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ROS mediate the hypoxic repression of the hepcidin gene by inhibiting C/EBPalpha and STAT-3

Cited 87 time in Web of Science Cited 92 time in Scopus
Authors
Choi, Si-On; Cho, Young-Suk; Kim, Hye-Lim; Park, Jong-Wan
Issue Date
2007-03-14
Publisher
Elsevier
Citation
Biochem Biophys Res Commun. 2007 Apr 27;356(1):312-7. Epub 2007 Mar 5.
Keywords
Acetylcysteine/pharmacologyAnimalsAnoxiaAntimicrobial Cationic Peptides/*genetics/metabolismBlotting, WesternCCAAT-Enhancer-Binding Protein-alpha/*metabolismCell HypoxiaCell Line, TumorDithiothreitol/pharmacologyDown-Regulation/drug effectsFree Radical Scavengers/pharmacologyGene Expression/drug effectsHumansHydrogen Peroxide/pharmacologyHypoxia-Inducible Factor 1/genetics/metabolismMiceMice, Inbred BALB COxidants/pharmacologyRNA InterferenceRNA, Messenger/genetics/metabolismReactive Oxygen Species/*metabolismReverse Transcriptase Polymerase Chain ReactionSTAT3 Transcription Factor/*metabolismTranscription, Genetic/drug effects
Abstract
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.
ISSN
0006-291X (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17349976

http://hdl.handle.net/10371/27753
DOI
https://doi.org/10.1016/j.bbrc.2007.02.137
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College of Medicine/School of Medicine (의과대학/대학원)Pharmacology (약리학전공)Journal Papers (저널논문_약리학전공)
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