Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, Jiangsu, PR China.
Toxicology. 2012 Oct 28;300(3):121-31. doi: 10.1016/j.tox.2012.06.004. Epub 2012 Jun 15.
Biphasic dose-response relationship induced by environmental agents is often characterized with the effect of low-dose stimulation and high dose inhibition. Some studies showed that arsenite may induce cell proliferation and apoptosis via biphasic dose-response relationship in human cells; however, mechanisms underlying this phenomenon are not well understood. Our present study shows that, for human keratinocytes (HaCaT) cells, a low concentration of arsenite activates extracellular signal-regulated kinases (ERKs), which leads to up-regulation of nuclear factor κB (NF-κB) binding to DNA and to elevated, NF-κB-dependent expression of mot-2 (a p53 inhibitor) and survivin (an inhibitor of apoptosis). Activation of p53 is blocked, and neoplastic transformation is enhanced. Inhibition of ERKs reduces cell proliferation and neoplastic transformation. In contrast, a high concentration of arsenite activates c-Jun N-terminal kinases (JNKs), positive regulators of p53, by binding to p53 and preventing its murine double minute 2 (mdm2)-mediated degradation. The elevated levels of p53 lead to repair of DNA damage and apoptosis. Inhibition of JNKs increases DNA damage but decreases apoptosis. By identifying a mechanism whereby ERKs and JNKs-mediated regulation of the p53-survivin signal pathway is involved in the biphasic effects of arsenite on human keratinocytes, our data expand understanding of arsenite-induced cell proliferation, neoplastic transformation, DNA damage, and apoptosis.
环境因素诱导的双相剂量反应关系通常表现为低剂量刺激和高剂量抑制的作用。一些研究表明，亚砷酸盐可能通过人细胞中的双相剂量反应关系诱导细胞增殖和凋亡；然而，这种现象的机制尚不清楚。我们的研究表明，对于人角质形成细胞 (HaCaT)，低浓度的亚砷酸盐激活细胞外信号调节激酶 (ERKs)，导致核因子 κB (NF-κB)与 DNA 结合的上调，以及 NF-κB 依赖性 mot-2（p53 抑制剂）和 survivin（凋亡抑制剂）的表达升高。p53 的激活被阻断，肿瘤转化增强。ERKs 的抑制减少细胞增殖和肿瘤转化。相比之下，高浓度的亚砷酸盐通过与 p53 结合并阻止其鼠双微体 2 (mdm2)介导的降解来激活 c-Jun N 端激酶 (JNKs)，p53 的正调节剂。升高的 p53 水平导致 DNA 损伤的修复和细胞凋亡。JNKs 的抑制增加了 DNA 损伤，但减少了细胞凋亡。通过确定 ERKs 和 JNKs 介导的 p53-survivin 信号通路的调节参与了亚砷酸盐对人角质形成细胞的双相作用的机制，我们的数据扩展了对亚砷酸盐诱导的细胞增殖、肿瘤转化、DNA 损伤和凋亡的理解。
