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

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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.

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Acknowledgement

This work was generously supported by the EEC Framework 6 (LSHM-CT-2006037296 EuroIron1) and the BMBF (HepatoSy-Iron_liver).

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Authors and Affiliations

  1. Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Im Neuenheimer Feld 153, 69120, Heidelberg, Germany

    Guillem Casanovas, Guillem Casanovas, Katarzyna Mleczko-Sanecka, Sandro Altamura & Martina U. Muckenthaler

  2. Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany

    Guillem Casanovas, Katarzyna Mleczko-Sanecka, Sandro Altamura, Matthias W. Hentze & Martina U. Muckenthaler

  3. European Molecular Biology Laboratory, Heidelberg, Germany

    Katarzyna Mleczko-Sanecka, Sandro Altamura & Matthias W. Hentze

Authors
  1. Guillem Casanovas
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  2. Katarzyna Mleczko-Sanecka
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  3. Sandro Altamura
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  4. Matthias W. Hentze
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  5. Martina U. Muckenthaler
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Corresponding author

Correspondence to Martina U. Muckenthaler.

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Supplementary Table 1

Primer pairs used for site-directed mutagenesis to generate luciferase reporter vectors (PPT 137 KB).

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Casanovas, G., Mleczko-Sanecka, K., Altamura, S. et al. Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD. J Mol Med 87, 471–480 (2009). https://doi.org/10.1007/s00109-009-0447-2

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  • DOI: https://doi.org/10.1007/s00109-009-0447-2

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