Complex cellular functions of the von Hippel–Lindau tumor suppressor gene: insights from model organisms

Abstract

The von Hippel–Lindau tumor suppressor gene (VHL) has attracted intensive interest not only because its mutations predispose carriers to devastating tumors, but also because it is involved in oxygen sensing under physiological conditions. VHL loss-of-function mutations result in organ-specific tumors, such as hemangioblastoma of the central nervous system and renal cell carcinoma, both untreatable with conventional chemotherapies. The VHL protein is best known as an E3 ubiquitin ligase that targets hypoxia-inducible factor-α (HIF-α), but many diverse, non-canonical cellular functions have also been assigned to VHL, mainly based on studies in cell culture systems. As such, although the HIF-dependent role of VHL is critical, the full spectrum of pathophysiological functions of VHL is still unresolved. Such understanding requires careful cross-referencing with physiologically relevant experimental models. Studies in model systems, such as Caenorhabditis elegans, Drosophila, zebrafish and mouse have provided critical in vivo confirmation of the VHL–HIF pathway, and verification of potentially important cellular functions including microtubule stabilization and epithelial morphogenesis. More recently, animal models have also suggested systemic roles of VHL in hematopoiesis, metabolic homeostasis and inflammation. In this review, the studies performed in model organisms will be summarized and placed in context with existing clinical and in vitro data.

Nucleoside diphosphate kinases (NDPKs) in animal development

“…The Hsu laboratory reported AWD as an interaction partner of Drosophila VHL in a yeast two-hybrid screen; later this interaction was further investigated and VHL, which encodes an E3 ubiquitin ligase, was found to stabilize the AWD protein through its non-canonical function [46,47]. Detailed analysis of awd loss-of-function mutants showed ectopic tracheal migration accompanied by overaccumulation of Breathless/FGFR on tracheal cell surfaces [48].…”

Clinical utility gene card for: von Hippel–Lindau (VHL)

“…The various functions of pVHL are not subject of this report and are described in many recent reports and reviews. 15,16,18 A high prevalence of renal cell cancers has been seen in patients with partial germline VHL deletions relative to patients with complete gene deletions. Deletion mapping revealed that development of RCC had an even greater correlation with retention of HSPC300 (C3orf10), located within the 30-kb region of chromosome 3p, immediately telomeric to VHL (52.3 vs 18.9%, Po0.001).…”

Changing Mechanisms of Action as a Strategy for Sequential Targeted Therapy of Metastatic Renal-Cell Carcinoma

“…It is known, that loss of VHL function, including somatic mutations and epigenetic defects, is found in 70-90% of the sporadic clear cell RCC [8]. The pathophysiologic mechanism of such strong association is currently not very understood [8,9].…”

“…Consequently HIF1α dimerise with HIF1β and activate the transcription of genes involved in vessel development (vascular endothelial growth factor, platelet-derived growth factor B, erythropoietin) and genes involved in glucose uptake and metabolism. Up-regulation of targeted genes involved in neovascularization by HIF1α offers the explanation of high vascularity of RCC [2,8]. Beside this, pVHL has numerous other functions in the processes of regulation of extracellular matrix, senescence, phosphorylation enhancers and other.…”

“…According to the type of mutation, patients are classified in different groups, predisposed to different types of tumors. Group of patients bearing deletions or nonsense mutations, most often develop RCC [2,8].…”