Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Institute of Engineering Biology and Health, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
Int J Mol Sci. 2021 Apr 19;22(8):4223. doi: 10.3390/ijms22084223.
Arsenic is one of the most common environmental pollutants eliciting serious public health issues; however, it is also a well-recognized chemotherapeutic agent for acute promyelocytic leukemia. The association between arsenic exposure and lung diseases has been established, but underlying molecular mechanisms are poorly defined. Here we investigated the toxicology of arsenic in airway epithelium. Arsenic rapidly induced the activating transcription factor ATF3 expression through the JNK and p38 pathways. The ATF3-deficient BEAS-2B cells were relatively resistant to apoptosis upon arsenic exposure, indicating a facilitatory role of ATF3 in arsenic-induced apoptosis. We further showed that ATF3 oppositely regulated the transcription of death receptor (DR5) and Bcl2-like 1 (Bcl-xL) by directly binding to the promoter DR5 and Bcl-xL. Altogether, our findings establish ATF3 as a pro-apoptotic protein in arsenic-induced airway epithelial apoptosis through transcriptionally regulating DR5 and Bcl-xL, highlighting the potential of ATF3 as an early and sensitive biomarker for arsenic-caused lung injury.
砷是一种常见的环境污染物，引发了严重的公共卫生问题；然而，它也是一种公认的治疗急性早幼粒细胞白血病的化疗药物。砷暴露与肺部疾病之间的关联已经确立，但潜在的分子机制尚不清楚。在这里，我们研究了砷对气道上皮的毒理学作用。砷通过 JNK 和 p38 途径迅速诱导激活转录因子 ATF3 的表达。在砷暴露下，ATF3 缺陷的 BEAS-2B 细胞相对不易发生凋亡，表明 ATF3 在砷诱导的凋亡中起促进作用。我们进一步表明，ATF3 通过直接结合 DR5 和 Bcl-xL 的启动子，相反地调节死亡受体 (DR5) 和 Bcl2 样 1 (Bcl-xL) 的转录。总之，我们的研究结果确立了 ATF3 通过转录调节 DR5 和 Bcl-xL，在砷诱导的气道上皮细胞凋亡中作为一种促凋亡蛋白，强调了 ATF3 作为砷引起的肺损伤的早期和敏感生物标志物的潜力。
