SAG E3泛素连接酶:生物学功能、作用机理及其相关的人类疾病  

SAG E3 Ubiquitin Ligase:Biological Functions,Mechanism of Action and Associated Human Diseases

作　　者：俞卿 孙毅 YU Qing;SUN Yi(Department of Thyroid Surgery,the Cancer Hospital of the University of Chinese Academy of Sciences(Zhejiang Cancer Hospital),Hangzhou 310022,China;Cancer Institute of the Second Affiliated Hospital,Hangzhou 310029,China;Institute of Translational Medicine,Zhejiang University School of Medicine,Hangzhou 310029,China;Cancer Center,Zhejiang University,Hangzhou 310058,China;Research Center for Life Science and Human Health,Binjiang Institute of Zhejiang University,Hangzhou 310053,China)

机构地区：[1]中国科学院大学附属肿瘤医院(浙江省肿瘤医院)甲状腺外科,杭州310022 [2]浙江大学医学院附属第二医院肿瘤研究所,杭州310029 [3]浙江大学转化医学研究院,杭州310029 [4]浙江大学癌症研究院,杭州310058 [5]浙江大学滨江研究院生命与大健康中心,杭州310053

出　　处：《中国细胞生物学学报》2022年第4期648-662,共15页Chinese Journal of Cell Biology

基　　金：国家重点研发计划(批准号:2021YFA1101000,2016YFA0501800,项目负责人:孙毅);国家自然科学基金(批准号:82102749,项目负责人:俞卿);浙江省自然科学基金(批准号:LD22H300003,项目负责人:孙毅)资助的课题。

摘　　要：凋亡敏感基因蛋白(Sensitive to Apoptosis Gene,SAG)是一种结构上进化保守的锌环指蛋白(zinc RING finger protein),1997年由该文笔者的实验室首次克隆,并于1999年发表。大量研究先后证实SAG不仅是一个具有抗氧化能力、可抑制金属离子或ROS诱导的细胞凋亡的蛋白,同时还是具有促癌作用的重要E3泛素连接酶,也是一个极富潜力的新型抗肿瘤靶点。SAG是泛素化和拟素化修饰的双重E3连接酶,通过介导Cullin-5蛋白的拟素化修饰参与形成CRL5或CRL1 E3泛素连接酶复合体,介导多种抑癌底物蛋白的泛素化降解,促进肿瘤细胞增生、存活、血管生成和肿瘤形成。此外,SAG还参与病毒的复制与合成,并与多种人类疾病相关。目前,靶向SAG的抗肿瘤小分子抑制剂正在研发中。该文回顾多年来在SAG的结构和功能方面的研究进展,综述SAG的生物学功能,重点阐述SAG促进肿瘤发生发展的功能和作用机理,并探讨和展望SAG的基础研究方向和以SAG为靶点的新型抗肿瘤药物的研发策略。SAG(Sensitive to Apoptosis Gene)is an evolutionarily conserved RING finger protein,firstly cloned in 1997 in the author’s laboratory and published in 1999.Numerous studies have demonstrated that SAG is not only an antioxidant protein that protects cells from apoptosis induced by metal ion or ROS,but also an important RING component of Cullin-RING ligases with oncogenic property,and being validated as an attractive anticancer target.SAG acts as an E3 ligase for both neddylation and ubiquitylation.Via neddylating Cullin-5,SAG activates CRL5,and then complexes with other components of CRL5 or CRL1 to promote ubiquitylation and degradation of many tumor suppressive substrates,leading to enhanced proliferation,survival,angiogenesis,and tumorigenesis.In addition,SAG is also involved in virus infection and associated with a few other human diseases.The drug discovery effort is currently under the way to identify small molecule inhibitors of SAG for anti-cancer applications.This review summarizes current knowledge and advancement in the field of SAG research,including its protein structure,biochemical activities,biological functions,especially in tumorigenesis,and mechanisms of action.Finally,the future perspectives in the basic research of SAG and SAG-targeting drug discovery efforts are proposed.

关 键 词：SAG Cullin-5 E3泛素连接酶 泛素化 拟素化 抗肿瘤 

分 类 号：R363[医药卫生—病理学]