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FLASH GENE
Symbol VHL contributors: mct/shn - updated : 13-07-2018
HGNC name von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase
HGNC id 12687
Corresponding disease
ECYT2 erythrocytosis/polycythemia, familial, 2
RCC1 hereditary renal cell carcinoma
VHL Von Hippel-Lindau disease, type 1
Location 3p25.3      Physical location : 10.183.318 - 10.193.744
Synonym name
  • elongin binding protein
  • protein G7
  • tumor suppressor gene(s), chromosome 3
  • von Hippel-Lindau syndrome
  • von Hippel-Lindau tumor suppressor
    • Synonym symbol(s) HRCA1, VHL1, TSG3A, RCA11, pVHL
    DNA
    TYPE functioning gene
    STRUCTURE 12.04 kb     3 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   transcription factor   HRE
    text structure
  • Sp1 response element
  • a functional hypoxia response element (HRE) within the VHL promoter (HIF1alpha binding )
  • E2F1-binding site in its promoter
  • a single ZNF350-binding site located in the VHL promoter region
    • MAPPING cloned Y linked N status confirmed
    Map pter - D3S691 - D3S1597 - VHL VHL - D3S611 - D3S3594 - cen
    Text [LOH in nasopharyngeal carcinoma], ((ovarian carcinoma)), LOH in ovarian cancer
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    3 splicing 2968 30 213 - 2015 26211615
  • pVHL30
  • linked with TP53 pathway regulation through complex formation with the CDKN2A oncosuppressor
    • 2 splicing 2845 19 172 - 2015 26211615
  • pVHL19
  • lacking an in-frame coding exon and internal region
  • missing the first 53 AAs
  • shorter isoform shows an unexpected high tendency to form homodimers, suggesting an additional isoform-specific binding specialization
    • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Endocrineadrenal gland   lowly Homo sapiens
    Nervousbrainhindbraincerebellum moderately Homo sapiens
     brain   moderately Homo sapiens
    Reproductivefemale systembreast    Homo sapiens
     female systemovary    Homo sapiens
     female systemuteruscervix highly Homo sapiens
     male systemprostate  highly Homo sapiens
    Respiratorylung     Homo sapiens
    Urinarykidneytubulecollecting duct   Homo sapiens
    Visualeye   highly Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier liningendometrium   Homo sapiens
    Nervouscentral   
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Urinarytubular cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    Text fetal brain and kidney (
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal acidic domain phosphorylated by casein kinase-2 for its tumor suppressor function
  • eight copies of a repeated pentamer GEExE in the N terminal region
  • putative glycan anchored membrane protein
  • a C terminal BC-box critical motif (binding elongin B)
    • HOMOLOGY
    interspecies ortholog to Vhl, Mus musculus
    ortholog to vhl, Danio rerio
    ortholog to Vhl, Rattus norvegicus
    Homologene
    FAMILY
  • ubiquitin ligase family
    • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus,nucleoplasm
    text
  • highly mobile cytoplasmic protein, which becomes an immobile centrosomal protein after ATP-depletion in living cells
    • basic FUNCTION
  • direct role in fibronectin matrix assembly (
  • tumor suppressor protein, playing a role in ciliary maintenance
  • control of extracellular matrix formation and cell cycle exit
  • having a crucial role in endochondral bone development and is necessary for normal chondrocyte proliferation
  • represses oncogenic beta-catenin signaling in renal carcinoma cells
  • ciliary protein that controls ciliogenesis in kidney cells, needed to orient the growth of microtubules toward the cell periphery
  • participates in many cellular processes including oxygen sensing, microtubule stability and primary cilia regulation
  • promoting E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and SNAIl
  • powerful putative tumour suppressor gene in human breast cancer
  • participates in the hypoxia-mediated degradation of plasma membrane Na-K-ATPase in a HIF-independent manner
  • functions as part of an E3 ubiquitin ligase complex that targets proteins for proteasomal degradation
  • probably requires additional co-operating signalling pathways for clear-cell RCC (renal cell carcinoma) initiation and tumorigenesis
  • controls cilia function and its inactivation may result in both malignant or nonmalignant growth of epithelial cells and that this effect is in part mediated through the accumulation of hypoxia-inducible factors
  • with RNF4 regulate the proteasomal degradation of SUMO-conjugated HIF2A
  • interferes with angiogenesis and also controls cell adhesion and invasion
  • destabilizes the F-box protein SKP2, a chief component of Skp, Cullin, F-box-containing complex that promotes DNA synthesis in the S phase
  • plays an important role in regulation of cytokinesis
  • directly binds SOCS1 to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction
  • VHL limits EGFR signaling by promoting CBL-independent poly-ubiquitylation of the activated receptor, which likely results in its degradation by proteasome
  • in the retinal pigment epithelium (RPE) is essential for normal ocular growth and vascular development
  • VHL-dependent regulation of HIF1A in the RPE is essential for normal RPE and iris development, ocular growth and vascular development in the anterior chamber, whereas VHL-dependent regulation of other downstream pathways is crucial for normal development and maintenance of the retinal vasculature
  • inhibits Hedgehog-Gli activation through suppression of GLI1 nuclear localization
  • inhibits ribosome biogenesis and protein synthesis
  • novel function of VHL in the response to DNA damage, demonstrating a negative-feedback loop between VHL and E2F1, which may shed new light on the explanation of the role of VHL in tumour suppression
  • direct evidence for a key role of VHL in mediating oriented cell division and faithful mitotic checkpoint function in the renal epithelium, emphasizing the importance of VHL as a controller of mitotic fidelity
  • regulates bone morphogenesis as its loss considerably alters size, shape and overall development of the skeletal elements
  • is important for endochondral bone development, since loss of VHL in chondrocytes causes severe dwarfism
  • subcellular translocation of VHL plays an important role in microtubular structure alteration-induced HIF1A regulation (pMID: 25779090)
    • CELLULAR PROCESS cell cycle
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • complexing with CUL2, elongin B, C complex Rbx/ROC1, VBP1 and an ubiquitin conjugating enzyme other than CDC34, either UBE2B, UBE2D1, UBE2L6 or others to form an active E3 ubiquitin ligase complex named the VCB-CUL2 complex
  • component of the E3 ubiquitin ligase complex
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • Elongin B and C (
  • von Hippel-Lindau binding protein 1, VBP1 (
  • cullin 2, CUL2 (
  • Sp1 transcription factor, Sp1 (
  • Fibronectin (
  • tricellulin, TRiC (
  • Hypoxia inducible factor-alpha, HIF-alpha (
  • heteronuclear ribonucleoprotein a2, hnRNPA2 (
  • Hypoxia-inducible factor 1, HIF1 (
  • VHL-interacting deubiquitinating enzyme 1, VDU1 (
  • translocation in renal carcinoma on chromosome 8 protein, TRC8 (
  • VDU1 and VDU2 (
  • Jade-1 (
  • HIF-3 alpha (
  • hyperphosphorylated Rpb1 (
  • RNA polymerase II subunit B7, RPB7 (
  • Tat-binding protein-1, TBP1 (
  • iron regulatory protein 2, IRP2 (
  • tumorous imaginal discs protein Tid56 homolog, TID1
  • p53 (
  • p22phox (
  • myogenin, MYOG (
  • PKCzetaII (
  • endogenously binds the neuronal kinesin-2 complex, KIF5C
  • beta(2)-adrenergic receptor, beta(2)AR (
  • SUMO E3 ligase PIASy
  • S-phase kinase-associated protein 2, E3 ubiquitin protein ligase, SKP2
  • MYBBPC1A is a novel substrate of VHL
  • SOCS1-cooperative negative regulator of JAK2
  • VHL inactivation decreases H3K4Me3 levels through KDM5C, which alters gene expression and suppresses tumor growth
  • ARF tumor suppressor interacts with VHL30, a longer VHL isoform
  • sprouty homolog 2 (Drosophila), SPRY2
  • controls hypoxia-inducible transcription factor (HIF1A)-mediated adaptation
  • possible regulation of VHL by NEK1 that may contribute to ciliary homeostasis and cystogenesis
  • VHL is a downstream target of E2F1, which harbours an E2F1-binding site in its promoter
  • suppresses androgen-induced cell proliferation, implicating a physiological role of VHL in androgen-induced signaling pathway
  • novel function of VHL in the regulation of AR transcription activity
  • CTNNB1 links VHL to AURKA and loss of primary cilia in renal cell carcinoma
  • NEK8 may be a new HIF target gene and VHL can down-regulate NEK8 via HIFs to maintain the primary cilia structure in human renal cancer cells
  • functional RWDD3/VHL interaction in VHL-related tumor progression
  • CUL2 interacts with both the VHL BC box and cullin box and a novel ELOC site
  • ZNF350 is a novel VHL interacting protein
  • VHL is confirmed to serve as a bridge component for the association of ZNF350 and EP300, which leads to an increase in ZNF350 transcriptional activity in the VHL promoter
  • mediate the ubiquitination of HIF1A in the nuclear compartment prior to HIF1A exportation to the cytoplasm, and VHL dynamic nuclear-cytoplasmic trafficking is indicated to be involved in the process of HIF1A degradation
  • VHL/CDKN2A interaction is specifically mediated by the 53 residue long pVHL30 N-terminal region, suggesting that this N-terminus acts as a further VHL interaction interface
  • VHL is an important regulator of CERKL, and VHL ubiquitinates CERKL for proteasomal degradation
  • DAAM2 promotes tumorigenesis by suppressing VHL expression
  • ZHX2 was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability
  • TFAM is hydroxylated by EGLN3 and subsequently bound by VHL, which stabilizes TFAM by preventing mitochondrial proteolysis
    • cell & other
    REGULATION
    Other downregulation HIF1A
    regulation by KIF5C (KIF5C driven mobility of cytoplasmic VHL might enable VHL to function as a tumour suppressor)
    ASSOCIATED DISORDERS
    corresponding disease(s) VHL , RCC1 , ECYT2
    related resource VonHippel-Lindau disease
    von Hippel-Lindau disease germline mutation database
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   LOH    
    in pheochromocytomas (in VHL, not sporadic)
    tumoral     --low  
    leading to constitutively elevated cyclin D1 and abnormal proliferation
    tumoral somatic mutation      
    in clear cell renal carcinoma associated with end-stage renal disease/acquired cystic disease
    tumoral       loss of function
    in kidney carcinoma, disrupting iron homeostasis in renal carcinoma cells
    tumoral somatic mutation      
    confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma
    tumoral       loss of function
    central role of VHL inactivation in the molecular pathogenesis of both familial and sporadic hemangioblastomas
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • extracellular fibronectin matrix assembly by VHL-/- mouse embryos and mouse embryo fibroblasts (MEFs)was grossly impaired (
  • loss of DVhl in Drosophila resulted in an ventral midline defect (
  • deletion of the Von Hippel-Lindau gene (Vhlh) from intrinsic glomerular cells of mice is sufficient to initiate a necrotizing crescentic glomerulonephritis and the clinical features that accompany rapidly progressive glomerulonephritis (
  • murine embryonic depletion of Vhlh within the pancreatic epithelium causes postnatal lethality due to severe hypoglycemia
  • mice homozygous for the R200W mutation developed polycythemia (
  • Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca(2+) concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance (
  • Vhl(2B/2B) mice displayed mid-gestational embryonic lethality, whereas adult Vhl(2B/+) mice exhibited susceptibility to carcinogen-promoted renal neoplasia (
  • pVHL-deficient RCC 786-O cells were multinucleated and polyploid (