The VHL tumor suppressor and HIF: Insights from genetic studies in mice

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA SY34-04 Patients with germ line mutations in the von Hippel-Lindau tumor suppressor, pVHL, develop a rare familial tumor syndrome, VHL disease. Major disease manifestations include hemangioblastomas of the retina and central nervous system, renal cysts and renal cell cancer of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. pVHL is also mutated in the majority of sporadic CC-RCCs, highlighting its critical and central role in the regulation of renal epithelial cell growth and differentiation. pVHL functions as the substrate recognition component of an E3-ubiquitin ligase and targets the oxygen-sensitive alpha-subunit of Hypoxia-Inducible Factor (HIF) for rapid proteasomal degradation under normoxia. HIFs belong to the PAS (Per-ARNT-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers, which consist of an oxygen-sensitive α-subunit and a constitutively expressed β-subunit, also known as the Arylhydrocarbon Receptor Nuclear Translocator (ARNT) or HIF-β. All three HIF α-subunits, HIF-1α, HIF-2α and HIF-3α are targeted by pVHL. This interaction is highly conserved between species, requires iron and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1α; Pro405 and Pro531 in human HIF-2α) within the oxygen-dependent degradation domain (ODD) of HIF-α and is necessary for the execution of HIF proteolysis under normoxia. Therefore, absence of pVHL results in HIF-α stabilization, increased HIF transcriptional activity and up-regulation of HIF target genes such as vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1) and erythropoietin (EPO) irrespective of oxygen levels. In mice, VHL-associated vascular tumorigenesis and renal cystogenesis can be modeled by conditional inactivation of pVHL in hepatocytes and proximal renal epithelial cells, resulting in constitutive activation of HIF-1 and HIF-2, and the subsequent development of cavernous liver hemangiomas (1, 2) and renal cysts (3, 4). Although VHL-associated liver hemangiomas and CNS hemangioblastomas are distinct with regard to their cellular origin, they share common histological features, such as endothelial cell proliferation, angiectasis and lipid droplet accumulation in neoplastic cells. We have used this conditional mouse model as a genetic tool to dissect the relative contribution of individual HIF transcription factors to VHL-associated vascular tumor development and renal cystogenesis. During this meeting findings from the analysis of tissue-specific VHL/HIF compound knockout mice will be discussed. References 1. Haase VH, Glickman JN, Socolovsky M, Jaenisch R. Vascular tumors in livers with targeted inactivation of the von Hippel- Lindau tumor suppressor. Proc Natl Acad Sci U S A 2001;98(4):1583-8. 2. Rankin EB, Higgins DF, Walisser JA, Johnson RS, Bradfield CA, Haase VH. Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Mol Cell Biol 2005 Apr;25(8):3163-72. 3. Rankin EB, Tomaszewski JE, Haase VH. Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res 2006 Mar 1;66(5):2576-83. 4. Haase VH. Hypoxia-inducible factors in the kidney. Am J Physiol Renal Physiol 2006 Aug;291(2):F271-81.