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Gene Review

VHL  -  von Hippel-Lindau tumor suppressor, E3...

Homo sapiens

Synonyms: HRCA1, Protein G7, RCA1, VHL1, Von Hippel-Lindau disease tumor suppressor, ...
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Disease relevance of VHL


Psychiatry related information on VHL

  • Although the genes regulated by the VHL gene product have not yet been identified, our findings are compatible with the hypothesis that VHL-mediated control of transcriptional elongation may have a role in normal human development [7].
  • We have earlier analyzed VHL mutations in RCCs from 102 Swedish patients identified in a case-control study and here examine associations between patient characteristics, including dietary habits and mutations, considering the type of mutation [8].

High impact information on VHL

  • Prolyl hydroxylation generates a binding site for a ubiquitin ligase complex containing the von Hippel-Lindau (VHL) tumor suppressor protein, which results in HIFalpha destruction [9].
  • While both folding and degradation of VHL require Hsp70, the chaperonin TRiC is essential for folding but is dispensable for degradation [10].
  • Conversely, the chaperone Hsp90 neither participates in VHL folding nor is required to maintain misfolded VHL solubility but is essential for its degradation [10].
  • The protein pVHL functions in a multi-subunit E3 ubiquitin ligase that targets the hypoxia-inducible transcription factor Hif1 alpha for proteasomal degradation during normoxia [11].
  • We establish that pVHL binds to Tat-binding protein-1 (TBP-1), a component of the 19S regulatory complex of the proteasome [11].

Chemical compound and disease context of VHL


Biological context of VHL


Anatomical context of VHL

  • Finally, extracellular fibronectin matrix assembly by VHL-/- mouse embryos and mouse embryo fibroblasts (MEFs), unlike their VHL+/+ counterparts, was grossly impaired [19].
  • Here we show that cells also produce a VHL protein (pVHL19) that appears to arise as a result of internal translation from the second methionine within the VHL ORF. pVHL30 resides primarily in the cytosol, with less amounts found in the nucleus or associated with cell membranes [20].
  • Furthermore, endogenous VEGF mRNA levels were suppressed in permanent RCC cell lines expressing wt-VHL, and nuclear run-on studies indicated that VHL regulation of VEGF occurs at least partly at the transcriptional level [21].
  • Alterations in the human VHL gene lead to VHL disease which is associated with various rare neoplasias, including haemangioblastoma of the central nervous system, retinal angioma, clear cell renal carcinoma and pheochromocytoma [22].
  • Based on evidence that the von Hippel-Lindau (VHL) tumor suppressor protein is associated with polysomes and interacts with translation regulatory factors, we set out to investigate the potential influence of pVHL on protein translation [23].

Associations of VHL with chemical compounds


Physical interactions of VHL


Enzymatic interactions of VHL

  • Finally, we demonstrate that VDU2 can also be ubiquitinated and degraded in a pVHL-dependent manner [32].

Regulatory relationships of VHL

  • VHL not only inhibits the transcription of VPF/VEGF but also plays a significant role in decreasing its mRNA stability [33].
  • Most pathogenic VHL mutations inhibit formation of the VHL/elonginB+C/CUL2 complex [34].
  • Carbonic anhydrase IX and signaling via the epidermal growth factor receptor (EGFR) are involved in tumor cell proliferation and are also up regulated by mutation in the VHL gene [35].
  • Here we show that the von Hippel-Lindau tumour suppressor protein pVHL negatively regulates CXCR4 expression owing to its capacity to target hypoxia-inducible factor (HIF) for degradation under normoxic conditions [36].
  • Furthermore, pVHL is able to promote the ubiquitination and the decay of transfected IRP2 [27].
  • The latter activity, which promotes Card9 phosphorylation, links pVHL to control of NF-kappaB activity and tumorigenesis [37].
  • Insensitivity of PL6 to hypoxia suggested that PL6 is regulated by VHL via a HIF-1-independent pathway [38].

Other interactions of VHL


Analytical, diagnostic and therapeutic context of VHL


  1. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Ang, S.O., Chen, H., Hirota, K., Gordeuk, V.R., Jelinek, J., Guan, Y., Liu, E., Sergueeva, A.I., Miasnikova, G.Y., Mole, D., Maxwell, P.H., Stockton, D.W., Semenza, G.L., Prchal, J.T. Nat. Genet. (2002) [Pubmed]
  2. The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Lisztwan, J., Imbert, G., Wirbelauer, C., Gstaiger, M., Krek, W. Genes Dev. (1999) [Pubmed]
  3. Identification of the RNA polymerase II subunit hsRPB7 as a novel target of the von Hippel-Lindau protein. Na, X., Duan, H.O., Messing, E.M., Schoen, S.R., Ryan, C.K., di Sant'Agnese, P.A., Golemis, E.A., Wu, G. EMBO J. (2003) [Pubmed]
  4. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Pause, A., Lee, S., Worrell, R.A., Chen, D.Y., Burgess, W.H., Linehan, W.M., Klausner, R.D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  5. Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. Pastore, Y., Jedlickova, K., Guan, Y., Liu, E., Fahner, J., Hasle, H., Prchal, J.F., Prchal, J.T. Am. J. Hum. Genet. (2003) [Pubmed]
  6. VHL mutations linked to type 2C von Hippel-Lindau disease cause extensive structural perturbations in pVHL. Knauth, K., Cartwright, E., Freund, S., Bycroft, M., Buchberger, A. J. Biol. Chem. (2009) [Pubmed]
  7. Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis. Richards, F.M., Schofield, P.N., Fleming, S., Maher, E.R. Hum. Mol. Genet. (1996) [Pubmed]
  8. Molecular epidemiology of VHL gene mutations in renal cell carcinoma patients: relation to dietary and other factors. Hemminki, K., Jiang, Y., Ma, X., Yang, K., Egevad, L., Lindblad, P. Carcinogenesis (2002) [Pubmed]
  9. Proline hydroxylation and gene expression. Kaelin, W.G. Annu. Rev. Biochem. (2005) [Pubmed]
  10. Folding and quality control of the VHL tumor suppressor proceed through distinct chaperone pathways. McClellan, A.J., Scott, M.D., Frydman, J. Cell (2005) [Pubmed]
  11. Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein. Corn, P.G., McDonald, E.R., Herman, J.G., El-Deiry, W.S. Nat. Genet. (2003) [Pubmed]
  12. Expression of HIF-1{alpha}, HIF-2{alpha} (EPAS1), and Their Target Genes in Paraganglioma and Pheochromocytoma with VHL and SDH Mutations. Pollard, P.J., El-Bahrawy, M., Poulsom, R., Elia, G., Killick, P., Kelly, G., Hunt, T., Jeffery, R., Seedhar, P., Barwell, J., Latif, F., Gleeson, M.J., Hodgson, S.V., Stamp, G.W., Tomlinson, I.P., Maher, E.R. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  13. Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Woodward, E.R., Eng, C., McMahon, R., Voutilainen, R., Affara, N.A., Ponder, B.A., Maher, E.R. Hum. Mol. Genet. (1997) [Pubmed]
  14. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. Eisenhofer, G., Walther, M.M., Huynh, T.T., Li, S.T., Bornstein, S.R., Vortmeyer, A., Mannelli, M., Goldstein, D.S., Linehan, W.M., Lenders, J.W., Pacak, K. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  15. Differential expression of erythropoietin and its receptor in von hippel-lindau-associated and multiple endocrine neoplasia type 2-associated pheochromocytomas. Vogel, T.W., Brouwers, F.M., Lubensky, I.A., Vortmeyer, A.O., Weil, R.J., Walther, M.M., Oldfield, E.H., Linehan, W.M., Pacak, K., Zhuang, Z. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  16. Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma. Gemmill, R.M., Zhou, M., Costa, L., Korch, C., Bukowski, R.M., Drabkin, H.A. Br. J. Cancer (2005) [Pubmed]
  17. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. Tanimoto, K., Makino, Y., Pereira, T., Poellinger, L. EMBO J. (2000) [Pubmed]
  18. The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity. Li, Z., Wang, D., Na, X., Schoen, S.R., Messing, E.M., Wu, G. EMBO J. (2003) [Pubmed]
  19. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Ohh, M., Yauch, R.L., Lonergan, K.M., Whaley, J.M., Stemmer-Rachamimov, A.O., Louis, D.N., Gavin, B.J., Kley, N., Kaelin, W.G., Iliopoulos, O. Mol. Cell (1998) [Pubmed]
  20. pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Iliopoulos, O., Ohh, M., Kaelin, W.G. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  21. The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mukhopadhyay, D., Knebelmann, B., Cohen, H.T., Ananth, S., Sukhatme, V.P. Mol. Cell. Biol. (1997) [Pubmed]
  22. Expression of the von Hippel-Lindau-binding protein-1 (Vbp1) in fetal and adult mouse tissues. Hemberger, M., Himmelbauer, H., Neumann, H.P., Plate, K.H., Schwarzkopf, G., Fundele, R. Hum. Mol. Genet. (1999) [Pubmed]
  23. von Hippel-Lindau protein-mediated repression of tumor necrosis factor alpha translation revealed through use of cDNA arrays. Galbán, S., Fan, J., Martindale, J.L., Cheadle, C., Hoffman, B., Woods, M.P., Temeles, G., Brieger, J., Decker, J., Gorospe, M. Mol. Cell. Biol. (2003) [Pubmed]
  24. Transcription-dependent nuclear-cytoplasmic trafficking is required for the function of the von Hippel-Lindau tumor suppressor protein. Lee, S., Neumann, M., Stearman, R., Stauber, R., Pause, A., Pavlakis, G.N., Klausner, R.D. Mol. Cell. Biol. (1999) [Pubmed]
  25. Hypoxia-inducible Factors in the First Trimester Human Lung. Groenman, F., Rutter, M., Caniggia, I., Tibboel, D., Post, M. J. Histochem. Cytochem. (2007) [Pubmed]
  26. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Lonergan, K.M., Iliopoulos, O., Ohh, M., Kamura, T., Conaway, R.C., Conaway, J.W., Kaelin, W.G. Mol. Cell. Biol. (1998) [Pubmed]
  27. The pathway for IRP2 degradation involving 2-oxoglutarate-dependent oxygenase(s) does not require the E3 ubiquitin ligase activity of pVHL. Wang, J., Pantopoulos, K. Biochim. Biophys. Acta (2005) [Pubmed]
  28. Cellular proteins that bind the von Hippel-Lindau disease gene product: mapping of binding domains and the effect of missense mutations. Kishida, T., Stackhouse, T.M., Chen, F., Lerman, M.I., Zbar, B. Cancer Res. (1995) [Pubmed]
  29. Synthetic peptides define critical contacts between elongin C, elongin B, and the von Hippel-Lindau protein. Ohh, M., Takagi, Y., Aso, T., Stebbins, C.E., Pavletich, N.P., Zbar, B., Conaway, R.C., Conaway, J.W., Kaelin, W.G. J. Clin. Invest. (1999) [Pubmed]
  30. Identification of a novel protein (VBP-1) binding to the von Hippel-Lindau (VHL) tumor suppressor gene product. Tsuchiya, H., Iseda, T., Hino, O. Cancer Res. (1996) [Pubmed]
  31. Human MutS homologue MSH4 physically interacts with von Hippel-Lindau tumor suppressor-binding protein 1. Her, C., Wu, X., Griswold, M.D., Zhou, F. Cancer Res. (2003) [Pubmed]
  32. Identification of a deubiquitinating enzyme subfamily as substrates of the von Hippel-Lindau tumor suppressor. Li, Z., Wang, D., Na, X., Schoen, S.R., Messing, E.M., Wu, G. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  33. Role of elongin-binding domain of von Hippel Lindau gene product on HuR-mediated VPF/VEGF mRNA stability in renal cell carcinoma. Datta, K., Mondal, S., Sinha, S., Li, J., Wang, E., Knebelmann, B., Karumanchi, S.A., Mukhopadhyay, D. Oncogene (2005) [Pubmed]
  34. Genomic organization and chromosomal localization of the human CUL2 gene and the role of von Hippel-Lindau tumor suppressor-binding protein (CUL2 and VBP1) mutation and loss in renal-cell carcinoma development. Clifford, S.C., Walsh, S., Hewson, K., Green, E.K., Brinke, A., Green, P.M., Gianelli, F., Eng, C., Maher, E.R. Genes Chromosomes Cancer (1999) [Pubmed]
  35. Targeted agents for the treatment of advanced renal cell carcinoma. Staehler, M., Rohrmann, K., Haseke, N., Stief, C.G., Siebels, M. Current drug targets. (2005) [Pubmed]
  36. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Staller, P., Sulitkova, J., Lisztwan, J., Moch, H., Oakeley, E.J., Krek, W. Nature (2003) [Pubmed]
  37. pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2. Yang, H., Minamishima, Y.A., Yan, Q., Schlisio, S., Ebert, B.L., Zhang, X., Zhang, L., Kim, W.Y., Olumi, A.F., Kaelin, W.G. Mol. Cell (2007) [Pubmed]
  38. Loss of PL6 protein expression in renal clear cell carcinomas and other VHL-deficient tumours. Ivanova, A.V., Vortmeyer, A., Ivanov, S.V., Nickerson, M.L., Maher, E.R., Lerman, M.I. J. Pathol. (2008) [Pubmed]
  39. Conjugation of the ubiquitin-like protein NEDD8 to cullin-2 is linked to von Hippel-Lindau tumor suppressor function. Liakopoulos, D., Büsgen, T., Brychzy, A., Jentsch, S., Pause, A. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  40. Mutations in the VHL gene in sporadic apparently congenital polycythemia. Pastore, Y.D., Jelinek, J., Ang, S., Guan, Y., Liu, E., Jedlickova, K., Krishnamurti, L., Prchal, J.T. Blood (2003) [Pubmed]
  41. Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von Hippel-Lindau tumor suppressor gene loss of function. Krieg, M., Marti, H.H., Plate, K.H. Blood (1998) [Pubmed]
  42. Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells. Beppu, K., Nakamura, K., Linehan, W.M., Rapisarda, A., Thiele, C.J. Cancer Res. (2005) [Pubmed]
  43. Comparative sequence analysis of the VHL tumor suppressor gene. Woodward, E.R., Buchberger, A., Clifford, S.C., Hurst, L.D., Affara, N.A., Maher, E.R. Genomics (2000) [Pubmed]
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