Journal of Molecular Medicine

, Volume 87, Issue 5, pp 471–480

Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD

  • Guillem Casanovas
  • Katarzyna Mleczko-Sanecka
  • Sandro Altamura
  • Matthias W. Hentze
  • Martina U. Muckenthaler
Original Article

DOI: 10.1007/s00109-009-0447-2

Cite this article as:
Casanovas, G., Mleczko-Sanecka, K., Altamura, S. et al. J Mol Med (2009) 87: 471. doi:10.1007/s00109-009-0447-2

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.

Keywords

Hereditary hemochromatosis Hemojuvelin SMAD Anemia of inflammation IL-6 

Supplementary material

109_2009_447_MOESM1_ESM.ppt (138 kb)
Supplementary Table 1Primer pairs used for site-directed mutagenesis to generate luciferase reporter vectors (PPT 137 KB).

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Guillem Casanovas
    • 1
    • 1
    • 2
  • Katarzyna Mleczko-Sanecka
    • 1
    • 2
    • 3
  • Sandro Altamura
    • 1
    • 2
    • 3
  • Matthias W. Hentze
    • 2
    • 3
  • Martina U. Muckenthaler
    • 1
    • 2
  1. 1.Department of Pediatric Oncology, Hematology and ImmunologyUniversity of HeidelbergHeidelbergGermany
  2. 2.Molecular Medicine Partnership UnitEuropean Molecular Biology LaboratoryHeidelbergGermany
  3. 3.European Molecular Biology LaboratoryHeidelbergGermany