Hypoxia regulates the ferrous iron uptake and reactive oxygen species level via divalent metal transporter 1 (DMT1) Exon1B by hypoxia-inducible factor-1

Authors

  • Dan Wang,

    1. Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong 226001, People's Republic of China
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    • The first two authors made the same contribution to this article.

  • Li-Hong Wang,

    1. Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong 226001, People's Republic of China
    2. Cancer Research Center, Xiamen University Medical College, Xiamen 361005, People's Republic of China
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    • The first two authors made the same contribution to this article.

  • Yu Zhao,

    1. Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong 226001, People's Republic of China
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  • Ya-Peng Lu,

    1. Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong 226001, People's Republic of China
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  • Li Zhu

    Corresponding author
    1. Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong 226001, People's Republic of China
    • Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong 226001, People's Republic of China
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    • Tel: 86 139 6298 8532. Fax: 86 513 85051796


Abstract

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.

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