Department of Laboratory Medicine and Pathology, University of California at Irvine, USA.
FEBS J. 2012 Nov;279(22):4121-30. doi: 10.1111/febs.12005. Epub 2012 Oct 4.
Nuclear factor erythroid-derived 2-related factor 1 (Nrf1) regulates cellular stress response genes, and has also been suggested to play a role in other cellular processes. We previously demonstrated that hepatocyte-specific deletion of Nrf1 in mice resulted in spontaneous apoptosis, inflammation, and development of liver tumors. Here, we showed that both fibroblasts derived from Nrf1 null mouse embryos and fibroblasts expressing a conditional Nrf1 allele showed increased micronuclei and formation of abnormal nuclei. Lentiviral shRNA-mediated knockdown of Nrf1 in SAOS-2 cells also resulted in increased micronuclei, abnormal mitosis and multi-nucleated cells. Metaphase analyses showed increased aneuploidy in Nrf1(-/-) embryonic fibroblasts. Nuclear defects in Nrf1-deficient cells were associated with decreased expression of various genes encoding kinetochore and mitotic checkpoint proteins. Our findings suggest that Nrf1 may play a role in maintaining genomic integrity, and that Nrf1 dysregulation may induce tumorigenesis.
红细胞衍生 2 相关因子 1（Nrf1）调节细胞应激反应基因，也被认为在其他细胞过程中发挥作用。我们之前的研究表明，在小鼠中特异性敲除肝细胞中的 Nrf1 会导致自发性细胞凋亡、炎症和肝肿瘤的发展。在这里，我们发现 Nrf1 缺失型小鼠胚胎衍生的成纤维细胞和表达条件性 Nrf1 等位基因的成纤维细胞均表现出微核增加和异常核形成。慢病毒 shRNA 介导的 SAOS-2 细胞中 Nrf1 的敲低也导致微核增加、异常有丝分裂和多核细胞形成。中期分析显示 Nrf1(-/-)胚胎成纤维细胞中的非整倍体增加。Nrf1 缺陷细胞中的核缺陷与各种着丝粒和有丝分裂检查点蛋白编码基因的表达降低有关。我们的研究结果表明，Nrf1 可能在维持基因组完整性方面发挥作用，而 Nrf1 失调可能导致肿瘤发生。
