Abstract
von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome that is characterized by the development of multiple vascular tumors and is caused by inactivation of the von Hippel-Lindau protein (pVHL). Here we show that pVHL, through its beta-domain, binds directly to hypoxia-inducible factor (HIF), thereby targeting HIF for ubiquitination in an alpha-domain-dependent manner. This is the first function to be ascribed to the pVHL beta-domain. Furthermore, we provide the first direct evidence that pVHL has a function analogous to that of an F-box protein, namely, to recruit substrates to a ubiquitination machine. These results strengthen the link between overaccumulation of HIF and development of VHL disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Extracts
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DNA-Binding Proteins / metabolism*
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Deferoxamine / pharmacology
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Elongin
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HeLa Cells
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Humans
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Ligases*
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Mutation
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Nuclear Proteins / metabolism*
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Oxygen / metabolism
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Protein Binding
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Protein Processing, Post-Translational* / drug effects
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Protein Structure, Tertiary
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Proteins / chemistry*
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Proteins / genetics
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Proteins / metabolism*
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Transcription Factors / metabolism
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Proteins*
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Ubiquitin-Protein Ligases*
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Ubiquitins / metabolism*
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Von Hippel-Lindau Tumor Suppressor Protein
Substances
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Cell Extracts
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DNA-Binding Proteins
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Elongin
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HIF1A protein, human
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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Ubiquitins
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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Ligases
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VHL protein, human
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Deferoxamine
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Oxygen