PT  - JOURNAL ARTICLE
AU  - Wenke Feng
AU  - Fei Ye
AU  - Wanli Xue
AU  - Zhanxiang Zhou
AU  - Y. James Kang
TI  - Copper Regulation of Hypoxia-Inducible Factor-1 Activity
AID  - 10.1124/mol.108.051516
DP  - 2009 Jan 01
TA  - Molecular Pharmacology
PG  - 174--182
VI  - 75
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/75/1/174.short
4100  - http://molpharm.aspetjournals.org/content/75/1/174.full
SO  - Mol Pharmacol2009 Jan 01; 75
AB  - 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-1α but reduced HIF-1α 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-1α binding to the HRE and the formation of the HIF-1 transcriptional complex. The American Society for Pharmacology and Experimental Therapeutics