Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells - Role of mitogen-activated protein kinases
Mechanism of sodium arsenite-mediated induction of heme oxygenase-1 in hepatoma cells - Role of mitogen-activated protein kinases
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DOI：
10.1074/jbc.273.15.8922
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发表时间：
1998-04-10
影响因子：
4.8
通讯作者：
Bonkovsky, HL
中科院分区：
文献类型：
--
作者：
Elbirt, KK;Whitmarsh, AJ;Bonkovsky, HL
血红素加氧酶-1是一种催化血红素降解的诱导酶，已被提出在保护细胞免受氧化应激相关损伤中发挥作用。我们研究了肿瘤启动子亚砷酸盐对鸡肝癌细胞系LMH中血红素加氧酶-1的诱导作用。我们确定了一个血红素加氧酶-1启动子驱动的荧光素酶报告结构，该结构在亚砷酸钠处理下高度可重复表达。该结构用于研究丝裂原活化蛋白（MAP）激酶在亚砷酸盐介导的血红素氧合酶-1基因表达中的作用。在LMH细胞中，亚砷酸钠、镉和热休克，而不是血红素，诱导MAP激酶细胞外调节激酶（ERK）、c-Jun n末端激酶（JNK）和p38的活性。为了研究这些MAP激酶是否参与介导血红素氧合酶-1基因表达，我们利用了ERK、JNK和p38 MAP激酶信号通路的组成性激活和显性负组分。AP-1位点参与亚砷诱导血红素氧化酶-1基因表达的研究。我们得出结论，MAP激酶ERK和p38参与了血红素加氧酶-1的诱导，并且至少有一个AP-1元件（位于转录起始位点上游- 1576个碱基对）参与了这一反应。
Heme oxygenase-1 is an inducible enzyme that catalyzes heme degradation and has been proposed to play a role in protecting cells against oxidative stress-related injury. We investigated the induction of heme oxygenase-1 by the tumor promoter arsenite in a chicken hepatoma cell line, LMH. We identified a heme oxygenase-1 promoter-driven luciferase reporter construct that was highly and reproducibly expressed in response to sodium arsenite treatment. This construct was used to investigate the role of mitogen-activated protein (MAP) kinases in arsenite-mediated heme oxygenase-1 gene expression. In LMH cells, sodium arsenite, cadmium, and heat shock, but not heme, induced activity of the MAP kinases extracellular-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. To examine whether these MAP kinases were involved in mediating heme oxygenase-1 gene expression, we utilized constitutively activated and dominant negative components of the ERK, JNK, and p38 MAP kinase signaling pathways. Involvement of an AP-1 site in arsenite induction of heme oxygenase-1 gene expression was studied. We conclude that the MAP kinases ERK and p38 are involved in the induction of heme oxygenase-1, and that at least one AP-1 element (located - 1576 base pairs upstream of the transcription start site) is involved in this response.