羟脑苷脂(CRBN)在来那度胺抗骨髓瘤活性中的分子机制  

Molecular Mechanism of CRBN in the Activity of Lenalidomide against Myeloma

作　　者：樊文静 范枝俏[3] 杨美娟 潘耀柱 白海[2] FAN Wen-Jing;FAN Zhi-Qiao;YANG Mei-Juan;PAN Yao-Zhu;BAI Hai(The Second Clinical Medical College of Lanzhou University,Lanzhou 730030,Gansu Province,China;The Center of Hematologic Diseases of Chinese PLA,Lanzhou Military Command General Hospital,Lanzhou 730050,Gansu Province,China;Gansu Unversity of Traditional Chinese Medicine,Lanzhou 730000,Gansu Province,China)

机构地区：[1]兰州大学第二临床医学院,甘肃兰州730030 [2]兰州军区兰州总医院全军血液病专科中心,甘肃兰州730050 [3]甘肃中医药大学,甘肃兰州730000

出　　处：《中国实验血液学杂志》2018年第4期1240-1243,共4页Journal of Experimental Hematology

摘　　要：羟脑苷脂(Cereblon,CRBN)是一种具有离子蛋白酶活性的大脑相关蛋白,可与DNA损伤结合蛋白-1(DDB1)、滞蛋白4(Cullin4,Cul4A或Cul4B)和调节因子Cullins 1(RoC1)相互作用形成功能性E3泛素连接酶复合物(CRBN-CRL4),结合底物后通过泛素-蛋白酶体途径进行蛋白水解。它也是免疫调节剂(IMiD)抗骨髓瘤作用的必需靶蛋白。来那度胺与CRBN结合时会招募新的底物,使其结合在CRBN-CRL4上,导致其泛素化和蛋白酶体依赖的降解增加,从而产生抗骨髓瘤活性。与该复合物结合的底物有IKZF1、IKZF3蛋白和谷氨酰胺合成酶(GS)等,来那度胺处理后的IKZF1和IKZF3的CRBN依赖性降解也是H2O2介导的氧化应激的结果。除了泛素化依赖外,来那度胺还能通过介导非泛素依赖性途径,以竞争性阻止CRBN结合CD147-MCT1,以调节其抗肿瘤活性;其还能通过调节miRNA水平,CRBN结合下游蛋白AGO2的表达在多发性骨髓瘤(MM)细胞中起作用。来那度胺抗骨髓瘤活性的分子机制有很多种,本文从泛素化途径和非泛素化途径2方面就CRBN在来那度胺抗骨髓瘤活性的分子机制作一综述。Cereblon（ CRBN） is a brain-associated protein with ionic protease activity,which interacts with DNA damage-binding protein-1（ DDB1）,Cullin 4（ Cul4 A or Cul4 B）,and regulator of Cullins 1（ RoC1） to form the functional E3 ubiquitin ligase complex（ CRBN-CRL4） that performs proteolysis via the ubiquitin-proteasome pathway.And CRBN is a necessary target protein for the anti-myeloma effect of immunomodulators. The combination of lenalidomide and CRBN recruited a new substrate that binds to the CRBN-CRL4 complex,leading to increased ubiquitination and proteasome-dependent degradation,thus resulting in anti-myeloma activity. The substrates binding to this complex are IKZF1,IKZF3 proteins and GS,etc. The CRBN-dependent degradation of IKZF1 and IKZF3 after lenalidomide treatment is also the result of H2O2-mediated oxidative stress. In addition to ubiquitination,lenalidomide also mediates ubiquitin-independent pathways that prevent CRBN from binding to CD147-MCT1 in a competitive manner to regulate its antitumor activity. Lenalidomide can also play a role in multiple myeloma（ MM） cells by modulating miRNA levels and CRBN binding to downstream protein AGO2 expression. Thus,there are many molecular mechanisms of lenalidomide anti-myeloma activity. This review summarizes the molecular mechanisms of CRBN in lenalidomide against myeloma activity in terms of ubiquitin-dependent and ubiquitin-independent pathways.

关 键 词：CRBN 来那度胺 多发性骨髓瘤 泛素连接酶复合物 

分 类 号：R733.3[医药卫生—肿瘤]