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Accelerated degradation of tumor suppressor gene products in human cancers

人类癌症中肿瘤抑制基因产物的加速降解

基本信息

批准号：
14380304
负责人：
KITAGAWA Masatoshi
金额：
$ 9.66万
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：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14380304/
关键词：
Ubiquitin ligase p27^<Kip1>RB protein Cell cycle cancer prognosis 癌

项目摘要

Ubiquitin-proteasome pathway is a key system that controls cellular levels of number of proteins. This pathway is responsible not only for the degradation of short-lived proteins but also tumor suppressors, transcription factors and cell cycle proteins. Ubiquitin-protein ligases determine the substrate specificity of ubiquitination. In this study, we analyzed the molecular mechanisms of proteolytic degradation of two major tumor suppressor gene products such as p27^<Kip1> and RB protein. Fast of all, we tried to identify the ubiquitin ligase for RB protein and analyze its function in malignant transformation process (1). The other project is identification of the down-regulation mechanisms of p27^<Kip1> (2).In this study, we demonstrated that Mdm2 promotes ubiqutination of RB protein as an ubiquitin ligase and proteasome-mediated degradation of it. Knockdown of Mdm2 significantly accumulated steady state levels of RB protein. In human lung cancer tissues, high expression of Mdm2 correlated with down regulation of RB protein. These results suggest that facilitation of degradation of RB protein by Mdm2 perturbs the tumor suppressor RB-pathway. On the other hand, we found that Cks1, a subcomponent of SCF-Skp2 ubiquitin ligase for p27-degradation, was post-translalionally regulated by ubiquitin-proteasome pathway. We also found high expression of Cks1 in human lung cancers. Therefore, altered degradation of these cell cycle proteins or tumor suppressors is thought to promote growth and malignancy of cancer.

泛素-蛋白酶体途径是控制细胞内蛋白质水平的关键系统。该途径不仅负责短寿命蛋白质的降解，还负责肿瘤抑制因子、转录因子和细胞周期蛋白的降解。泛素-蛋白质连接酶决定泛素化的底物特异性。在这项研究中，我们分析了两种主要的肿瘤抑制基因产物如p27^和RB蛋白的蛋白水解降解的分子机制<Kip1>。首先，我们试图鉴定RB蛋白的泛素连接酶，并分析其在恶性转化过程中的功能（1）。另一个项目是鉴定p27的下调机制^<Kip1>（2）。在这项研究中，我们证明Mdm 2作为一种泛素连接酶促进RB蛋白的泛素化和蛋白酶体介导的RB蛋白的降解。Mdm 2的敲低显著地积累了RB蛋白的稳态水平。在人肺癌组织中，Mdm 2的高表达与RB蛋白的下调相关。这些结果表明，Mdm 2促进RB蛋白的降解扰乱了肿瘤抑制因子RB通路。另一方面，我们发现，Cks 1，SCF-Skp 2泛素连接酶的p27降解的一个亚组分，后泛素-蛋白酶体途径的调节。我们还发现Cks 1在人肺癌中高表达。因此，这些细胞周期蛋白或肿瘤抑制因子的降解改变被认为促进癌症的生长和恶性。