1932

Abstract

The von Hippel–Lindau () gene is a two-hit tumor suppressor gene and is linked to the development of the most common form of kidney cancer, clear cell renal carcinoma; blood vessel tumors of the retina, cerebellum, and spinal cord called hemangioblastomas; and tumors of the sympathoadrenal nervous system called paragangliomas. The gene product, pVHL, is the substrate recognition subunit of a cullin-dependent ubiquitin ligase that targets the α subunits of hypoxia-inducible factor (HIF) for destruction when oxygen is plentiful. Mounting evidence implicates HIF2 in the pathogenesis of pVHL-defective tumors and has provided a conceptual foundation for the development of drugs to treat them that inhibit HIF2-responsive gene products such as VEGF and, more recently, HIF2 itself. pVHL has additional, noncanonical functions that are cancer relevant, including roles related to the primary cilium, chromosome stability, extracellular matrix formation, and survival signaling.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-030617-050527
2018-03-04
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/2/1/annurev-cancerbio-030617-050527.html?itemId=/content/journals/10.1146/annurev-cancerbio-030617-050527&mimeType=html&fmt=ahah

Literature Cited

  1. Aiello LP, George DJ, Cahill MT, Wong JS, Cavallerano J. et al. 2002. Rapid and durable recovery of visual function in a patient with von Hippel-Lindau syndrome after systemic therapy with vascular endothelial growth factor receptor inhibitor SU5416. Ophthalmology 109:1745–51 [Google Scholar]
  2. Albers J, Rajski M, Schonenberger D, Harlander S, Schraml P. et al. 2013. Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice. EMBO Mol. Med. 5:949–64 [Google Scholar]
  3. An J, Fisher M, Rettig MB. 2005. VHL expression in renal cell carcinoma sensitizes to bortezomib (PS-341) through an NF-κB-dependent mechanism. Oncogene 24:1563–70 [Google Scholar]
  4. An J, Rettig MB. 2005. Mechanism of von Hippel-Lindau protein-mediated suppression of nuclear factor kappa B activity. Mol. Cell Biol. 25:7546–56 [Google Scholar]
  5. Astrom K, Cohen JE, Willett-Brozick JE, Aston CE, Baysal BE. 2003. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum. Genet. 113:228–37 [Google Scholar]
  6. Basten SG, Willekers S, Vermaat JS, Slaats GG, Voest EE. et al. 2013. Reduced cilia frequencies in human renal cell carcinomas versus neighboring parenchymal tissue. Cilia 2:2 [Google Scholar]
  7. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E. 1999. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J. Clin. Investig. 103:159–65 [Google Scholar]
  8. Benjamin LE, Hemo I, Keshet E. 1998. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125:1591–98 [Google Scholar]
  9. Bertout JA, Majmundar AJ, Gordan JD, Lam JC, Ditsworth D. et al. 2009. HIF2α inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. PNAS 106:14391–96 [Google Scholar]
  10. Beyer S, Kristensen MM, Jensen KS, Johansen JV, Staller P. 2008. The histone demethylases JMJD1A and JMJD2B are transcriptional targets of hypoxia-inducible factor HIF. J. Biol. Chem. 283:36542–52 [Google Scholar]
  11. Bishop T, Gallagher D, Pascual A, Lygate CA, de Bono JP. et al. 2008. Abnormal sympathoadrenal development and systemic hypotension in PHD3−/− mice. Mol. Cell Biol. 28:3386–400 [Google Scholar]
  12. Bommi-Reddy A, Almeciga I, Sawyer J, Geisen C, Li W. et al. 2008. Kinase requirements in human cells: III. Altered kinase requirements in VHL−/− cancer cells detected in a pilot synthetic lethal screen. PNAS 105:16484–89 [Google Scholar]
  13. Bondeson DP, Mares A, Smith IE, Ko E, Campos S. et al. 2015. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11:611–17 [Google Scholar]
  14. Bracken CP, Fedele AO, Linke S, Balrak W, Lisy K. et al. 2006. Cell-specific regulation of hypoxia-inducible factor (HIF)-1α and HIF-2α stabilization and transactivation in a graded oxygen environment. J. Biol. Chem. 281:22575–85 [Google Scholar]
  15. Briggs KJ, Koivunen P, Cao S, Backus KM, Olenchock BA. et al. 2016. Paracrine induction of HIF by glutamate in breast cancer: EglN1 senses cysteine. Cell 166:126–39 [Google Scholar]
  16. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH. et al. 2004. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893–904 [Google Scholar]
  17. Cancer Genome Atlas Res. Netw. 2013. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499:43–49 [Google Scholar]
  18. Chen W, Hill H, Christie A, Kim MS, Holloman E. et al. 2016. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539:112–17 [Google Scholar]
  19. Chen ZX, Wallis K, Fell SM, Sobrado VR, Hemmer MC. et al. 2014. RNA helicase A is a downstream mediator of KIF1Bβ tumor-suppressor function in neuroblastoma. Cancer Discov 4:434–51 [Google Scholar]
  20. Chitalia VC, Foy RL, Bachschmid MM, Zeng L, Panchenko MV. et al. 2008. Jade-1 inhibits Wnt signalling by ubiquitylating β-catenin and mediates Wnt pathway inhibition by pVHL. Nat. Cell Biol. 10:1208–16 [Google Scholar]
  21. Cho H, Du X, Rizzi JP, Liberzon E, Chakraborty AA. et al. 2016. On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models. Nature 539:107–11 [Google Scholar]
  22. Choo Z, Koh RY, Wallis K, Koh TJ, Kuick CH. et al. 2016. XAF1 promotes neuroblastoma tumor suppression and is required for KIF1Bβ-mediated apoptosis. Oncotarget 7:34229–39 [Google Scholar]
  23. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI. et al. 2015. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373:1814–23 [Google Scholar]
  24. Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN. et al. 2016. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 17:917–27 [Google Scholar]
  25. Choueiri TK, Motzer RJ. 2017. Systemic therapy for metastatic renal-cell carcinoma. N. Engl. J. Med. 376:354–66 [Google Scholar]
  26. Clifford S, Cockman M, Smallwood A, Mole D, Woodward E. et al. 2001. Contrasting effects on HIF-1α regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum. Mol. Genet. 10:1029–38 [Google Scholar]
  27. Dahia PL. 2017. Pheochromocytomas and paragangliomas, genetically diverse and minimalist, all at once!. Cancer Cell 31:159–61 [Google Scholar]
  28. Datta K, Nambudripad R, Pal S, Zhou M, Cohen HT, Mukhopadhyay D. 2000. Inhibition of insulin-like growth factor-I-mediated cell signaling by the von Hippel-Lindau gene product in renal cancer. J. Biol. Chem. 275:20700–6 [Google Scholar]
  29. Datta K, Sundberg C, Karumanchi SA, Mukhopadhyay D. 2001. The 104–123 amino acid sequence of the β-domain of von Hippel-Lindau gene product is sufficient to inhibit renal tumor growth and invasion. Cancer Res 61:1768–75 [Google Scholar]
  30. Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM. 2006. The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1α. Cancer Res 66:3688–98 [Google Scholar]
  31. Dere R, Perkins AL, Bawa-Khalfe T, Jonasch D, Walker CL. 2015. β-catenin links von Hippel–Lindau to Aurora kinase A and loss of primary cilia in renal cell carcinoma. J. Am. Soc. Nephrol. 26:553–64 [Google Scholar]
  32. Ding XF, Zhou J, Hu QY, Liu SC, Chen G. 2015. The tumor suppressor pVHL down-regulates never-in-mitosis A-related kinase 8 via hypoxia-inducible factors to maintain cilia in human renal cancer cells. J. Biol. Chem. 290:1389–94 [Google Scholar]
  33. Dondeti VR, Wubbenhorst B, Lal P, Gordan JD, D'Andrea K. et al. 2012. Integrative genomic analyses of sporadic clear cell renal cell carcinoma define disease subtypes and potential new therapeutic targets. Cancer Res 72:112–21 [Google Scholar]
  34. Dor Y, Djonov V, Abramovitch R, Itin A, Fishman G. et al. 2002. Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J 21:1939–47 [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. 17:1801–6 [Google Scholar]
  36. Favier J, Kempf H, Corvol P, Gasc JM. 1999. Cloning and expression pattern of EPAS1 in the chicken embryo: colocalization with tyrosine hydroxylase. FEBS Lett 462:19–24 [Google Scholar]
  37. Feldman DR, Baum MS, Ginsberg MS, Hassoun H, Flombaum CD. et al. 2009. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 27:1432–39 [Google Scholar]
  38. Fisher R, Horswell S, Rowan A, Salm MP, de Bruin EC. et al. 2014. Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution. Genome Biol 15:433 [Google Scholar]
  39. Foxler DE, Bridge KS, James V, Webb TM, Mee M. et al. 2012. The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat. Cell Biol. 14:201–8 [Google Scholar]
  40. Frew IJ, Minola A, Georgiev S, Hitz M, Moch H. et al. 2008.a Combined Vhlh and Pten mutation causes genital tract cystadenoma and squamous metaplasia. Mol. Cell Biol. 28:4536–48 [Google Scholar]
  41. Frew IJ, Smole Z, Thoma CR, Krek W. 2013. Genetic deletion of the long isoform of the von Hippel–Lindau tumour suppressor gene product alters microtubule dynamics. Eur. J. Cancer 49:2433–40 [Google Scholar]
  42. Frew IJ, Thoma CR, Georgiev S, Minola A, Hitz M. et al. 2008.b pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J 27:1747–57 [Google Scholar]
  43. Gameiro PA, Yang J, Metelo AM, Pérez-Carro R, Baker R. et al. 2013. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab 17:372–85 [Google Scholar]
  44. Gao C, Cao W, Bao L, Zuo W, Xie G. et al. 2010. Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation. Nat. Cell Biol. 12:781–90 [Google Scholar]
  45. Gao W, Li W, Xiao T, Liu XS, Kaelin WG Jr.. 2017. Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL−/− clear cell renal carcinoma. PNAS 114:1027–32 [Google Scholar]
  46. Gerlinger M, Horswell S, Larkin J, Rowan AJ, Salm MP. et al. 2014. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 46:225–33 [Google Scholar]
  47. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D. et al. 2012. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366:883–92 [Google Scholar]
  48. Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. 2012. Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer 12:89–103 [Google Scholar]
  49. Girmens JF, Erginay A, Massin P, Scigalla P, Gaudric A, Richard S. 2003. Treatment of von Hippel-Lindau retinal hemangioblastoma by the vascular endothelial growth factor receptor inhibitor SU5416 is more effective for associated macular edema than for hemangioblastomas. Am. J. Ophthalmol. 136:194–96 [Google Scholar]
  50. Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. 2007. HIF-2α promotes hypoxic cell proliferation by enhancing c-Myc transcriptional activity. Cancer Cell 11:335–47 [Google Scholar]
  51. Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN. et al. 2008. HIF-α effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14:435–46 [Google Scholar]
  52. Grosfeld A, Stolze IP, Cockman ME, Pugh CW, Edelmann M. et al. 2007. Interaction of hydroxylated collagen IV with the von Hippel-Lindau tumor suppressor. J. Biol. Chem. 282:13264–69 [Google Scholar]
  53. Guo G, Gui Y, Gao S, Tang A, Hu X. et al. 2011. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat. Genet. 44:17–19 [Google Scholar]
  54. Guo J, Chakraborty AA, Liu P, Gan W, Zheng X. et al. 2016. pVHL suppresses kinase activity of Akt in a proline-hydroxylation–dependent manner. Science 353:929–32 [Google Scholar]
  55. Han T, Goralski M, Gaskill N, Capota E, Kim J. et al. 2017. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356:eaal3755 [Google Scholar]
  56. Harten SK, Shukla D, Barod R, Hergovich A, Balda MS. 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 E-cadherin. Mol. Biol. Cell 20:1089–101 [Google Scholar]
  57. Hasanov E, Chen G, Chowdhury P, Weldon J, Ding Z. et al. 2017. Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL. Oncogene 36:3450–63 [Google Scholar]
  58. Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W. 2003. Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat. Cell Biol. 5:64–70 [Google Scholar]
  59. Hergovich A, Lisztwan J, Thoma CR, Wirbelauer C, Barry RE, Krek W. 2006. Priming-dependent phosphorylation and regulation of the tumor suppressor pVHL by glycogen synthase kinase 3. Mol. Cell Biol. 26:5784–96 [Google Scholar]
  60. Hoffman MA, Ohh M, Yang H, Klco JM, Ivan M, Kaelin WG Jr.. 2001. von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum. Mol. Genet. 10:1019–27 [Google Scholar]
  61. Hrisomalos FN, Maturi RK, Pata V. 2010. Long-term use of intravitreal bevacizumab (avastin) for the treatment of von Hippel-Lindau associated retinal hemangioblastomas. Open Ophthalmol. J. 4:66–69 [Google Scholar]
  62. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R. et al. 2007. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356:2271–81 [Google Scholar]
  63. Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C. et al. 2005. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8:143–53 [Google Scholar]
  64. Jech M, Alvarado-Cabrero I, Albores-Saavedra J, Dahia PL, Tischler AS. 2006. Genetic analysis of high altitude paragangliomas. Endocr. Pathol. 17:201–2 [Google Scholar]
  65. Kaelin WG Jr.. 2008. The von Hippel–Lindau tumour suppressor protein: O2 sensing and cancer. Nat. Rev. Cancer 8:865–73 [Google Scholar]
  66. Kaelin WG Jr., Ratcliffe PJ. 2008. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30:393–402 [Google Scholar]
  67. Keith B, Johnson RS, Simon MC. 2012. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 12:9–22 [Google Scholar]
  68. Kim JJ, Lee SB, Jang J, Yi SY, Kim SH. et al. 2015. WSB1 promotes tumor metastasis by inducing pVHL degradation. Genes Dev 29:2244–57 [Google Scholar]
  69. Kim WY, Safran M, Buckley MR, Ebert BL, Glickman J. et al. 2006. Failure to prolyl hydroxylate hypoxia-inducible factor α phenocopies VHL inactivation in vivo. EMBO J 25:4650–62 [Google Scholar]
  70. Kondo K, Kim WY, Lechpammer M, Kaelin WG Jr.. 2003. Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth. PLOS Biol 1:439–44 [Google Scholar]
  71. Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG. 2002. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1:237–46 [Google Scholar]
  72. Koochekpour S, Jeffers M, Wang P, Gong C, Taylor G. et al. 1999. 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. 19:5902–12 [Google Scholar]
  73. Krieg AJ, Rankin EB, Chan D, Razorenova O, Fernandez S, Giaccia AJ. 2010. Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1α enhances hypoxic gene expression and tumor growth. Mol. Cell Biol. 30:344–53 [Google Scholar]
  74. Kronke J, Fink EC, Hollenbach PW, MacBeth KJ, Hurst SN. et al. 2015. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523:183–88 [Google Scholar]
  75. Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN. et al. 2014. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343:301–5 [Google Scholar]
  76. Kucejova B, Pena-Llopis S, Yamasaki T, Sivanand S, Tran TA. et al. 2011. Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma. Mol. Cancer Res. 9:1255–65 [Google Scholar]
  77. Kurban G, Duplan E, Ramlal N, Hudon V, Sado Y. et al. 2008. Collagen matrix assembly is driven by the interaction of von Hippel–Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2. Oncogene 27:1004–12 [Google Scholar]
  78. Kwiatkowski DJ, Choueiri TK, Fay AP, Rini BI, Thorner AR. et al. 2016. Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin. Cancer Res. 22:2445–52 [Google Scholar]
  79. Latif F, Tory K, Gnarra J, Yao M, Duh F-M. et al. 1993. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–20 [Google Scholar]
  80. Lee S, Nakamura E, Yang H, Wei W, Linggi MS. et al. 2005. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 8:155–67 [Google Scholar]
  81. Lee SB, Frattini V, Bansal M, Castano AM, Sherman D. et al. 2016. An ID2-dependent mechanism for VHL inactivation in cancer. Nature 529:172–77 [Google Scholar]
  82. Lehmann H, Vicari D, Wild PJ, Frew IJ. 2015. Combined deletion of Vhl and Kif3a accelerates renal cyst formation. J. Am. Soc. Nephrol. 26:2778–88 [Google Scholar]
  83. Li B, Qiu B, Lee DS, Walton ZE, Ochocki JD. et al. 2014. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513:251–55 [Google Scholar]
  84. Li L, Shen C, Nakamura E, Ando K, Signoretti S. et al. 2013. SQSTM1 is a pathogenic target of 5q copy number gains in kidney cancer. Cancer Cell 24:738–50 [Google Scholar]
  85. Li S, Fell SM, Surova O, Smedler E, Wallis K. et al. 2016. The 1p36 tumor suppressor KIF 1Bβ is required for calcineurin activation, controlling mitochondrial fission and apoptosis. Dev. Cell 36:164–78 [Google Scholar]
  86. Lolkema MP, Mans DA, Ulfman LH, Volpi S, Voest EE, Giles RH. 2008. Allele-specific regulation of primary cilia function by the von Hippel–Lindau tumor suppressor. Eur. J. Hum. Genet. 16:73–78 [Google Scholar]
  87. Lu G, Middleton RE, Sun H, Naniong M, Ott CJ. et al. 2014. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343:305–9 [Google Scholar]
  88. Lu H, Dalgard CL, Mohyeldin A, McFate T, Tait AS, Verma A. 2005. Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J. Biol. Chem. 280:41928–39 [Google Scholar]
  89. Lutz MS, Burk RD. 2006. Primary cilium formation requires von Hippel-Lindau gene function in renal-derived cells. Cancer Res 66:6903–7 [Google Scholar]
  90. Ma W, Tessarollo L, Hong SB, Baba M, Southon E. et al. 2003. Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene. Cancer Res 63:5320–28 [Google Scholar]
  91. Macias D, Fernandez-Aguera MC, Bonilla-Henao V, Lopez-Barneo J. 2014. Deletion of the von Hippel–Lindau gene causes sympathoadrenal cell death and impairs chemoreceptor-mediated adaptation to hypoxia. EMBO Mol. Med. 6:1577–92 [Google Scholar]
  92. Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV. et al. 2002. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1:459–68 [Google Scholar]
  93. Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM, Klausner RD. 2002. The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 1:247–55 [Google Scholar]
  94. Metelo AM, Noonan HR, Li X, Jin Y, Baker R. et al. 2015. Pharmacological HIF2α inhibition improves VHL disease–associated phenotypes in zebrafish model. J. Clin. Investig. 125:1987–97 [Google Scholar]
  95. Migliorini D, Haller S, Merkler D, Pugliesi-Rinaldi A, Koka A. et al. 2015. Recurrent multiple CNS hemangioblastomas with VHL disease treated with pazopanib: a case report and literature review. CNS Oncol 4:387–92 [Google Scholar]
  96. Montagner M, Enzo E, Forcato M, Zanconato F, Parenti A. et al. 2012. SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors. Nature 487:380–84 [Google Scholar]
  97. Montani M, Heinimann K, von Teichman A, Rudolph T, Perren A, Moch H. 2010. VHL-gene deletion in single renal tubular epithelial cells and renal tubular cysts: further evidence for a cyst-dependent progression pathway of clear cell renal carcinoma in von Hippel-Lindau disease. Am. J. Surg. Pathol. 34:806–15 [Google Scholar]
  98. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C. et al. 2008. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–56 [Google Scholar]
  99. Nakaigawa N, Yao M, Baba M, Kato S, Kishida T. et al. 2006. Inactivation of von Hippel-Lindau gene induces constitutive phosphorylation of MET protein in clear cell renal carcinoma. Cancer Res 66:3699–705 [Google Scholar]
  100. Nargund AM, Pham CG, Dong Y, Wang PI, Osmangeyoglu HU. et al. 2017. The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma. Cell Rep 18:2893–906 [Google Scholar]
  101. Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO. et al. 1998. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol. Cell 1:959–68 [Google Scholar]
  102. Okazaki A, Gameiro PA, Christodoulou D, Laviollette L, Schneider M. et al. 2017. Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers. J. Clin. Investig. 127:1631–45 [Google Scholar]
  103. Okuda H, Saitoh K, Hirai S, Iwai K, Takaki Y. et al. 2001. The von Hippel-Lindau tumor suppressor protein mediates ubiquitination of activated atypical protein kinase C. J. Biol. Chem. 276:43611–17 [Google Scholar]
  104. Pal SK, Sonpavde G, Agarwal N, Vogelzang NJ, Srinivas S. et al. 2017. Evolution of circulating tumor DNA profile from first-line to subsequent therapy in metastatic renal cell carcinoma. Eur. Urol. 72:557–64 [Google Scholar]
  105. Panchenko MV, Zhou MI, Cohen HT. 2004. von Hippel-Lindau partner Jade-1 is a transcriptional co-activator associated with histone acetyltransferase activity. J. Biol. Chem. 279:56032–41 [Google Scholar]
  106. Pantuck AJ, An J, Liu H, Rettig MB. 2010. NF-κB–dependent plasticity of the epithelial to mesenchymal transition induced by von Hippel-Lindau inactivation in renal cell carcinomas. Cancer Res 70:752–61 [Google Scholar]
  107. Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A, Leng N, Pavia-Jimenez A. et al. 2012. BAP1 loss defines a new class of renal cell carcinoma. Nat. Genet. 44:751–59 [Google Scholar]
  108. Pillai S, Gopalan V, Lo CY, Liew V, Smith RA, Lam AK. 2017. Silent genetic alterations identified by targeted next-generation sequencing in pheochromocytoma/paraganglioma: a clinicopathological correlations. Exp. Mol. Pathol. 102:41–46 [Google Scholar]
  109. Pollard P, Loenarz C, Mole D, McDonough M, Gleadle J. et al. 2008. Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1α. Biochem. J. 416:387–94 [Google Scholar]
  110. Prochilo T, Savelli G, Bertocchi P, Abeni C, Rota L. et al. 2013. Targeting VEGF-VEGFR pathway by sunitinib in peripheral primitive neuroectodermal tumor, paraganglioma and epithelioid hemangioendothelioma: three case reports. Case Rep. Oncol. 6:90–97 [Google Scholar]
  111. Pugacheva EN, Jablonski SA, Hartman TR, Henske EP, Golemis EA. 2007. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129:1351–63 [Google Scholar]
  112. Purdue MP, Johansson M, Zelenika D, Toro JR, Scelo G. et al. 2011. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3. Nat. Genet. 43:60–65 [Google Scholar]
  113. Qiu B, Ackerman D, Sanchez DJ, Li B, Ochocki JD. et al. 2015. HIF2α-dependent lipid storage promotes endoplasmic reticulum homeostasis in clear-cell renal cell carcinoma. Cancer Discov 5:652–67 [Google Scholar]
  114. Rankin EB, Higgins DF, Walisser JA, Johnson RS, Bradfield CA, Haase VH. 2005. Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Mol. Cell Biol. 25:3163–72 [Google Scholar]
  115. Rankin EB, Rha J, Unger TL, Wu CH, Shutt HP. et al. 2008. Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene 27:5354–58 [Google Scholar]
  116. Rankin EB, Tomaszewski JE, Haase VH. 2006. Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res 66:2576–83 [Google Scholar]
  117. Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ. 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. 25:5675–86 [Google Scholar]
  118. Reiling JH, Hafen E. 2004. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev 18:2879–92 [Google Scholar]
  119. Rini BI, Garcia JA, Cooney MM, Elson P, Tyler A. et al. 2010. Toxicity of sunitinib plus bevacizumab in renal cell carcinoma. J. Clin. Oncol. 28:e284–85 [Google Scholar]
  120. Roberts AM, Watson IR, Evans AJ, Foster DA, Irwin MS, Ohh M. 2009. Suppression of hypoxia-inducible factor 2α restores p53 activity via Hdm2 and reverses chemoresistance of renal carcinoma cells. Cancer Res 69:9056–64 [Google Scholar]
  121. Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M. et al. 2011. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov 1:248–59 [Google Scholar]
  122. Rogers JL, Bayeh L, Scheuermann TH, Longgood J, Key J. et al. 2013. Development of inhibitors of the PAS-B domain of the HIF-2α transcription factor. J. Med. Chem. 56:1739–47 [Google Scholar]
  123. Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. 2001. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. PNAS 98:8554–59 [Google Scholar]
  124. Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y. et al. 2013. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. 45:860–67 [Google Scholar]
  125. Schermer B, Ghenoiu C, Bartram M, Muller RU, Kotsis F. et al. 2006. The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J. Cell Biol. 175:547–54 [Google Scholar]
  126. Scheuermann TH, Li Q, Ma HW, Key J, Zhang L. et al. 2013. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat. Chem. Biol. 9:271–76 [Google Scholar]
  127. Scheuermann TH, Tomchick DR, Machius M, Guo Y, Bruick RK, Gardner KH. 2009. Artificial ligand binding within the HIF2α PAS-B domain of the HIF2 transcription factor. PNAS 106:450–55 [Google Scholar]
  128. Schietke RE, Hackenbeck T, Tran M, Gunther R, Klanke B. et al. 2012. Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts. PLOS ONE 7:e31034 [Google Scholar]
  129. Schlisio S, Kenchappa RS, Vredeveld LC, George RE, Stewart R. et al. 2008. The kinesin KIF1Bβ acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev 22:884–93 [Google Scholar]
  130. Schoenfeld A, Davidowitz E, Burk R. 2001. Endoplasmic reticulum/cytosolic localization of von Hippel-Lindau gene products is mediated by a 64-amino acid region. Int. J. Cancer 91:457–67 [Google Scholar]
  131. Schonenberger D, Harlander S, Rajski M, Jacobs RA, Lundby AK. et al. 2016. Formation of renal cysts and tumors in Vhl/Trp53-deficient mice requires HIF1α and HIF2α. Cancer Res 76:2025–36 [Google Scholar]
  132. Schraml P, Frew IJ, Thoma CR, Boysen G, Struckmann K. et al. 2009. Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia. Mod Pathol 22:31–36 [Google Scholar]
  133. Selak MA, Armour SM, Mackenzie ED, Boulahbel H, Watson DG. et al. 2005. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7:77–85 [Google Scholar]
  134. Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG. et al. 2010. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res 70:8981–87 [Google Scholar]
  135. Semenza GL. 2012. Hypoxia-inducible factors in physiology and medicine. Cell 148:399–408 [Google Scholar]
  136. Shen C, Beroukhim R, Schumacher SE, Zhou J, Chang M. et al. 2011. Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene. Cancer Discov 1:222–35 [Google Scholar]
  137. Shiao YH, Resau JH, Nagashima K, Anderson LM, Ramakrishna G. 2000. The von Hippel-Lindau tumor suppressor targets to mitochondria. Cancer Res 60:2816–19 [Google Scholar]
  138. Singla V, Reiter JF. 2006. The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 313:629–33 [Google Scholar]
  139. Stickle NH, Chung J, Klco JM, Hill RP, Kaelin WG Jr., Ohh M. 2004. pVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development. Mol. Cell Biol. 24:3251–61 [Google Scholar]
  140. Takayanagi S, Mukasa A, Tanaka S, Nomura M, Omata M. et al. 2017. Differences in genetic and epigenetic alterations between von Hippel–Lindau disease–related and sporadic hemangioblastomas of the central nervous system. Neuro-Oncology 19:1228–36 [Google Scholar]
  141. Thoma CR, Frew IJ, Hoerner CR, Montani M, Moch H, Krek W. 2007. pVHL and GSK3β are components of a primary cilium-maintenance signalling network. Nat. Cell Biol. 9:588–95 [Google Scholar]
  142. Thoma CR, Matov A, Gutbrodt KL, Hoerner CR, Smole Z. et al. 2010. Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability. J. Cell Biol. 190:991–1003 [Google Scholar]
  143. Thoma CR, Toso A, Gutbrodt KL, Reggi SP, Frew IJ. et al. 2009. VHL loss causes spindle misorientation and chromosome instability. Nat. Cell Biol. 11:994–1001 [Google Scholar]
  144. Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E. et al. 2006. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat. Med. 12:122–27 [Google Scholar]
  145. Troilo A, Alexander I, Muehl S, Jaramillo D, Knobeloch KP, Krek W. 2014. HIF1α deubiquitination by USP8 is essential for ciliogenesis in normoxia. EMBO Rep 15:77–85 [Google Scholar]
  146. Uehara T, Minoshima Y, Sagane K, Sugi NH, Mitsuhashi KO. et al. 2017. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat. Chem. Biol. 13:675–80 [Google Scholar]
  147. van Rooijen E, Voest EE, Logister I, Bussmann J, Korving J. et al. 2010. von Hippel-Lindau tumor suppressor mutants faithfully model pathological hypoxia-driven angiogenesis and vascular retinopathies in zebrafish. Dis. Model. Mech. 3:343–53 [Google Scholar]
  148. Voss MH, Hakimi AA, Pham CG, Brannon AR, Chen YB. et al. 2014. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin. Cancer Res. 20:1955–64 [Google Scholar]
  149. Wallace EM, Rizzi JP, Han G, Wehn PM, Cao Z. et al. 2016. A small-molecule antagonist of HIF2α is efficacious in preclinical models of renal cell carcinoma. Cancer Res 76:5491–500 [Google Scholar]
  150. Welander J, Andreasson A, Juhlin CC, Wiseman RW, Backdahl M. et al. 2014. Rare germline mutations identified by targeted next-generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma. J. Clin. Endocrinol. Metab. 99:E1352–60 [Google Scholar]
  151. Wellmann S, Bettkober M, Zelmer A, Seeger K, Faigle M. et al. 2008. Hypoxia upregulates the histone demethylase JMJD1A via HIF-1. Biochem. Biophys. Res. Commun. 372:892–97 [Google Scholar]
  152. Wolff NC, Vega-Rubin-de-Celis S, Xie XJ, Castrillon DH, Kabbani W, Brugarolas J. 2011. Cell-type-dependent regulation of mTORC1 by REDD1 and the tumor suppressors TSC1/TSC2 and LKB1 in response to hypoxia. Mol. Cell Biol. 31:1870–84 [Google Scholar]
  153. Wu D, Potluri N, Lu J, Kim Y, Rastinejad F. 2015. Structural integration in hypoxia-inducible factors. Nature 524:303–8 [Google Scholar]
  154. Xia X, Lemieux ME, Li W, Carroll JS, Brown M. et al. 2009. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. PNAS 106:4260–65 [Google Scholar]
  155. Xu J, Li H, Wang B, Xu Y, Yang J. et al. 2010. VHL inactivation induces HEF1 and Aurora kinase A. J. Am. Soc. Nephrol. 21:2041–46 [Google Scholar]
  156. Xu X, Hou Y, Yin X, Bao L, Tang A. et al. 2012. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell 148:886–95 [Google Scholar]
  157. Yang H, Minamishima YA, Yan Q, Schlisio S, Ebert BL. et al. 2007. pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-κB agonist Card9 by CK2. Mol. Cell 28:15–27 [Google Scholar]
  158. Yang J, Jubb AM, Pike L, Buffa FM, Turley H. et al. 2010. The histone demethylase JMJD2B is regulated by estrogen receptor α and hypoxia, and is a key mediator of estrogen induced growth. Cancer Res 70:6456–66 [Google Scholar]
  159. Yeh IT, Lenci RE, Qin Y, Buddavarapu K, Ligon AH. et al. 2008. A germline mutation of the KIF1Bβ gene on 1p36 in a family with neural and nonneural tumors. Hum. Genet. 124:279–85 [Google Scholar]
  160. Zeng L, Bai M, Mittal AK, El-Jouni W, Zhou J. et al. 2013. Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell carcinoma. Cancer Res 73:5371–80 [Google Scholar]
  161. Zhang Q, Taulman PD, Yoder BK. 2004. Cystic kidney diseases: All roads lead to the cilium. Physiology 19:225–30 [Google Scholar]
  162. Zhang Q, Yang H. 2012. The roles of VHL-dependent ubiquitination in signaling and cancer. Front. Oncol. 2:35 [Google Scholar]
  163. Zhou MI, Foy RL, Chitalia VC, Zhao J, Panchenko MV. et al. 2005. Jade-1, a candidate renal tumor suppressor that promotes apoptosis. PNAS 102:11035–40 [Google Scholar]
  164. Zhou MI, Wang H, Foy RL, Ross JJ, Cohen HT. 2004. Tumor suppressor von Hippel-Lindau (VHL) stabilization of Jade-1 protein occurs through plant homeodomains and is VHL mutation dependent. Cancer Res 64:1278–86 [Google Scholar]
  165. Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT. 2002. The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. J. Biol. Chem. 277:39887–39898 [Google Scholar]
  166. 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 [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030617-050527
Loading
/content/journals/10.1146/annurev-cancerbio-030617-050527
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error