Transcription factor Nrf2 activation by inorganic arsenic in cultured keratinocytes: involvement of hydrogen peroxide
Transcription factor Nrf2 activation by inorganic arsenic in cultured keratinocytes: involvement of hydrogen peroxide
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DOI：
10.1016/s0014-4827(03)00341-0
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发表时间：
2003-11-01
影响因子：
3.7
通讯作者：
Waalkes, MP
中科院分区：
文献类型：
--
作者：
Pi, JB;Qu, W;Waalkes, MP
无机砷是一种有充分证据的人类致癌物，针对皮肤。正如砷所显示的那样，氧化应激的诱导可能与这种类金属的致癌机制有关。转录因子Nrf2在许多抗氧化反应编码基因的调控中起着关键作用。酵素。因此，我们研究了无机砷(亚砷酸钠)对永生化人角质形成细胞系HaCaT细胞中Nrf2表达和定位的影响。我们首次发现，砷在转录和蛋白水平上增强了细胞中Nrf2的表达，并激活了这些细胞中Nrf2相关基因的表达。此外，砷暴露导致Nrf2的核积聚，并与Nrf2介导的氧化反应基因的下游激活有关。砷同时增加Nrf2活性调节因子Keap1的表达。砷诱导的Keap1表达和核内Nrf2积聚的协同诱导表明，Keap1在砷诱导的Nrf2激活中起重要作用。此外，当细胞被过氧化氢酶(H_2O_2)清除剂如过氧化氢酶-聚乙二醇酯(PEG-CAT)或TIron处理时，砷诱导的Nrf2核积聚被抑制，而细胞通透性的超氧化物歧化酶(SOD)模拟化合物CuDIPSH则促进Nrf2核积聚。这些结果表明，H_2O_2而不是O-2(-)是核内Nrf2积累的中介。另一项研究表明，砷导致细胞内过氧化氢产生增加，而且过氧化氢本身在转录和蛋白水平上都有能力增加HaCaT细胞中Nrf2的表达。综上所述，这些数据清楚地表明，砷在多个水平上增加了Nrf2的表达和活性，而过氧化氢是这一过程的中介之一。(C)2003 Elsevier Inc.保留所有权利。
Inorganic arsenic is a well-documented human carcinogen that targets the skin. The induction of oxidative stress, as shown with arsenic, may have a bearing on the carcinogenic mechanism of this metalloid. The transcription factor Nrf2 is a key player in the regulation of genes encoding for many antioxidative response. enzymes. Thus, the effect of inorganic arsenic (as sodium arsenite) on Nrf2 expression and localization was studied in HaCaT cells, an immortalized human keratinocyte cell line. We found, for the first time, that arsenic enhanced cellular expression of Nrf2 at the transcriptional and protein levels and activated expression of Nrf2-related genes in these cells. In addition, arsenic exposure caused nuclear accumulation of Nrf2 in association with downstream activation of Nrf2-mediated oxidative response genes. Arsenic simultaneously increased the expression of Keap1, a regulator of Nrf2 activity. The coordinated induction of Keap1 expression and nuclear Nrf2 accumulation induced by arsenic suggests that Keap1 is important to arsenic-induced Nrf2 activation. Furthermore, when cells were pretreated with scavengers of hydrogen peroxide (H2O2) such as catalase-polyethylene glycol (PEG-CAT) or Tiron, arsenic-induced nuclear Nrf2 accumulation was suppressed, whereas CuDIPSH, a cell-permeable superoxide dismutase (SOD) mimic compound that produces H2O2 from superoxide (.O-2(-)), enhanced Nrf2 nuclear accumulation. These results indicate that H2O2, rather than .O-2(-), is the mediator of nuclear Nrf2 accumulation. Additional study showed that arsenic causes increased cellular H2O2 production and that H2O2 itself has the ability to increase Nrf2 expression at both the transcription and protein levels in HaCaT cells. Taken together, these data clearly show that arsenic increases Nrf2 expression and activity at multiple levels and that H2O2 is one of the mediators of this process. (C) 2003 Elsevier Inc. All rights reserved.