Abstract
The hemochromatosis proteins HFE, transferrin receptor 2 (TfR2) and hemojuvelin (HJV, HFE2) positively control expression of the major iron regulatory hormone hepcidin. HJV is a bone morphogenetic protein (BMP) co-receptor that enhances the cellular response to BMP cytokines via the phosphorylation of SMAD proteins. In this study, we show that two highly conserved and sequence-identical BMP-responsive elements located at positions -84/-79 (BMP-RE1) and -2,255/-2,250 (BMP-RE2) of the human hepcidin promoter are critical for both the basal hepcidin mRNA expression and the hepcidin response to BMP-2 and BMP-6. While BMP-RE1 and BMP-RE2 show additive effects in responding to HJV-mediated BMP signals, only BMP-RE1 that is located in close proximity to a previously identified STAT-binding site is important for the hepcidin response to IL-6. These data identify a missing link between the HJV/BMP signaling pathways and hepcidin transcription, and further define the connection between inflammation and BMP-dependent hepcidin promoter activation. As such, they provide important new information furthering our understanding of disorders of iron metabolism and the anemia of inflammation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antimicrobial Cationic Peptides / genetics*
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Base Sequence
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Binding Sites / genetics
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Bone Morphogenetic Protein 2 / pharmacology
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Bone Morphogenetic Protein 6 / pharmacology
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Bone Morphogenetic Proteins / pharmacology*
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Cell Line, Tumor
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GPI-Linked Proteins
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Gene Expression Regulation / drug effects
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Hemochromatosis Protein
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Hepcidins
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Humans
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Interleukin-6 / pharmacology
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Luciferases / genetics
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Luciferases / metabolism
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Membrane Proteins / metabolism
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Molecular Sequence Data
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Phosphorylation
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Promoter Regions, Genetic / genetics*
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RNA, Small Interfering / genetics
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Response Elements / genetics*
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Reverse Transcriptase Polymerase Chain Reaction
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STAT Transcription Factors / metabolism
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Sequence Homology, Nucleic Acid
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Smad Proteins / metabolism
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Transfection
Substances
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Antimicrobial Cationic Peptides
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BMP2 protein, human
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Protein 6
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Bone Morphogenetic Proteins
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GPI-Linked Proteins
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HAMP protein, human
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HJV protein, human
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Hemochromatosis Protein
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Hepcidins
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Interleukin-6
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Membrane Proteins
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RNA, Small Interfering
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Recombinant Fusion Proteins
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STAT Transcription Factors
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Smad Proteins
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Luciferases