Deciphering the mechanisms underlying cancer development induced by deregulation of proteolysis

破译蛋白水解失调诱导癌症发展的机制

• 批准号: 17013067
• 负责人: NAKAYAMA Keiichi
• 金额: $ 30.46万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17013067/
• 关键词: 細胞周期; ユビキチン; タンパク質分解; サイクリン; がん; p27; c-Myc; ユビキチン化; アポトーシス; Fbw7; p53; コンディショナルノックアウトマウス; KPC; プロテアソーム; Skp2; 発がん; UBLドメイン; UBAドメイン

Regulation of the exit of cells from the cell cycle is important in the development of multicellular organisms and is also implicated in the maintenance of stem cells. Furthermore, defects in cell cycle exit are thought to be a major cause of cancer. However, the mechanisms responsible for regulation of cell cycle exit have remained largely unknown. Fbw7 is the F-box protein subunit of an SCF-type ubiquitin ligase complex that targets positive regulators of the cell cycle including c-Myc for ubiquitylation and subsequent degradation by the 26S proteasome in order to promote cell cycle exit. Consistent with such a function, mutations of the Fbxw7 gene have been detected in various human malignancies. We have recently generated conventional and conditional Fbxw7 knockout mice and examined stem cells, progenitor cells, and differentiated cells in the mutant animals for cell cycle defects. Here we summarize the pleiotropic phenotypes of Fbxw7 deficiency in various cell types including T cells, hematopoietic stem cells, and embryonic fibroblasts. Such phenotypes have provided insight into the biological roles of Fbxw7 in cell cycle exit, stem cell maintenance, and oncosuppression.

调节细胞从细胞周期的出口对多细胞生物的发展很重要，也与干细胞的维持有关。此外，细胞周期出口中的缺陷被认为是癌症的主要原因。但是，负责调节细胞周期出口的机制在很大程度上尚不清楚。 FBW7是SCF型泛素连接酶复合物的F-box蛋白亚基，它针对细胞周期的阳性调节剂，包括c-myc的泛素化和26S蛋白酶体的随后降解，以促进细胞周期出口。与这种功能一致，在各种人类恶性肿瘤中已经检测到FBXW7基因的突变。我们最近产生了常规和条件的FBXW7基因敲除小鼠，并检查了突变动物中的干细胞，祖细胞和分化细胞，以解决细胞周期缺陷。在这里，我们总结了在包括T细胞，造血干细胞和胚胎成纤维细胞在内的各种细胞类型中FBXW7缺乏症的多效性表型。这种表型提供了对FBXW7在细胞周期出口，干细胞维持和Oncospression中的生物学作用的见解。

项目成果

Fbw7 is a key regulator of cell cycle exit during development

Fbw7 是发育过程中细胞周期退出的关键调节因子

• 发表时间: 2006
• 作者: Nakayama;K.I.
• 通讯作者: K.I.

Fbxo45 Forms a Novel Ubiquitin Ligase Complex and Is Required for Neuronal Development

• DOI: 10.1128/mcb.00364-09
• 发表时间: 2009-07-01
• 期刊: MOLECULAR AND CELLULAR BIOLOGY
• 影响因子: 5.3
• 作者: Saiga, Toru;Fukuda, Takaichi;Nakayama, Keiichi I.
• 通讯作者: Nakayama, Keiichi I.

Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence

• DOI: 10.1038/ncb1491
• 发表时间: 2006-11-01
• 期刊: NATURE CELL BIOLOGY
• 影响因子: 21.3
• 作者: Takahashi, Akiko;Ohtani, Naoko;Hara, Eiji
• 通讯作者: Hara, Eiji

Promotion of neurite extension by protrudin requires its interaction with VAMP-associated protein (VAP)

Protrudin 促进神经突延伸需要与 VAMP 相关蛋白 (VAP) 相互作用

• 发表时间: 2009
• 期刊: Journal of Biological Chemistry 284
• 作者: Saita;S.;Shirane;M.;Natume;T.;Iemura;S.;Nakayama;K.I.
• 通讯作者: K.I.

Comprehensive elucidation of enzyme-substrate relationship in ubiquitylation by differential proteomics : Say good-bye to western blotting

通过差异蛋白质组学全面阐明泛素化中酶与底物的关系：告别蛋白质印迹

• 发表时间: 2010
• 作者: Nakayama;K.I.
• 通讯作者: K.I.