Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD.
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.
Casanovas
Guillem
G
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Im Neuenheimer Feld 153, 69120, Heidelberg, Germany.
Mleczko-Sanecka
Katarzyna
K
Altamura
Sandro
S
Hentze
Matthias W
MW
Muckenthaler
Martina U
MU
D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D055418:Bone Morphogenetic Protein 6 / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D051785:Smad Proteins / Q000378:metabolism; D014162:Transfection
D023181:Antimicrobial Cationic Peptides; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015850:Interleukin-6; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D050791:STAT Transcription Factors; D051785:Smad Proteins; D008156:Luciferases