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Hypoxia results in adaptive changes in the transcription of a range of genes including erythropoietin. An important mediator is hypoxia-inducible factor-1 (HIF-1), a DNA binding complex shown to contain at least two basic helix-loop-helix PAS-domain (bHLH-PAS) proteins, HIF-1alpha and aryl hydrocarbon nuclear receptor translocator (ARNT). In response to hypoxia, HIF-1alpha is activated and accumulates rapidly in the cell. Endothelial PAS domain protein 1 (EPAS-1) is a recently identified bHLH-PAS protein with 48% identity to HIF-1alpha, raising the question of its role in responses to hypoxia. We developed specific antibodies and studied expression and regulation of EPAS-1 mRNA and protein across a range of human cell lines. EPAS-1 was widely expressed, and strongly induced by hypoxia at the level of protein but not mRNA. Comparison of the effect of a range of activating and inhibitory stimuli showed striking similarities in the EPAS-1 and HIF-1alpha responses. Although major differences were observed in the abundance of EPAS-1 and HIF-1alpha in different cell types, differences in the inducible response were subtle with EPAS-1 protein being slightly more evident in normoxic and mildly hypoxic cells. Functional studies in a mutant cell line (Ka13) expressing neither HIF-1alpha nor EPAS-1 confirmed that both proteins interact with hypoxically responsive targets, but suggest target specificity with greater EPAS-1 transactivation (relative to HIF-1alpha transactivation) of the VEGF promoter than the LDH-A promoter.


Journal article



Publication Date





2260 - 2268


Institute of Molecular Medicine and the Department of Cellular Science, John Radcliffe Hospital, Oxford, UK.


Cell Line, COS Cells, Hela Cells, CHO Cells, Animals, Mice, Inbred BALB C, Humans, Cricetulus, Mice, Cobalt, Deferoxamine, Onium Compounds, L-Lactate Dehydrogenase, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Endothelial Growth Factors, DNA-Binding Proteins, Trans-Activators, Nuclear Proteins, Receptors, Aryl Hydrocarbon, Recombinant Fusion Proteins, Transcription Factors, RNA, Messenger, Lymphokines, Iron Chelating Agents, Transfection, Cell Hypoxia, Gene Expression Regulation, Cricetinae, Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Transcription Factors, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Promoter Regions, Genetic, Transcriptional Activation