The protein encoded by the VHL gene is a component of the protein complex that includes elongin B, elongin C, and cullin-2, and possesses ubiquitin ligase E3 activity.
This complex is involved in the ubiquitination and degradation of a hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen.
RNA polymerase II subunit POLR2G/RPB7 is also reported to be a target of this protein. Alternatively spliced transcript variants encoding distinct isoforms have been observed.
Function
The VHL protein forms a complex that function as ubiquitin ligases. A main substrate for this activity is HIF-1 (hypoxia inducible transcription factor 1), which regulates several genes, including VEGF and PDGF. Lack of VHL activity prevents ubiquitination and degradation of HIF-1 and is associated with increased levels of angiogenic growth factors.
VHL is part of an SCF related E3-ubiquitin ligase complex with ’gatekeeper’ function in renal carcinoma.
The von Hippel-Lindau (pVHL) protein plays an important role in hypoxia sensing. It binds to the hydroxylated hypoxia-inducible factor 1 alpha (HIF-1 alpha) and serves as a recognition component of an E3-ubiquitin ligase complex.
In hypoxia or secondary to a mutated VHL gene, the nondegraded HIF-1 alpha forms a heterodimer with HIF-beta and leads to increased transcription of hypoxia-inducible genes, including erythropoietin (EPO).
Pathology
Germ line mutations of the von Hippel Lindau (VHL) gene on chromosome 3p are associated with hereditary renal cell cancers, pheochromocytomas, hemangioblastomas of the central nervous system, retinal angiomas, and renal cysts. Mutations of the VHL gene have also been noted in sporadic renal cell cancers.
The autosomal dominant cancer-predisposition von Hippel-Lindau syndrome is due to inheritance of a single mutated allele of VHL.
Somatic mutations in renal cell carcinoma
homozygous VHL germline mutation in congenital polycythemia (12844285)
Features
VHL interacting proteins
References
Maher ER. Von Hippel-Lindau disease. Curr Mol Med. 2004 Dec;4(8):833-42. PMID: 15579030
Barry RE, Krek W. The von Hippel-Lindau tumour suppressor: a multi-faceted inhibitor of tumourigenesis. Trends Mol Med. 2004 Sep;10(9):466-72. PMID: 15350900
George DJ, Kaelin WG Jr. The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med. 2003 Jul 31;349(5):419-21. PMID: 12890838
Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002 Sep;2(9):673-82. PMID: 12209156
Kaelin WG Jr, Maher ER. The VHL tumour-suppressor gene paradigm. Trends Genet. 1998 Oct;14(10):423-6. PMID: 9820032