Dynamic, site-specific interaction of hypoxia-inducible factor-1alpha with the von Hippel-Lindau tumor suppressor protein.
Hypoxia-inducible factor (HIF)-1alpha is a transcription factor that plays a critical role in regulating genes involved in erythropoiesis and angiogenesis. Recent evidence indicates that the von Hippel-Lindau tumor suppressor protein (VHL) is part of a ubiquitin ligase complex that promotes the degradation of HIF-1alpha under normoxic conditions. Under hypoxic conditions, ... HIF-1alpha is markedly stabilized. A critical issue in understanding the hypoxic response is the identification of hypoxia-regulated steps. We show here that hypoxia and cobalt treatment modulate the capacity of a HIF-1alpha fragment comprising residues 531-652 to coimmunoprecipitate with VHL. Hypoxia and cobalt both significantly diminish the interaction, and furthermore, normoxia treatment after hypoxia rapidly normalizes it. This HIF-1alpha fragment confers hypoxia and cobalt inducibility on a heterologous protein. Significantly, contained within this fragment is a short 27-residue sequence that behaves identically in all respects noted above. Finally, evidence is provided to show that cobalt and hypoxia both induce a posttranslational modification (or loss of one) in HIF-1alpha that affects its binding to VHL. We propose that dynamic, site-specific interaction of HIF-1alpha with VHL provides one mechanism by which HIF-1alpha can be regulated.
Mesh Terms:
Amino Acid Sequence, Animals, Binding Sites, COS Cells, Cell Hypoxia, Cobalt, DNA-Binding Proteins, Fungal Proteins, Hela Cells, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Ligases, Molecular Sequence Data, Nuclear Proteins, Precipitin Tests, Proteins, Recombinant Fusion Proteins, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Substrate Specificity, Transcription Factors, Transfection, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
Amino Acid Sequence, Animals, Binding Sites, COS Cells, Cell Hypoxia, Cobalt, DNA-Binding Proteins, Fungal Proteins, Hela Cells, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Ligases, Molecular Sequence Data, Nuclear Proteins, Precipitin Tests, Proteins, Recombinant Fusion Proteins, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Substrate Specificity, Transcription Factors, Transfection, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
Cancer Res.
Date: May. 15, 2001
PubMed ID: 11358837
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