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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. This Article Full Text (PDF) All Versions of this Article: 2004-10-3980v1 105/12/4613    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Martin, F. Articles by Wenger, R. H Search for Related Content PubMed PubMed Citation Articles by Martin, F. Articles by Wenger, R. H Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 14, 2004 Accepted February 18, 2005 Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation Falk Martin, Tobias Linden, Dorthe M Katschinski, Felix Oehme, Ingo Flamme, Chinmay K Mukhopadhyay, Katrin Eckhardt, Juliane Troger, Sandra Barth, Gieri Camenisch, and Roland H Wenger* Carl-Ludwig-Institute of Physiology, University of Leipzig, Leipzig, Germany Institute of Physiology, University of Lubeck, Lubeck, Germany Cell Physiology Group, Medical Faculty, Martin-Luther-University Halle, Halle, Germany Institute for Cardiovascular Research, Bayer HealthCare AG, Wuppertal, Germany The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA Institute of Physiology, University of Zurich, Zurich, Switzerland * Corresponding author; email: roland.wenger{at}access.unizh.ch. 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 VEGF and Glut-1) mRNA levels in hepatoma cells which was due to transcriptional induction of the ceruloplasmin gene 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. O. Simmons, C.-Y. Fan, and R. Ramabhadran Cellular Stress Response Pathway System as a Sentinel Ensemble in Toxicological Screening Toxicol. Sci., October 1, 2009; 111(2): 202 - 225. [Abstract] [Full Text] [PDF] S. Barth, F. Edlich, U. Berchner-Pfannschmidt, S. Gneuss, G. Jahreis, P. A. Hasgall, J. Fandrey, R. H. Wenger, and G. 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