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Copper Regulation of Hypoxia-Inducible Factor-1 Activity

Departments of Medicine (W.F., F.Y., W.X., Z.Z., Y.J.K.) and Pharmacology and Toxicology (Y.J.K.), University of Louisville School of Medicine, Louisville, Kentucky

Previous studies have demonstrated that copper up-regulates hypoxia-inducible factor 1 (HIF-1). The present study was undertaken to test the hypothesis that copper is required for HIF-1 activation. Treatment of HepG2 cells with a copper chelator tetraethylenepentamine (TEPA) or short interfering RNA targeting copper chaperone for superoxide dismutase 1 (CCS) suppressed hypoxia-induced activation of HIF-1. Addition of excess copper relieved the suppression by TEPA, but not that by CCS gene silencing, indicating the requirement of copper for activation of HIF-1, which is CCS-dependent. Copper deprivation did not affect production or stability of HIF-1 but reduced HIF-1 binding to the hypoxia-responsive element (HRE) of target genes and to p300, a component of HIF-1 transcriptional complex. Copper probably inhibits the factor inhibiting HIF-1 to ensure the formation of HIF-1 transcriptional complex. This study thus defines that copper is required for HIF-1 activation through the regulation of HIF-1 binding to the HRE and the formation of the HIF-1 transcriptional complex.

Address correspondence to: Dr. Y. James Kang, 511 South Floyd Street, MDR530, University of Louisville School of Medicine, Louisville, KY 40202. E-mail: yjkang01{at}louisville.edu