泛素连接酶FBW7的肿瘤抑制作用和机制  

Tumor Suppressor Function and Mechanism of Ubiquitin Ligase FBW7

作　　者：郭晓强[1,2] 沈永青[1] 王越甲[1] 段相林[1] 

机构地区：[1]河北师范大学生命科学学院铁代谢分子生物学研究室,河北石家庄050016 [2]解放军白求恩军医学院生物化学教研室,河北石家庄050081

出　　处：《中国生物化学与分子生物学报》2011年第11期998-1006,共9页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金(No.30870265);河北省自然基金项目(No.C2010000410)~~

摘　　要：泛素-蛋白酶体系统是一个主要的蛋白质降解调节通路,在细胞分裂过程中发挥着重要作用,其成员在肿瘤中频繁存在着表达异常现象.FBW7又名AGO、hCDC4、FBXW7和SEL-10,是一种拥有7串联WD40重复结构域的F-box蛋白,可作为SCF型泛素连接酶(E3)复合物的底物识别亚基发挥作用.FBW7是一种肿瘤抑制蛋白,其基因在多种肿瘤包括直肠癌、胃癌、卵巢癌和白血病中存在着基因突变或缺失.FBW7可直接结合和靶向作用多种转录激活因子或原癌基因,如周期蛋白E、c-Myc、c-Jun、Notch、MCL1、KLF5和mTOR等并对其进行泛素化修饰和随后的26S蛋白酶体降解.肿瘤抑制蛋白FBW7的研究对肿瘤发生机制的理解具有重要意义,同时也为肿瘤的诊断和治疗提供了新的靶点.本文综述了FBW7的特征、肿瘤抑制作用及机制.The ubiquitin-proteasome system（UPS） is a major regulatory pathway of protein degradation and plays an important role in cellular division,whose members are frequently aberrantly expressed in cancer.FBW7（F-box and WD repeat domain-containing domain protein 7）,also known as AGO,hCDC4,SEL-10 and FBXW7,is an F-box protein with 7 tandemed WD40（tryptophan-aspartic acid 40） repeats which is a substrate recognition subunit of SCF（SKP1-cullin-1-F-box protein）-type ubiquitin ligase（E3） complex.FBW7 is a tumor suppressor,and its gene is frequently mutated or deleted in various human cancers including colorectal,gastric,ovarian and leukemias.FBW7 can bind directly to and target multiple transcriptional activators and protooncogenes including cyclin E,c-Myc,c-Jun,Notch,MCL1,KLF5 and mTOR for ubiquitylation and subsequent degradation by the 26S proteasome.These studies on FBW7 as tumor suppressor are vitally important for understanding of tumorigenesis and provide a novel target of cancer diagnosis and treatment.This review outlined the characteristics,tumor suppressor function and mechanism of FBW7.

关 键 词：泛素-蛋白酶体系统 泛素连接酶 FBW7 肿瘤抑制蛋白 

分 类 号：Q55[生物学—生物化学]