Copper regulation of hypoxia-inducible factor-1 activity.
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-1alpha but reduced HIF-1alpha 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-1alpha binding to the HRE and the formation of the HIF-1 transcriptional complex.
Feng
Wenke
W
Departments of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Ye
Fei
F
Xue
Wanli
W
Zhou
Zhanxiang
Z
Kang
Y James
YJ
D001686:Biological Phenomena; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection
D051793:Hypoxia-Inducible Factor 1; D034741:RNA, Small Interfering; D003300:Copper; D008156:Luciferases