Abstract
Hepcidin plays a major role in the regulation of iron homeostasis. Several bone morphogenetic proteins (BMPs) are strong inducers of hepcidin (Hamp1, HAMP) expression. Hemojuvelin, a protein critical for maintaining appropriate levels of hepcidin, acts as a coreceptor for BMP2 and BMP4, thereby providing a link between iron homeostasis and the BMP-signaling pathway. We show that a robust BMP, hemojuvelin, and SMAD1 response by murine Hamp1 is dependent on a distal BMP responsive element (BMP-RE2), the adjacent bZIP, HNF4alpha/COUP binding sites, and plus or minus 50 bp of the flanking area within -1.6 to -1.7 kb of the Hamp1 promoter. Furthermore, the STAT site and the BMP responsive element (BMP-RE1) located in the proximal 260-bp region of the Hamp1 promoter are also indispensable for maximal activation of hepcidin transcription. The homologous motifs in the distal and proximal regions of the human HAMP promoter act in a manner similar to the murine Hamp1 promoter. Therefore, we propose that the regulation of hepcidin by the BMP pathway involves the formation of a complex of liver-specific and response-specific transcription factors bound to the distal BMP-RE2 /bZIP/HNF4alpha/COUP region and to the proximal BMP-RE1/STAT region possibly by physical association of the 2 regions.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Animals
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Antimicrobial Cationic Peptides / genetics*
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Antimicrobial Cationic Peptides / metabolism
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Basic-Leucine Zipper Transcription Factors / genetics
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Basic-Leucine Zipper Transcription Factors / metabolism
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Bone Morphogenetic Proteins / metabolism*
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COUP Transcription Factors / genetics
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COUP Transcription Factors / metabolism
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Cloning, Molecular
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Electrophoretic Mobility Shift Assay
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GPI-Linked Proteins
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Gene Expression Regulation*
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Hemochromatosis Protein
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Hepatocyte Nuclear Factor 4 / genetics
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Hepatocyte Nuclear Factor 4 / metabolism
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Hepcidins
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / metabolism
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mutagenesis, Site-Directed
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Promoter Regions, Genetic
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT Transcription Factors / genetics
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STAT Transcription Factors / metabolism
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Signal Transduction / physiology*
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Smad1 Protein / genetics
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Smad1 Protein / metabolism
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Transcription Factors / genetics*
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Transfection
Substances
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Antimicrobial Cationic Peptides
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Basic-Leucine Zipper Transcription Factors
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Bone Morphogenetic Proteins
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COUP Transcription Factors
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GPI-Linked Proteins
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HAMP protein, human
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HFE protein, human
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HJV protein, human
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Hamp protein, mouse
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Hemochromatosis Protein
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Hepatocyte Nuclear Factor 4
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Hepcidins
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Histocompatibility Antigens Class I
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Membrane Proteins
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Recombinant Proteins
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STAT Transcription Factors
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Smad1 Protein
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Transcription Factors