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.

细胞退出细胞周期的调节对于多细胞生物体的发育非常重要，并且还涉及干细胞的维持。此外，细胞周期退出缺陷被认为是癌症的主要原因。然而，负责调节细胞周期退出的机制仍然很大程度上未知。 Fbw7 是 SCF 型泛素连接酶复合物的 F-box 蛋白亚基，其靶向细胞周期的正调节因子（包括 c-Myc），进行泛素化并随后被 26S 蛋白酶体降解，以促进细胞周期退出。与这种功能相一致的是，在各种人类恶性肿瘤中都检测到了 Fbxw7 基因的突变。我们最近培育了常规和条件性 Fbxw7 基因敲除小鼠，并检查了突变动物中的干细胞、祖细胞和分化细胞的细胞周期缺陷。在这里，我们总结了包括 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 缺陷的多效性表型。这些表型让我们深入了解 Fbxw7 在细胞周期退出、干细胞维持和肿瘤抑制中的生物学作用。

项目成果

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.

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.

Molecular dissection of the interaction between p27 and Kip1 ubiquitylation-promoting complex, the ubiquitin ligase that regulates proteolysis of p27 in G1 phase

• DOI: 10.1074/jbc.m500866200
• 发表时间: 2005-05-06
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Kotoshiba, S;Kamura, T;Nakayama, KI
• 通讯作者: Nakayama, KI

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

KDM7 is a dual demethylase for histone H3 Lys 9 and Lys 27 and functions in brain development

• DOI: 10.1101/gad.1864410
• 发表时间: 2010-03-01
• 期刊: GENES & DEVELOPMENT
• 影响因子: 10.5
• 作者: Tsukada, Yu-ichi;Ishitani, Tohru;Nakayama, Keiichi I.
• 通讯作者: Nakayama, Keiichi I.