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 a-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. Germ-line mutations in the von Hippel-Lindau tumor (VHL) suppressor can be found in patients with VHL disease, a rare familial tumor syndrome characterized by the development of highly vascularized tumors in multiple organs. Major clinical manifestations of VHL disease include hemangioblastomas of the retina and central nervous system (CNS), renal cysts and renal cell carcinoma of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. 1 The VHL tumor suppressor is also mutated in the majority of sporadic CC-RCCs, 2 highlighting its critical and central role in the regulation of cell growth and differentiation of epithelial kidney cells. Although the molecular function of the VHL gene product, pVHL, was initially not known when it was first identified by positional cloning in 1993, 3 observations that oxygen-dependent regulation of hypoxia-inducible genes was lost in VHL-deficient cell lines suggested a role for pVHL in oxygen sensing. [4][5][6] In a seminal paper, Maxwell et al. 7 showed that pVHL was critical for targeting the a-subunit of hypoxia-inducible factor (HIF) for oxygen-dependent proteolysis, thus providing a direct molecular link between VHLassociated tumorigenesis and oxygen sensing via HIF. HIFs belong to the PAS (Per-arylhydrocarbon receptor nuclear translocator (ARNT)-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers. They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, also known as ARNT or HIF-b. pVHL associates with the elongins B and C, cullin2 and Rbx [8][9][10][11][12] and functions as the substrate recognition component of an E3-ubiquitin ligase that ubiquitylates HIF-a. [13][14][15][16][17][18][19] All three HIF a-subunits, HIF-1a, HIF-2a and HIF-3a interact with pVHL. 7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in ...

Hypoxia-Inducible Transcription Factors Stabilization in the Thick Ascending Limb Protects against Ischemic Acute Kidney Injury

“…Although these findings complement previous data showing that systemic and nonselective cellular stabilization of HIF protects against ischemic 29,31 and toxic renal injury, 28,30 this study extends these results by demonstrating that Vhl deletion in a specific nephron segment is sufficient to achieve renal protection. Moreover, in contrast to previously published mice with cell type specific inactivation of Vhl, 32 the phenotype of animals with Vhl deletion in TALs was surprisingly normal, indicating that Vhl pathology is context-dependent.…”

“…25,26 Previous studies have shown that systemic hypoxia or pharmacologic approaches to stabilize HIF can protect the kidney against subsequent ischemic or toxic injury. [27][28][29][30][31] In addition, Vhl knockout strategies have been successfully applied to stabilize HIF genetically 32 and acute ubiquitous inactivation of Vhl has recently been shown to ameliorate ischemic AKI. 33 All of these approaches have so far not allowed defining the role of specific parts of the nephron in AKI protection.…”

Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis

“…This observation has remained an enigma since this report by Gnarra et al (27) was published in 1997. Vhl −/− mice die during gestation (27), but simultaneous inactivation of both Vhl alleles in kidney epithelial cells similarly failed to induce renal tumorigenesis (28)(29)(30)(31). These experiments are confounded by lack of knowledge about the cell type of origin of ccRCC and restricted Cre expression (28-31); however, as we show, even when Vhl is inactivated in multipotent NPCs, Vhl loss is insufficient for renal tumorigenesis.…”

Deletion of von Hippel–Lindau Protein Converts Renin-Producing Cells into Erythropoietin-Producing Cells

“…To mimic chronic hypoxia, we stabilized hypoxia inducible transcription factors by the deletion of the von Hippel-Lindau protein (pVHL). 10 pVHL mediates oxygen-dependent proteasomal degradation of hypoxiainducible transcription factor-a (HIF-a) protein and thereby, acts as a negative regulator of HIF. 11 Cell-specific deletion of Vhl, therefore, activates HIF-regulated pathways in these cells.…”