Skip to main content

Advertisement

SpringerLink
Log in

Von Hippel-Lindau syndrome: molecular mechanisms of the disease

  • Educational Series
  • Molecular and Cellular Biology of Cancer
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene is responsible for the development of renal carcinomas, pheochromocytomas and tumours in other organs. The gene product (pVHL) is a central component in the oxygen-sensing pathway through its role in the regulation of the hypoxia-inducible factor (HIF). Loss of pVHL leads to activation of the HIF pathway in normoxia with the concomitant increase in tumour vascularisation due to the up-regulation of pro-angiogenic genes. However, although the role of pVHL in the regulation of HIF has proved to be important for tumour growth, other pVHL functions independent of HIF have been reported and help to explain why loss of VHL leads to renal cancer. Studies aimed to characterise other molecular pathways that shed light on its physiological roles as a gatekeeper gene in kidney and other organs will be very helpful for the development of novel anticancer therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Latif F, Tory K, Gnarra J et al (1993) Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320

    Article  PubMed  CAS  Google Scholar 

  2. Iwai K, Yamanaka K, Kamura T et al (1999) Identification of the von Hippel-lindau tumorsuppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci U S A 96:12436–12441

    Article  PubMed  CAS  Google Scholar 

  3. Lisztwan J, Imbert G, Wirbelauer C et al (1999) The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev 13:1822–1833

    Article  PubMed  CAS  Google Scholar 

  4. Kaelin WG Jr (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2:673–682

    Article  PubMed  CAS  Google Scholar 

  5. Ang SO, Chen H, Hirota K et al (2002) Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32:614–621

    Article  PubMed  CAS  Google Scholar 

  6. Hickey MM, Lam JC, Bezman NA et al (2007) von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J Clin Invest 117:3879–3889

    PubMed  CAS  Google Scholar 

  7. Clifford SC, Prowse AH, Affara NA et al (1998) Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis. Genes Chromosomes Cancer 22:200–209

    Article  PubMed  CAS  Google Scholar 

  8. Kim WY, Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol 22:4991–5004

    Article  PubMed  CAS  Google Scholar 

  9. Rankin EB, Tomaszewski JE, Haase VH (2006) Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res 66:2576–2583

    Article  PubMed  CAS  Google Scholar 

  10. Zimmer M, Doucette D, Siddiqui N, Iliopoulos O (2004) Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL-/- tumors. Mol Cancer Res 2:89–95

    PubMed  CAS  Google Scholar 

  11. Schoenfeld A, Davidowitz EJ, Burk RD (1998) A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci U S A 95:8817–8822

    Article  PubMed  CAS  Google Scholar 

  12. Gnarra JR, Duan DR, Weng Y et al (1996) Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal carcinoma. Biochim Biophys Acta 1242:201–210

    PubMed  Google Scholar 

  13. Blankenship C, Naglich JG, Whaley JM et al (1999) Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. Oncogene 18:1529–1535

    Article  PubMed  CAS  Google Scholar 

  14. Iliopoulos O, Ohh M, Kaelin WG Jr (1998) pVHL19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc Natl Acad Sci U S A 95:11661–11666

    Article  PubMed  CAS  Google Scholar 

  15. Maxwell PH, Wiesener MS, Chang GW et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275

    Article  PubMed  CAS  Google Scholar 

  16. Maher ER, Kaelin WG Jr (1997) von Hippel-Lindau disease. Medicine (Baltimore) 76:381–391

    Article  CAS  Google Scholar 

  17. Hsu T, Adereth Y, Kose N, Dammai V (2006) Endocytic function of von Hippel-Lindau tumor suppressor protein regulates surface localization of fibroblast growth factor receptor 1 and cell motility. J Biol Chem 281:12069–12080

    Article  PubMed  CAS  Google Scholar 

  18. Kamada M, Suzuki K, Kato Y et al (2001) von Hippel-Lindau protein promotes the assembly of actin and vinculin and inhibits cell motility. Cancer Res 61:4184–4189

    PubMed  CAS  Google Scholar 

  19. Koochekpour S, Jeffers M, Wang PH et al (1999) The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factorinduced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol 19:5902–5912

    PubMed  CAS  Google Scholar 

  20. Bluyssen HA, Lolkema MP, van Beest M et al (2004) Fibronectin is a hypoxia-independent target of the tumor suppressor VHL. FEBS Lett 556:137–142

    Article  PubMed  CAS  Google Scholar 

  21. Hergovich A, Lisztwan J, Barry R et al (2003) Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat Cell Biol 5:64–70

    Article  PubMed  CAS  Google Scholar 

  22. Lolkema MP, Mans DA, Snijckers CM et al (2007) The von Hippel-Lindau tumour suppressor interacts with microtubules through kinesin-2. FEBS Lett 581:4571–4576

    Article  PubMed  CAS  Google Scholar 

  23. Calzada MJ, Esteban MA, Feijoo-Cuaresma M et al (2006) von Hippel-Lindau tumor suppressor protein regulates the assembly of intercellular junctions in renal cancer cells through hypoxiainducible factor-independent mechanisms. Cancer Res 66:1553–1560

    Article  PubMed  CAS  Google Scholar 

  24. Davidowitz EJ, Schoenfeld AR, Burk RD (2001) VHL induces renal cell differentiation and growth arrest through integration of cell-cell and cell-extracellular matrix signaling. Mol Cell Biol 21:865–874

    Article  PubMed  CAS  Google Scholar 

  25. Esteban MA, Tran MG, Harten SK et al (2006) Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res 66:3567–3575

    Article  PubMed  CAS  Google Scholar 

  26. Esteban-Barragan MA, Avila P, Alvarez-Tejado M et al (2002) Role of the von Hippel-Lindau tumor suppressor gene in the formation of beta1-integrin fibrillar adhesions. Cancer Res 62:2929–2936

    PubMed  CAS  Google Scholar 

  27. Krishnamachary B, Zagzag D, Nagasawa H et al (2006) Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res 66:2725–2731

    Article  PubMed  CAS  Google Scholar 

  28. Lewis MD, Roberts BJ (2003) Role of nuclear and cytoplasmic localization in the tumour-suppressor activity of the von Hippel-Lindau protein. Oncogene 22:3992–3997

    Article  PubMed  CAS  Google Scholar 

  29. Bindra RS, Vasselli JR, Stearman R et al (2002) VHL-mediated hypoxia regulation of cyclin D1 in renal carcinoma cells. Cancer Res 62:3014–3019

    PubMed  CAS  Google Scholar 

  30. Kim M, Yan Y, Lee K et al (2004) Ectopic expression of von Hippel-Lindau tumor suppressor induces apoptosis in 786-O renal cell carcinoma cells and regresses tumor growth of 786-O cells in nude mouse. Biochem Biophys Res Commun 320:945–950

    Article  PubMed  CAS  Google Scholar 

  31. Roe JS, Kim H, Lee SM et al (2006) p53 stabilization and transactivation by a von Hippel-Lindau protein. Mol Cell 22:395–405

    Article  PubMed  CAS  Google Scholar 

  32. Yang H, Minamishima YA, Yan Q et al (2007) pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2. Mol Cell 28:15–27

    Article  PubMed  CAS  Google Scholar 

  33. Kurban G, Duplan E, Ramlal N et al (2007) Collagen matrix assembly is driven by the interaction of von Hippel-Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2. Oncogene 27:1004–1213

    Article  PubMed  CAS  Google Scholar 

  34. Ohh M, Yauch RL, Lonergan KM et al (1998) The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell 1:959–968

    Article  PubMed  CAS  Google Scholar 

  35. Esteban MA, Harten SK, Tran MG, Maxwell PH (2006) Formation of primary cilia in the renal epithelium is regulated by the von hippel-lindau tumor suppressor protein. J Am Soc Nephrol 17:1801–1806

    Article  PubMed  CAS  Google Scholar 

  36. Barry RE, Krek W (2004) The von Hippel-Lindau tumour suppressor: a multi-faceted inhibitor of tumourigenesis. Trends Mol Med 10:466–472

    Article  PubMed  CAS  Google Scholar 

  37. Cockman ME, Masson N, Mole DR et al (2000) Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 275:25733–25741

    Article  PubMed  CAS  Google Scholar 

  38. Tanimoto K, Makino Y, Pereira T, Poellinger L (2000) Mechanism of regulation of the hypoxiainducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J 19:4298–4309

    Article  PubMed  CAS  Google Scholar 

  39. Ohh M, Park CW, Ivan M et al (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2:423–427

    Article  PubMed  CAS  Google Scholar 

  40. Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294:1337–1340

    Article  PubMed  CAS  Google Scholar 

  41. Jaakkola P, Mole DR, Tian YM et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472

    Article  PubMed  CAS  Google Scholar 

  42. Masson N, Willam C, Maxwell PH et al (2001) Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 20:5197–5206

    Article  PubMed  CAS  Google Scholar 

  43. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  PubMed  CAS  Google Scholar 

  44. Kondo K, Klco J, Nakamura E et al (2002) Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1:237–246

    Article  PubMed  CAS  Google Scholar 

  45. Maranchie JK, Vasselli JR, Riss J et al (2002) The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 1:247–255

    Article  PubMed  CAS  Google Scholar 

  46. Kondo K, Kim WY Lechpammer M, Kaelin WG Jr (2003) Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 1:E83

    Article  PubMed  Google Scholar 

  47. Raval RR, Lau KW, Tran MG et al (2005) Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol 25:5675–5686

    Article  PubMed  CAS  Google Scholar 

  48. Mandriota SJ, Turner KJ, Davies DR et al (2002) HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1:459–468

    Article  PubMed  CAS  Google Scholar 

  49. Clifford SC, Cockman ME, Smallwood AC et al (2001) Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum Mol Genet 10:1029–1038

    Article  PubMed  CAS  Google Scholar 

  50. Li L, Zhang L, Zhang X et al (2007) Hypoxia-inducible factor linked to differential kidney cancer risk seen with type 2A and type 2B VHL mutations. Mol Cell Biol 27:5381–5392

    Article  PubMed  CAS  Google Scholar 

  51. Hu CJ, Wang LY, Chodosh LA et al (2003) Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 23:9361–9374

    Article  PubMed  CAS  Google Scholar 

  52. Evans AJ, Russell RC, Roche O et al (2007) VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol 27:157–169

    Article  PubMed  CAS  Google Scholar 

  53. Harten SK, Shukla D, Barod R et al (2009) Regulation of renal epithelial tight junctions by the von Hippel-Lindau tumor suppressor gene involves occludin and claudin 1 and is independent of Ecadherin. Mol Biol Cell 20:1089–1101

    Article  PubMed  CAS  Google Scholar 

  54. Bangiyeva V, Rosenbloom A, Alexander AE et al (2009) Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes. BMC Cancer 9:229

    Article  PubMed  CAS  Google Scholar 

  55. Hughes MD, Kapllani E, Alexander AE et al (2007) HIF-2alpha downregulation in the absence of functional VHL is not sufficient for renal cell differentiation. Cancer Cell Int 7:13

    Article  PubMed  CAS  Google Scholar 

  56. Singla V, Reiter JF (2006) The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science 313:629–633

    Article  PubMed  CAS  Google Scholar 

  57. Nauli SM, Zhou J (2004) Polycystins and mechanosensation in renal and nodal cilia. Bioessays 26:844–856

    Article  PubMed  CAS  Google Scholar 

  58. Lutz MS, Burk RD (2006) Primary cilium formation requires von hippel-lindau gene function in renal-derived cells. Cancer Res 66:6903–6907

    Article  PubMed  CAS  Google Scholar 

  59. Thoma CR, Frew IJ, Hoerner CR et al (2007) pVHL and GSK3beta are components of a primary cilium-maintenance signalling network. Nat Cell Biol 9:588–595

    Article  PubMed  CAS  Google Scholar 

  60. Schermer B, Ghenoiu C, Bartram M et al (2006) The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J Cell Biol 175:547–554

    Article  PubMed  CAS  Google Scholar 

  61. Lolkema MP, Mans DA, Ulfman LH et al (2008) Allele-specific regulation of primary cilia function by the von Hippel-Lindau tumor suppressor. Eur J Hum Genet 16:73–78

    Article  PubMed  CAS  Google Scholar 

  62. Yamazaki H, Nakata T, Okada Y, Hirokawa N (1995) KIF3A/B: a heterodimeric kinesin superfamily protein that works as a microtubule plus end-directed motor for membrane organelle transport. J Cell Biol 130:1387–1399

    Article  PubMed  CAS  Google Scholar 

  63. Kuehn EW, Walz G, Benzing T (2007) Von hippel-lindau: a tumor suppressor links microtubules to ciliogenesis and cancer development. Cancer Res 67:4537–4540

    Article  PubMed  CAS  Google Scholar 

  64. Hergovich A, Lisztwan J, Thoma CR et al (2006) Priming-dependent phosphorylation and regulation of the tumor suppressor pVHL by glycogen synthase kinase 3. Mol Cell Biol 26:5784–5796

    Article  PubMed  CAS  Google Scholar 

  65. Kurban G, Hudon V, Duplan E et al (2006) Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res 66:1313–1319

    Article  PubMed  CAS  Google Scholar 

  66. Feijoo-Cuaresma M, Méndez F, Maqueda A et al (2008) Inadequate activation of the GTPase RhoA contributes to the lack of fibronectin matrix assembly in von Hippel-Lindau protein-defective renal cancer cells. J Biol Chem 283:24982–24990

    Article  PubMed  CAS  Google Scholar 

  67. Grosfeld A, Stolze IP, Cockman ME et al (2007) Interaction of hydroxylated collagen IV with the von hippel-lindau tumor suppressor. J Biol Chem 282:13264–13269

    Article  PubMed  CAS  Google Scholar 

  68. Tang N, Mack F, Haase VH et al (2006) pVHL function is essential for endothelial extracellular matrix deposition. Mol Cell Biol 26:2519–2530

    Article  PubMed  CAS  Google Scholar 

  69. Wierzbicka-Patynowski I, Schwarzbauer JE (2003) The ins and outs of fibronectin matrix assembly. J Cell Sci 116:3269–3276

    Article  PubMed  CAS  Google Scholar 

  70. Pankov R, Cukierman E, Katz BZ et al (2000) Integrin dynamics and matrix assembly: tensindependent translocation of alpha(5)beta(1) integrins promotes early fibronectin fibrillogenesis. J Cell Biol 148:1075–1090

    Article  PubMed  CAS  Google Scholar 

  71. Hoffman MA, Ohh M, Yang H et al (2001) von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 10:1019–1027

    Article  PubMed  CAS  Google Scholar 

  72. Struckmann K, Mertz K, Steu S et al (2008) pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma. J Pathol 214:464–471

    Article  PubMed  CAS  Google Scholar 

  73. Pause A, Lee S, Lonergan KM, Klausner RD (1998) The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci U S A 95:993–998

    Article  PubMed  CAS  Google Scholar 

  74. Zatyka M, Fernandes da Silva N, Clifford SC et al (2002) Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. Cancer Res 62:3803–3811

    PubMed  CAS  Google Scholar 

  75. Schoenfeld AR, Parris T, Eisenberger A et al (2000) The von Hippel-Lindau tumor suppressor gene protects cells from UV-mediated apoptosis. Oncogene 19:5851–5857

    Article  PubMed  CAS  Google Scholar 

  76. Kim M, Katayose Y, Li Q et al (1998) Recombinant adenovirus expressing Von Hippel-Lindau-mediated cell cycle arrest is associated with the induction of cyclin-dependent kinase inhibitor p27Kip1. Biochem Biophys Res Commun 253:672–677

    Article  PubMed  CAS  Google Scholar 

  77. Young AP, Schlisio S, Minamishima YA et al (2008) VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat Cell Biol 10:361–369

    Article  PubMed  CAS  Google Scholar 

  78. Guo Y, Schoell MC, Freeman RS (2009) The von Hippel-Lindau protein sensitizes renal carcinoma cells to apoptotic stimuli through stabilization of BIM(EL). Oncogene 28:1864–1874

    Article  PubMed  CAS  Google Scholar 

  79. An J, Rettig MB (2005) Mechanism of von Hippel-Lindau protein-mediated suppression of nuclear factor kappa B activity. Mol Cell Biol 25:7546–7556

    Article  PubMed  CAS  Google Scholar 

  80. Qi H, Ohh M (2003) The von Hippel-Lindau tumor suppressor protein sensitizes renal cell carcinoma cells to tumor necrosis factor-induced cytotoxicity by suppressing the nuclear factor-kappaB-dependent antiapoptotic pathway. Cancer Res 63:7076–7080

    PubMed  CAS  Google Scholar 

  81. Zhou MI, Wang H, Foy RL et al (2004) Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent. Cancer Res 64:1278–1286

    Article  PubMed  CAS  Google Scholar 

  82. Zhou MI, Wang H, Ross JJ et al (2002) The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. J Biol Chem 277:39887–39898

    Article  PubMed  CAS  Google Scholar 

  83. Berndt JD, Moon RT, Major MB (2009) Betacatenin gets jaded and von Hippel-Lindau is to blame. Trends Biochem Sci 34:101–104

    Article  PubMed  CAS  Google Scholar 

  84. Escudier B (2007) Anti-VEGF therapy for renal cell carcinoma. Clin Adv Hematol Oncol 5:530–531

    PubMed  Google Scholar 

  85. Motzer RJ, Rini BI, Bukowski RM et al (2006) Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516–2524

    Article  PubMed  CAS  Google Scholar 

  86. Escudier B, Lassau N, Angevin E et al (2007) Phase I trial of sorafenib in combination with IFN alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma. Clin Cancer Res 13:1801–1809

    Article  PubMed  CAS  Google Scholar 

  87. Hudson CC, Liu M, Chiang GG et al (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004–7014

    Article  PubMed  CAS  Google Scholar 

  88. Thomas GV, Tran C, Mellinghoff IK et al (2006) Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12:122–127

    Article  PubMed  CAS  Google Scholar 

  89. Hudes G, Carducci M, Tomczak P et al (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281

    Article  PubMed  CAS  Google Scholar 

  90. Motzer RJ, Escudier B, Oudard S et al (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebocontrolled phase III trial. Lancet 372:449–456

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/ Diego de León, 62, ES-28006, Madrid, Spain

    María J. Calzada

Authors
  1. María J. Calzada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to María J. Calzada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Calzada, M.J. Von Hippel-Lindau syndrome: molecular mechanisms of the disease. Clin Transl Oncol 12, 160–165 (2010). https://doi.org/10.1007/s12094-010-0485-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-010-0485-9

Keywords

Search

Navigation