von hippel lindau tumor suppressor protein


Summary: A ubiquitin-protein ligase that mediates OXYGEN-dependent polyubiquitination of HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT. It is inactivated in VON HIPPEL-LINDAU SYNDROME.

Top Publications

  1. 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
    ..These results show that SENP1 plays a key role in the regulation of the hypoxic response through regulation of HIF1alpha stability and that SUMOylation can serve as a direct signal for ubiquitin-dependent degradation. ..
  2. Sufan R, Moriyama E, Mariampillai A, Roche O, Evans A, Alajez N, et al. Oxygen-independent degradation of HIF-alpha via bioengineered VHL tumour suppressor complex. EMBO Mol Med. 2009;1:66-78 pubmed publisher
    ..These findings introduce the concept and feasibility of 'bio-tailored' enzymes in the treatment of HIF-overexpressing tumours. ..
  3. 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
    ..Together, our data reveal unexpectedly strong structural defects of type 2C-associated pVHL mutant proteins that are likely to affect both HIF-1/2alpha-related and -unrelated pVHL functions in the pathogenesis of pheochromocytomas. ..
  4. 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
    ..Our experiments support a model in which the representative Type 2B R167Q mutant pVhl produces a unique profile of HIF dysregulation, thereby promoting tissue-specific effects on cell growth, development and tumor predisposition. ..
  5. 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
    ..Therefore pVHL can serve as an adaptor for both a ubiquitin conjugating enzyme and a kinase. The latter activity, which promotes Card9 phosphorylation, links pVHL to control of NF-kappaB activity and tumorigenesis. ..
  6. 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
  7. Neumann H, Eng C. The approach to the patient with paraganglioma. J Clin Endocrinol Metab. 2009;94:2677-83 pubmed publisher
    ..Adrenal and extraadrenal retroperitoneal tumors should be operated by surgeons highly experienced in minimal invasive, endoscopic techniques. ..
  8. Kuntz E, Yusenko M, Nagy A, Kovacs G. Oligoarray comparative genomic hybridization of renal cell tumors that developed in patients with acquired cystic renal disease. Hum Pathol. 2010;41:1345-9 pubmed publisher
    ..We suggest that not only the morphology but also the genetics of renal cell tumors associated with acquired cystic renal disease may differ from those occurring in the general population. ..
  9. Kurihara T, Kubota Y, Ozawa Y, Takubo K, Noda K, Simon M, et al. von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina. Development. 2010;137:1563-71 pubmed publisher
    ..Our results suggest that not only macrophages but also tissue oxygen-sensing mechanisms regulate the transition from the fetal to the adult circulatory system in the retina. ..

More Information


  1. Yun J, Kim Y, Tomida A, Choi C. Regulation of DNA topoisomerase IIalpha stability by the ECV ubiquitin ligase complex. Biochem Biophys Res Commun. 2009;389:5-9 pubmed publisher
    ..These results demonstrate that ECV acts as E3 ubiquitin ligase targeting GRDD-independent topo IIalpha to the ubiquitin-proteasome pathway. ..
  2. Ciotti P, Garuti A, Gulli R, Ballestrero A, Bellone E, Mandich P. Germline mutations in the von Hippel-Lindau gene in Italian patients. Eur J Med Genet. 2009;52:311-4 pubmed publisher
    ..In addition, an RQ-PCR protocol was validated in order to introduce it in the routine VHL laboratory diagnosis. ..
  3. Aggelis V, Craven R, Peng J, Harnden P, Cairns D, Maher E, et al. Proteomic identification of differentially expressed plasma membrane proteins in renal cell carcinoma by stable isotope labelling of a von Hippel-Lindau transfectant cell line model. Proteomics. 2009;9:2118-30 pubmed publisher
    ..These results illustrate the potential of this approach for identifying VHL-dependent proteins that may be important in tumorigenesis. ..
  4. Irisarri M, Lavista Llanos S, Romero N, Centanin L, Dekanty A, Wappner P. Central role of the oxygen-dependent degradation domain of Drosophila HIFalpha/Sima in oxygen-dependent nuclear export. Mol Biol Cell. 2009;20:3878-87 pubmed publisher
    ..HIFalpha/Sima nucleo-cytoplasmic localization is the result of a dynamic equilibrium between nuclear import and nuclear export, and nuclear export is modulated by oxygen tension. ..
  5. Ferchichi I, Stambouli N, Marrackchi R, Arlot Y, Prigent C, Fadiel A, et al. Experimental and computational studies indicate specific binding of pVHL protein to Aurora-A kinase. J Phys Chem B. 2010;114:1486-97 pubmed publisher
    ..In addition, the detailed Aurora-A/pVHL binding structure obtained will be valuable for the design of future Aurora-A inhibitors as therapeutic agents. ..
  6. Patard J, Rioux Leclercq N, Masson D, Zerrouki S, Jouan F, Collet N, et al. Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma. Br J Cancer. 2009;101:1417-24 pubmed publisher
    ..Stratifying CCRCCs according to VHL and VEGF status may help tailor therapeutic strategy. ..
  7. Balci S, Aypar E, Beksac M, Bartsch O. A severely mentally and motor retarded girl with monosomy 3pter-->p25 and trisomy 8q24-->qter due to a familial reciprocal translocation t(3;8)(p25;q24). Genet Couns. 2009;20:125-32 pubmed
    ..A familial translocation t(3;8) is very rare and there are no previous reports on terminal monosomy 3p (pter-->p25) and terminal trisomy 8q (q24-->qter)...
  8. Ricketts C, Zeegers M, Lubinski J, Maher E. Analysis of germline variants in CDH1, IGFBP3, MMP1, MMP3, STK15 and VEGF in familial and sporadic renal cell carcinoma. PLoS ONE. 2009;4:e6037 pubmed publisher
  9. 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
    ..Whether it represents an early or late event of the disease merits additional study. Additional studies regarding the serum levels of HIF-1alpha and vascular endothelial growth factor would be mechanistically interesting. ..
  10. Weidemann A, Krohne T, Aguilar E, Kurihara T, Takeda N, Dorrell M, et al. Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina. Glia. 2010;58:1177-85 pubmed publisher
    ..Thus, we demonstrate that astrocytes in the retina have highly divergent roles during developmental, physiological angiogenesis, and ischemia-driven, pathological neovascularization. ..
  11. Tan S, Pal M, Tan M, Wong M, Tam F, Teo J, et al. Regulation of cell proliferation and migration by TAK1 via transcriptional control of von Hippel-Lindau tumor suppressor. J Biol Chem. 2009;284:18047-58 pubmed publisher
    ..Dysfunctional regulation of TAK1 may contribute to the pathology of non-healing chronic inflammatory wounds and psoriasis. ..
  12. Kim J, Rini B, Hansel D. Von Hippel Lindau syndrome. Adv Exp Med Biol. 2010;685:228-49 pubmed
    ..Further details regardingvariegated molecular pathways and mechanisms ofVHLS are emerging with the subsequent advent of novel treatment protocols that are currently in clinical trials. ..
  13. Hasani Ranjbar S, Amoli M, Ebrahim Habibi A, Haghpanah V, Hejazi M, Soltani A, et al. Mutation screening of VHL gene in a family with malignant bilateral pheochromocytoma: from isolated familial pheochromocytoma to von Hippel-Lindau disease. Fam Cancer. 2009;8:465-71 pubmed publisher
    ..VHL type 2 presenting with both pheochromocytoma and retinal angioma in this family found to be associated with the new missense mutation (c499 C>T) of VHL gene. ..
  14. Shen H, Adem A, Ylaya K, Wilson A, He M, Lorang D, et al. Deciphering von Hippel-Lindau (VHL/Vhl)-associated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations. PLoS ONE. 2009;4:e4897 pubmed publisher
    ..The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases. ..
  15. Kubo A, Yoshida T, Kobayashi N, Yokoyama T, Mimura T, Nishiguchi T, et al. Efficient generation of dopamine neuron-like cells from skin-derived precursors with a synthetic peptide derived from von Hippel-Lindau protein. Stem Cells Dev. 2009;18:1523-32 pubmed publisher
    ..The generated dopamine neuron-like cells are expected to serve as donor cells for neuronal repair for PD. ..
  16. Evans D, Howard E, Giblin C, Clancy T, Spencer H, Huson S, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A:327-32 pubmed publisher
    ..Estimates for NF1, NF2, FAP, and VHL are in line with previous estimates, and we provide the first estimates of birth incidence and de novo mutation rate for GS...
  17. Higashida T, Jitsuki S, Kubo A, Mitsushima D, Kamiya Y, Kanno H. Skin-derived precursors differentiating into dopaminergic neuronal cells in the brains of Parkinson disease model rats. J Neurosurg. 2010;113:648-55 pubmed publisher
    ..This study suggests that transplantation of skin-derived precursors, differentiated into neuronal cells using VHL peptide, can improve PD-like symptoms by enabling production of dopamine in the striata in a PD model of rats. ..
  18. Codreanu C, Duet M, Hautefort C, Wassef M, Guichard J, Giraud S, et al. Endolymphatic sac tumors in von Hippel-Lindau disease: report of three cases. Otol Neurotol. 2010;31:660-4 pubmed publisher
    ..The type of VHL mutation might predict the aggressiveness. ..
  19. Roos F, Roberts A, Hwang I, Moriyama E, Evans A, Sybingco S, et al. Oncolytic targeting of renal cell carcinoma via encephalomyocarditis virus. EMBO Mol Med. 2010;2:275-88 pubmed publisher
    ..These findings provide compelling pre-clinical evidence for the usage of EMCV in the treatment of CCRCC and potentially other tumours with elevated HIF/NF-kappaB-survival signature. ..
  20. Mortimer N, Moberg K. Regulation of Drosophila embryonic tracheogenesis by dVHL and hypoxia. Dev Biol. 2009;329:294-305 pubmed publisher
    ..The identification of an early stage of tracheal development that is vulnerable to hypoxia is an important addition to models of the invertebrate hypoxic response. ..
  21. Bangiyeva V, Rosenbloom A, Alexander A, Isanova B, Popko T, Schoenfeld A. Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes. BMC Cancer. 2009;9:229 pubmed publisher
    ..VHL has both HIF-alpha dependent and HIF-alpha independent functions in regulating tight junctions and cell morphology that likely impact the clinical phenotypes seen in VHL disease. ..
  22. Kawanami D, Mahabeleshwar G, Lin Z, Atkins G, Hamik A, Haldar S, et al. Kruppel-like factor 2 inhibits hypoxia-inducible factor 1alpha expression and function in the endothelium. J Biol Chem. 2009;284:20522-30 pubmed publisher
    ..These observations identify KLF2 as a novel inhibitor of HIF-1alpha expression and function. Therefore, KLF2 may be a target for modulating the angiogenic response in disease states. ..
  23. Oya M. Renal cell carcinoma: biological features and rationale for molecular-targeted therapy. Keio J Med. 2009;58:1-11 pubmed
    ..This review highlights the biological features of RCC that are relevant to molecular-targeted therapy. ..
  24. Berndt J, Moon R, Major M. Beta-catenin gets jaded and von Hippel-Lindau is to blame. Trends Biochem Sci. 2009;34:101-4 pubmed publisher
    ..Thus, the loss of VHL, as seen in clear cell renal cell carcinoma, could lead to tumor formation through beta-catenin de-repression. ..
  25. Semenza G. Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. Blood. 2009;114:2015-9 pubmed publisher
    ..Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects. ..
  26. Chan S, Zhang Y, Hemann C, Mahoney C, Zweier J, Loscalzo J. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab. 2009;10:273-84 pubmed publisher
    ..These results identify important mechanistic connections among microRNA, iron-sulfur cluster biology, hypoxia, and mitochondrial function, with broad implications for cellular metabolism and adaptation to cellular stress. ..
  27. Montani M, Heinimann K, von Teichman A, Rudolph T, Perren A, Moch H. VHL-gene deletion in single renal tubular epithelial cells and renal tubular cysts: further evidence for a cyst-dependent progression pathway of clear cell renal carcinoma in von Hippel-Lindau disease. Am J Surg Pathol. 2010;34:806-15 pubmed publisher
    ..Our in vivo results support a model in which renal cysts represent precursor lesions for clear cell renal cell carcinoma and arise from single renal tubular epithelial cells owing to von Hippel-Lindau gene deletion. ..
  28. Boysen G, Wollscheid B, Bausch Fluck D, Schraml P, Moch H. [Identification of VHL-associated changes in clear cell renal carcinoma: the application of combined genome and expression analyses]. Pathologe. 2009;30 Suppl 2:188-92 pubmed publisher
    ..Here we summarize recent studies focussing on this aspect of RCC and present a systems biology concept for the identification of novel tumor markers. These could be applied to improve future diagnosis and therapy of RCC. ..
  29. Vieira J, Henrique R, Ribeiro F, Barros Silva J, Peixoto A, Santos C, et al. Feasibility of differential diagnosis of kidney tumors by comparative genomic hybridization of fine needle aspiration biopsies. Genes Chromosomes Cancer. 2010;49:935-47 pubmed publisher
    ..2%, respectively. The positive predictive value and specificity of copy number profiles was 100%. We demonstrate that genetic diagnosis by CGH on FNA biopsies can improve differential diagnosis in patients with kidney tumors. ..
  30. Gkialas I, Papadopoulos G. New therapeutic approaches in the management of metastatic renal cell carcinoma. J BUON. 2009;14:399-404 pubmed
    ..Over the past few years considerable advances in the understanding of biology and underlying molecular pathways in RCC have resulted in the development of targeted therapies for this disease. ..
  31. Illingworth C, Loenarz C, Schofield C, Domene C. Chemical basis for the selectivity of the von Hippel Lindau tumor suppressor pVHL for prolyl-hydroxylated HIF-1alpha. Biochemistry. 2010;49:6936-44 pubmed publisher
  32. Sevilla M, Hermsen M, Weiss M, Grimbergen A, Balbin M, Llorente J, et al. Chromosomal changes in sporadic and familial head and neck paragangliomas. Otolaryngol Head Neck Surg. 2009;140:724-9 pubmed publisher
    ..Additional genes and mechanisms may need to be studied, especially in the group of sporadic PGL showing no chromosomal aberrations. ..
  33. Wells G, Schroth W, Brauch H, Ross E. Bilateral renal-cell carcinoma associated with an acquired VHL mutation and long-term trichloroethylene exposure. Clin Nephrol. 2009;71:708-13 pubmed
  34. Tennant D, Frezza C, MacKenzie E, Nguyen Q, Zheng L, Selak M, et al. Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. Oncogene. 2009;28:4009-21 pubmed publisher
    ..We also show that derivatized alpha-ketoglutarate can permeate multiple layers of cells, reducing HIF1alpha levels and its target genes in vivo. ..
  35. Xiao W, Ai J, Habermacher G, Volpert O, Yang X, Zhang A, et al. U19/Eaf2 binds to and stabilizes von hippel-lindau protein. Cancer Res. 2009;69:2599-606 pubmed publisher
    ..The above observations argue that U19/Eaf2 can modulate HIF1alpha and angiogenesis, possibly via direct binding and stabilization of pVHL. ..
  36. Obradors A, Fernandez E, Rius M, Oliver Bonet M, Martínez Fresno M, Benet J, et al. Outcome of twin babies free of Von Hippel-Lindau disease after a double-factor preimplantation genetic diagnosis: monogenetic mutation analysis and comprehensive aneuploidy screening. Fertil Steril. 2009;91:933.e1-7 pubmed publisher
    ..The DF-PGD can be a useful tool to increase implantation of transfered embryos in PGD for monogenic diseases. ..
  37. Kong H, Lee S, Beebe K, Scroggins B, Gupta G, Lee M, et al. Emetine promotes von Hippel-Lindau-independent degradation of hypoxia-inducible factor-2? in clear cell renal carcinoma. Mol Pharmacol. 2010;78:1072-8 pubmed publisher
    ..These data support the use of emetine or structurally related compounds as useful leads for the identification of novel HIF-2? inhibitors. ..
  38. Luu V, Boysen G, Struckmann K, Casagrande S, von Teichman A, Wild P, et al. Loss of VHL and hypoxia provokes PAX2 up-regulation in clear cell renal cell carcinoma. Clin Cancer Res. 2009;15:3297-304 pubmed publisher
    ..We conclude that in ccRCC, PAX2 reactivation is driven by HIF-dependent mechanisms following pVHL loss. ..
  39. Massoud T, Paulmurugan R, Gambhir S. A molecularly engineered split reporter for imaging protein-protein interactions with positron emission tomography. Nat Med. 2010;16:921-6 pubmed publisher
  40. Krishnan J, Suter M, Windak R, Krebs T, Felley A, Montessuit C, et al. Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab. 2009;9:512-24 pubmed publisher
    ..We propose a model in which activation of the HIF1alpha-PPARgamma axis by pathologic stress underlies key changes in cell metabolism that are characteristic of and contribute to common forms of heart disease. ..
  41. 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
    ..dHPLC is an effective screening tool for the detection of germline mutations in SDHB, SDHD, and VHL and has application for diagnostic germline mutation analysis in pheochromocytoma patients. ..
  42. Zanotelli D, Bruder E, Wight E, Troeger C. Bilateral papillary cystadenoma of the mesosalpinx: a rare manifestation of Von Hippel-Lindau disease. Arch Gynecol Obstet. 2010;282:343-6 pubmed publisher
    ..Patient surveillance is important, because in the course of VHL-associated tumors malignant lesions may arise that are relevant for the prognosis...
  43. Duchi S, Fagnocchi L, Cavaliere V, Hsouna A, Gargiulo G, Hsu T. Drosophila VHL tumor-suppressor gene regulates epithelial morphogenesis by promoting microtubule and aPKC stability. Development. 2010;137:1493-503 pubmed publisher
    ..The results establish a developmental function of the VHL gene that is relevant to its tumor-suppressor activity. ..
  44. Levy M, Lin F, Xu H, Dhall D, Spaulding B, Wang H. S100P, von Hippel-Lindau gene product, and IMP3 serve as a useful immunohistochemical panel in the diagnosis of adenocarcinoma on endoscopic bile duct biopsy. Hum Pathol. 2010;41:1210-9 pubmed publisher
  45. Mettu P, Agrón E, Samtani S, Chew E, Wong W. Genotype-phenotype correlation in ocular von Hippel-Lindau (VHL) disease: the effect of missense mutation position on ocular VHL phenotype. Invest Ophthalmol Vis Sci. 2010;51:4464-70 pubmed publisher
    ..These genotype-phenotype correlations can assist in the prognostic counseling and follow-up of VHL patients and may provide a basis for molecular inferences on ocular VHL disease pathogenesis. ..
  46. Linehan W, Srinivasan R, Schmidt L. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol. 2010;7:277-85 pubmed publisher
    ..Targeting the fundamental metabolic abnormalities in kidney cancer provides a unique opportunity for the development of more-effective forms of therapy for this disease. ..
  47. Wenger R, Hoogewijs D. Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells. Am J Physiol Renal Physiol. 2010;298:F1287-96 pubmed publisher
  48. van Rooijen E, Voest E, Logister I, Korving J, Schwerte T, Schulte Merker S, et al. Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia. Blood. 2009;113:6449-60 pubmed publisher
    ..They will contribute to our understanding of hypoxic signaling, hematopoiesis, and VHL-associated disease progression. ..
  49. Pressler B, Williams L, Ramos Vara J, Anderson K. Sequencing of the von Hippel-Lindau gene in canine renal carcinoma. J Vet Intern Med. 2009;23:592-7 pubmed publisher
    ..Although similarities between canine and human RCC merit further investigation of the dog as a model for some subtypes of renal tumors, the lower prevalence of VHL mutations suggests that oncogenesis in these 2 species differs. ..
  50. Krawczyk A, Hasse Lazar K, Pawlaczek A, Szpak Ulczok S, Krajewska J, Paliczka Cieślak E, et al. Germinal mutations of RET, SDHB, SDHD, and VHL genes in patients with apparently sporadic pheochromocytomas and paragangliomas. Endokrynol Pol. 2010;61:43-8 pubmed
    ..Pol J Endocrinol 2010; 61 (1): 43-48). ..
  51. Champion K, Guinea M, Dammai V, Hsu T. Endothelial function of von Hippel-Lindau tumor suppressor gene: control of fibroblast growth factor receptor signaling. Cancer Res. 2008;68:4649-57 pubmed publisher
    ..Thus, partial loss of function of VHL in endothelium may be a contributing factor in tumor angiogenesis through a HIF-VEGF-independent mechanism. ..
  52. Rahma O, Ashtar E, Ibrahim R, Toubaji A, Gause B, Herrin V, et al. A pilot clinical trial testing mutant von Hippel-Lindau peptide as a novel immune therapy in metastatic renal cell carcinoma. J Transl Med. 2010;8:8 pubmed publisher
    ..Accordingly, developing mutant VHL peptides as vaccines for RCC warrants further investigation in larger trials. 98C0139. ..
  53. Gaal J, van Nederveen F, Erlic Z, Korpershoek E, Oldenburg R, Boedeker C, et al. Parasympathetic paragangliomas are part of the Von Hippel-Lindau syndrome. J Clin Endocrinol Metab. 2009;94:4367-71 pubmed publisher
    ..Clinicians should be aware of the potential occurrence of parasympathetic paragangliomas in VHL disease. ..