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

Abstract

The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive alpha-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype.

Figure 1

Hepatic vascular tumors in mice that lack pVHL in hepatocytes. (a) Gross photograph of a liver with multiple cavernous hemangiomas (arrows). (b) Histological features of cavernous liver hemangiomas. A paraffin-embedded tissue section stained with H&E is shown. Asterisks depict endothelial cell-lined, blood-filled cavities and areas of hemorrhage. VHL-associated liver hemangiomas are typically associated with macro- and microvesicular hepatocellular accumulation of neutral lipids, here depicted by arrows. Lipid accumulation is also a feature of stromal cells, the neoplastic component of VHL-associated central nervous system hemangioblastomas^,

Figure 2

Mice that lack pVHL in the proximal renal tubule develop tubular and glomerular cysts. (a) Gross in situ photograph of a kidney from a male PEPCK-Cre mutant with two macroscopically visible cysts (arrows). The PEPCK-Cre transgene was used to inactivate pVHL in the proximal renal tubule. Genetic analysis with compound knockout mice demonstrated that this phenotype was HIF dependent. (b-d) Histological features of cystic changes found in H&E-stained paraffin sections from VHL-deficient kidneys. A large cortical cyst (b), a cluster of renal tubular cysts lined by cuboidal epithelium (asterisks in c) and an area of glomerular cysts (number sign in d) are shown. CC-RCC or dysplastic changes in cysts were not found in VHL-deficient kidneys. Magnification is × 100

Figure 3

Schematic illustrating the role of pVHL and HIF in the development of the VHL phenotype. While activation of HIF signaling is required and sufficient for vascular tumor development, renal cystogenesis in humans may be a result of HIF activation ± loss of HIF-independent functions of pVHL. CC-RCC development most likely requires additional mutations in other tumor suppressor genes or in certain oncogenes. (a) Gross photography of a liver hemangioma found in a VHL mutant mouse. (b, c) Human renal cell carcinoma of the clear cell type (CC-RCC); (b) gross photography; (c) PAS stain of CC-RCC, clear cells are depicted by arrows, magnification × 400; images (b, c) were kindly provided by Dr. John Tomaszewski, Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA