Submitted May 29, 2008
Accepted August 22, 2008
Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness
Jaroslav Truksa, Pauline Lee*, and Ernest Beutler
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, United States
* Corresponding author; email: plee{at}scripps.edu.
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 co-receptor 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, HNF4
/COUP binding sites, and +/- 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/HNF4/COUP region and to the proximal BMP-RE1/STAT region possibly by physical association of the two regions.
