Regulation of tumor suppressor RB pathway via ubiquitin system.

通过泛素系统调节肿瘤抑制 RB 通路。

• 批准号: 16370060
• 负责人: KITAGAWA Masatoshi
• 金额: $ 9.92万
• 依托单位: Hamamatsu University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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/grant/KAKENHI-PROJECT-16370060/
• 关键词: Cell cycle; RB; ubiquitin; プロテアソーム; RBタンパク質; 癌化; Mdm2

Retinoblastoma gene product (pRB) plays critical roles in regulation of the cell cycle and tumor suppression. It is known that downregulation of pRB can stimulate carcinogenesis via abrogation of the pRB pathway, although the mechanism has not been elucidated. In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB. pRB was efficiently ubiquitinated by wild-type Mdm2 in vivo as well as in vitro, but other RB family proteins were not. Mutant Mdm2 with a substitution in the RING finger domain showed dominant-negative stabilization of pRB. Both knockout and knockdown of Mdm2 caused accumulation of pRB. Moreover, Mdm2 inhibited pRB-mediated flat formation of Saos-2 cells. Downregulation of pRB expression was correlated with a high level of expression of Mdm2 in human lung cancers. These results suggest that Mdm2 regulates function of pRB via ubiquitin-dependent degradation of pRB.

视网膜母细胞瘤基因产物（PRB）在调节细胞周期和肿瘤抑制中起关键作用。众所周知，尽管尚未阐明该机理，但PRB的下调可以通过废除PRB途径刺激癌变。在这项研究中，我们发现MDM2是一种p53的泛素连接酶，促进了PRB的泛素依赖性降解。 PRB在体内和体外被野生型MDM2有效地泛素化，但其他RB家族蛋白却没有。在环形结构域中取代的突变MDM2显示出PRB的显性阴性稳定。 MDM2的敲除和敲除引起PRB的积累。此外，MDM2抑制了PRB介导的SAOS-2细胞的扁平形成。 PRB表达的下调与人类肺癌中MDM2的高表达相关。这些结果表明，MDM2通过PRB的泛素依赖性降解来调节PRB的功能。

项目成果

Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69.

BS69 抑制腺病毒 E1A 蛋白的泛素依赖性降解。

• 发表时间: 2006
• 期刊: Biochem Biophys Res Commun. 339
• 作者: Isobe;T et al.
• 通讯作者: T et al.

Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in mice obstructive nephropathy.

泛素依赖性降解导致 Smad7 表达下调，导致小鼠梗阻性肾病肾纤维化。

• 发表时间: 2004
• 期刊: Proc.Nathl.Acad.Sci.USA 101(23)
• 作者: Fukasawa;H.
• 通讯作者: H.

Immunohistochemical and genetic features of gastric and the metastatic liver GISTs, sequential analyses.

胃和转移性肝 GIST 的免疫组织化学和遗传特征，序贯分析。

• 发表时间: 2006
• 期刊: Cancer Sci. 97
• 作者: Nabetani;A.;Ishikawa;F.;Kikuchi.H.et al.
• 通讯作者: Kikuchi.H.et al.

Treatment with anti-TGF-β antibody ameliorates progressive nephritis by inhibiting Smad/TGF-β signaling.

使用抗 TGF-β 抗体治疗可通过抑制 Smad/TGF-β 信号传导来改善进行性肾炎。

• 发表时间: 2004
• 期刊: Kidney Int. 65
• 作者: Fukasawa;H. et al.
• 通讯作者: H. et al.

Contribution of the constitutive and inducible degradation of Smad3 by the ubiquitin-proteasome pathway to transforming growth factor-β signaling.

泛素-蛋白酶体途径对 Smad3 的组成型和诱导型降解对转化生长因子-β 信号传导的贡献。

• 发表时间: 2004
• 期刊: J.Interferon & Cytokine Research 24
• 作者: Chiharu Uchida et al.;Makio Hayakawa et al.;Yasumichi Inoue et al.
• 通讯作者: Yasumichi Inoue et al.