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  • Review Article
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Molecular basis of the VHL hereditary cancer syndrome

Nature Reviews Cancer volume 2, pages 673–682 (2002)Cite this article

Key Points

  • The von Hippel–Lindau (VHL) disease is caused by the germ-line mutation of the VHL tumour-suppressor gene.

  • Kidney cancer and blood-vessel tumours (haemangioblastomas) of the central nervous system, are the two leading causes of morbidity and mortality in VHL disease.

  • Somatic VHL mutations are also common in sporadic haemangioblastoma and kidney cancer.

  • The VHL gene product, pVHL, is a component of an SCF (Skp1–Cdc53–F-box)-like ubiquitin-ligase complex that targets the α-subunits of the hypoxia-inducible factor (HIF) heterodimeric transcription factor for polyubiquitylation and proteasomal degradation.

  • pVHL recognizes the HIF α-subunits only after specific proline residues within these subunits are hydroxylated by members of the EGLN family. This, and the fact that the hydroxylation is inherently oxygen dependent, is integral to how mammalian cells sense and respond to changes in oxygen.

  • Overproduction of growth factors encoded by HIF target genes, such as vascular endothelial growth factor (VEGF), platelet-derived growth-factor B chain (PDGFβ) and transforming growth-factor-α (TGFα) probably contribute to tumour formation following pVHL inactivation.

Abstract

The von Hippel–Lindau hereditary cancer syndrome was first described about 100 years ago. The unusual clinical features of this disorder predicted a role for the von Hippel–Lindau gene (VHL) in the oxygen-sensing pathway. Indeed, recent studies of this gene have helped to decipher how cells sense changes in oxygen availability, and have revealed a previously unappreciated role of prolyl hydroxylation in intracellular signalling. These studies, in turn, are laying the foundation for the treatment of a diverse set of disorders, including cancer, myocardial infarction and stroke.

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Figure 1: von Hippel–Lindau-associated tumours.
Figure 2: SCF-like ubiquitin ligases.
Figure 3: Regulation of HIF-α by pVHL.
Figure 4: Histopathology of haemangioblastomas.
Figure 5: Potential therapeutics based on the pVHL–HIF pathway.

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References

  1. Collins, E. T. Intra-ocular growths (two cases, brother and sister, with peculiar vascular new growth, probably retinal, affecting both eyes). Trans. Ophthalmol. Soc. UK 14, 141–149 (1894).

    Google Scholar 

  2. von Hippel, E. Ueber eine sehr seltene Erkrankung der Nethaut. Graefe Arch. Ophthalmol. 59, 83–106 (1904).

    Google Scholar 

  3. Lindau, A. Zur Frage der Angiomatosis Retinae und Ihrer Hirncomplikation. Acta Ophthalmol. 4, 193–226 (1927).

    Google Scholar 

  4. Richard, S., Campello, C., Taillandier, L., Parker, F. & Resche, F. Haemangioblastoma of the central nervous system in von Hippel–Lindau disease. J. Intern. Med. 243, 547–553 (1998).

    CAS  PubMed  Google Scholar 

  5. Maher, E. & Kaelin, W. G. von Hippel–Lindau disease. Medicine 76, 381–391 (1997).

    CAS  PubMed  Google Scholar 

  6. Seizinger, B. R. et al. Von Hippel–Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 332, 268–269 (1988).

    CAS  PubMed  Google Scholar 

  7. Latif, F. et al. Identification of the von Hippel–Lindau disease tumor suppressor gene. Science 260, 1317–1320 (1993).Describes the identification and cloning of the VHL tumour-suppressor gene. The gene was authenticated by the demonstration of intragenic mutations in affected members of VHL kindreds.

    CAS  PubMed  Google Scholar 

  8. Woodward, E. et al. Comparative sequence analysis of the VHL tumor suppressor gene. Genomics 65, 253–265 (2000).

    CAS  PubMed  Google Scholar 

  9. Epstein, A. et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001).This paper, along with reference 10 , shows that the C. elegans and Drosophila egl-9 genes, hydroxylate the HIF-α proteins that are identified in these two species, respectively, and that the three human EGL-9 orthologues can hydroxylate human HIF-1α in vitro.

    CAS  PubMed  Google Scholar 

  10. Bruick, R. & McKnight, S. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Stolle, C. et al. Improved detection of germline mutations in the von Hippel–Lindau disease tumor suppressor gene. Hum. Mutat. 12, 417–423 (1998).

    CAS  PubMed  Google Scholar 

  12. Chen, F. et al. Germline mutations in the von Hippel–Lindau disease tumor suppressor gene: correlations with phenotype. Hum. Mutat. 5, 66–75 (1995).

    CAS  PubMed  Google Scholar 

  13. Zbar, B. et al. Germline mutations in the von Hippel–Lindau (VHL) gene in families from North America, Europe, and Japan. Hum. Mutat. 8, 348–357 (1996).

    CAS  PubMed  Google Scholar 

  14. Neumann, H. & Bender, B. Genotype–phenotype correlations in von Hippel–Lindau disease. J. Intern. Med. 243, 541–545 (1998).

    CAS  PubMed  Google Scholar 

  15. Kanno, H. et al. Somatic mutations of the von Hippel–Lindau tumor supressor gene in sporadic central nervous systems hemangioblastomas. Cancer Res. 54, 4845–4847 (1994).

    CAS  PubMed  Google Scholar 

  16. Shuin, T. et al. Germline and somatic mutations in von Hippel–Lindau disease gene and its significance in the development of kidney cancer. Contrib. Nephrol. 128, 1–10 (1999).

    CAS  PubMed  Google Scholar 

  17. Gnarra, J. R. et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nature Genet. 7, 85–90 (1994).

    CAS  PubMed  Google Scholar 

  18. Vortmeyer, A. et al. von Hippel–Lindau gene deletion detected in the stromal cell component of a cerebellar hemangioblastoma associated with von Hippel–Lindau disease. Hum. Pathol. 28, 540–543 (1997).

    CAS  PubMed  Google Scholar 

  19. Zhuang, Z. et al. A microscopic dissection technique for archival DNA analysis of specific cell populations in lesions <1mm in size. Am. J. Path. 146, 620–625 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhuang, Z. et al. Detection of von Hippel–Lindau disease gene mutations in paraffin-embedded sporadic renal cell carcinoma specimens. Mod Pathol 9, 838–842 (1996).

    CAS  PubMed  Google Scholar 

  21. Clifford, S., Prowse, A., Affara, N., Buys, C. & Maher, E. 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 Chromosom. Cancer 22, 200–209 (1998).

    CAS  PubMed  Google Scholar 

  22. Foster, K. et al. Somatic mutations of the von Hippel–Lindau disease tumor suppressor gene in non-familial clear cell renal carcinoma. Hum. Mol. Genet. 3, 2169–2173 (1994).

    CAS  PubMed  Google Scholar 

  23. Gallou, C. et al. Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC. Hum. Mutat. 13, 464–475 (1999).

    CAS  PubMed  Google Scholar 

  24. Herman, J. G. et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl Acad. Sci. USA 91, 9700–9704 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Lubensky, I. A. et al. Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel–Lindau disease patients. Am. J. Pathol. 149, 2089–2094 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Shuin, T. et al. Frequent somatic mutations and loss of heterozygosity of the von Hippel–Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res. 54, 2852–2855 (1994).

    CAS  PubMed  Google Scholar 

  27. Whaley, J. M. et al. Germ-line mutations in the von Hippel–Lindau tumor suppressor gene are similar to somatic von Hippel–Lindau abberations in sporadic renal cell carcinoma. Am. J. Hum. Genet. 55, 1092–1102 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Neumann, H. et al. Germ-line mutations in nonsyndromic pheochromocytoma. N. Engl. J. Med. 346, 1459–1466 (2002).

    CAS  PubMed  Google Scholar 

  29. Neumann, H. P. H. et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel–Lindau disease. N. Engl. J. Med. 329, 1531–1538 (1993).

    CAS  PubMed  Google Scholar 

  30. Bender, B. et al. Differential genetic alterations in von Hippel–Lindau syndrome-associated and sporadic pheochromocytomas. J. Clin. Endocrinol. Metab. 85, 4568–4574 (2000).

    CAS  PubMed  Google Scholar 

  31. Woodward, E. et al. Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Hum. Mol. Genet. 6, 1051–1056 (1997).

    CAS  PubMed  Google Scholar 

  32. Bar, M. et al. Sporadic phaeochromocytomas are rarely associated with germline mutations in the von Hippel–Lindau and RET genes. Clin Endocrinol 47, 707–712 (1997).

    CAS  Google Scholar 

  33. Brauch, H. et al. Sporadic pheochromocytomas are rarely associated with germline mutations in the VHL tumor suppressor gene or the RET protooncogene. J. Clin. Endocrinol. Metab. 82, 4101–4104 (1997).

    CAS  PubMed  Google Scholar 

  34. Iliopoulos, O., Kibel, A., Gray, S. & Kaelin, W. G. Tumor suppression by the human von Hippel–Lindau gene product. Nature Med. 1, 822–826 (1995).This paper was the first to identify the VHL gene product, pVHL, in cells, and the first to show that restoring pVHL function in VHL−/− renal carcinoma cells suppressed their ability to form tumours in nude mice.

    CAS  PubMed  Google Scholar 

  35. Iliopoulos, O., Ohh, M. & Kaelin, W. pVHL19 is a biologically active product of the von Hippel–Lindau gene arising from internal translation initiation. Proc. Natl Acad. Sci. USA 95, 11661–11666 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Blankenship, C., Naglich, J., Whaley, J., Seizinger, B. & Kley, N. Alternate choice of initiation codon produces a biologically active product of the von Hippel–Lindau gene with tumor suppressor activity. Oncogene 18, 1529–1535 (1999).

    CAS  PubMed  Google Scholar 

  37. Schoenfeld, A., Davidowitz, E. & Burk, R. 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. USA 95, 8817–8822 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Los, M. et al. Expression pattern of the von Hippel–Lindau protein in human tissues. Lab. Invest. 75, 231–238 (1996).

    CAS  PubMed  Google Scholar 

  39. Corless, C. L., Kibel, A., Iliopoulos, O. & Kaelin, W. G. J. Immunostaining of the von Hippel–Lindau gene product (pVHL) in normal and neoplastic human tissues. Hum. Pathol. 28, 459–464 (1997).

    CAS  PubMed  Google Scholar 

  40. Lee, S. et al. Transcription-dependent nuclear-cytoplasmic trafficking is required for the function of the von Hippel–Lindau tumor suppressor protein. Mol. Cell. Biol. 19, 1486–1497 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Groulx, I., Bonicalzi, M. & Lee, S. Ran-mediated nuclear export of the von Hippel–Lindau tumor suppressor protein occurs independently of its assembly with cullin-2. J. Biol. Chem. 275, 8991–9000 (2000).

    CAS  PubMed  Google Scholar 

  42. Bonicalzi, M., Groulx, I., de Paulsen, N. & Lee, S. Role of exon 2-encoded β-domain of the von Hippel–Lindau tumor suppressor protein. J Biol Chem 12, 1407–1416 (2001).

    Google Scholar 

  43. Duan, D. R. et al. Characterization of the VHL tumor suppressor gene product: localization, complex formation, and the effect of natural inactivating mutations. Proc. Natl Acad. Sci. USA 92, 6459–6463 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Duan, D. R. et al. Inhibition of transcriptional elongation by the VHL tumor suppressor protein. Science 269, 1402–1406 (1995).This paper and reference 47 were the first to show that pVHL binds to elongins B and C.

    CAS  PubMed  Google Scholar 

  45. Pause, A. 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. USA 94, 2156–2161 (1997).This paper and reference 48 were the first to show that the pVHL complex also contains CUL2, and therefore provided an indication that pVHL might be involved in polyubiquitylation.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Pause, A., Peterson, B., Schaffar, G., Stearman, R. & Klausner, R. Studying interactions of four proteins in the yeast two-hybrid system: structural resemblance of the pVHL/elongin BC/hCUL-2 complex with the ubiquitin ligase complex SKP1/cullin/F-box protein. Proc. Natl Acad. Sci. USA 96, 9533–9538 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kibel, A., Iliopoulos, O., DeCaprio, J. D. & Kaelin, W. G. Binding of the von Hippel–Lindau tumor suppressor protein to elongin B and C. Science 269, 1444–1446 (1995).

    CAS  PubMed  Google Scholar 

  48. Lonergan, K. M. et al. Regulation of hypoxia-inducible mRNAs by the von Hippel–Lindau protein requires binding to complexes containing elongins B/C and Cul2. Mol. Cell. Biol. 18, 732–741 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kishida, T., Stackhouse, T. M., Chen, F., Lerman, M. I. & Zbar, B. Cellular proteins that bind the von Hippel–Lindau disease gene product: mapping of binding domains and the effect of missense mutations. Cancer Res. 55, 4544–4548 (1995).

    CAS  PubMed  Google Scholar 

  50. Bai, C. et al. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell 86, 263–274 (1996).

    CAS  PubMed  Google Scholar 

  51. Deshaies, R. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu. Rev. Cell Dev. Biol. 15, 435–467 (1999).

    CAS  PubMed  Google Scholar 

  52. Stebbins, C. E., Kaelin, W. G. & Pavletich, N. P. Structure of the VHL–elongin-C–elongin-B complex: implications for VHL tumor suppressor function. Science 284, 455–461 (1999).This paper described the three-dimensional structure of the pVHL–elongin-B–elongin-C complex, which revealed the presence of two frequently mutated subdomains, α and β.

    CAS  PubMed  Google Scholar 

  53. Lisztwan, J., Imbert, G., Wirbelauer, C., Gstaiger, M. & Krek, W. The von Hippel–Lindau tumor suppressor protein is a component of an E3 ubiquitin–protein ligase activity. Genes Dev. 13, 1822–1833 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Iwai, K. et al. Identification of the von Hippel–Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc. Natl Acad. Sci. USA 96, 12436–12441 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Kamura, T. et al. Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 284, 657–661 (1999).

    CAS  PubMed  Google Scholar 

  56. Siemeister, G. et al. Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel–Lindau tumor suppressor protein. Cancer Res. 56, 2299–2301 (1996).

    CAS  PubMed  Google Scholar 

  57. Gnarra, J. R. et al. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the VHL tumor suppressor gene product. Proc. Natl Acad. Sci. USA 93, 10589–10594 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Stratmann, R., Krieg, M., Haas, R. & Plate, K. Putative control of angiogenesis in hemangioblastomas by the von Hippel–Lindau tumor suppressor gene. J. Neuropathol. Exp. Neurol. 56, 1242–1252 (1997).

    CAS  PubMed  Google Scholar 

  59. Iliopoulos, O., Jiang, C., Levy, A. P., Kaelin, W. G. & Goldberg, M. A. Negative regulation of hypoxia-inducible genes by the von Hippel–Lindau protein. Proc. Natl Acad. Sci. USA 93, 10595–10599 (1996).This paper showed that cells lacking pVHL produced high levels of hypoxia-inducible mRNAs irrespective of changes in oxygen. In keeping with this, references 56 and 57 reported that cells lacking pVHL overproduce VEGF mRNA.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Semenza, G. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu. Rev. Cell Dev. Biol. 15, 551–578 (1999).

    CAS  PubMed  Google Scholar 

  61. Maxwell, P. et al. The von Hippel–Lindau gene product is necessary for oxgyen-dependent proteolysis of hypoxia-inducible factor-α subunits. Nature 399, 271–275 (1999).A landmark paper showing that cells lacking pVHL do not degrade HIF-α subunits.

    CAS  PubMed  Google Scholar 

  62. Cockman, M. et al. Hypoxia inducible factor-α binding and ubiquitylation by the von Hippel–Lindau tumor suppressor protein. J. Biol. Chem. 275, 25733–25741 (2000).This paper and references 63–65 were the first to show directly that pVHL polyubiquitylates HIF-α subunits.

    CAS  PubMed  Google Scholar 

  63. Ohh, M. et al. Ubiquitination of HIF requires direct binding to the von Hippel–Lindau protein β-domain. Nature Cell Biol. 2, 423–427 (2000).

    CAS  PubMed  Google Scholar 

  64. Kamura, T. et al. Activation of HIF1α ubiquitination by a reconstituted von Hippel–Lindau tumor suppressor complex. Proc. Natl Acad. Sci. USA 97, 10430–10435 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Tanimoto, K., Makino, Y., Pereira, T. & Poellinger, L. Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel–Lindau tumor suppressor protein. EMBO J. 19, 4298–4309 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Ivan, M. et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468 (2001).This paper and reference 67 were the first to show that the interaction of pVHL with HIF-α is regulated by oxygen-dependent prolyl hydroxylation.

    CAS  PubMed  Google Scholar 

  67. Jaakkola, P. et al. Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

    CAS  PubMed  Google Scholar 

  68. Yu, F., White, S., Zhao, Q. & Lee, F. HIF1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc. Natl Acad. Sci. USA 98, 9630–9635 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Yu, F., White, S., Zhao, Q. & Lee, F. Dynamic, site-specific interaction of hypoxia-inducible factor-1α with the von Hippel–Lindau tumor suppressor protein. Cancer Res. 61, 4136–4142 (2001).

    CAS  PubMed  Google Scholar 

  70. Hon, W. C. et al. Structural basis for the recognition of hydroxyproline in HIF1α by pVHL. Nature 417, 975–978 (2002).This paper and reference 71 report the structure of pVHL bound to HIF-1α, and explain the requirement for prolyl hydroxylation.

    CAS  PubMed  Google Scholar 

  71. Min, J.-H. et al. Structure of a pVHL–HIF1α complex: hydroxyproline recognition in intracellular signaling. Science 296, 1886–1889 (2002).

    CAS  PubMed  Google Scholar 

  72. Schofield, C. J. & Zhang, Z. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Curr. Opin. Struct. Biol. 9, 722–731 (1999).

    CAS  PubMed  Google Scholar 

  73. Kivirikko, K. I. & Myllyharju, J. Prolyl 4-hydroxylases and their protein disulfide isomerase subunit. Matrix Biol. 16, 357–368 (1998).

    CAS  PubMed  Google Scholar 

  74. Taylor, M. S. Characterization and comparative analysis of the EGLN gene family. Gene 275, 125–132 (2001).

    CAS  PubMed  Google Scholar 

  75. Ivan, M. et al. Biochemical purification and pharmacological inhibition of a mammalian HIF prolyl hydroxylase. Proc. Natl Acad. Sci. USA (in the press).

  76. Bruick, R. & McKnight, S. Transcription. Oxygen sensing gets a second wind. Science 295, 807–808 (2002).

    CAS  PubMed  Google Scholar 

  77. Lando, D. et al. Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 295, 858–861 (2002).

    CAS  PubMed  Google Scholar 

  78. Sang, N., Fang, J., Srinivas, V., Leshchinsky, I. & Caro, J. Carboxyl-terminal transactivation activity of hypoxia-inducible factor-1α is governed by a von Hippel–Lindau protein-independent, hydroxylation-regulated association with p300/CBP. Mol. Cell. Biol. 22, 2984–2992 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Freedman, S. et al. Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1α. Proc. Natl Acad. Sci. USA 99, 5367–5372 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Dames, S., Martinez-Yamout, M., de Guzman, R., Dyson, H. & Wright, P. From the cover: structural basis for HIF-1α/CBP recognition in the cellular hypoxic response. Proc. Natl Acad. Sci. USA 99, 5271–5276 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Hewitson, K. S. et al. Hypoxia-inducible Factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J. Biol. Chem. 277, 26351–26355 (2002).

    CAS  PubMed  Google Scholar 

  82. Wykoff, C., Pugh, C., Maxwell, P., Harris, A. & Ratcliffe, P. Identification of novel hypoxia dependent and independent target genes of the von Hippel–Lindau (VHL) tumour suppressor by mRNA differential expression profiling. Oncogene 19, 6297–3605 (2000).

    CAS  PubMed  Google Scholar 

  83. Gothie, E., Richard, D., Berra, E., Pages, G. & Pouyssegur, J. Identification of alternative spliced variants of human hypoxia-inducible factor-1α. J. Biol. Chem. 275, 6922–6927 (2000).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  85. Elson, D. et al. Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α. Genes Dev. 15, 2520–2532 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Vincent, K. et al. Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1α/VP16 hybrid transcription factor. Circulation 102, 2255–2261 (2000).

    CAS  PubMed  Google Scholar 

  87. Okuda, H. et al. Direct interaction of the β-domain of VHL tumor suppressor protein with the regulatory domain of atypical PKC isotypes. Biochem. Biophys. Res. Commun. 263, 491–497 (1999).

    CAS  PubMed  Google Scholar 

  88. Okuda, H. et al. The von Hippel–Lindau (VHL) tumor suppressor protein mediates ubiquitination of activated atypical protein kinase C. J. Biol. Chem. 276, 43611–43617 (2001).

    CAS  PubMed  Google Scholar 

  89. Pal, S., Claffey, K., Dvorak, H. & Mukhopadhyay, D. The von Hippel–Lindau gene product inhibits vascular permeability factor/vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase C pathways. J. Biol. Chem. 272, 27509–27512 (1997).

    CAS  PubMed  Google Scholar 

  90. Pal, S., Claffey, K., Cohen, H. & Mukhopadhyay, D. Activation of Sp1-mediated vascular permeability factor/vascular endothelial growth factor transcription requires specific interaction with protein kinase C. J. Biol. Chem. 273, 26277–26280 (1998).

    CAS  PubMed  Google Scholar 

  91. Cohen, H. et al. An important von Hippel–Lindau tumor suppressor domain mediates Sp1-binding and self-association. Biochem. Biophys. Res. Commun. 266, 43–50 (1999).

    CAS  PubMed  Google Scholar 

  92. Mukhopadhyay, D., Knebelmann, B., Cohen, H., Ananth, S. & Sukhatme, V. The von Hippel–Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol. Cell. Biol. 17, 5629–5639 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Feldman, D., Thulasiraman, V., Ferreyra, R. & Frydman, J. Formation of the VHL–elongin-B/C tumor suppressor complex is mediated by the chaperonin TRiC. Mol. Cell 4, 1051–1061 (1999).

    CAS  PubMed  Google Scholar 

  94. Hansen, W. et al. Diverse effects of mutations in exon II of the von Hippel–Lindau (VHL) tumor suppressor gene on the interaction of pVHL with the cytosolic chaperonin and pVHL-dependent ubiquitin ligase activity. Mol. Cell. Biol. 22, 1947–1960 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  96. Lieubeau-Teillet, B. et al. von Hippel–Lindau gene-mediated growth suppression and induction of differentiation in renal cell carcinoma cells grown as multicellular tumor spheroids. Cancer Res. 58, 4957–4962 (1998).

    CAS  PubMed  Google Scholar 

  97. Esteban-Barragan, M. et al. Role of the von Hippel–Lindau tumor suppressor gene in the formation of β1-integrin fibrillar adhesions. Cancer Res, 62, 2929–2936 (2002).

    CAS  Google Scholar 

  98. Schoenfeld, A., Davidowitz, E. & Burk, R. Endoplasmic reticulum/cytosolic localization of von Hippel–Lindau gene products is mediated by a 64-amino acid region. Int. J. Cancer 91, 457–467 (2001).

    CAS  PubMed  Google Scholar 

  99. Gorospe, M. et al. Protective function of von Hippel–Lindau protein against impaired protein processing in renal carcinoma cells. Mol. Cell. Biol. 19, 1289–1300 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Bohling, T. et al. Expression of growth factors and growth factor receptors in capillary hemangioblastoma. J. Neuropathol. Exp. Neurol. 55, 522–527 (1996).

    CAS  PubMed  Google Scholar 

  102. Flamme, I., Krieg, M. & Plate, K. Up-regulation of vascular endothelial growth factor in stromal cells of hemangioblastomas is correlated with up-regulation of the transcription factor HRF/HIF-2α. Am. J. Pathol. 153, 25–29 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Grossniklaus, H., Thomas, J., Vigneswaran, N. & Jarrett, W. H. Retinal hemangioblastoma. A histologic, immunohistochemical, and ultrastructural evaluation. Ophthalmology 99, 140–145 (1992).

    CAS  PubMed  Google Scholar 

  104. Morii, K., Tanaka, R., Washiyama, K., Kumanishi, T. & Kuwano, R. Expression of vascular endothelial growth factor in capillary hemangioblastoma. Biochem. Biophys. Res. Commun. 194, 749–755 (1993).

    CAS  PubMed  Google Scholar 

  105. Reifenberger, G., Reifenberger, J., Bilzer, T., Wechsler, W. & Collins, V. Coexpression of transforming growth factor-α and epidermal growth factor receptor in capillary hemangioblastomas of the central nervous system. Am. J. Pathol. 147, 245 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Wizigmann-Voos, S., Breier, G., Risau, W. & Plate, K. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel–Lindau disease-associated and sporadic hemangioblastomas. Cancer Res. 55, 1358–1364 (1995).

    CAS  PubMed  Google Scholar 

  107. Chan, C. et al. VHL gene deletion and enhanced VEGF gene expression detected in the stromal cells of retinal angioma. Arch. Ophthalmol. 117, 625–630 (1999).

    CAS  PubMed  Google Scholar 

  108. Knebelmann, B., Ananth, S., Cohen, H. & Sukhatme, V. Transforming growth factor-α is a target for the von Hippel–Lindau tumor suppressor. Cancer Res. 58, 226–231 (1998).

    CAS  PubMed  Google Scholar 

  109. Reference deleted in proof.

  110. Benjamin, L. E. & Keshet, E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc. Natl Acad. Sci. USA 94, 8761–8766 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Dor, Y. et al. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J. 21, 1939–1947 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Drake, C. & Little, C. Exogenous vascular endothelial growth factor induces malformed and hyperfused vessels during embryonic neovascularization. Proc. Natl Acad. Sci. USA 92, 7657–7661 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Haase, V., Glickman, J., Socolovsky, M. & Jaenisch, R. Vascular tumors in livers with targeted inactivation of the von Hippel–Lindau tumor suppressor. Proc. Natl Acad. Sci. USA 98, 1583–1588 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Morita, R. et al. Allelotype of renal cell carcinoma. Cancer Res. 51, 820–823 (1991).

    CAS  PubMed  Google Scholar 

  115. Thrash-Bingham, C. A. et al. Comprehensive allelotyping of human renal cell carcinomas using microsatellite DNA probes. Proc. Natl Acad. Sci. USA 92, 2854–2858 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Morita, R. et al. Common regions of deletion on chromosomes 5q, 6q, and 10q in renal cell carcinoma. Cancer Res. 51, 5817–5820 (1991).

    CAS  PubMed  Google Scholar 

  117. Foster, K. et al. Molecular genetic investigation of sporadic renal cell carcinoma: analysis of allele loss on chromosomes 3p, 5q, 11p, 17 and 22. Br. J. Cancer 69, 230–234 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Kenck, C., Bugert, P., Wilhelm, M. & Kovacs, G. Duplication of an approximately 1.5 Mb DNA segment at chromosome 5q22 indicates the locus of a new tumour gene in nonpapillary renal cell carcinomas. Oncogene 14, 1093–1098 (1997).

    CAS  PubMed  Google Scholar 

  119. Pause, A., Lee, S., Lonergan, K. M. & Klausner, R. D. The von Hippel–Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc. Natl Acad. Sci. USA 95, 993–998 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Davidowitz, E., Schoenfeld, A. & Burk, R. VHL induces renal cell differentiation and growth arrest through integration of cell–cell and cell–extracellular-matrix signaling. Mol. Cell. Biol. 21, 865–874 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Chen, F. et al. Suppression of growth of renal carcinoma cells by the von Hippel–Lindau tumor suppressor gene. Cancer Res. 55, 4804–4807 (1995).

    CAS  PubMed  Google Scholar 

  122. Kondo, K., Klco, J., Nakamura, E. & Kaelin, W. G. Inhibition of HIF is necessary for tumor suppression by the von Hippel–Lindau protein. Cancer Cell 1, 237–246 (2002).

    CAS  PubMed  Google Scholar 

  123. Maranchie, J. K. et al. The contribution of VHL substrate binding and HIF1α to the phenotype of VHL Loss in renal cell carcinoma. Cancer Cell 1, 247–255 (2002).

    CAS  PubMed  Google Scholar 

  124. de Paulsen, N. et al. Role of transforming growth factor-α in VHL−/− clear cell renal carcinoma cell proliferation: a possible mechanism coupling von Hippel–Lindau tumor suppressor inactivation and tumorigenesis. Proc. Natl Acad. Sci. USA 98, 1387–1392 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Mydlo, J. et al. Expression of transforming growth factor-α and epidermal growth factor receptor messenger RNA in neoplastic and nonneoplastic human kidney tissue. Cancer Res. 49, 3407–3411 (1989).

    CAS  PubMed  Google Scholar 

  126. Lager, D., Slagel, D. & Palechek, P. The expression of epidermal growth factor receptor and transforming growth factor-α in renal cell carcinoma. Mod Pathol. 7, 544–548 (1994).

    CAS  PubMed  Google Scholar 

  127. Lowden, D. et al. Renal cysts in transgenic mice expressing transforming growth factor-α. J. Lab. Clin. Med. 124, 386–394 (1994).

    CAS  PubMed  Google Scholar 

  128. Hofstra, R. M. W. et al. Extensive mutation scanning of RET in sporadic medullary thyroid carcinoma and of RET and VHL in sporadic pheochromocytoma reveals involvement of these genes in only a minority of cases. J. Clin. Endocrinol. Metab. 81, 2881–2884 (1996).

    CAS  PubMed  Google Scholar 

  129. Tian, H., Hammer, R., Matsumoto, A., Russell, D. & McKnight, S. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev. 12, 3320–3324 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Kroll, S. et al. von Hippel–Lindau protein induces hypoxia-regulated arrest of tyrosine hydroxylase transcript elongation in pheochromocytoma cells. J. Biol. Chem. 274, 30109–30114 (1999).

    CAS  PubMed  Google Scholar 

  131. 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. 62, 1682–1687 (2002).

    CAS  PubMed  Google Scholar 

  132. Field, S. J. et al. E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 85, 549–561 (1996).

    CAS  PubMed  Google Scholar 

  133. Ryan, H., Lo, J. & Johnson, R. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J. 17, 3005–3015 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Ryan, H. et al. Hypoxia-inducible factor-1α is a positive factor in solid tumor growth. Cancer Res. 60, 4010–4015 (2000).

    CAS  PubMed  Google Scholar 

  135. Maxwell, P. et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc. Natl Acad. Sci. USA 94, 8104–8109 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Keshet, E. & Ben-Sasson, S. Anticancer drug targets: approaching angiogenesis. J. Clin. Invest. 104, 1497–1501 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Gibbs, J. Mechanism-based target identification and drug discovery in cancer research. Science 287, 1969 (2000).

    CAS  PubMed  Google Scholar 

  138. Drevs, J. et al. Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Res. 60, 4819–4824 (2000).

    CAS  PubMed  Google Scholar 

  139. Prewett, M., Rothman, M., Feldman, M., Bander, N. & Hicklin, D. Mouse–human chimeric anti-epidermal growth factor receptor antibody C225 inhibits the growth of human renal cell carcinoma xenografts in nude mice. Clin. Cancer Res. 4, 2957–2966 (1998).

    CAS  PubMed  Google Scholar 

  140. Ciardiello, F. et al. Cooperative inhibition of renal cancer growth by anti-epidermal growth factor receptor antibody and protein kinase A antisense oligonucleotide. J. Natl Cancer Inst. 90, 1087–1094 (1998).

    CAS  PubMed  Google Scholar 

  141. Sweeney, W., Chen, Y., Nakanishi, K., Frost, P. & Avner, E. Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int. 57, 33–40 (2000).

    CAS  PubMed  Google Scholar 

  142. Aiello, L. et al. Rapid and durable recovery of visual function in a patient with von Hippel–Lindau syndrome and optic nerve head hemangioma following systemic treatment with the VEGF receptor inhibitor SU5416. Ophthalmology (in the press).

  143. Richard, S. et al. Paradoxical secondary polycythemia in von Hippel–Lindau patients treated with anti-vascular endothelial growth factor receptor therapy. Blood 99, 3851–3853 (2002).

    CAS  PubMed  Google Scholar 

  144. Fabbro, D., Parkinson, D. & Matter, A. Protein tyrosine kinase inhibitors: new treatment modalities? Curr. Opin. Pharmacol. 2, 374–381 (2002).

    CAS  PubMed  Google Scholar 

  145. Nwogu, J. I. et al. Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilation after myocardial infarction. Circulation 104, 2216–2221 (2001).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The author thanks Adrian Gaudric, David Goldfarb and Mika Niemela for the use of clinical photographs, and dedicates this paper to von Hippel–Lindau patients and their families.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Dana–Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    William G. Kaelin Jr

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  1. William G. Kaelin Jr
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DATABASES

Cancer.gov

pancreatic cancer

renal-cell carcinoma

LocusLink

ARNT

CBP

CCT

CUL2

EGFR

EGLN1

EGLN2

EGLN3

elongin B

elongin C

EPO

FIH1

HIF-1α

HIF-2α

HIF-3α

KDR

PDGF-β

PDGFR

PKC

Rbx1

SP1

tyrosine hydroxylase

VEGF

VHL

OMIM

stroke

von Hippel–Lindau syndrome

Saccharomyces Genome Database

Skp1

Cdc53

WormBase

egl-9

FURTHER INFORMATION

Universal Mutation Database

VHL Family Alliance

Glossary

PHAEOCHROMOCYTOMA

A neuroendocrine tumour that typically arises in the adrenal medulla. These tumours can be benign or malignant. Symptoms often relate to the ability of these tumours to secrete catecholamines.

LASER PHOTOCOAGULATION

A process in which a laser is focused on a specific area of the retina. Localized coagulation is induced by the conversion of light energy to heat.

RETINAL DETACHMENT

A condition in which the retina — the specialized lining inside the eye that is responsible for transducing light signals — detaches from the underlying layers of the eye.

MACULA

A specific area of the retina that corresponds to the posterior pole of the eyeball in the visual axis. At its centre is the fovea centralis, which is crucial for visual acuity.

DIALYSIS

A process for treating patients with inadequate kidney function. Haemodialysis involves exposing blood to solute across a semipermeable membrane. Peritoneal dialysis involves instilling and removing large volumes of solute in the peritoneal cavity. Dialysis allows the removal of toxic substances from the blood and the correction of certain electrolyte imbalances.

KNUDSON 2-HIT MODEL

In 1971, Knudson noted that the differences between hereditary and sporadic retinoblastoma, with respect to age-specific incidence and propensity for multifocality, could be accounted for if the development of retinoblastoma required two rate-limiting mutations ('hits') and if one of these hits had already occurred in the germ line of the hereditary patients. Later, he speculated that the two hits might be the inactivation of the maternal and paternal copies of a tumour-suppressor gene — a prediction that was later proved to be correct.

DOMINANT NEGATIVE

A defective protein that inhibits the function of its wild-type counterpart.

RAN

A small GTP-binding protein that is a key component of the nuclear–cytoplasmic transport machinery.

CULLIN

A member of a family of proteins first identified in Caenorhabditis elegans that has a similar amino-acid sequence to Cdc53 in yeast. These proteins are integral components of SCF (Skp1–Cdc53–F-Box)-like ubiquitin-ligase complexes. In this context, they serve as a bridge between the substrate-recognition and ubiquitin-conjugation components of the complex.

F-BOX PROTEIN

A protein that contains a collinear motif first identified in cyclin F. This motif allows binding to Skp1-like proteins, and hence recruitment of F-box proteins to SCF (Skp1–Cdc53–F-box) complexes. F-box proteins recognize specific substrates and present them for polyubiquitylation by other components of the SCF complex.

HYPOXIA-INDUCIBLE GENES

A gene for which mRNA abundance is markedly enhanced under conditions of low oxygen. In the laboratory, low-oxygen conditions are usually achieved with environments that contain 1% oxygen or less. Air contains 21% oxygen.

P300 AND CBP

Two large nuclear proteins that serve as co-activators when bound to DNA through other transcription factors.

TIMPS

Tissue inhibitors of metalloproteinases; a family of proteins that inhibit the functions of the matrix metalloproteinases.

MMPS

Matrix metalloproteinases. This protein family degrades specific proteins that are found in the extracellular matrix.

LASER-CAPTURE MICRODISSECTION

A method for selectively removing and analysing specific cells from a histological tissue section. A laser light is focused on the cells of interest. The heat energy results in the cells adhering to a specialized solid support.

FIELD DEFECT

An alteration (such as a mutation) that involves most or all of the cells in a contiguous region (field).

HOMOLOGOUS RECOMBINATION

The process by which segments of homologous DNA are exchanged between two DNA duplexes that share high sequence similarity. Often used to inactivate a gene of interest.

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Kaelin, W. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2, 673–682 (2002). https://doi.org/10.1038/nrc885

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