Regulation of degradation of p27Kip1, one of CDK inhibitory protein, for cancer therapy

CDK 抑制蛋白之一 p27Kip1 降解的调节用于癌症治疗

• 批准号: 10558105
• 负责人: KITAGAWA Masatoshi
• 金额: $ 6.27万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10558105/
• 关键词: p27ィイD1Kip1ィエD1; ubiquitination; proteasome; lung cancer; cyclin-dependent kinase; サイクリン依存性キナーゼ阻害分子; ユビキチン-プロテアソーム; 蛋白分解; プロセッシング

It has been reported that the cyclin dependent kinase inhibitory proteins (CDK inhibitor) , such as p27ィイD1Kip1ィエD1 negatively regulates the G1-CDK activity in normal cells. In most cancer cells, up-regulation of G1-cyclin dependent kinase (G1-CDK) activity contributes in their malignant growth. First of all, we study the expression of p27ィイD1Kip1ィエD1 in human lung cancer using immunohistoichemistry. We found that p27ィイD1Kip1ィエD1 labeling index was decreased and p27ィイD1Kip1ィエD1 degradation activity was up-regulated in cancerious lung tissues, compared with nonneoplastic lung tissues. Therefore, it is important to study the mechanisms of p27ィイD1Kip1ィエD1 degradation. In the next study, we found that p27ィイD1Kip1ィエD1 was eliminated by two independent mechanisms, ubiquitin-mediated degradation and ubiquitin-independent processing. These tow activity was significantly high during progression from G1 to S phase. These finding suggested that inhibitor of p27ィイD1Kip1ィエD1 degradation is a potential drug for cancer therapy.

有报道称，细胞周期蛋白依赖性激酶抑制蛋白（CDK抑制剂），如p27激酶D1 Kip 1 Kip在大多数癌细胞中，G1-细胞周期蛋白依赖性激酶（G1-CDK）活性的上调有助于其恶性生长。首先，我们采用免疫组织化学方法研究了p27 ~（kip 1）~（kip 1）~（kip 1）在人肺癌中的表达。我们发现，与非肿瘤性肺组织相比，肺癌组织中p27激酶D1 Kip 1激酶D1标记指数降低，p27激酶D1 Kip 1激酶D1降解活性上调。因此，研究p27激酶D1 Kip 1激酶D1降解机制具有重要意义。在接下来的研究中，我们发现p27泛素D1 Kip 1泛素D1通过两种独立的机制被消除，即泛素介导的降解和不依赖于泛素的加工。从G_1期到S期，这两种酶的活性显著升高。这些发现表明p27激酶D1 Kip 1激酶D1降解抑制剂是一种潜在的肿瘤治疗药物。

项目成果

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Kitagawa,M.: "An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of β-catenin."EMBO J.. 8. 2401-2410 (1999)

Kitakawa, M.：“F-box 蛋白 FWD1 介导 β-catenin 的泛素依赖性蛋白水解。” EMBO J.. 8. 2401-2410 (1999)