Oxygen- and dioxin-regulated gene expression in mouse hepatoma cells
Oxygen- and dioxin-regulated gene expression in mouse hepatoma cells
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DOI：
10.1038/ki.1997.81
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发表时间：
1997-02-01
影响因子：
19.6
通讯作者：
Wenger, RH
中科院分区：
文献类型：
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作者：
Gassmann, M;Kvietikova, I;Wenger, RH
氧调节转录因子HIF-1 α和二恶英受体AhR具有共同的helerodi聚化伙伴ARNT (HIF-1 β)，这一发现提出了氧和二恶英信号转导途径之间是否存在串扰的问题。为了回答这个问题，我们研究了一种缺乏arnt的突变细胞系（Hepa1C4），它已经失去了对二恶英的反应能力。结果表明，ARNT的存在对于缺氧诱导的HIF-1 DNA结合以及由EPO 3'缺氧反应元件（HRE）介导的氧调节报告基因活性是必不可少的。然而，在Hepa1C4细胞中，缺氧诱导血管内皮生长因子（VEGF）基因的作用仅部分消失，这表明可能存在不依赖hif -1的氧信号通路。通过缺氧和/或二恶英类似物ICZ治疗小鼠Hepa1肝癌细胞，我们进一步研究了HIF-1和AhR/ARNT DNA结合活性以及氧和异种生物反应基因的调节。缺氧诱导的VEGF表达与icz处理无关，而icz诱导的细胞色素P-450IA1表达在细胞缺氧处理后略有降低。有趣的是,缺氧诱导与报告基因连接的异种反应元件（XRE）的增强子功能，但含有hre的报告基因的表达不受ICZ处理的影响。
The discovery that the oxygen-regulated transcription factor HIF-1 alpha and the dioxin receptor AhR share the common helerodimerization partner ARNT (HIF-1 beta) raised the question whether a cross-talk between oxygen and dioxin signal transduction pathways exists. To answer this question we investigated an ARNT-deficient mutant cell line (Hepa1C4), which has lost its capability of responding to dioxin. The results demonstrate that the presence of ARNT is indispensable for hypoxia-inducible HIF-1 DNA binding as well as for oxygen-regulated reporter gene activity mediated by the EPO 3' hypoxia response element (HRE). Hypoxic induction of the vascular endothelial growth factor (VEGF) gene, however, was only partially abrogated in Hepa1C4 cells, suggesting that HIF-1-independent oxygen signaling pathways might exist. We further studied HIF-1 and AhR/ARNT DNA binding activity as well as the regulation of oxygen- and xenobiotic-responsive genes by treating mouse Hepa1 hepatoma cells with hypoxia and/or the dioxin analogue ICZ. Hypoxia-inducible VEGF expression was found to be independent of ICZ-treatment, whereas ICZ-inducible cytochrome P-450IA1 expression was slightly reduced by hypoxic treatment of the cells. Interestingly; the enhancer function of a xenobiotic response element (XRE) linked to a reporter gene was induced by hypoxia, but expression of a HRE-containing reporter gene was not affected by ICZ treatment.