Hypoxia regulates the ferrous iron uptake and reactive oxygen species level via divalent metal transporter 1 (DMT1) Exon1B by hypoxia‐inducible factor‐1
Hypoxia regulates the ferrous iron uptake and reactive oxygen species level via divalent metal transporter 1 (DMT1) Exon1B by hypoxia‐inducible factor‐1
复制标题
DOI：
10.1002/iub.363
复制
发表时间：
2010-08
期刊：
影响因子：
4.6
通讯作者：
Dan Wang;Lihong Wang;Yu Zhao;Yapeng Lu;Li Zhu
中科院分区：
文献类型：
--
作者：
Dan Wang;Lihong Wang;Yu Zhao;Yapeng Lu;Li Zhu
研究表明，缺氧可增加多种参与铁稳态的蛋白的表达，包括铜蓝蛋白、转铁蛋白和转移受体。二价金属转运蛋白1 （DMT1）是一种跨膜蛋白，在二价金属离子（尤其是铁）的转运中起重要作用。虽然已有研究表明DMT1外显子1a受缺氧调节，但对DMT1外显子1b与缺氧之间的关系知之甚少。缺氧诱导因子1 （Hypoxia inducible factor 1, HIF - 1）是一种在哺乳动物细胞缺氧时稳定的转录因子。在这项研究中，我们利用生物信息学和生物学方法的结合，在DMT1外显子1b启动子的- 327至- 323（‐ACGTG‐）位置发现了一个功能性缺氧反应元件（HRE）。缺氧后细胞总铁和亚铁摄取增加，DMT1 RNA干扰后细胞总铁和亚铁摄取减少。+铁响应元件（IRE） DMT1外显子1b过表达也改变了活性氧（ROS）。这些发现暗示DMT1外显子1b是HIF‐1的靶基因。缺氧可能通过调节DMT1的表达影响细胞铁摄取。当铁过量存在时，细胞可能会被ROS的产生所破坏。©2010 IUBMB IUBMB生活，62(8):629-636,2010。
Hypoxia has been shown to increase the expression of a variety of proteins involved in iron homeostasis, including ceruloplasmin, transferrin, and transferring receptor. Divalent metal transporter 1 (DMT1) is a transmembrane protein that is important in divalent metal ion transport, in particular iron. Although previous studies have provided that DMT1 exon1A is regulated by hypoxia, little is known about the relationship between DMT1 exon1B and hypoxia. Hypoxia‐inducible factor 1 (HIF‐1) is a transcription factor which is stabilized when mammalian cells are subjected to hypoxia. In this study, we have identified a functional hypoxia‐response element (HRE) at position of −327 to −323 (‐ACGTG‐) in DMT1 exon1B promoter using a combination of bioinformatics and biological approaches. Both the total cellular iron and ferrous uptake increased after hypoxia, decreased after DMT1 RNA interference. Reactive oxygen species (ROS) were also changed by +iron responsive element (IRE) DMT1 exon1B overexpression. These findings implicated DMT1 exon1B was a target gene for HIF‐1. Hypoxia might affect cellular iron uptake through regulating the expression of DMT1. When iron was present in excess, cells might be damaged by the ROS production. © 2010 IUBMB IUBMB Life, 62(8): 629–636, 2010.