S-Space College of Medicine/School of Medicine (의과대학/대학원) Pharmacology (약리학전공) Journal Papers (저널논문_약리학전공)
ROS mediate the hypoxic repression of the hepcidin gene by inhibiting C/EBPalpha and STAT-3
- Choi, Si-On; Cho, Young-Suk; Kim, Hye-Lim; Park, Jong-Wan
- Issue Date
- Biochem Biophys Res Commun. 2007 Apr 27;356(1):312-7. Epub 2007 Mar 5.
- Acetylcysteine/pharmacology; Animals; Anoxia; Antimicrobial Cationic Peptides/*genetics/metabolism; Blotting, Western; CCAAT-Enhancer-Binding Protein-alpha/*metabolism; Cell Hypoxia; Cell Line, Tumor; Dithiothreitol/pharmacology; Down-Regulation/drug effects; Free Radical Scavengers/pharmacology; Gene Expression/drug effects; Humans; Hydrogen Peroxide/pharmacology; Hypoxia-Inducible Factor 1/genetics/metabolism; Mice; Mice, Inbred BALB C; Oxidants/pharmacology; RNA Interference; RNA, Messenger/genetics/metabolism; Reactive Oxygen Species/*metabolism; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor/*metabolism; Transcription, Genetic/drug effects
- Hepcidin, a liver peptide, systemically inhibits iron utilization and is downregulated under hypoxic conditions. However, little is known about the mechanism underlying the hypoxic suppression of hepcidin. Here, we tested the possibility that HIF-1 and ROS are involved in hepcidin regulation. Hepcidin mRNA, pre-mRNA, and protein levels were reduced in mouse livers and in HepG2 cells after hypoxic incubation, and HIF-1 overexpression and knock-down studies showed that hepcidin regulation is independent of HIF-1. On the other hand, ROS levels were significantly elevated in hypoxic HepG2 cells, and anti-oxidants prevented the hypoxic down-regulation of hepcidin. Conversely, a prooxidant, H(2)O(2), suppressed hepcidin expression in these cells even in normoxia. Of the various transcription factors examined, C/EBPalpha and STAT-3 were found to dissociate from hepcidin promoter under hypoxia, but to become fully engaged after anti-oxidant treatment. These results suggest that ROS repress the hepcidin gene by preventing C/EBPalpha and STAT-3 binding to hepcidin promoter during hypoxia.
- 0006-291X (Print)
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