Atlas of Genetics and Cytogenetics in Oncology and Haematology


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VHL (von Hippel-Lindau tumor suppressor)

Identity

HGNC (Hugo) VHL
LocusID (NCBI) 7428
Location 3p25.3
Location_base_pair Starts at 10183319 and ends at 10195354 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note Tumour suppressor

DNA/RNA

 
Description The VHL gene spans 10 kb and is composed of three exons.
Transcription The VHL gene encodes a 4.7 kb mRNA which is widely expressed in both foetal and adult tissues. An alternatively spliced VHL transcript has been detected reflecting the absence of exon 2 (isoform II) but no endogenous associated protein has been reported.

Protein

 
Description The full-length VHL protein, pVHL, contains 213 amino-acids (28-30 kDa) ("pVHL30") A second major VHL-gene product arises by internal translation initiation from the codon 54 methionine, producing a 160 amino-acid protein (18-19 kDa) ("pVHL19").
Expression pVHL is widely expressed in both foetal and adult human tissues.
Localisation The pVHL is largely a cytoplasmic protein but appears to shuttle between the cytoplasm and nucleus.
Function pVHL interacts with three other proteins, elongin C and B and Cullin 2 (CUL2), in a complex referred to as VCB-CUL2. pVHL has two main structural domains: an N-terminal domain composed mainly of b-sheets (the b domain) and a smaller C-terminal domain between aminoacids 155-192 composed mainly of a helices (a-domain). The a domain consists of three a helices that combines with a fourth a helice donated by elongin C. The b-domain is on the opposite side of the a domain and is free to contact other protein.
  • VHL and angiogenesis
    A main function of the pVHL is to negatively regulate hypoxia-inducible mRNAs such as the mRNA encoding VEGF, EPO, PDGF and the glucose-transporter GLUT-1. pVHL plays a critical role in targeting the hypoxia-inducible transcription factor HIF-1a for degradation by the proteasome. HIF-1a contribute to form the HIF-1 transcriptional complex responsible for activation of genes involved in metabolism, angiogenesis and apoptosis. The VCB-CUL2 complex has been demonstrated as a ubiquitin-ligase system presenting many similarities with the SCF system ("Skp1-CUL1-Fbox protein"). HIF is normally degraded under normoxic conditions and binding to VHL is dependent on hydroxylation of Pro 564 in HIF-1a (Figure 1). When the VHL gene is mutated, absence of HIF degradation is responsible for abnormal accumulation of VEGF and other hypoxia-inducible mRNA explaining the angiogenic phenotype of VHL tumours.
    pVHL may also downregulate VEGF production by direct binding and inhibiting to the transcriptional activator SP1.
    In homozygous VHL knock-out mice, embryos will die early because of a major disorder of placental vasculogenesis .
  • Other functions
    pVHL plays a role in
    1- ability of cells to exit the cell cycle and enter the quiescent state.
    2- assembly of extracellular fibronectin matrix.
    3- degradation of TGFa LYT10, TGFb, and carbonic anhydrases CA9 and CA12.
    4- regulation of the urokinase-type plasminogen activator system.
    5- inhibition of the hepatocyte growth factor-induced invasion in renal cell carcinoma.
    6- a direct interaction with atypical protein kinase C (PKC) z and l has also recently been demonstrated.
    Thus, VHL appears as a multifunctional gene and may play a gatekeeper role specially in kidney.
  • Homology The primary sequence structure of pVHL shows minimal homology to any know protein but evolutionary conservation of the pVHL is very strong except for the first 53 amino acids.

    Mutations

    Germinal Germline mutations cause von Hippel-Lindau disease. VHL mutations are heterogeneous and distributed widely throughout the coding sequence except 5' for the translation initiation site for pVHL19. There is a few recurrent mutations and only one founder effect is known, originating from Germany (T292C resulting in a Tyr98His substitution).
    Point mutations occur in about 60% of cases (Figure 2) and large deletions in about 40%. VHL 1 (without pheochromocytoma) is mainly produced by mutations responsible for truncated protein (deletions, frameshift mutations and nonsense mutations). VHL type 2 (with high risk of pheochromocytoma) is mainly produced by missense mutations. Type 2B is the potentially "full" form of the disease (frequent mutations: Arg167Gln, Arg167Trp). Type 2A is associated with a very low risk of clear cell renal cell cancer (RCC) (common mutation: Tyr98His). Type 2C is characterized by the occurrence of pheochromocytoma only (example: Leu188Val).
    Between 10 and 15% of cryptic VHL cases could be explained by de novo mutations and there are some cases of germline mosaicism.
    There is some evidence that genetic modifiers may influence the phenotypic expression of the disease.
    Somatic Mutations are encountered in 60 % of sporadic clear cell RCC. In addition, 15% of tumours show evidence of inactivation by methylation. VHL alterations have been associated with occupational exposure to trichlorethylene.
    Somatic mutations are also frequent in CNS sporadic hemangioblastoma but rarer in sporadic endolymphatic sac tumours, pancreatic serous cystadenomas and endocrine tumours, epididymal cystadenomas and pheochromocytomas.

    Implicated in

    Entity von Hippel-Lindau disease
    Disease Von Hippel-Lindau (VHL) disease is a hereditary devastating cancer syndrome, predisposing to the development of various benign and malignant tumours ( Central nervous system hemangioblastomas and Retinal hemangioblastomas , endolymphatic sac tumours ID: >, clear cell renal cell cancer and/or renal cysts, pheochromocytoma, pancreatic cysts and neuroendocrine tumours, epididymal and broad ligament cystadenomas). VHL disease is the first cause of
      
    Entity Sporadic renal cell carcinomas
      
    Entity Sporadic hemangioblastomas
      

    Other Solid tumors implicated (Data extracted from papers in the Atlas)

    Solid Tumors AmeloblastomID5945 MedulloblastomaID5065 rhab5004 rhabID5004

    External links

    Nomenclature
    HGNC (Hugo)VHL   12687
    Cards
    AtlasVHLID132
    Entrez_Gene (NCBI)VHL  7428  von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase
    GeneCards (Weizmann)VHL
    Ensembl (Hinxton) [Gene_View]  chr3:10183319-10195354 [Contig_View]  VHL [Vega]
    cBioPortalVHL
    AceView (NCBI)VHL
    Genatlas (Paris)VHL
    WikiGenes7428
    SOURCE (Princeton)NM_000551 NM_198156
    Genomic and cartography
    GoldenPath (UCSC)VHL  -  3p25.3   chr3:10183319-10195354 +  3p25.3   [Description]    (hg19-Feb_2009)
    EnsemblVHL - 3p25.3 [CytoView]
    Mapping of homologs : NCBIVHL [Mapview]
    OMIM144700   171300   193300   263400   608537   
    Gene and transcription
    Genbank (Entrez)AA361862 AF088066 AK304002 AK309560 AK315799
    RefSeq transcript (Entrez)NM_000551 NM_198156
    RefSeq genomic (Entrez)AC_000135 NC_000003 NC_018914 NG_008212 NT_022517 NW_001838876 NW_004929309
    Consensus coding sequences : CCDS (NCBI)VHL
    Cluster EST : UnigeneHs.517792 [ NCBI ]
    CGAP (NCI)Hs.517792
    Alternative Splicing : Fast-db (Paris)GSHG0020578
    Gene ExpressionVHL [ NCBI-GEO ]     VHL [ SEEK ]   VHL [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP40337 (Uniprot)
    NextProtP40337  [Medical]
    With graphics : InterProP40337
    Splice isoforms : SwissVarP40337 (Swissvar)
    Domains : Interpro (EBI)Tumour_suppress_VHL-disease [organisation]   VHL_alpha_dom [organisation]   VHL_beta_dom [organisation]   VHL_tumour_suppress_b/a_dom [organisation]  
    Related proteins : CluSTrP40337
    Domain families : Pfam (Sanger)VHL (PF01847)   
    Domain families : Pfam (NCBI)pfam01847   
    DMDM Disease mutations7428
    Blocks (Seattle)P40337
    PDB (SRS)1LM8    1LQB    1VCB    3ZRC    3ZRF    3ZTC    3ZTD    3ZUN    4AJY    4AWJ    4B95    4B9K    4BKS    4BKT   
    PDB (PDBSum)1LM8    1LQB    1VCB    3ZRC    3ZRF    3ZTC    3ZTD    3ZUN    4AJY    4AWJ    4B95    4B9K    4BKS    4BKT   
    PDB (IMB)1LM8    1LQB    1VCB    3ZRC    3ZRF    3ZTC    3ZTD    3ZUN    4AJY    4AWJ    4B95    4B9K    4BKS    4BKT   
    PDB (RSDB)1LM8    1LQB    1VCB    3ZRC    3ZRF    3ZTC    3ZTD    3ZUN    4AJY    4AWJ    4B95    4B9K    4BKS    4BKT   
    Peptide AtlasP40337
    HPRD01905
    IPIIPI00027969   IPI00336024   IPI00910957   IPI00939404   
    Protein Interaction databases
    DIP (DOE-UCLA)P40337
    IntAct (EBI)P40337
    BioGRIDVHL
    InParanoidP40337
    Interologous Interaction database P40337
    IntegromeDBVHL
    STRING (EMBL)VHL
    Ontologies - Pathways
    Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  cell morphogenesis  ubiquitin-protein transferase activity  protein binding  nucleus  nucleoplasm  nucleolus  mitochondrion  endoplasmic reticulum  cytosol  regulation of transcription, DNA-templated  proteolysis  response to stress  transcription factor binding  negative regulation of cell proliferation  membrane  protein ubiquitination  protein ubiquitination  enzyme binding  negative regulation of apoptotic process  intermediate filament cytoskeleton  positive regulation of cell differentiation  positive regulation of transcription, DNA-templated  protein stabilization  regulation of transcription from RNA polymerase II promoter in response to hypoxia  negative regulation of transcription from RNA polymerase II promoter in response to hypoxia  cellular response to hypoxia  
    Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  cell morphogenesis  ubiquitin-protein transferase activity  protein binding  nucleus  nucleoplasm  nucleolus  mitochondrion  endoplasmic reticulum  cytosol  regulation of transcription, DNA-templated  proteolysis  response to stress  transcription factor binding  negative regulation of cell proliferation  membrane  protein ubiquitination  protein ubiquitination  enzyme binding  negative regulation of apoptotic process  intermediate filament cytoskeleton  positive regulation of cell differentiation  positive regulation of transcription, DNA-templated  protein stabilization  regulation of transcription from RNA polymerase II promoter in response to hypoxia  negative regulation of transcription from RNA polymerase II promoter in response to hypoxia  cellular response to hypoxia  
    Pathways : BIOCARTAVEGF, Hypoxia, and Angiogenesis [Genes]    Hypoxia-Inducible Factor in the Cardiovascular System [Genes]   
    Pathways : KEGGHIF-1 signaling pathway    Ubiquitin mediated proteolysis    Pathways in cancer    Renal cell carcinoma   
    Protein Interaction DatabaseVHL
    Wikipedia pathwaysVHL
    Gene fusion - rearrangments
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)VHL
    snp3D : Map Gene to Disease7428
    SNP (GeneSNP Utah)VHL
    SNP : HGBaseVHL
    Genetic variants : HAPMAPVHL
    Exome VariantVHL
    1000_GenomesVHL 
    Cancer Gene: CensusVHL 
    Somatic Mutations in Cancer : COSMICVHL 
    CONAN: Copy Number AnalysisVHL 
    Mutations and Diseases : HGMDVHL
    Genomic VariantsVHL  VHL [DGVbeta]
    dbVarVHL
    ClinVarVHL
    Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
    Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
    Diseases
    OMIM144700    171300    193300    263400    608537   
    MedgenVHL
    GENETestsVHL
    Disease Genetic AssociationVHL
    Huge Navigator VHL [HugePedia]  VHL [HugeCancerGEM]
    General knowledge
    Homologs : HomoloGeneVHL
    Homology/Alignments : Family Browser (UCSC)VHL
    Phylogenetic Trees/Animal Genes : TreeFamVHL
    Chemical/Protein Interactions : CTD7428
    Chemical/Pharm GKB GenePA37307
    Drug Sensitivity VHL
    Clinical trialVHL
    Other databases
    Other databaseUMD-VHL (von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase - von Hippel-Lindau syndrome). Curator: C. Béroud
    Other databaseVON HIPPEL-LINDAU SYNDROME
    Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=VHL
    Probes
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    CoreMineVHL
    iHOPVHL
    OncoSearchVHL

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    Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes.
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    FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity.
    Mahon PC, Hirota K, Semenza GL
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    PMID 11641274
     
    Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3'-kinase/Akt signaling pathway.
    Blancher C, Moore JW, Robertson N, Harris AL
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    The pVHL-associated SCF ubiquitin ligase complex: molecular genetic analysis of elongin B and C, Rbx1 and HIF-1alpha in renal cell carcinoma.
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    PMID 11526493
     
    Role of disease-causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL.
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    PMID 11550286
     
    The von Hippel-Lindau protein interacts with heteronuclear ribonucleoprotein a2 and regulates its expression.
    Pioli PA, Rigby WF
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    PMID 11517223
     
    Association of GSTT1 non-null and NAT1 slow/rapid genotypes with von Hippel-Lindau tumour suppressor gene transversions in sporadic renal cell carcinoma.
    Gallou C, Longuemaux S, Delomˆ©nie C, Mˆ©jean A, Martin N, Martinet S, Palais G, Bouvier R, Droz D, Krishnamoorthy R, Junien C, Bˆ©roud C, Dupret JM
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    PMID 11505222
     
    Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1alpha in clear cell renal carcinomas.
    Wiesener MS, Mˆºnchenhagen PM, Berger I, Morgan NV, Roigas J, Schwiertz A, Jˆºrgensen JS, Gruber G, Maxwell PH, Lˆning SA, Frei U, Maher ER, Grˆne HJ, Eckardt KU
    Cancer research. 2001 ; 61 (13) : 5215-5222.
    PMID 11431362
     
    Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth.
    Baba M, Hirai S, Kawakami S, Kishida T, Sakai N, Kaneko S, Yao M, Shuin T, Kubota Y, Hosaka M, Ohno S
    Oncogene. 2001 ; 20 (22) : 2727-2736.
    PMID 11420685
     
    VHL gene alterations in renal cell carcinoma patients: novel hotspot or founder mutations and linkage disequilibrium.
    Ma X, Yang K, Lindblad P, Egevad L, Hemminki K
    Oncogene. 2001 ; 20 (38) : 5393-5400.
    PMID 11536052
     
    DHPLC-based germline mutation screening in the analysis of the VHL tumor suppressor gene: usefulness and limitations.
    Klein B, Weirich G, Brauch H
    Human genetics. 2001 ; 108 (5) : 376-384.
    PMID 11409863
     
    VHL and FHIT locus loss of heterozygosity is common in all renal cancer morphotypes but differs in pattern and prognostic significance.
    Velickovic M, Delahunt B, Stˆrkel S, Grebem SK
    Cancer research. 2001 ; 61 (12) : 4815-4819.
    PMID 11406557
     
    Dynamic, site-specific interaction of hypoxia-inducible factor-1alpha with the von Hippel-Lindau tumor suppressor protein.
    Yu F, White SB, Zhao Q, Lee FS
    Cancer research. 2001 ; 61 (10) : 4136-4142.
    PMID 11358837
     
    Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease.
    Clifford SC, Cockman ME, Smallwood AC, Mole DR, Woodward ER, Maxwell PH, Ratcliffe PJ, Maher ER
    Human molecular genetics. 2001 ; 10 (10) : 1029-1038.
    PMID 11331613
     
    von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF.
    Hoffman MA, Ohh M, Yang H, Klco JM, Ivan M, Kaelin WG Jr
    Human molecular genetics. 2001 ; 10 (10) : 1019-1027.
    PMID 11331612
     
    VHL tumor suppressor regulates Cl-/HCO3- exchange and Na+/H+ exchange activities in renal carcinoma cells.
    Karumanchi SA, Jiang L, Knebelmann B, Stuart-Tilley AK, Alper SL, Sukhatme VP
    Physiological genomics. 2001 ; 5 (3) : 119-128.
    PMID 11285365
     
    Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes.
    Kim MS, Kwon HJ, Lee YM, Baek JH, Jang JE, Lee SW, Moon EJ, Kim HS, Lee SK, Chung HY, Kim CW, Kim KW
    Nature medicine. 2001 ; 7 (4) : 437-443.
    PMID 11283670
     
    Regulation of STRA13 by the von Hippel-Lindau tumor suppressor protein, hypoxia, and the UBC9/ubiquitin proteasome degradation pathway.
    Ivanova AV, Ivanov SV, Danilkovitch-Miagkova A, Lerman MI
    The Journal of biological chemistry. 2001 ; 276 (18) : 15306-15315.
    PMID 11278694
     
    Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer.
    Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, Merrill MJ, Proescholdt MA, Oldfield EH, Lee J, Zavada J, Waheed A, Sly W, Lerman MI, Stanbridge EJ
    The American journal of pathology. 2001 ; 158 (3) : 905-919.
    PMID 11238039
     
    Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor.
    Haase VH, Glickman JN, Socolovsky M, Jaenisch R
    Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (4) : 1583-1588.
    PMID 11171994
     
    Role of transforming growth factor-alpha in von Hippel--Lindau (VHL)(-/-) clear cell renal carcinoma cell proliferation: a possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis.
    de Paulsen N, Brychzy A, Fournier MC, Klausner RD, Gnarra JR, Pause A, Lee S
    Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (4) : 1387-1392.
    PMID 11171960
     
    VHL induces renal cell differentiation and growth arrest through integration of cell-cell and cell-extracellular matrix signaling.
    Davidowitz EJ, Schoenfeld AR, Burk RD
    Molecular and cellular biology. 2001 ; 21 (3) : 865-874.
    PMID 11154273
     
    Role of exon 2-encoded beta -domain of the von Hippel-Lindau tumor suppressor protein.
    Bonicalzi ME, Groulx I, de Paulsen N, Lee S
    The Journal of biological chemistry. 2001 ; 276 (2) : 1407-1416.
    PMID 11024059
     
    Genotype-phenotype correlation in von Hippel-Lindau syndrome.
    Friedrich CA
    Human molecular genetics. 2001 ; 10 (7) : 763-767.
    PMID 11257110
     
    The von Hippel-Lindau tumor suppressor protein.
    Ivan M, Kaelin WG Jr
    Current opinion in genetics & development. 2001 ; 11 (1) : 27-34.
    PMID 11163147
     
    The von Hippel-Lindau tumor suppressor gene.
    Kondo K, Kaelin WG Jr
    Experimental cell research. 2001 ; 264 (1) : 117-125.
    PMID 11237528
     
    Insights into the role of the von Hippel-Lindau gene product. A key player in hypoxic regulation.
    Maxwell PH, Pugh CW, Ratcliffe PJ
    Experimental nephrology. 2001 ; 9 (4) : 235-240.
    PMID 11423722
     
    The HIF pathway: implications for patterns of gene expression in cancer.
    Wykoff CC, Pugh CW, Harris AL, Maxwell PH, Ratcliffe PJ
    Novartis Foundation symposium. 2001 ; 240 : 212-225.
    PMID 11727931
     
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    Contributor(s)

    Written01-2002Stéphane Richard
    Génétique Oncologique EPHE, Faculté de Médecine Paris-Sud, 63 av Gabriel Péri, 94276 LE KREMLIN BICETRE, France

    Citation

    This paper should be referenced as such :
    Richard, S
    VHL (von Hippel-Lindau tumor suppressor)
    Atlas Genet Cytogenet Oncol Haematol. 2002;6(2):106-110.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Genes/VHLID132.html

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