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      FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity.

      Genes & development

      Amino Acid Sequence, Animals, Cell Hypoxia, physiology, Cells, Cultured, DNA Primers, chemistry, DNA-Binding Proteins, Fungal Proteins, metabolism, Gene Expression Regulation, Glutathione Transferase, Histone Deacetylases, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, In Vitro Techniques, Ligases, Luciferases, Mixed Function Oxygenases, Molecular Sequence Data, Nuclear Proteins, genetics, Oxygen, Polymerase Chain Reaction, Protein Conformation, Rabbits, Repressor Proteins, Reticulocytes, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Signal Transduction, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Tumor Suppressor Proteins, Two-Hybrid System Techniques, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein

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          Hypoxia-inducible factor 1 (HIF-1) is a master regulator of oxygen homeostasis that controls angiogenesis, erythropoiesis, and glycolysis via transcriptional activation of target genes under hypoxic conditions. O(2)-dependent binding of the von Hippel-Lindau (VHL) tumor suppressor protein targets the HIF-1alpha subunit for ubiquitination and proteasomal degradation. The activity of the HIF-1alpha transactivation domains is also O(2) regulated by a previously undefined mechanism. Here, we report the identification of factor inhibiting HIF-1 (FIH-1), a protein that binds to HIF-1alpha and inhibits its transactivation function. In addition, we demonstrate that FIH-1 binds to VHL and that VHL also functions as a transcriptional corepressor that inhibits HIF-1alpha transactivation function by recruiting histone deacetylases. Involvement of VHL in association with FIH-1 provides a unifying mechanism for the modulation of HIF-1alpha protein stabilization and transcriptional activation in response to changes in cellular O(2) concentration.

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