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Molecular and Cellular Biology, April 2005, p. 3163-3172, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.3163-3172.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice

Erinn B. Rankin,1,2 Debra F. Higgins,1 Jacqueline A. Walisser,3 Randall S. Johnson,4 Christopher A. Bradfield,3 and Volker H. Haase1,2*

Department of Medicine,1 Cell and Molecular Biology Graduate Group, Program in Cell Growth and Cancer, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,2 McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin,3 Molecular Biology Section, Division of Biological Sciences, University of California—San Diego, La Jolla, California4

Received 3 September 2004/ Returned for modification 7 October 2004/ Accepted 11 January 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-1{alpha} (Hif-1{alpha}) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1{alpha} 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.

* Corresponding author. Mailing address: Department of Medicine, 700 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104-6144. Phone: (215) 573-1830. Fax: (215) 898-0189. E-mail: vhaase{at}mail.med.upenn.edu.

Molecular and Cellular Biology, April 2005, p. 3163-3172, Vol. 25, No. 8
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.8.3163-3172.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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