Von Hippel Lindau Tumor Suppressor (vHL)

HRCA1; RCA1; VHL1; Von Hippel-Lindau Syndrome

SPN	N996
HGNC	12687
MGI	103223
PubMed	8493574
RGD	3960
UniProt	P40337
Wiki	VHL

The Von Hippel–Lindau tumor suppressor protein is encoded by the VHL gene and when inactivated is associated with Von Hippel–Lindau disease.

The protein encoded by this 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.

Reference

"Identification of the von Hippel-Lindau disease tumor suppressor gene."
Science 260:1317-1320(1993) [PubMed] [Europe PMC] [Abstract]

"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]

"The DNA sequence, annotation and analysis of human chromosome 3."
Nature 440:1194-1198(2006) [PubMed] [Europe PMC] [Abstract]

"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]

"Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis."
Hum. Mol. Genet. 5:639-644(1996) [PubMed] [Europe PMC] [Abstract]

"The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins."
Proc. Natl. Acad. Sci. U.S.A. 94:2156-2161(1997) [PubMed] [Europe PMC] [Abstract]

"A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor."
Proc. Natl. Acad. Sci. U.S.A. 95:8817-8822(1998) [PubMed] [Europe PMC] [Abstract]

"Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C."
Science 269:1444-1446(1995) [PubMed] [Europe PMC] [Abstract]

"pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation."
Proc. Natl. Acad. Sci. U.S.A. 95:11661-11666(1998) [PubMed] [Europe PMC] [Abstract]

"Formation of the VHL-elongin BC tumor suppressor complex is mediated by the chaperonin TRiC."
Mol. Cell 4:1051-1061(1999) [PubMed] [Europe PMC] [Abstract]

"Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein."
EMBO J. 19:4298-4309(2000) [PubMed] [Europe PMC] [Abstract]

"Muf1, a novel elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase."
J. Biol. Chem. 276:29748-29753(2001) [PubMed] [Europe PMC] [Abstract]

"FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity."
Genes Dev. 15:2675-2686(2001) [PubMed] [Europe PMC] [Abstract]

"Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein."
J. Biol. Chem. 277:4656-4662(2002) [PubMed] [Europe PMC] [Abstract]

"The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1."
J. Biol. Chem. 277:39887-39898(2002) [PubMed] [Europe PMC] [Abstract]

"The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway."
Oncogene 21:3507-3516(2002) [PubMed] [Europe PMC] [Abstract]

"SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia."
Cell 131:584-595(2007) [PubMed] [Europe PMC] [Abstract]

"Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline."
J. Biol. Chem. 284:9050-9058(2009) [PubMed] [Europe PMC] [Abstract]

"Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL."
Sci. Signal. 2:RA33-RA33(2009) [PubMed] [Europe PMC] [Abstract]

"The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity."
Nat. Cell Biol. 14:201-208(2012) [PubMed] [Europe PMC] [Abstract]

"Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling."
Science 296:1886-1889(2002) [PubMed] [Europe PMC] [Abstract]

"Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL."
Nature 417:975-978(2002) [PubMed] [Europe PMC] [Abstract]

"Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function."
Science 284:455-461(1999) [PubMed] [Europe PMC] [Abstract]

"Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas."
Cancer Res. 54:4845-4847(1994) [PubMed] [Europe PMC] [Abstract]

"Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines."
Oncogene 9:1599-1604(1994) [PubMed] [Europe PMC] [Abstract]

"Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype."
Hum. Mol. Genet. 3:1303-1308(1994) [PubMed] [Europe PMC] [Abstract]

"Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype."
Hum. Mutat. 5:66-75(1995) [PubMed] [Europe PMC] [Abstract]

"Germline mutations in the von Hippel-Lindau disease (VHL) gene in Japanese VHL. Clinical Research Group for VHL in Japan."
Hum. Mol. Genet. 4:2233-2237(1995) [PubMed] [Europe PMC] [Abstract]

"Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma."
J. Med. Genet. 32:885-886(1995) [PubMed] [Europe PMC] [Abstract]

"Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas."
J. Med. Genet. 32:934-937(1995) [PubMed] [Europe PMC] [Abstract]

"Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations."
J. Med. Genet. 33:328-332(1996) [PubMed] [Europe PMC] [Abstract]

"Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan."
Hum. Mutat. 8:348-357(1996) [PubMed] [Europe PMC] [Abstract]

"Germline mutations detected in the von Hippel-Lindau disease tumor suppressor gene by Southern blot and direct genomic DNA sequencing."
Hum. Mutat. Suppl. 1:S31-S33(1998) [PubMed] [Europe PMC] [Abstract]

"Three novel mutations in the von Hippel-Lindau tumour suppressor gene in Italian patients."
Hum. Mutat. Suppl. 1:S268-S270(1998) [PubMed] [Europe PMC] [Abstract]

"Variable penetrance of familial pheochromocytoma associated with the von Hippel-Lindau gene mutation, S68W."
Hum. Mutat. 12:71-71(1998) [PubMed] [Europe PMC] [Abstract]

"Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene."
Hum. Mutat. 12:417-423(1998) [PubMed] [Europe PMC] [Abstract]

"Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma."
Hum. Mutat. 12:424-430(1998) [PubMed] [Europe PMC] [Abstract]

"Germline mutations in the vhl gene in patients presenting with phaeochromocytomas."
Int. J. Cancer 77:337-340(1998) [PubMed] [Europe PMC] [Abstract]

Unpublished observations (MAY-1999)

"Two distinct phenotypes caused by two different missense mutations in the same codon of the VHL gene."
Am. J. Med. Genet. 87:163-167(1999) [PubMed] [Europe PMC] [Abstract]

"Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC."
Hum. Mutat. 13:464-475(1999) [PubMed] [Europe PMC] [Abstract]

"Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma."
Blood 99:3562-3565(2002) [PubMed] [Europe PMC] [Abstract]

"Germ-line mutations in nonsyndromic pheochromocytoma."
N. Engl. J. Med. 346:1459-1466(2002) [PubMed] [Europe PMC] [Abstract]

"Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia."
Am. J. Hum. Genet. 73:412-419(2003) [PubMed] [Europe PMC] [Abstract]

"Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas."
Cancer Res. 63:5615-5621(2003) [PubMed] [Europe PMC] [Abstract]

Erratum
Am. J. Hum. Genet. 74:598-598(2004)

"Mutations in the VHL gene in sporadic apparently congenital polycythemia."
Blood 101:1591-1595(2003) [PubMed] [Europe PMC] [Abstract]

"The von Hippel-Lindau (VHL) germline mutation V84L manifests as early-onset bilateral pheochromocytoma."
Am. J. Med. Genet. A 140:685-690(2006) [PubMed] [Europe PMC] [Abstract]

"Patterns of somatic mutation in human cancer genomes."
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]