The LIV-1-GRPEL1 axis adjusts cell fate during anti-mitotic agent-damaged mitosis
The LIV-1-GRPEL1 axis adjusts cell fate during anti-mitotic agent-damaged mitosis
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LIV-1-GRPEL1 轴在抗有丝分裂剂损伤的有丝分裂过程中调节细胞命运
DOI：
10.1016/j.ebiom.2019.09.054
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发表时间：
2019-11-01
期刊：
影响因子：
11.1
通讯作者：
Chen, Gang
中科院分区：
文献类型：
--
作者：
Chen, Pingbo;Wang, Beibei;Chen, Gang
背景：了解细胞对有丝分裂毒物的反应具有重要的生物医学和临床意义。然而，它仍然是未知的细胞死亡或生存是如何确定在暴露于抗有丝分裂drugs.Methods：SLC 39 A6（LIV-1）和GrpE样1（GRPEL 1）有丝分裂出口和凋亡的生物学效应进行了评估，在体外和体内使用流式细胞术，蛋白质印迹，异种移植和延时成像。通过GST pull down、免疫沉淀和质谱分析来评估蛋白质之间的相互作用和GRPEL 1的泛素化。结果：LIV-1的过表达导致直接的细胞凋亡。LIV-1耗尽后，通过快速退出停滞的有丝分裂来逃避抗有丝分裂剂诱导的杀伤。LIV-1与GRPEL 1相互作用并通过阻止GRPEL 1的泛素化来稳定GRPEL 1蛋白。LIV-1-GRPEL 1轴缺失通过诱导PP 2A-B55 α磷酸酶活性来减少有丝分裂停滞，同时通过使AIF结合并阻止后者释放到细胞核中来抑制细胞凋亡。解释：这些数据表明LIV-1-GRPEL 1轴通过与PP 2A B55 α和AIF相互作用双重调节有丝分裂退出以及凋亡。它的发现构成了一个概念上的进步，在受损的有丝分裂细胞命运的决定性机制。基金：国家自然科学基金委员会国家妇产科临床研究中心。(c)2019年，任作家。由爱思唯尔公司出版
Background: Understanding how cells respond to mitotic poisons is of great biomedical and clinical significance. However, it remains unknown how cell-death or survival is determined during exposure to anti-mitotic drugs.Methods: The biological effects of SLC39A6 (LIV-1) and GrpE-like 1 (GRPEL1) on mitotic exit and apoptosis were evaluated both in vitro and in vivo using flow cytometry, western blotting, xenografts and time-lapse imaging. The interactions between proteins and the ubiquitination of GRPEL1 were assessed by GST pull down, immunoprecipitation and mass spectrometry analysis. The expression of LIV-1 in cancers was assessed by immunohistochemistry.Findings: Overexpression of LIV-1 led to direct apoptosis. Depleted for LIV-1 evade anti-mitotic agent-induced killing through a rapid exit from arrested mitosis. LIV-1 interacts with GRPEL1 and Stabilizes GRPEL1 Protein by Preventing Ubiquitylation of GRPEL1. LIV-1-GRPEL1 axis depletion works to reduce the mitotic arrest by inducing PP2A-B55 alpha aphosphates activity, while inhibit apoptosis by banding AIF and preventing the latter's release into the nucleus. Loss of function in this axis was frequent in multiple types of human epithelial cancer.Interpretation: These data demonstrate that LIV-1-GRPEL1 axis dually regulates mitotic exit as well as apoptosis by interacting with PP2A B55 alpha and AIF. Its discovery constitutes a conceptual advance for the decisive mechanism of cell fate during damaged mitosis. Fund: National Clinical Research Center for Obstetric and Gynecologic Diseases, the National Natural Science Foundation of China. (c) 2019 The Authors. Published by Elsevier B.V.