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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4613-4619.
Prepublished online as a Blood First Edition Paper on March 1, 2005; DOI 10.1182/blood-2004-10-3980.
 Previous Article | Table of Contents | Next Article 
HEMATOPOIESIS
Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation
Falk Martin,
Tobias Linden,
Dörthe M. Katschinski,
Felix Oehme,
Ingo Flamme,
Chinmay K. Mukhopadhyay,
Katrin Eckhardt,
Juliane Tröger,
Sandra Barth,
Gieri Camenisch, and
Roland H. Wenger
From the Carl-Ludwig-Institute of Physiology, University of Leipzig, Germany; Institute of Physiology, University of Lübeck, Germany; Cell Physiology Group, Medical Faculty, Martin-Luther-University Halle, Germany; Institute for Cardiovascular Research, Bayer HealthCare AG, Wuppertal, Germany; 5th Lerner Research Institute, Cleveland Clinic Foundation, OH; and the Institute of Physiology, University of Zürich, Switzerland.
Cellular oxygen partial pressure is sensed by a family of prolyl-4-hydroxylase domain (PHD) enzymes that modify hypoxia-inducible factor (HIF) subunits. Upon hydroxylation under normoxic conditions, HIF is bound by the von Hippel-Lindau tumor suppressor protein and targeted for proteasomal destruction. Since PHD activity is dependent on oxygen and ferrous iron, HIF-1 mediates not only oxygen- but also iron-regulated transcriptional gene expression. Here we show that copper (CuCl2) stabilizes nuclear HIF-1 under normoxic conditions, resulting in hypoxia-response element (HRE)-dependent reporter gene expression. In in vitro hydroxylation assays CuCl2 inhibited prolyl-4-hydroxylation independently of the iron concentration. Ceruloplasmin, the main copper transport protein in the plasma and a known HIF-1 target in vitro, was also induced in vivo in the liver of hypoxic mice. Both hypoxia and CuCl2 increased ceruloplasmin (as well as vascular endothelial growth factor [VEGF] and glucose transporter 1 [Glut-1]) mRNA levels in hepatoma cells, which was due to transcriptional induction of the ceruloplasmin gene (CP) promoter. In conclusion, our data suggest that PHD/HIF/HRE-dependent gene regulation can serve as a sensory system not only for oxygen and iron but also for copper metabolism, regulating the oxygen-, iron- and copper-binding transport proteins hemoglobin, transferrin, and ceruloplasmin, respectively. (Blood. 2005;105:4613-4619)
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