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.

据报道，细胞周期蛋白依赖性激酶抑制蛋白（CDK抑制剂），例如P27 D1KIP1E D1对正常细胞中的G1-CDK活性负调节。在大多数癌细胞中，G1-周期蛋白依赖性激酶（G1-CDK）的上调有助于其恶性生长。首先，我们研究了使用免疫疗法的人类肺癌中p27 D1KIP1E D1的表达。我们发现，与非肿瘤肺组织相比，P27 D1KIP1E D1标记指数得到了改善，P27 D1KIP1E D1降解活性在癌性肺组织中上调。因此，研究p27 D1KIP1E D1降解的机制很重要。在下一项研究中，我们发现P27 D1KIP1E D1通过两种独立的机制，即泛素介导的降解和泛素无关的处理来消除。在从G1到S相的进展过程中，这些拖曳活性显着高。这些发现表明，p27 D1KIP1 D1降解的抑制剂是癌症治疗的潜在药物。

项目成果

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