Persistent expression of Nqo1 by p62-mediated Nrf2 activation facilitates p53-dependent mitotic catastrophe
Persistent expression of Nqo1 by p62-mediated Nrf2 activation facilitates p53-dependent mitotic catastrophe
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DOI：
10.1016/j.bbrc.2011.07.101
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发表时间：
2011-08-26
影响因子：
3.1
通讯作者：
Shin, Jaekyoon
中科院分区：
文献类型：
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作者：
Bui, Chi-Bao;Shin, Jaekyoon
由于染色体分离异常导致有丝分裂延长，使细胞进入 G1 期而无需胞质分裂，随后触发 p53 依赖性细胞死亡程序，称为有丝分裂灾难。未能经历有丝分裂灾难的细胞会产生非整倍性，从而带来肿瘤发生的风险。在本报告中，我们表明p62介导的Nrf2非典型激活导致Nqo1的持续表达，这对于有丝分裂灾难期间p53的稳定发挥着关键作用。随着长时间暴露于诺考达唑（一种微管解聚剂），p62缺陷的HCT116细胞表现出多倍体群体的积累，并且凋亡细胞的出现有限，这归因于p53的稳定性减弱。组合基因操作分析证实，p62-Keap1-Nrf2-Nqo1 层级的调控级联对于 p53 有丝分裂灾难的稳定是必需的。这与 Nqo1 作为 p53 蛋白酶体降解看门人的作用一致。因此，我们首次证明了非经典 Nrf2 途径与延长有丝分裂时 p53 依赖性细胞死亡程序之间的功能联系。 (C) 2011 Elsevier Inc. 保留所有权利。
Prolonged mitosis due to aberrant chromosome segregation permits cells to enter the G1 phase without cytokinesis and subsequently triggers the p53-dependent cell death program, known as mitotic catastrophe. Cells which fail to go through mitotic catastrophe create aneuploidy,posing a risk of oncogenesis. In the present report, we show that p62-mediated non-canonical activation of Nrf2 leads to the persistent expression of Nqo1, which plays a critical role for p53 stabilization during mitotic catastrophe. With prolonged exposure to nocodazole, a microtubule-depolymerizing agent, p62-deficient HCT116 cells exhibited an accumulation of a polyploid population with a limited appearance of apoptotic cells, which was attributable to the attenuated stabilization of p53. Combinatorial gene manipulation analysis verified that the regulatory cascade with a hierarchy of p62-Keap1-Nrf2-Nqo1 is required for p53 stabilization for mitotic catastrophe. This is consistent with the role of Nqo1 as a gatekeeper for proteasomal degradation of p53. Thus, we demonstrate for the first time the functional connection between the non-canonical Nrf2 pathway and p53-dependent cell death program upon prolonged mitosis. (C) 2011 Elsevier Inc. All rights reserved.