Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice.

Rankin EB, Higgins DF, Walisser JA, Johnson RS, Bradfield CA, Haase VH
Mol Cell Biol. 2005 25 (8): 3163-72

PMID: 15798202 · PMCID: PMC1069599 · DOI:10.1128/MCB.25.8.3163-3172.2005

Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1alpha (Hif-1alpha) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1alpha did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.

MeSH Terms (24)

Animals Aryl Hydrocarbon Receptor Nuclear Translocator DNA-Binding Proteins Erythropoietin Gene Deletion Gene Expression Genes, Tumor Suppressor Gene Silencing Hemangioma, Cavernous Hepatocytes Hypoxia-Inducible Factor 1, alpha Subunit Liver Liver Neoplasms Mice Mice, Knockout Phosphotransferases (Alcohol Group Acceptor) Polycythemia Receptors, Aryl Hydrocarbon Transcription Factors Tumor Suppressor Proteins Ubiquitin-Protein Ligases Vascular Endothelial Growth Factor A von Hippel-Lindau Disease Von Hippel-Lindau Tumor Suppressor Protein

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