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      Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation.

      Molecular and Cellular Biology

      Transcriptional Activation, Transfection, Cell Hypoxia, genetics, physiology, Cell Line, DNA, Complementary, Basic Helix-Loop-Helix Transcription Factors, Gene Expression Profiling, Gene Expression Regulation, Glycolysis, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Oligonucleotide Array Sequence Analysis, RNA, Messenger, metabolism, Trans-Activators, Transcription Factors, Animals, Base Sequence

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          Transcriptional responses to hypoxia are primarily mediated by hypoxia-inducible factor (HIF), a heterodimer of HIF-alpha and the aryl hydrocarbon receptor nuclear translocator subunits. The HIF-1alpha and HIF-2alpha subunits are structurally similar in their DNA binding and dimerization domains but differ in their transactivation domains, implying they may have unique target genes. Previous studies using Hif-1alpha(-/-) embryonic stem and mouse embryonic fibroblast cells show that loss of HIF-1alpha eliminates all oxygen-regulated transcriptional responses analyzed, suggesting that HIF-2alpha is dispensable for hypoxic gene regulation. In contrast, HIF-2alpha has been shown to regulate some hypoxia-inducible genes in transient transfection assays and during embryonic development in the lung and other tissues. To address this discrepancy, and to identify specific HIF-2alpha target genes, we used DNA microarray analysis to evaluate hypoxic gene induction in cells expressing HIF-2alpha but not HIF-1alpha. In addition, we engineered HEK293 cells to express stabilized forms of HIF-1alpha or HIF-2alpha via a tetracycline-regulated promoter. In this first comparative study of HIF-1alpha and HIF-2alpha target genes, we demonstrate that HIF-2alpha does regulate a variety of broadly expressed hypoxia-inducible genes, suggesting that its function is not restricted, as initially thought, to endothelial cell-specific gene expression. Importantly, HIF-1alpha (and not HIF-2alpha) stimulates glycolytic gene expression in both types of cells, clearly showing for the first time that HIF-1alpha and HIF-2alpha have unique targets.

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