Abstract
Hypoxia-inducible factors (HIF1α/HIF2α) are key transcription factors that promote angiogenesis. The overexpression of degradation-resistant HIF mutants is considered a promising pro-angiogenic therapeutic tool. We compared the transcriptional activity of HIF1α/HIF2α mutants that obtained their resistance to oxygen-dependent degradation either by deletion of their entire oxygen-dependent degradation (ODD) domain or by replacement of prolyl residues that are crucial for oxygen-dependent degradation. Although all HIF mutants translocated into the nucleus, HIF1α and HIF2α mutants inclosing the point mutations were significantly more effective in trans-activating the target gene VEGF and in inducing tube formation of endothelial cells than mutants lacking the complete ODD domain.
© 2011 Landes Bioscience
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Binding Sites / genetics
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Cell Line
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Cell Nucleus / metabolism
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Endothelial Cells / metabolism
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Endothelial Cells / physiology
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Gene Deletion*
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HEK293 Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Immunoblotting
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Luciferases / genetics
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Luciferases / metabolism
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Mice
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Microscopy, Fluorescence
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Neovascularization, Physiologic
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Oxygen / metabolism
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Point Mutation*
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Reverse Transcriptase Polymerase Chain Reaction
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Transcription, Genetic / genetics*
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Transcriptional Activation
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Transfection
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Hypoxia-Inducible Factor 1, alpha Subunit
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Vascular Endothelial Growth Factor A
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endothelial PAS domain-containing protein 1
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Luciferases
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Oxygen