VHL, the story of a tumour suppressor gene

Abstract

Since the Von Hippel-Lindau (VHL) disease tumour suppressor gene VHL was identified in 1993 as the genetic basis for a rare disorder, it has proved to be of wide medical and scientific interest. VHL tumour suppressor protein (pVHL) plays a key part in cellular oxygen sensing by targeting hypoxia-inducible factors for ubiquitylation and proteasomal degradation. Early inactivation of VHL is commonly seen in clear-cell renal cell carcinoma (ccRCC), and insights gained from the functional analysis of pVHL have provided the foundation for the routine treatment of advanced-stage ccRCC with novel targeted therapies. However, recent sequencing studies have identified additional driver genes that are involved in the pathogenesis of ccRCC. As our understanding of the importance of VHL matures, it is timely to review progress from its initial description to current knowledge of VHL biology, as well as future prospects for novel medical treatments for VHL disease and ccRCC.

Genetic alterations in Japanese extrahepatic biliary tract cancer

“…Although mutations of VHL have been less frequently reported in BTC than RCC, immunohistochemical staining revealed decreased VHL expression levels in (31/33; 93.9%) of GBC cases (56). Genetic alterations induce loss of VHL, which increases survival rate through the increased expression of VEGF, PDGF, TGF-β, GLUT1 and FGF genes (57). Patients suffering from RCC with a VHL mutation are often treated by tyrosine kinase inhibitors, anti-vascular endothelial growth factor (VGF) antibodies and mechanistic target of rapamycin inhibitors (58).…”

The epigenetic landscape of renal cancer

“…The majority of the inactivating events are point mutations 4,15,20,21 . The VHL disease tumour suppressor protein (pVHL) has multiple functions 22 , and is best known as a regulator of oxygen and energy sensing via the targeted degradation of the hypoxia-inducible factors (HIF) 1 and HIF2 [Au: Refs OK?]. pVHL also regulates key cellular processes including glucose uptake and metabolism, angiogenesis, pH homeostasis, chemotaxis, proliferation and survival, apoptosis, transcription regulation and cellular senescence through both HIF-dependent and HIF-independent mechanisms 22 ( FIG.…”

“…The two HIF proteins (HIF1α and HIF2α) have contradictory roles in renal tumour progression: HIF1α has tumour-suppressing activity, whereas HIF2α is oncogenic [189][190][191] . pVHL decreases HIF1α and HIF2α protein levels 22 and induces the expression of miR-30c-2-3p and miR-30a-3p, which target HIF2α transcripts for degradation. Loss of pVHL, therefore, increases HIF1α and HIF2α protein levels and promotes HIF2α transcription through the loss of miR-30c-2-3p and miR-30a-3p 192 .…”

Actin Cytoskeletal Organization in Drosophila Germline Ring Canals Depends on Kelch Function in a Cullin-RING E3 Ligase

“…pVHL, the product of the VHL tumor-suppressor gene, functions as a SRS for a CRL2 ubiquitin ligase, targeting HIF1a, HIF2a, and other proteins for ubiquitylation and destruction (Frew and Krek 2008;Gossage et al 2015). However, the pVHL protein also binds to and stabilizes microtubules (Hergovich et al 2003; Thoma et al 2009Thoma et al , 2010.…”