Abstract
The von Hippel-Lindau tumor suppressor pVHL regulates the stability of hypoxia-inducible factors (HIF)-1 and -2, oxygen-sensitive basic helix-loop-helix transcription factors, which mediate the hypoxic induction of angiogenic growth factors such as vascular endothelial growth factor. Loss of pVHL function results in constitutive activation of HIF-1 and HIF-2 and is associated with the development of highly vascularized tumors in multiple organs. We have used a conditional gene-targeting approach to investigate the relative contributions of HIF-1 and HIF-2 to VHL-associated vascular tumorigenesis in a mouse model of liver hemangiomas. Here we demonstrate genetically that conditional inactivation of HIF-2alpha suppressed the development of VHL-associated liver hemangiomas and that angiogenic gene expression in hepatocytes is predominantly regulated by HIF-2 and not by HIF-1. These findings suggest that HIF-2 is the dominant HIF in the pathogenesis of VHL-associated vascular tumors and that pharmacologic targeting of HIF-2 may be an effective strategy for their treatment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / physiology*
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic*
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Hemangioma / blood supply
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Hemangioma / metabolism
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Hemangioma / pathology*
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Hepatocytes / metabolism
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / physiology
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Integrases / metabolism
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Liver Neoplasms / blood supply
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology*
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Neovascularization, Pathologic
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Oligonucleotide Array Sequence Analysis
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism*
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Von Hippel-Lindau Tumor Suppressor Protein / physiology*
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von Hippel-Lindau Disease
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Biomarkers, Tumor
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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endothelial PAS domain-containing protein 1
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Von Hippel-Lindau Tumor Suppressor Protein
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Cre recombinase
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Integrases
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VHL protein, mouse