VHL

Summary

Gene Symbol: VHL
Description: von Hippel-Lindau tumor suppressor
Alias: HRCA1, RCA1, VHL1, pVHL, von Hippel-Lindau disease tumor suppressor, elongin binding protein, protein G7, von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase
Species: human
Products:     VHL

Top Publications

  1. Knauth K, Cartwright E, Freund S, Bycroft M, Buchberger A. VHL mutations linked to type 2C von Hippel-Lindau disease cause extensive structural perturbations in pVHL. J Biol Chem. 2009;284:10514-22 pubmed publisher
    b>pVHL (von Hippel-Lindau tumor suppressor protein) is the substrate recognition subunit of the CBC(VHL) ubiquitin ligase complex promoting the degradation of hypoxia-inducible factor subunits, HIF-1/2alpha...
  2. Czyzyk Krzeska M, Meller J. von Hippel-Lindau tumor suppressor: not only HIF's executioner. Trends Mol Med. 2004;10:146-9 pubmed
    Loss of von Hippel-Lindau (VHL) protein function results in an autosomal-dominant cancer syndrome known as VHL disease, which manifests as angiomas of the retina, hemangioblastomas of the central nervous system, renal clear-cell ..
  3. Chitalia V, Foy R, Bachschmid M, Zeng L, Panchenko M, Zhou M, et al. Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nat Cell Biol. 2008;10:1208-16 pubmed publisher
    The von Hippel-Lindau protein pVHL suppresses renal tumorigenesis in part by promoting the degradation of hypoxia-inducible HIF-alpha transcription factors; additional mechanisms have been proposed...
  4. Kanno H, Sato H, Yokoyama T, Yoshizumi T, Yamada S. The VHL tumor suppressor protein regulates tumorigenicity of U87-derived glioma stem-like cells by inhibiting the JAK/STAT signaling pathway. Int J Oncol. 2013;42:881-6 pubmed publisher
    ..was to investigate the inhibitory mechanism of this pathway acting through the tumor suppressor von Hippel-Lindau (VHL) protein in glioma cancer stem cells...
  5. Stickle N, Cheng L, Watson I, Alon N, Malkin D, Irwin M, et al. Expression of p53 in renal carcinoma cells is independent of pVHL. Mutat Res. 2005;578:23-32 pubmed
    ..Recently, the expression of pVHL in RCC cells was demonstrated to elevate the expression of p53 by inducing the binding of RNA-stabilizing protein ..
  6. Guo Y, Schoell M, Freeman R. The von Hippel-Lindau protein sensitizes renal carcinoma cells to apoptotic stimuli through stabilization of BIM(EL). Oncogene. 2009;28:1864-74 pubmed publisher
    ..to etoposide and UV radiation-induced death compared to the same cells stably expressing the wild-type VHL protein (pVHL)...
  7. Hubbi M, Luo W, Baek J, Semenza G. MCM proteins are negative regulators of hypoxia-inducible factor 1. Mol Cell. 2011;42:700-12 pubmed publisher
    ..Exposure to hypoxia leads to MCM2-7 downregulation in diverse cell types. These studies reveal a function of MCM proteins apart from their DNA helicase activity and establish a direct link between HIF-1 and the cell-cycle machinery. ..
  8. McNeill A, Rattenberry E, Barber R, Killick P, MacDonald F, Maher E. Genotype-phenotype correlations in VHL exon deletions. Am J Med Genet A. 2009;149A:2147-51 pubmed publisher
    Von Hippel-Lindau (VHL) syndrome is a dominantly inherited familial cancer syndrome caused by mutations in the VHL gene...
  9. Arjumand W, Sultana S. Role of VHL gene mutation in human renal cell carcinoma. Tumour Biol. 2012;33:9-16 pubmed publisher
    ..The VHL mRNA encodes a protein (pVHL) that contains 213 amino acid residues which migrate with an apparent molecular weight of 24 to 30 kDa...

More Information

Publications92

  1. Ghosh A, Shanafelt T, Cimmino A, Taccioli C, Volinia S, Liu C, et al. Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells. Blood. 2009;113:5568-74 pubmed publisher
    ..We have examined the status of the von Hippel-Lindau gene product (pVHL) that is responsible for HIF-1alpha degradation and found it to be at a notably low level in CLL B cells compared ..
  2. Baek J, Liu Y, McDonald K, Wesley J, Hubbi M, Byun H, et al. Spermidine/spermine-N1-acetyltransferase 2 is an essential component of the ubiquitin ligase complex that regulates hypoxia-inducible factor 1alpha. J Biol Chem. 2007;282:23572-80 pubmed
    ..is subjected to O(2)-dependent prolyl hydroxylation leading to ubiquitination by the von Hippel-Lindau protein (VHL)-Elongin C ubiquitin-ligase complex and degradation by the 26 S proteasome...
  3. Asakawa T, Esumi M, Endo S, Kida A, Ikeda M. Tongue cancer patients have a high frequency of allelic loss at the von Hippel-Lindau gene and other loci on 3p. Cancer. 2008;112:527-34 pubmed
    ..study, loss of heterozygosity (LOH) was evaluated at several loci within 3p, including the von Hippel-Lindau gene (VHL), in samples of tongue squamous cell carcinoma...
  4. van Houwelingen K, van Dijk B, Hulsbergen van de Kaa C, Schouten L, Gorissen H, Schalken J, et al. Prevalence of von Hippel-Lindau gene mutations in sporadic renal cell carcinoma: results from The Netherlands cohort study. BMC Cancer. 2005;5:57 pubmed
    Biallelic von Hippel-Lindau (VHL) gene defects, a rate-limiting event in the carcinogenesis, occur in approximately 75% of sporadic clear-cell Renal Cell Carcinoma (RCC)...
  5. Cai Q, Verma S, Kumar P, Ma M, Robertson E. Hypoxia inactivates the VHL tumor suppressor through PIASy-mediated SUMO modification. PLoS ONE. 2010;5:e9720 pubmed publisher
    ..In normoxia, the tumor suppressor protein VHL acts as an E3 ubiquitin ligase to target HIFalpha for proteolytic destruction...
  6. Miller F, Kentsis A, Osman R, Pan Z. Inactivation of VHL by tumorigenic mutations that disrupt dynamic coupling of the pVHL.hypoxia-inducible transcription factor-1alpha complex. J Biol Chem. 2005;280:7985-96 pubmed
    The von Hippel-Lindau (VHL) gene product, pVHL, targets the alpha subunit of the hypoxia-inducible transcription factor (HIF-alpha) for ubiquitin-dependent degradation...
  7. Hes F, Van der Luijt R, Janssen A, Zewald R, de Jong G, Lenders J, et al. Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification. Clin Genet. 2007;72:122-9 pubmed
    The current clinical diagnosis of Von Hippel-Lindau (VHL) disease demands at least one specific [corrected] VHL manifestation in a patient with familial VHL disease, or, in a [corrected] sporadic patient, at least two or more ..
  8. Zia M, Rmali K, Watkins G, Mansel R, Jiang W. The expression of the von Hippel-Lindau gene product and its impact on invasiveness of human breast cancer cells. Int J Mol Med. 2007;20:605-11 pubmed
    The von Hippel-Lindau (VHL) gene is located on the short arm of chromosome 3, the mutations of which lead to the development of von Hippel-Lindau disease...
  9. Li L, Zhang L, Zhang X, Yan Q, Minamishima Y, Olumi A, et al. Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations. Mol Cell Biol. 2007;27:5381-92 pubmed
    ..The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the alpha subunits of the heterodimeric transcription factor ..
  10. Baek J, Mahon P, Oh J, Kelly B, Krishnamachary B, Pearson M, et al. OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha. Mol Cell. 2005;17:503-12 pubmed
    ..by oxygen-dependent prolyl hydroxylation, which is required for binding of the von Hippel-Lindau protein (VHL), the recognition component of an E3 ubiquitin ligase that targets HIF-1alpha for ubiquitination and degradation...
  11. Ampofo E, Kietzmann T, Zimmer A, Jakupovic M, Montenarh M, Götz C. Phosphorylation of the von Hippel-Lindau protein (VHL) by protein kinase CK2 reduces its protein stability and affects p53 and HIF-1alpha mediated transcription. Int J Biochem Cell Biol. 2010;42:1729-35 pubmed publisher
    ..The VHL protein can be phosphorylated by protein kinase CK2 at serines 33, 38 and 43...
  12. Schermer B, Ghenoiu C, Bartram M, Muller R, Kotsis F, Höhne M, et al. The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J Cell Biol. 2006;175:547-54 pubmed
    ..In this study, we demonstrate that the von Hippel-Lindau (VHL) protein (pVHL) is a ciliary protein that controls ciliogenesis in kidney cells...
  13. Harten S, Shukla D, Barod R, Hergovich A, Balda M, Matter K, et al. Regulation of renal epithelial tight junctions by the von Hippel-Lindau tumor suppressor gene involves occludin and claudin 1 and is independent of E-cadherin. Mol Biol Cell. 2009;20:1089-101 pubmed publisher
    ..Loss of function of the tumor suppressor VHL leads to many features of EMT, and it has been hypothesized that the pivotal mediator is down-regulation of the ..
  14. Thoma C, Toso A, Gutbrodt K, Reggi S, Frew I, Schraml P, et al. VHL loss causes spindle misorientation and chromosome instability. Nat Cell Biol. 2009;11:994-1001 pubmed publisher
    ..Here we show that the von Hippel-Lindau (VHL) tumour suppressor protein, pVHL, which is inactivated in hereditary and sporadic forms of renal cell carcinoma, localizes to the mitotic spindle in ..
  15. Yang C, Huntoon K, Ksendzovsky A, Zhuang Z, Lonser R. Proteostasis modulators prolong missense VHL protein activity and halt tumor progression. Cell Rep. 2013;3:52-9 pubmed publisher
    ..We found a quantitative reduction of missense mutant VHL protein (pVHL) in tumors associated with physiologic mRNA expression...
  16. Hervouet E, Demont J, Pecina P, Vojtiskova A, Houstek J, Simonnet H, et al. A new role for the von Hippel-Lindau tumor suppressor protein: stimulation of mitochondrial oxidative phosphorylation complex biogenesis. Carcinogenesis. 2005;26:531-9 pubmed
    ..We show that the presence of wild-type VHL protein (pVHL) increased mitochondrial DNA and respiratory chain protein contents and permitted the cells to rely on their ..
  17. Knauth K, Bex C, Jemth P, Buchberger A. Renal cell carcinoma risk in type 2 von Hippel-Lindau disease correlates with defects in pVHL stability and HIF-1alpha interactions. Oncogene. 2006;25:370-7 pubmed
    The von Hippel-Lindau (VHL) tumor suppressor protein is the substrate binding subunit of the CBC(VHL) E3 ubiquitin ligase complex. Mutations in the VHL gene cause a variety of tumors with complex genotype/phenotype correlations...
  18. Meyer Rochow G, Smith J, Richardson A, Marsh D, Sidhu S, Robinson B, et al. Denaturing high performance liquid chromatography detection of SDHB, SDHD, and VHL germline mutations in pheochromocytoma. J Surg Res. 2009;157:55-62 pubmed publisher
    ..disease, Neurofibromatosis Type 1, and the pheochromocytoma/paraganglioma syndromes caused by mutations in the RET, VHL, NF1, SDHB, and SDHD genes, respectively...
  19. Lolkema M, Mehra N, Jorna A, van Beest M, Giles R, Voest E. The von Hippel-Lindau tumor suppressor protein influences microtubule dynamics at the cell periphery. Exp Cell Res. 2004;301:139-46 pubmed
    The von Hippel-Lindau (VHL) protein protects microtubules (MTs) from destabilization by nocodazole treatment. Based on this fixed-cell assay with static end points, VHL has been reported to directly stabilize the MT cytoskeleton...
  20. Martella M, Salviati L, Casarin A, Trevisson E, Opocher G, Polli R, et al. Molecular analysis of two uncharacterized sequence variants of the VHL gene. J Hum Genet. 2006;51:964-8 pubmed
    Mutations in the VHL gene cause von Hippel-Lindau disease, a cancer predisposing syndrome characterized by a variety of benign and malignant neoplasms...
  21. Patocs A, Gergics P, Balogh K, Toth M, Fazakas F, Liko I, et al. Ser80Ile mutation and a concurrent Pro25Leu variant of the VHL gene in an extended Hungarian von Hippel-Lindau family. BMC Med Genet. 2008;9:29 pubmed publisher
    Von Hippel-Lindau disease (VHL) is a rare autosomal dominant disease characterized by development of cystic and tumorous lesions at multiple sites, including the brain, spinal cord, kidneys, adrenals, pancreas, epididymis and eyes...
  22. Charbotel B, Gad S, Caïola D, Beroud C, Fevotte J, Bergeret A, et al. Trichloroethylene exposure and somatic mutations of the VHL gene in patients with Renal Cell Carcinoma. J Occup Med Toxicol. 2007;2:13 pubmed publisher
    We investigated the association between exposure to trichloroethylene (TCE) and mutations in the von Hippel-Lindau (VHL) gene and the subsequent risk for renal cell carcinoma (RCC)...
  23. Wright T, Rathmell W. Identification of Ror2 as a hypoxia-inducible factor target in von Hippel-Lindau-associated renal cell carcinoma. J Biol Chem. 2010;285:12916-24 pubmed publisher
    ..We found that Ror2 was indeed associated with the pVHL loss in RCC as well as with VHL somatic mutations tightly coordinated with the induction of RCC...
  24. Thoma C, Frew I, Hoerner C, Montani M, Moch H, Krek W. pVHL and GSK3beta are components of a primary cilium-maintenance signalling network. Nat Cell Biol. 2007;9:588-95 pubmed
    ..premalignant renal cysts and arises because of functional inactivation of the VHL tumour suppressor gene product, pVHL. Here, we show that pVHL and glycogen synthase kinase (GSK)3beta are key components of an interlinked signalling ..
  25. Mannelli M, Castellano M, Schiavi F, Filetti S, Giacchè M, Mori L, et al. Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009;94:1541-7 pubmed publisher
    ..according to their family history, the presence of lesions outside adrenals/paraganglia considered syndromic for VHL disease, MEN2, and NF1, and the number and types of pheochromocytomas and/or paragangliomas...
  26. Benetatos L, Dasoula A, Syed N, Hatzimichael E, Crook T, Bourantas K. Methylation analysis of the von Hippel-Lindau gene in acute myeloid leukaemia and myelodysplastic syndromes. Leukemia. 2008;22:1293-5 pubmed
  27. Harten S, Esteban M, Maxwell P. Identification of novel VHL regulated genes by transcriptomic analysis of RCC10 renal carcinoma cells. Adv Enzyme Regul. 2009;49:43-52 pubmed publisher
  28. Chacon Camacho O, Rodriguez Dennen F, Camacho Molina A, Rasmussen A, Alonso Vilatela E, Zenteno J. Clinical and molecular features of familial and sporadic cases of von Hippel-Lindau disease from Mexico. Clin Exp Ophthalmol. 2010;38:277-83 pubmed publisher
    von Hippel-Lindau disease (VHL) is an uncommon autosomal dominant condition predisposing to the development of tumours in a variety of body organs and caused by germline mutations in VHL, a tumour suppressor gene located on 3p...
  29. Cowey C, Rathmell W. VHL gene mutations in renal cell carcinoma: role as a biomarker of disease outcome and drug efficacy. Curr Oncol Rep. 2009;11:94-101 pubmed
    ..Alteration of the von Hippel-Lindau gene (VHL) by mutation, loss of heterozygosity, and promoter methylation has been found to be important to RCC pathogenesis...
  30. Chen J, Wu Y, Shao P, Cao Q, Qin C, Li P, et al. Association between VHL single nucleotide polymorphism (rs779805) and the susceptibility to prostate cancer in Chinese. DNA Cell Biol. 2012;31:790-6 pubmed publisher
    The Von Hippel-Lindau (VHL) tumor suppressor gene is a crucial regulator of the hypoxia response pathway and plays an important role in tumorigenesis, particularly in tumor growth and vascularization...
  31. Sudarshan S, Karam J, Brugarolas J, Thompson R, Uzzo R, Rini B, et al. Metabolism of kidney cancer: from the lab to clinical practice. Eur Urol. 2013;63:244-51 pubmed publisher
    ..The search strategy included the following terms: renal cancer, metabolism, HIF, VHL. Significant progress has been made in the understanding of the metabolic derangements present in renal cancer...
  32. Smits K, Schouten L, van Dijk B, Hulsbergen van de Kaa C, Wouters K, Oosterwijk E, et al. Genetic and epigenetic alterations in the von hippel-lindau gene: the influence on renal cancer prognosis. Clin Cancer Res. 2008;14:782-7 pubmed publisher
    Inactivation of the von Hippel-Lindau (VHL) gene is considered as an early event in renal cancer tumorigenesis. The prognostic relevance of these changes, however, is not clear and previous results are contradictory...
  33. Micale L, Muscarella L, Marzulli M, Augello B, Tritto P, D Agruma L, et al. VHL frameshift mutation as target of nonsense-mediated mRNA decay in Drosophila melanogaster and human HEK293 cell line. J Biomed Biotechnol. 2009;2009:860761 pubmed publisher
    ..Different types of germline mutations in the VHL gene cause the von Hippel-Lindau disease, a dominantly inherited familial cancer syndrome with a marked phenotypic ..
  34. Gallou C, Chauveau D, Richard S, Joly D, Giraud S, Olschwang S, et al. Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions. Hum Mutat. 2004;24:215-24 pubmed
    von Hippel-Lindau (VHL) disease arises from mutations in the VHL gene and predisposes patients to develop a variety of tumors in different organs. In the kidney, single or multiple cysts and renal cell carcinomas (RCC) may occur...
  35. Cheng J, Kang X, Zhang S, Yeh E. SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell. 2007;131:584-95 pubmed
    ..Hypoxia induces SUMOylation of HIF1alpha, which promotes its binding to a ubiquitin ligase, von Hippel-Lindau (VHL) protein, through a proline hydroxylation-independent mechanism, leading to its ubiquitination and degradation...
  36. Tan M, Gu Q, He H, Pamarthy D, Semenza G, Sun Y. SAG/ROC2/RBX2 is a HIF-1 target gene that promotes HIF-1 alpha ubiquitination and degradation. Oncogene. 2008;27:1404-11 pubmed
    ..the second family member of ROC1/RBX1, a component of SCF (Skp1, Cullin, F-box protein) and VCB (von Hippel-Lindau (VHL), Cullin and Elongin B/C) E3 ubiquitin ligases...
  37. Kaelin W. The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res. 2004;10:6290S-5S pubmed
    ..The VHL gene product, pVHL, is the substrate recognition module of an E3 ubiquitin ligase that targets the hypoxia-inducible factor (HIF) for ..
  38. Maina E, Morris M, Zatyka M, Raval R, Banks R, Richards F, et al. Identification of novel VHL target genes and relationship to hypoxic response pathways. Oncogene. 2005;24:4549-58 pubmed
    ..are highly vascular, but it is unclear to what extent HIF-dependent and HIF-independent mechanisms account for pVHL tumour suppressor activity...
  39. Evans A, Russell R, Roche O, Burry T, Fish J, Chow V, et al. VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol. 2007;27:157-69 pubmed
    The product of the von Hippel-Lindau gene (VHL) acts as the substrate-recognition component of an E3 ubiquitin ligase complex that ubiquitylates the catalytic alpha subunit of hypoxia-inducible factor (HIF) for oxygen-dependent ..
  40. Yang H, Minamishima Y, Yan Q, Schlisio S, Ebert B, Zhang X, et al. pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2. Mol Cell. 2007;28:15-27 pubmed
    The VHL tumor suppressor protein (pVHL) is part of an E3 ubiquitin ligase that targets HIF for destruction. pVHL-defective renal carcinoma cells exhibit increased NF-kappaB activity but the mechanism is unclear...
  41. Chen L, Han L, Zhang K, Shi Z, Zhang J, Zhang A, et al. VHL regulates the effects of miR-23b on glioma survival and invasion via suppression of HIF-1?/VEGF and ?-catenin/Tcf-4 signaling. Neuro Oncol. 2012;14:1026-36 pubmed publisher
    ..Luciferase assay and Western blot analysis revealed that VHL is a direct target of miR-23b. Restoring expression of VHL inhibited glioma proliferation and invasion...
  42. Moore L, Nickerson M, Brennan P, Toro J, Jaeger E, Rinsky J, et al. Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. PLoS Genet. 2011;7:e1002312 pubmed publisher
    Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis...
  43. Siu W, Ma R, Lam C, Mak C, Yuen Y, Lo F, et al. Molecular basis of von Hippel-Lindau syndrome in Chinese patients. Chin Med J (Engl). 2011;124:237-41 pubmed
    Von Hippel-Lindau (VHL) syndrome is an autosomal dominant familial cancer syndrome predisposing the affected individuals to multiple tumours in various organs. The genetic basis of VHL in Southern Chinese is largely unknown...
  44. Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac de Paillerets B, Chabre O, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol. 2005;23:8812-8 pubmed
    ..Clinical data and blood samples were collected, and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened. Neurofibromatosis type 1 was diagnosed from phenotypic criteria...
  45. Hoebeeck J, Vandesompele J, Nilsson H, De Preter K, Van Roy N, De Smet E, et al. The von Hippel-Lindau tumor suppressor gene expression level has prognostic value in neuroblastoma. Int J Cancer. 2006;119:624-9 pubmed
    ..The critical deleted region encompasses the locus of the von Hippel-Lindau gene (VHL, 3p25)...
  46. Lutz M, Burk R. Primary cilium formation requires von hippel-lindau gene function in renal-derived cells. Cancer Res. 2006;66:6903-7 pubmed
    Biallelic inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, occurs in the majority of renal clear cell carcinomas (RCC)...
  47. Pettman R, Crowley A, Riddell C, Ludman M. VHL P25L is not a pathogenic von Hippel-Lindau mutation: a family study. Mol Diagn Ther. 2006;10:239-42 pubmed
    von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome in which affected individuals may develop CNS and retinal hemangioblastomas, pheochromocytomas, renal cell carcinoma, and cysts of various organs...
  48. Hatzimichael E, Dranitsaris G, Dasoula A, Benetatos L, Stebbing J, Crook T, et al. Von Hippel-Lindau methylation status in patients with multiple myeloma: a potential predictive factor for the development of bone disease. Clin Lymphoma Myeloma. 2009;9:239-42 pubmed publisher
    ..It is an attractive hypothesis that loss of expression of the von Hippel-Lindau (VHL) gene, resulting in constitutive activation of hypoxia-inducible factor-1alpha (HIF-1alpha), contributes to ..
  49. Van Dijk B, Schouten L, Oosterwijk E, Hulsbergen van de Kaa C, Kiemeney L, Goldbohm R, et al. Cigarette smoking, von Hippel-Lindau gene mutations and sporadic renal cell carcinoma. Br J Cancer. 2006;95:374-7 pubmed
    We investigated whether smoking is associated with mutations in the Von Hippel-Lindau (VHL) gene in 337 cases of sporadic renal cell carcinoma (RCC) among 120 852 people followed for 11...
  50. Peruzzi B, Athauda G, Bottaro D. The von Hippel-Lindau tumor suppressor gene product represses oncogenic beta-catenin signaling in renal carcinoma cells. Proc Natl Acad Sci U S A. 2006;103:14531-6 pubmed
    Loss of von Hippel-Lindau (VHL) tumor suppressor gene function occurs in familial and most sporadic clear cell renal cell carcinoma (RCC), resulting in the aberrant expression of genes that control cell proliferation, invasion, and ..
  51. Mikhaylova O, Ignacak M, Barankiewicz T, Harbaugh S, Yi Y, Maxwell P, et al. The von Hippel-Lindau tumor suppressor protein and Egl-9-Type proline hydroxylases regulate the large subunit of RNA polymerase II in response to oxidative stress. Mol Cell Biol. 2008;28:2701-17 pubmed publisher
    ..clear cell carcinoma (RCC) is frequently associated with loss of the von Hippel-Lindau (VHL) tumor suppressor (pVHL), which inhibits ubiquitylation and degradation of the alpha subunits of hypoxia-inducible transcription factor...
  52. Russell R, Ohh M. NEDD8 acts as a 'molecular switch' defining the functional selectivity of VHL. EMBO Rep. 2008;9:486-91 pubmed publisher
    The von Hippel-Lindau (VHL) tumour suppressor protein is important in the E3 ubiquitin ligase ECV (Elongin B/C-CUL2-VHL)-mediated destruction of hypoxia-inducible factor and the promotion of fibronectin (FN) extracellular matrix assembly...
  53. Sufan R, Ohh M. Role of the NEDD8 modification of Cul2 in the sequential activation of ECV complex. Neoplasia. 2006;8:956-63 pubmed
    ..ligase complex, which is composed of elongins B and C, Rbx1, Cul2, and the substrate-conferring von Hippel-Lindau (VHL) tumor-suppressor protein that targets the catalytic alpha subunit of hypoxia-inducible factor (HIF) for oxygen-..
  54. Fu J, Menzies K, Freeman R, Taubman M. EGLN3 prolyl hydroxylase regulates skeletal muscle differentiation and myogenin protein stability. J Biol Chem. 2007;282:12410-8 pubmed
    ..hypoxia-inducible factor-alpha for ubiquitination by a ubiquitin ligase complex containing the von Hippel-Lindau (VHL) tumor suppressor. We now report that EGLN3 levels increase during C2C12 skeletal myoblast differentiation...
  55. Liu Y, Baek J, Zhang H, Diez R, Cole R, Semenza G. RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha. Mol Cell. 2007;25:207-17 pubmed
    ..degradation of the HIF-1alpha subunit is mediated by prolyl hydroxylase (PHD), the von Hippel-Lindau (VHL)/Elongin-C/Elongin-B E3 ubiquitin ligase complex, and the proteasome...
  56. Gordan J, Lal P, Dondeti V, Letrero R, Parekh K, Oquendo C, et al. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell. 2008;14:435-46 pubmed publisher
    ..Interestingly, ccRCCs with intact VHL, as well as pVHL-deficient HIF-1alpha/HIF-2alpha-expressing ccRCCs, exhibited enhanced Akt/mTOR and ERK/MAPK signaling...
  57. Hacker K, LEE C, Rathmell W. VHL type 2B mutations retain VBC complex form and function. PLoS ONE. 2008;3:e3801 pubmed publisher
    ..Our interaction analysis supported previous observations that VHL Type 2B mutations disrupt the interaction between pVHL and Elongin C but maintain partial regulation of HIF...
  58. Kamura T, Maenaka K, Kotoshiba S, Matsumoto M, Kohda D, Conaway R, et al. VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes Dev. 2004;18:3055-65 pubmed
    ..SOCS-box proteins recruit substrates to the ECS complex and are linked to Cullin-Rbx via Elongin B/C. VHL has been implicated as a SOCS-box protein, but lacks a C-terminal sequence (downstream of the BC box) of the SOCS ..
  59. Foxler D, Bridge K, James V, Webb T, Mee M, Wong S, et al. The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat Cell Biol. 2012;14:201-8 pubmed publisher
    ..the PHDs hydroxylate two conserved proline residues on HIF-1?, which leads to binding of the von Hippel-Lindau (VHL) tumour suppressor, the recognition component of a ubiquitin-ligase complex, initiating HIF-1? ubiquitylation and ..
  60. Xin H, Brown J, Gong C, Fan H, Brewer G, Gnarra J. Association of the von Hippel-Lindau protein with AUF1 and posttranscriptional regulation of VEGFA mRNA. Mol Cancer Res. 2012;10:108-20 pubmed publisher
    ..b>pVHL controls oxygen-responsive gene expression at the transcriptional and posttranscriptional levels...
  61. McClellan A, Scott M, Frydman J. Folding and quality control of the VHL tumor suppressor proceed through distinct chaperone pathways. Cell. 2005;121:739-48 pubmed
    ..Analysis of the chaperone requirements for degradation of misfolded variants of a cytosolic protein, the VHL tumor suppressor, reveals that distinct chaperone pathways mediate its folding and quality control...
  62. Zhang J, Huang Y, Pan J, Liu D, Zhou L, Xue W, et al. Germline mutations in the von Hippel-Lindau disease (VHL) gene in mainland Chinese families. J Cancer Res Clin Oncol. 2008;134:1211-8 pubmed publisher
    von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. To date, more than 500 VHL families have been reported worldwide...
  63. Rechsteiner M, von Teichman A, Nowicka A, Sulser T, Schraml P, Moch H. VHL gene mutations and their effects on hypoxia inducible factor HIF?: identification of potential driver and passenger mutations. Cancer Res. 2011;71:5500-11 pubmed publisher
    ..Nonsense and frameshift mutations abrogate the function of the VHL protein (pVHL), whereas missense mutations can have different effects...
  64. Karhausen J, Kong T, Narravula S, Colgan S. Induction of the von Hippel-Lindau tumor suppressor gene by late hypoxia limits HIF-1 expression. J Cell Biochem. 2005;95:1264-75 pubmed
    ..The von Hippel-Lindau tumor suppressor (pVHL) is a component of the E3 ubiquitin ligase complex and targets HIF-alpha to proteasomal degradation, but also is ..
  65. Maher E, Neumann H, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19:617-23 pubmed publisher
    The autosomal dominantly inherited disorder von Hippel-Lindau disease (VHL) is caused by germline mutations in the VHL tumour suppressor gene (TSG)...
  66. Lee C, Hickey M, Sanford C, McGuire C, Cowey C, Simon M, et al. VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo. Oncogene. 2009;28:1694-705 pubmed publisher
    ..Type 2B mutant pVHL is predicted to be defective in hypoxia inducible factor (HIF)-alpha regulation...
  67. Cascon A, Pita G, Burnichon N, Landa I, López Jiménez E, Montero Conde C, et al. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab. 2009;94:1701-5 pubmed publisher
    ..Two hundred thirty-seven nonrelated probands were analyzed for the major susceptibility genes: VHL, RET, SDHB, SDHC, and SDHD...
  68. Korpershoek E, Van Nederveen F, Dannenberg H, Petri B, Komminoth P, Perren A, et al. Genetic analyses of apparently sporadic pheochromocytomas: the Rotterdam experience. Ann N Y Acad Sci. 2006;1073:138-48 pubmed
    ..alone or as a component of the multiple endocrine neoplasia Type 2 (MEN2) syndrome (RET gene), Von Hippel-Lindau (VHL) disease (VHL gene), neurofibromatosis Type 1 (NF1 gene), or familial pheochromocytoma-paraganglioma (PCC-PGL) ..
  69. Boedeker C, Erlic Z, Richard S, Kontny U, Gimenez Roqueplo A, Cascon A, et al. Head and neck paragangliomas in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2009;94:1938-44 pubmed publisher
    ..Heritable non-SDHx HNP might occur in von Hippel-Lindau disease (VHL, VHL gene), multiple endocrine neoplasia type 2 (MEN2, RET gene), and neurofibromatosis type 1 (NF1, NF1 gene)...
  70. Koch C, Brouwers F, Vortmeyer A, Tannapfel A, Libutti S, Zhuang Z, et al. Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma. BMC Cancer. 2006;6:131 pubmed
    ..Recent studies suggest a "second hit" mechanism resulting in amplification of mutant RET. Somatic VHL gene alterations are implicated in the pathogenesis of MEN2 pheochromocytomas...
  71. Wang W, Chen H, Tseng Y, Lai Y. Identification of somatic mutations in the von Hippel-Lindau (VHL) gene in a patient with renal cell carcinoma. J Formos Med Assoc. 2009;108:886-93 pubmed publisher
    One of the known causal molecular events in renal cell carcinoma is somatic mutation in the von Hippel-Lindau (VHL) gene. Our study describes a 51-year-old Taiwanese man who had bilateral renal cell carcinoma...
  72. Forman J, Worth C, Bickerton G, Eisen T, Blundell T. Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel-Lindau disease and suggests molecular mechanisms of tumorigenesis. Proteins. 2009;77:84-96 pubmed publisher
    ..database tools to understand and predict the phenotypes associated with missense mutations in the VHL gene product, pVHL. The protein product pVHL is known to interact with elongin B, elongin C, and the HIF substrate...
  73. Roe J, Kim H, Lee S, Kim S, Cho E, Youn H. p53 stabilization and transactivation by a von Hippel-Lindau protein. Mol Cell. 2006;22:395-405 pubmed
    ..factor-alpha (HIFalpha) is a well-documented substrate of von Hippel-Lindau tumor suppressor protein (pVHL), it remains unclear whether the dysregulation of HIF is sufficient to account for de novo tumorigenesis in VHL-..
  74. Erlic Z, Hoffmann M, Sullivan M, Franke G, Peczkowska M, Harsch I, et al. Pathogenicity of DNA variants and double mutations in multiple endocrine neoplasia type 2 and von Hippel-Lindau syndrome. J Clin Endocrinol Metab. 2010;95:308-13 pubmed publisher
    ..This observation of coincident DNA variants, both reported as pathogenic, in two known susceptibility genes prompted the question of their pathogenic relevance...
  75. Kim J, Jung C, Cho Y, Lee J, Lee S, Kim H, et al. Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma. Oncol Rep. 2005;13:859-64 pubmed
    Somatic inactivation of the von Hippel-Lindau (VHL) gene is the most frequent genetic event observed in clear cell renal cell carcinoma (CC-RCC)...
  76. Gergics P, Patocs A, Toth M, Igaz P, Szucs N, Liko I, et al. Germline VHL gene mutations in Hungarian families with von Hippel-Lindau disease and patients with apparently sporadic unilateral pheochromocytomas. Eur J Endocrinol. 2009;161:495-502 pubmed publisher
    Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome caused by mutations or deletions of the VHL tumor-suppressor gene...
  77. Kaelin W. The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res. 2007;13:680s-684s pubmed
    ..Somatic VHL mutations are also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the alpha-subunits of the heterodimeric transcription factor ..
  78. Kanno T, Kamba T, Yamasaki T, Shibasaki N, Saito R, Terada N, et al. JunB promotes cell invasion and angiogenesis in VHL-defective renal cell carcinoma. Oncogene. 2012;31:3098-110 pubmed publisher
    ..Although the best-characterized function of the VHL protein (pVHL) is regulation of hypoxia-inducible factor-? (HIF?), pVHL also controls the development of pheochromocytoma through ..
  79. Nordstrom O Brien M, van der Luijt R, van Rooijen E, van den Ouweland A, Majoor Krakauer D, Lolkema M, et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010;31:521-37 pubmed publisher
    Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well...
  80. Nickerson M, Jaeger E, Shi Y, Durocher J, Mahurkar S, Zaridze D, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res. 2008;14:4726-34 pubmed publisher
    ..a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC)...
  81. Megumi Y, Miyauchi Y, Sakurai H, Nobeyama H, Lorick K, Nakamura E, et al. Multiple roles of Rbx1 in the VBC-Cul2 ubiquitin ligase complex. Genes Cells. 2005;10:679-91 pubmed
    ..Taken together, these results indicate that various mechanisms regulate both the activities and the stability of cullin-based ligases. ..
  82. Grosfeld A, Stolze I, Cockman M, Pugh C, Edelmann M, Kessler B, et al. Interaction of hydroxylated collagen IV with the von hippel-lindau tumor suppressor. J Biol Chem. 2007;282:13264-9 pubmed
    The von Hippel-Lindau tumor suppressor (pVHL) targets hydroxylated alpha-subunits of hypoxia-inducible factor (HIF) for ubiquitin-mediated proteasomal destruction through direct interaction with the hydroxyproline binding pocket in its ..
  83. Cai Q, Knight J, Verma S, Zald P, Robertson E. EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors. PLoS Pathog. 2006;2:e116 pubmed
    ..directly functions as a component of the EC5S ubiquitin complex targeting the tumor suppressors von Hippel-Lindau (VHL) and p53 for degradation...