Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness.
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.
Truksa
Jaroslav
J
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Lee
Pauline
P
Beutler
Ernest
E
D020816:Amino Acid Motifs; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D051836:COUP Transcription Factors / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D024202:Electrophoretic Mobility Shift Assay; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D000071020:Hemochromatosis Protein; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection
D023181:Antimicrobial Cationic Peptides; D050976:Basic-Leucine Zipper Transcription Factors; D019485:Bone Morphogenetic Proteins; D051836:COUP Transcription Factors; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C103673:HFE protein, human; C481006:HJV protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D051557:Hepatocyte Nuclear Factor 4; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011994:Recombinant Proteins; D050791:STAT Transcription Factors; D051898:Smad1 Protein; D014157:Transcription Factors