Molecular basis of the VHL hereditary cancer syndrome (original) (raw)

• 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
• von Hippel, E. Ueber eine sehr seltene Erkrankung der Nethaut. Graefe Arch. Ophthalmol. 59, 83–106 (1904).
  Google Scholar
• Lindau, A. Zur Frage der Angiomatosis Retinae und Ihrer Hirncomplikation. Acta Ophthalmol. 4, 193–226 (1927).
  Google Scholar
• 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
• Maher, E. & Kaelin, W. G. von Hippel–Lindau disease. Medicine 76, 381–391 (1997).
  CAS PubMed Google Scholar
• 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
• 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
• Woodward, E. et al. Comparative sequence analysis of the VHL tumor suppressor gene. Genomics 65, 253–265 (2000).
  CAS PubMed Google Scholar
• 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
• Bruick, R. & McKnight, S. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• Neumann, H. & Bender, B. Genotype–phenotype correlations in von Hippel–Lindau disease. J. Intern. Med. 243, 541–545 (1998).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Neumann, H. et al. Germ-line mutations in nonsyndromic pheochromocytoma. N. Engl. J. Med. 346, 1459–1466 (2002).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Deshaies, R. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu. Rev. Cell Dev. Biol. 15, 435–467 (1999).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Kivirikko, K. I. & Myllyharju, J. Prolyl 4-hydroxylases and their protein disulfide isomerase subunit. Matrix Biol. 16, 357–368 (1998).
  CAS PubMed Google Scholar
• Taylor, M. S. Characterization and comparative analysis of the EGLN gene family. Gene 275, 125–132 (2001).
  CAS PubMed Google Scholar
• Ivan, M. et al. Biochemical purification and pharmacological inhibition of a mammalian HIF prolyl hydroxylase. Proc. Natl Acad. Sci. USA (in the press).
• Bruick, R. & McKnight, S. Transcription. Oxygen sensing gets a second wind. Science 295, 807–808 (2002).
  CAS PubMed Google Scholar
• Lando, D. et al. Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 295, 858–861 (2002).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Reference deleted in proof.
• 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
• 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
• 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
• 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
• Morita, R. et al. Allelotype of renal cell carcinoma. Cancer Res. 51, 820–823 (1991).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Keshet, E. & Ben-Sasson, S. Anticancer drug targets: approaching angiogenesis. J. Clin. Invest. 104, 1497–1501 (1999).
  CAS PubMed PubMed Central Google Scholar
• Gibbs, J. Mechanism-based target identification and drug discovery in cancer research. Science 287, 1969 (2000).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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).
• 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
• Fabbro, D., Parkinson, D. & Matter, A. Protein tyrosine kinase inhibitors: new treatment modalities? Curr. Opin. Pharmacol. 2, 374–381 (2002).
  CAS PubMed Google Scholar
• 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