Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice.
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.
Rankin
Erinn B
EB
Department of Medicine, 700 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104-6144, USA.
Higgins
Debra F
DF
Walisser
Jacqueline A
JA
Johnson
Randall S
RS
Bradfield
Christopher A
CA
Haase
Volker H
VH
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006392:Hemangioma, Cavernous / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008099:Liver / Q000098:blood supply / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011086:Polycythemia / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000378:metabolism
C497397:Arnt protein, mouse; D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D017853:Phosphotransferases (Alcohol Group Acceptor); C023916:phosphoglycerol kinase