Abstract
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates cellular and systemic homeostatic responses to reduced O(2) availability in mammals, including angiogenesis, erythropoiesis, and glycolysis. HIF-1 activity is controlled by the O(2)-regulated expression of the HIF-1alpha subunit. Under nonhypoxic conditions, HIF-1alpha protein is subject to ubiquitination and proteasomal degradation. Here we report that missense mutations and/or deletions involving several different regions of HIF-1alpha result in constitutive expression and transcriptional activity in nonhypoxic cells. We demonstrate that hypoxia results in decreased ubiquitination of HIF-1alpha and that missense mutations increase HIF-1alpha expression under nonhypoxic conditions by blocking ubiquitination.
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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Cell Line
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Cell Nucleus / metabolism
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation*
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Helix-Loop-Helix Motifs
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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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Macromolecular Substances
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Mutagenesis, Site-Directed
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Mutation, Missense*
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Oxygen / physiology*
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Point Mutation
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Protein Processing, Post-Translational
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Sequence Deletion*
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Transcription Factors / genetics
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Transfection
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Ubiquitins / metabolism*
Substances
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DNA-Binding Proteins
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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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Macromolecular Substances
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Nuclear Proteins
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Recombinant Proteins
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Transcription Factors
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Ubiquitins
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Oxygen