Department of Forensic Pathology, School of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China.
Int J Mol Sci. 2020 Mar 16;21(6):2014. doi: 10.3390/ijms21062014.
Increasing evidence indicates that human exposure to inorganic arsenic causes cutaneous diseases and skin cancers. Nuclear factor erythroid 2-like 1 (NRF1) belongs to the cap "n" collar (CNC) basic-region leucine zipper (bZIP) transcription factor family and regulates antioxidant response element (ARE) genes. The human gene is transcribed into multiple isoforms, which contain 584, 616, 742, 761, or 772 amino acids. We previously demonstrated that the long isoforms of NRF1 (i.e., NRF1-742, NRF1-761 and NRF1-772) are involved in the protection of human keratinocytes from acute arsenic cytotoxicity by enhancing the cellular antioxidant response. The aim of the current study was to investigate the roles of NRF1-742 and NRF1-772 in the arsenic-induced antioxidant response and cytotoxicity. We found that overexpression of or in human HaCaT keratinocytes decreased susceptibility to arsenic-induced apoptosis and cytotoxicity. In addition, we characterized the different protein bands observed for NRF1-742 and NRF1-772 by western blotting. The posttranslational modifications and nuclear translocation of these isoforms differed and were partially affected by arsenic exposure. Antioxidant protein levels were increased in the and 772-overexpressing cell lines. The upregulation of antioxidant protein levels was partly due to the translation of nuclear factor erythroid 2-like 2 (NRF2) and its increased nuclear transport. Overall, overexpression of and protected HaCaT cells from arsenic-induced cytotoxicity, mainly through translational modifications and the promotion of antioxidant gene expression.
越来越多的证据表明，人类接触无机砷会导致皮肤疾病和皮肤癌。核因子红细胞 2 样 1（NRF1）属于帽子“n”领（CNC）碱性区域亮氨酸拉链（bZIP）转录因子家族，调节抗氧化反应元件（ARE）基因。人 基因转录为多个同工型，包含 584、616、742、761 或 772 个氨基酸。我们之前证明，NRF1 的长同工型（即 NRF1-742、NRF1-761 和 NRF1-772）通过增强细胞抗氧化反应参与保护人角质形成细胞免受急性砷细胞毒性，当前研究的目的是研究 NRF1-742 和 NRF1-772 在砷诱导的抗氧化反应和细胞毒性中的作用。我们发现，人 HaCaT 角质形成细胞中 或 的过表达降低了对砷诱导的细胞凋亡和细胞毒性的敏感性。此外，我们通过蛋白质印迹法对 NRF1-742 和 NRF1-772 观察到的不同蛋白条带进行了表征。这些同工型的翻译后修饰和核易位不同，部分受到砷暴露的影响。抗氧化蛋白水平在 和 772 过表达细胞系中增加。抗氧化蛋白水平的上调部分归因于核因子红细胞 2 样 2（NRF2）的翻译及其核转运增加。总体而言，和 的过表达保护 HaCaT 细胞免受砷诱导的细胞毒性，主要通过翻译后修饰和促进抗氧化基因表达。
