去泛素化酶USP4调节SMAD4蛋白单泛素化并调控TGF-β/Activin信号的研究

项目名称： 去泛素化酶USP4调节SMAD4蛋白单泛素化并调控TGF-β/Activin信号的研究

项目编号： No.31471315

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 张龙

作者单位： 浙江大学

项目金额： 100万元

中文摘要： TGF-β超家族信号通路在多细胞生物胚胎发育和维持组织内稳态方面发挥着重要的作用，该通路的失调会导致癌症的发生。TGF-β抑制早期肿瘤的发生但在肿瘤发生后期却促进肿瘤的转移。因而在恶性肿瘤中该通路被视为抗肿瘤药物的作用靶点。为此，在肿瘤发展晚期特异地抑制TGF-β信号的研究显得尤为重要。去泛素化酶（DUB）是一类优良的小分子药物靶点。申请人前期通过对DUB家族的筛选发现以USP4为代表的几个去泛素化酶蛋白可激活TGF-β和Activin信号。USP4与SMAD4相互作用,很可能去除抑制SMAD4转录活性的单泛素化修饰从而同时上调TGF-β和Activin信号并促进肿瘤细胞的迁移，侵润和转移。本项目旨在阐明USP4调控肿瘤转移的分子机理和它增强TGF-β和Activin信号的原因。以此为基础搭建以DUB活性为读出的小分子药物筛选模型，为指导临床实践和以DUB活性为目的的药物筛选提供理论基础。

中文关键词： 去泛素化酶；SMAD4蛋白；单泛素化；转移生长因子beta/激活素；肿瘤转移

英文摘要： TGF-β signaling plays critical roles in embryonic development and the maintenance of tissue homeostasis in all metazoans. Deregulation of TGF-β activity results in cancer development. In normal and premalignant cells, TGF-β enforces homeostasis and suppresses tumor progression directly through cell autonomous regulation of apoptosis and growth arrest or indirectly through blockage of paracrine factor production in the tumor stroma. In advanced cancers, the TGF-β pathway acts as an oncogenic factor and is considered to be a therapeutic target. Deubiquitination enzymes are druggable. In previous study, we screened out USP4 as a TGF-β/Activin pathway activator. USP4 interacted with SMAD4 and could remove the mono-ubiquitin-modification from SMAD4. The mono-ubiquitination modification on SMAD4 was reported to potently inhibit transcriptional activity of SMAD complex. We hypothesized that USP4 activates both TGF-β and Activin signaling via removing the mono-Ubiquitin modification on SMAD4. We aim to identify the mechanism of which USP4 activates TGF-β/Activin pathway and figure out whether USP4 promotes TGF-β/Activin-mediated EMT (epithelial to mesenchymal transition), migration and metastasis. We also aim to build up a drug screen model targeting deubiquitination enzymes (USP4, in this study）in tumor therapy. Upon successful conclusion of this work, we will have proposed a new TGF-β/Activin regulation model and provided reference for clinical therapy in the future.

英文关键词： Deubiquitinating enzyme;SMAD4 protein;Monoubiquitination;TGF-β/Activin;Metastasis