核出口信号
泛素连接酶
细胞周期蛋白
泛素
癌症研究
多西紫杉醇
细胞周期蛋白B1
细胞生物学
细胞周期蛋白B
生物
化学
细胞质
生物化学
细胞周期
细胞周期蛋白依赖激酶1
癌症
细胞核
细胞凋亡
遗传学
基因
作者
ShunLi Dong,Xiaohui Wang,ShuMin Yang,FanFan Guo,Jingjing Zhang,Cheng Ji,LiangRong Shi,Yan Cheng,Yan-Wei Hu,ZhenYun Li,Lei Peng,Lingchuan Guo,Wei-Dong Zhu,Xingcong Ren,Jin-Ming Yang,Yi Zhang
标识
DOI:10.1016/j.bcp.2023.115533
摘要
In this study, we uncovered the nuclear export of nucleus accumbens-associated protein-1 (NAC1) as a novel mechanism involved in ovarian cancer resistance to taxanes, the chemotherapeutic drugs commonly used in treatment of this malignancy. We showed that NAC1, a nuclear factor of the BTB/POZ gene family, has a nuclear export signal (NES) at the N terminus (aa 17-28), and this NES critically contributes to the NAC1 nuclear-cytoplasmic shuttling when tumor cells were treated with docetaxel. Mechanistically, the nuclear-exported NAC1 bound to cullin3 (Cul3) and Cyclin B1 via its BTB and BOZ domains respectively, and the cyto-NAC1-Cul3 E3 ubiquitin ligase complex promotes the ubiquitination and degradation of Cyclin B1, thereby facilitating mitotic exit and leading to cellular resistance to docetaxel. We also showed in in vitro and in vivo experiments that TP-CH-1178, a membrane-permeable polypeptide against the NAC1 NES motif, blocked the nuclear export of NAC1, interfered with the degradation of Cyclin B1 and sensitized ovarian cancer cells to docetaxel. This study not only reveals a novel mechanism by which the NAC1 nuclear export is regulated and Cyclin B1 degradation and mitotic exit are impacted by the NAC1-Cul3 complex, but also provides the nuclear-export pathway of NAC1 as a potential target for modulating taxanes resistance in ovarian cancer and other malignancies.
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