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 hemochromatosisHemojuvelinSMADAnemia of inflammationIL-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