechanism of carcinogenesis by dysregulation of cell cycle via abnormal ubiquitin-mediated proteolysis

异常泛素介导的蛋白水解作用导致细胞周期失调的致癌机制

• 批准号: 23689074
• 负责人: KUDO Yasusei
• 金额: $ 17.64万
• 依托单位: The University of Tokushima (2012-2013)Hiroshima University (2011)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (A)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23689074/
• 关键词: 細胞周期; ユビキチン分解; 癌; APC/Cユビキチンリガーゼ複合体; 細胞分裂; APC/C; Geminin; Aurora-A

In the present study, we focused on the APC/C ubiquitin ligase complex that is involved in the degradation of cell division-related proteins. We found that the speed of ubiquitylation process is dependent on the sequence of degradation domain. Moreover, we found that one of the APC/C substrate, geminin is phosphorylated at mitosis, and this phosphorylation leads to DNA synthesis by preventing from APC/C-mediated proteolysis at mitosis. We also found that knockdown of Emi1 which is an APC/C inhibitor enhances the sensitivity of anti-cancer drug. These findings indicate that ubiquitin-mediated proteolysis via APC/C ubiquitin ligase is essential to cell cycle regulation and suggest that abnormal regulation of APC/C-mediated proteolysis may be involved in carcinogenesis.

在本研究中，我们重点关注参与细胞分裂相关蛋白降解的 APC/C 泛素连接酶复合物。我们发现泛素化过程的速度取决于降解域的序列。此外，我们发现 APC/C 底物之一 Geminin 在有丝分裂时被磷酸化，这种磷酸化通过阻止 APC/C 介导的有丝分裂蛋白水解而导致 DNA 合成。我们还发现，敲除APC/C抑制剂Emi1可以增强抗癌药物的敏感性。这些发现表明，通过 APC/C 泛素连接酶进行的泛素介导的蛋白水解对于细胞周期调节至关重要，并表明 APC/C 介导的蛋白水解的异常调节可能与癌发生有关。

项目成果

SCFSSTrcp mediates stress-induced Cdc25B ubiquitylation through cooperation of an atypical consensus sequence and PEST

SCFSSTrcp 通过非典型共有序列和 PEST 的配合介导应激诱导的 Cdc25B 泛素化

• 发表时间: 2011
• 期刊: J Cell Sci
• 影响因子: 4
• 作者: Uchida;S.;Watanabe;N.;Kudo;Y.;et al
• 通讯作者: et al

分裂期キナーゼAurora-AによるDNAライセンス化抑制因子Gemininの安定化機構

有丝分裂激酶 Aurora-A 对 DNA 许可抑制因子 Geminin 的稳定机制

• 发表时间: 2012
• 作者: 常松貴明;工藤保誠;高田 隆
• 通讯作者: 高田 隆

Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis.

• DOI: 10.1038/ncomms2859
• 发表时间: 2013
• 期刊: Nature communications
• 影响因子: 16.6

SCF^<ßTrcp>mediates stress-induced Cdc25B ubiquitylation through cooperation of an atypical consensus sequence and PEST

SCF^<ßTrcp>通过非典型共有序列和 PEST 的配合介导应激诱导的 Cdc25B 泛素化

• 发表时间: 2011
• 期刊: J Cell Sci
• 影响因子: 4
• 作者: Uchida;S.;Watanabe;N.;Kudo;Y.;Yoshioka;K.;Matsunaga;T.;Ishizuka;Y.;Nakagama;H.;Poon;R.Y.C.;Yamashita;K.
• 通讯作者: K.

Overexpression of Receptor for Hyaluronan-Mediated Motility (RHAMM) in MC3T3-E1 induces the proliferation and differentiation through phosphorypation of ERK1/2

MC3T3-E1 中透明质酸介导的运动受体 (RHAMM) 的过表达通过 ERK1/2 磷酸化诱导增殖和分化

• 发表时间: 2012
• 期刊: J Bone Miner Metabol
• 作者: Hatano;H.;Shigeishi;H.;Kudo;Y.;et al
• 通讯作者: et al