Copper and Hypoxia-Inducible Transcription Factor Regulation of Gene Expression

Abstract The master regulator of oxygen homeostasis, hypoxia-inducible transcription factor (HIF), is a heterodimer composed of HIF-1α or HIF-2α and HIF1β, and it controls a diversity of cellular events. Under hypoxic condition, HIF-1 specifically upregulates the expression of a group of genes involved in angiogenesis. This specificity of HIF-1 regulation of gene expression requires copper, which promotes HIF-1 transcriptional complex formation and its interaction with hypoxia-response element. A long-term ischemic stress causes copper efflux from tissues, leading to suppressed expression of angiogenesis genes, not other genes. The copper-dependent and copper-independent HIF-1 regulation of angiogenesis provides a fundamental understanding of ischemic disease and of experimental and clinical approaches for intervention.