Hypoxia regulates the ferrous iron uptake and reactive oxygen species level via divalent metal transporter 1 (DMT1) Exon1B by hypoxia-inducible factor-1.
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.
Wang
Dan
D
Department of Biochemistry, Institute for Nautical Medicine, Nantong University, Nantong, People's Republic of China.
Wang
Li-Hong
LH
Zhao
Yu
Y
Lu
Ya-Peng
YP
Zhu
Li
L
D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D049109:Cell Proliferation; D005091:Exons / Q000235:genetics; D005296:Ferrous Compounds / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013054:Spectrophotometry, Atomic; D014158:Transcription, Genetic; D014162:Transfection; D000099236:Solute Carrier Family 11, Member 2
D027682:Cation Transport Proteins; D005296:Ferrous Compounds; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron; D008156:Luciferases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000099236:Solute Carrier Family 11, Member 2; C497442:HIF1A protein, human