Vhl

Summary

Gene Symbol: Vhl
Description: von Hippel-Lindau tumor suppressor
Alias: Vhlh, von Hippel-Lindau disease tumor suppressor, pVHL, von Hippel-Lindau protein, von Hippel-Lindau syndrome homolog, von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase
Species: rat
Products:     Vhl

Top Publications

  1. Mekhail K, Gunaratnam L, Bonicalzi M, Lee S. HIF activation by pH-dependent nucleolar sequestration of VHL. Nat Cell Biol. 2004;6:642-7 pubmed
    ..HIF is activated by hypoxia, but undergoes degradation by the VHL (von Hippel-Lindau) tumour suppressor protein in the presence of oxygen...
  2. Teng M, Jiang X, Zhang Q, Zhang J, Zhang D, Liang G, et al. Microtubular stability affects pVHL-mediated regulation of HIF-1alpha via the p38/MAPK pathway in hypoxic cardiomyocytes. PLoS ONE. 2012;7:e35017 pubmed publisher
    ..The von Hippel-Lindau tumor suppressor protein (pVHL), as a ubiquitin ligase, is best understood as a negative regulator of HIF-1?...
  3. Pause A, Lee S, Worrell R, Chen D, Burgess W, Linehan W, et al. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc Natl Acad Sci U S A. 1997;94:2156-61 pubmed
    ..The VHL protein (pVHL) has been shown to form a stable complex with elongin B and elongin C, two factors that stabilize and activate the ..
  4. Shiao Y, Ramakrishna G, Anderson L, Perantoni A, Rice J, Diwan B. Down-regulation of von Hippel-Lindau protein in N-nitroso compound-induced rat non-clear cell renal tumors. Cancer Lett. 2002;179:33-8 pubmed
    Non-clear cell rat kidney tumors, inducible by N-nitroso compounds but lacking mutations in the von Hippel--Lindau (VHL) coding sequence, were examined for other VHL alterations...
  5. Perrotta S, Nobili B, Ferraro M, Migliaccio C, Borriello A, Cucciolla V, et al. Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster. Blood. 2006;107:514-9 pubmed
    ..It results from a Von Hippel-Lindau (VHL) gene mutation (C598T) that causes increased HIF-1alpha activity and erythrocyte production in the face of normoxia...
  6. Rafty L, Khachigian L. von Hippel-Lindau tumor suppressor protein represses platelet-derived growth factor B-chain gene expression via the Sp1 binding element in the proximal PDGF-B promoter. J Cell Biochem. 2002;85:490-5 pubmed
    VHL is the causative gene for von Hippel-Lindau disease and sporadic clear cell renal cancer. It has been shown that pVHL can suppress the expression of certain genes that are overexpressed in renal carcinomas...
  7. Tang N, Mack F, Haase V, Simon M, Johnson R. pVHL function is essential for endothelial extracellular matrix deposition. Mol Cell Biol. 2006;26:2519-30 pubmed
    The tumor suppressor von Hippel-Lindau protein (pVHL) is critical for cellular molecular oxygen sensing, acting to target degradation of the hypoxia-inducible factor alpha transcription factor subunits under normoxic conditions...
  8. Li J, French B, Wu Y, Vanketesh R, Montgomery R, Bardag Gorce F, et al. Liver hypoxia and lack of recovery after reperfusion at high blood alcohol levels in the intragastric feeding model of alcohol liver disease. Exp Mol Pathol. 2004;77:184-92 pubmed
    ..HIF-alpha degradation regulation revealed that prolyl 4-hydroxylase (P4ha1) and von Hippel-Lindau syndrome homolog (Vhl) were both up-regulated at the troughs compared with the peaks...
  9. Schnell P, Ignacak M, Bauer A, Striet J, Paulding W, Czyzyk Krzeska M. Regulation of tyrosine hydroxylase promoter activity by the von Hippel-Lindau tumor suppressor protein and hypoxia-inducible transcription factors. J Neurochem. 2003;85:483-91 pubmed
    ..TH is also regulated by the von Hippel-Lindau tumor suppressor protein (pVHL)...

More Information

Publications48

  1. Bauer A, Paulding W, Striet J, Schnell P, Czyzyk Krzeska M. Endogenous von Hippel-Lindau tumor suppressor protein regulates catecholaminergic phenotype in PC12 cells. Cancer Res. 2002;62:1682-7 pubmed
    ..PC12 cells that express VHL antisense RNA had 5-10-fold reduced levels of endogenous pVHL and 2-3-fold increased levels of TH protein and mRNA...
  2. Mahon P, Hirota K, Semenza G. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 2001;15:2675-86 pubmed
    ..O(2)-dependent binding of the von Hippel-Lindau (VHL) tumor suppressor protein targets the HIF-1alpha subunit for ubiquitination and proteasomal degradation...
  3. Lolkema M, Mans D, Snijckers C, van Noort M, van Beest M, Voest E, et al. The von Hippel-Lindau tumour suppressor interacts with microtubules through kinesin-2. FEBS Lett. 2007;581:4571-6 pubmed
    ..Recent studies indicate that this regulation is linked to microtubule-dependent functions of pVHL such as orienting microtubule growth and increasing plus-end microtubule stability, however little is known how ..
  4. Duan D, Humphrey J, Chen D, Weng Y, Sukegawa J, Lee S, et al. Characterization of the VHL tumor suppressor gene product: localization, complex formation, and the effect of natural inactivating mutations. Proc Natl Acad Sci U S A. 1995;92:6459-63 pubmed
    The human VHL tumor suppressor gene has been implicated in the inherited disorder von Hippel-Lindau disease and in sporadic renal carcinoma...
  5. 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...
  6. Kim W, Kaelin W. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004;22:4991-5004 pubmed
    ..The VHL tumor suppressor protein (pVHL), through its oxygen-dependent polyubiquitylation of hypoxia-inducible factor (HIF), plays a central role in the ..
  7. Lange C, Luhmann U, Mowat F, Georgiadis A, West E, Abrahams S, et al. Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development. Development. 2012;139:2340-50 pubmed publisher
    ..In particular, the von Hippel-Lindau tumour suppressor protein (pVhl) controls hypoxia-inducible transcription factor (HIF)-mediated adaptation...
  8. Curley S, Lott S, Luca J, Frazier M, Killary A. Surgical decision-making affected by clinical and genetic screening of a novel kindred with von Hippel-Lindau disease and pancreatic islet cell tumors. Ann Surg. 1998;227:229-35 pubmed
    We report a unique, previously undescribed multigeneration kindred with von Hippel-Lindau (VHL) disease in whom clinical or genetic screening led to the detection of surgically resectable neoplastic disease in several family members...
  9. Semenza G. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda). 2009;24:97-106 pubmed publisher
    ..HIF-1 also mediates maladaptive responses to chronic continuous and intermittent hypoxia, which underlie the development of pulmonary and systemic hypertension, respectively. ..
  10. Parsanejad M, Zhang Y, Qu D, Irrcher I, Rousseaux M, Aleyasin H, et al. Regulation of the VHL/HIF-1 pathway by DJ-1. J Neurosci. 2014;34:8043-50 pubmed publisher
    ..Here, we identify Von Hippel Lindau (VHL) protein as a critical DJ-1-interacting protein...
  11. Seeburg P, Wisden W, Verdoorn T, Pritchett D, Werner P, Herb A, et al. The GABAA receptor family: molecular and functional diversity. Cold Spring Harb Symp Quant Biol. 1990;55:29-40 pubmed
  12. Melnikov A, Scholtens D, Talamonti M, Bentrem D, Levenson V. Methylation profile of circulating plasma DNA in patients with pancreatic cancer. J Surg Oncol. 2009;99:119-22 pubmed publisher
    ..76% sensitivity and 59% specificity of the biomarker, which included promoters of CCND2, SOCS1, THBS1, PLAU, and VHL. Differential methylation profiling of plasma DNA can detect ductal adenocarcinoma of the pancreas with significant ..
  13. Murakami K, Kanno H, Yamamoto I, Saito T. Lavendustin A enhances axon elongation in VHL gene-transfected neural stem cells. Neuroreport. 2004;15:611-4 pubmed
    ..from neural stem cells obtained from adult rat hippocampal cells transfected with the von Hippel-Lindau (VHL) gene...
  14. Choy M, Movassagh M, Bennett M, Foo R. PKB/Akt activation inhibits p53-mediated HIF1A degradation that is independent of MDM2. J Cell Physiol. 2010;222:635-9 pubmed publisher
    ..In summary, we propose that p53-induced HIF1A degradation is not exclusively MDM2-mediated, but reversible by PKB/Akt phosphorylation. ..
  15. 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
    In the authors' previous study, they observed that amino acids 157-171 of von Hippel-Lindau protein (VHL peptide) induced neuronal differentiation of skin-derived precursors...
  16. Shiao Y, Resau J, Nagashima K, Anderson L, Ramakrishna G. The von Hippel-Lindau tumor suppressor targets to mitochondria. Cancer Res. 2000;60:2816-9 pubmed
    Subcellular localization of von Hippel-Lindau (VHL) tumor suppressor may clarify its role in tumorigenesis. In rat kidney, we observed a granular cytoplasmic immunostaining of VHL, as seen in human tissues...
  17. Walker C, Ahn Y, Everitt J, Yuan X. Renal cell carcinoma development in the rat independent of alterations at the VHL gene locus. Mol Carcinog. 1996;15:154-61 pubmed
    Germline alterations of the human von Hippel-Lindau (VHL) tumor suppressor gene predispose to renal cell carcinoma and a constellation of other tumor types found in VHL disease...
  18. Ivanova A, Vortmeyer A, Ivanov S, Nickerson M, Maher E, Lerman M. Loss of PL6 protein expression in renal clear cell carcinomas and other VHL-deficient tumours. J Pathol. 2008;214:46-57 pubmed
    Mutations in the von Hippel-Lindau tumour suppressor gene (VHL) cause the VHL hereditary cancer syndrome and occur in most sporadic clear cell renal cell cancers (CC-RCCs)...
  19. Audenet F, Yates D, Cancel Tassin G, Cussenot O, Roupret M. Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine. BJU Int. 2012;109:1864-70 pubmed publisher
    ..and What does the study add? Sporadic clear cell Renal Cell Carcinoma (ccRCC) is dominated by nutations of the VHL gene located on chromosome 3p in up to 90% of cases...
  20. Hao J, Chen X, Fu T, Liu J, Yu M, Han W, et al. The Expression of VHL (Von Hippel-Lindau) After Traumatic Spinal Cord Injury and Its Role in Neuronal Apoptosis. Neurochem Res. 2016;41:2391-400 pubmed publisher
    The VHL (Von Hippel-Lindau) gene is a tumor suppressor gene, which is best known as an E3 ubiquitin ligase that negatively regulates the hypoxia inducible factor...
  21. Park S, Dadak A, Haase V, Fontana L, Giaccia A, Johnson R. Hypoxia-induced gene expression occurs solely through the action of hypoxia-inducible factor 1alpha (HIF-1alpha): role of cytoplasmic trapping of HIF-2alpha. Mol Cell Biol. 2003;23:4959-71 pubmed
  22. Kikuchi Y, Kobayashi E, Nishizawa M, Hamazaki S, Okada S, Hino O. Cloning of the rat homologue of the von Hippel-Lindau tumor suppressor gene and its non-somatic mutation in rat renal cell carcinomas. Jpn J Cancer Res. 1995;86:905-9 pubmed
    Recently, von Hippel-Lindau (VHL) gene mutations were detected in non-inherited, sporadic human renal cell carcinomas (RCs) at a high frequency...
  23. Duan D, Pause A, Burgess W, Aso T, Chen D, Garrett K, et al. Inhibition of transcription elongation by the VHL tumor suppressor protein. Science. 1995;269:1402-6 pubmed
    Germline mutations in the von Hippel-Lindau tumor suppressor gene (VHL) predispose individuals to a variety of tumors, including renal carcinoma, hemangioblastoma of the central nervous system, and pheochromocytoma...
  24. Zhou M, Wang H, Ross J, Kuzmin I, Xu C, Cohen H. The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. J Biol Chem. 2002;277:39887-98 pubmed
    The von Hippel-Lindau disease gene (VHL) is the causative gene for most adult renal cancers. However, the mechanism by which VHL protein functions as a renal tumor suppressor remains largely unknown...
  25. Assadi F, Brackbill E. Bilateral pheochromocytomas and congenital anomalies associated with a de novo germline mutation in the von Hippel-Lindau gene. Am J Kidney Dis. 2003;41:E3 pubmed
    ..reaction (PCR)-amplified gnomic DNA identified a missense mutation at nucleotide 451 of the von Hippel-Lindau (VHL) gene (A451G) that changes a codon for serine (AGT) to one for glycine (GGT) at amino acid position 80 (S80G)...
  26. Chen G, Chan F, Zhang X, Chan P. Identification of differently expressed genes in chemical carcinogen-induced rat bladder cancers. J Huazhong Univ Sci Technolog Med Sci. 2009;29:220-6 pubmed publisher
    ..Also, 15 genes were significantly down-regulated in the rat bladder TCCs and they included B7.1, TNFr1, APOA1 and VHL. The results of cDNA microarray analysis demonstrated that normal rat bladder epithelia and bladder TCC exhibited ..
  27. Pagé E, Chan D, Giaccia A, Levine M, Richard D. Hypoxia-inducible factor-1alpha stabilization in nonhypoxic conditions: role of oxidation and intracellular ascorbate depletion. Mol Biol Cell. 2008;19:86-94 pubmed
    ..We show that hydroxylation on proline 402 is altered by Ang II, decreasing pVHL binding to HIF-1alpha and allowing HIF-1alpha protein to escape subsequent ubiquitination and degradation ..
  28. Biju M, Neumann A, Bensinger S, Johnson R, Turka L, Haase V. Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Mol Cell Biol. 2004;24:9038-47 pubmed
    The von Hippel-Lindau gene product (pVHL) targets the alpha subunit of basic helix-loop-helix transcription factor hypoxia-inducible factor (HIF) for proteasomal degradation...
  29. Wang Y, Luk J, Ikeda K, Man K, Chu A, Kaneda K, et al. Regulatory role of vHL/HIF-1alpha in hypoxia-induced VEGF production in hepatic stellate cells. Biochem Biophys Res Commun. 2004;317:358-62 pubmed
    ..of COX-2 and hypoxia-inducible factor-1-alpha (HIF-1alpha), but rapidly effected degradation of von Hippel-Lindau (vHL) protein...
  30. Schmitt A, Schmid S, Rudolph T, Anlauf M, Prinz C, Kloppel G, et al. VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors. Endocr Relat Cancer. 2009;16:1219-27 pubmed publisher
    ..Sporadic PET rarely harbors somatic VHL mutations, but the chromosomal location of the VHL gene is frequently deleted in sporadic PET...
  31. Kudo Y, Kakinuma Y, Iguchi M, Sato T, Sugiura T, Furihata M, et al. Modification in the von Hippel-Lindau protein is involved in the progression of experimentally induced rat glomerulonephritis. Nephron Exp Nephrol. 2007;106:e97-106 pubmed
    ..However, a role of the von Hippel-Lindau (VHL) protein in GN and mechanisms by which HV regulates the pathogenesis of GN remains unclear...
  32. Yamazaki Y, Kanno H, Maeda K, Yoshida T, Kobayashi N, Kubo A, et al. Engrafted VHL peptide-delivered bone marrow stromal cells promote spinal cord repair in rats. Neuroreport. 2010;21:287-92 pubmed publisher
    ..Recently, neuronal differentiation of neural progenitor/stem cells by an intracellular delivery of a pVHL-derived synthetic peptide (VHL peptide) has been shown...
  33. Kuznetsova A, Meller J, Schnell P, Nash J, Ignacak M, Sanchez Y, et al. von Hippel-Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination. Proc Natl Acad Sci U S A. 2003;100:2706-11 pubmed
    ..hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha) that binds von Hippel-Lindau tumor suppressor protein (pVHL)...
  34. 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...
  35. 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 ..
  36. Kamura T, Koepp D, Conrad M, Skowyra D, Moreland R, Iliopoulos O, et al. Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science. 1999;284:657-61 pubmed
    The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in most human kidney cancers...
  37. 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...
  38. Jiang X, Zhang D, Zhang H, Huang Y, Teng M. Role of Ran-regulated nuclear-cytoplasmic trafficking of pVHL in the regulation of microtubular stability-mediated HIF-1α in hypoxic cardiomyocytes. Sci Rep. 2015;5:9193 pubmed publisher
    ..The von Hippel-Lindau tumor suppressor protein (pVHL) has been shown to mediate the ubiquitination of HIF-1α in the nuclear compartment prior to HIF-1α ..
  39. Mekhail K, Khacho M, Carrigan A, Hache R, Gunaratnam L, Lee S. Regulation of ubiquitin ligase dynamics by the nucleolus. J Cell Biol. 2005;170:733-44 pubmed
    ..We have assessed the kinetic properties of the murine double minute protein (MDM2) and von Hippel-Lindau (VHL) ubiquitin ligases in living cells under physiological conditions that alter the stability of their respective p53 ..