Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Hypoxia / physiology*
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Cells, Cultured
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DNA Primers / chemistry
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DNA-Binding Proteins
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Fungal Proteins / metabolism
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Gene Expression Regulation
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Glutathione Transferase / metabolism
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Histone Deacetylases / metabolism
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit
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In Vitro Techniques
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Ligases / metabolism*
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Luciferases / metabolism
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Mixed Function Oxygenases
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Molecular Sequence Data
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oxygen / metabolism
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Polymerase Chain Reaction
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Protein Conformation
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Rabbits
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Reticulocytes / metabolism
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Saccharomyces cerevisiae
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Saccharomyces cerevisiae Proteins*
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Sequence Homology, Amino Acid
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Signal Transduction / physiology
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Transcription Factors / genetics*
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Transcription Factors / metabolism*
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Transcription, Genetic
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Transcriptional Activation
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Tumor Suppressor Proteins*
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Two-Hybrid System Techniques
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Ubiquitin-Protein Ligases*
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Von Hippel-Lindau Tumor Suppressor Protein
Substances
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DNA Primers
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DNA-Binding Proteins
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Fungal Proteins
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GAL4 protein, S cerevisiae
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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Repressor Proteins
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Saccharomyces cerevisiae Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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Mixed Function Oxygenases
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Luciferases
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HIF1AN protein, human
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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Glutathione Transferase
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Histone Deacetylases
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Ligases
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VHL protein, human
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Oxygen