Vhl gene

VHL is the acronym for "Von Hippel-Lindau Tumor Suppressor" a protein encoded by the VHL gene located on chromosome 3p25. Germline mutations in this gene are, among other things, the cause of the Von Hippel-Lindau synxdrome.

The VHL tumor suppressor protein (pVHL) plays a key role in cellular oxygen measurement by targeting hypoxia-inducible factors for ubiquitylation and proteasomal degradation. The VHL protein (pVHL) is part of a protein complex consisting of elongin B, elongin C and cullin-2 and has ubiquitin ligase E3 activity. It exists in four different isoforms:

• pVHL-213
• pVHL-160
• pVHL-172 and
• pVHL-X1.

Ubiquitination of proteins in the proteasome is a kind of "labelling" that initiates the subsequent degradation of a protein. In this process, the pVHL complex binds to so-called "hypoxia-induced factors (HIFs)", which are subsequently ubiquitinated. These hypoxia-induced factors (HIFs) must first be hydroxylated in order for pVHL to bind to two proline molecules. This process depends on the oxygen concentration. Accordingly, pVHL plays an important role in the cellular perception of oxygen deficiency, the cellular signaling pathway and the oxygen-dependent gene expression. Among the factors that are increasingly expressed during oxygen deficiency is the "Vascular Endothelial Growth Factor(VEGF)", which is also important for angiogenesis in tumor parenchyma.

Germline VHL mutations lead to 2 disease entities:

• Von Hippel-Lindau syndrome with multiple cysts and a number of rare tumors such as hemangioblastomas, pheochromocytomas and renal cell carcinomas, caused by an inherited germ line mutation with inactivation of one allele and another somatic mutation ("second hit"). Hereditary VHL inactivation leads to premalignant renal cysts. The transformation of these cysts into renal cell carcinomas probably requires additional genetic modifications. The restoration of VHL function in VHL - / - renal cell carcinomas is sufficient to inhibit tumour development in vivo.
• Familial erythrocytosis type 2, also called "Chuvash polycythemia", after the autonomous Russian region Chuvash, with autosomal recessive polycythemia. This is caused by a homozygous mutation of the VHL gene, a point mutation (C598T) with an amino acid exchange (R200W), called the "canonical" mutation of VHL. Note: The disease is more common in Ischia in Italy and among the Chuvash people in the Russian autonomous region of Chuvash. There is no increased tumor rate.

Early inactivation of VHL is observed in > 50% of sporadic clear cell renal cell carcinomas (ccRCC) and findings from functional analysis of pVHL have laid the foundation for routine treatment of advanced ccRCC with novel targeted therapies (Gossage L et al. 2015).

Due to the disturbed and reduced function of the pVHL protein complex, fewer hypoxia-induced factors (HIFs) are ubiquitinated and degraded. Hypoxic cells or cells lacking pVHL accumulate high levels of HIFs that activate the transcription of a variety of genes, including vascular endothelial growth factor, platelet-derived growth factor B, and transforming growth factor alpha.

This lack of oxygen results in erythrocythaemia or polycythaemia, comparable to an altitude training of the organism.

1. Gossage L et al (2015) VHL, the story of a tumour suppressor gene. Nat Rev Cancer 15:55-64.
2. Lenglet M et al (2018) Identification of a new <i>VHL</i> exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease. Blood 132:469-483.
3. William G Kaelin Jr WG (2004) The Von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer Review Clin Cancer Res 10: 6290S-5S