The von Hippel-Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma

Kim WY, Kaelin WG. Role of VHL Gene mutation in human cancer. J Clin Oncol 2004;22:4991–5004.

Makino Y, Cao R, Svensson K, et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 2001;414:550–4.

Makino Y, Kanopka A, Wilson WJ, Tanaka H, Poellinger L. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3α locus. J Biol Chem 2002;277:32405–8.

Maynard MA, Evans AJ, Hosomi T, Hara S, Jewett MA, Ohh M. Human HIF-3α4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma. FASEB J 2005;19:1396–406.

Ivan M, Kondo K, Yang H, et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001;292:464–8.

Yu F, White S, Zhao Q, Lee F. HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci U S A 2001;98:9630–5.

Jaakkola P, Mole D, Tian Y, et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001;292:468–72.

Masson N, Willam C, Maxwell P, Pugh C, Ratcliffe P. Independent function of two destruction domains in hypoxia-inducible factor-a chains activated by prolyl hydroylation. EMBO J 2001;20:5197–206.

Chan DA, Sutphin PD, Yen SE, Giaccia AJ. Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1α. Mol Cell Biol 2005;25:6415–26.

Epstein A, Gleadle J, McNeill L, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001;107:43–54.

Bruick R, McKnight S. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001;294:1337–40.

Ivan M, Haberberger T, Gervasi DC, et al. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci U S A 2002;99:13459–64.

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 2000;19:4298–309.

Cockman M, Masson N, Mole D, et al. Hypoxia inducible factor-α binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 2000;275:25733–41.

Kamura T, Sato S, Iwain K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. Activation of HIF1α ubiquitination by a reconstituted von Hippel-Lindau tumor suppressor complex. Proc Natl Acad Sci U S A 2000;97:10430–5.

Ohh M, Park CW, Ivan M, et al. Ubiquitination of HIF requires direct binding to the von Hippel-Lindau protein β domain. Nat Cell Biol 2000;2:423–7.

Maxwell P, Weisner M, Chang G-W, et al. The von Hippel-Lindau gene product is necessary for oxygen-dependent proteolysis of hypoxia-inducible factor α subunits. Nature 1999;399:271–5.

Iliopoulos O, Jiang C, Levy AP, Kaelin WG, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A 1996;93:10595–9.

Kaelin WG. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2002;2:673–82.

Hoffman M, Ohh M, Yang H, Klco J, Ivan M, Kaelin WJ. von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 2001;10:1019–27.

Clifford S, Cockman M, Smallwood A, et al. Contrasting effects on HIF-1α regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum Mol Genet 2001;10:1029–38.

Lee S, Nakamura E, Yang H, et al. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 2005;8:155–67.

Okuda H, Hirai S, Takaki Y, 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 1999;263:491–7.

Okuda H, Saitoh K, Hirai S, et al. The von Hippel-Lindau tumor suppressor protein mediates ubiquitination of activated atypical protein kinase C. J Biol Chem 2001;276:43611–7.

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 1997;272:27509–12.

Mandriota SJ, Turner KJ, Davies DR, et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 2002;1:459–68.

Iliopoulos O, Kibel A, Gray S, Kaelin WG. Tumor suppression by the human von Hippel-Lindau gene product. Nat Med 1995;1:822–6.

Gnarra JR, Zhou S, Merrill MJ, et al. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the VHL tumor suppressor gene product. Proc Natl Acad Sci U S A 1996;93:10589–94.

Pause A, Lee S, Lonergan KM, Klausner RD. The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci U S A 1998;95:993–8.

Lieubeau-Teillet B, Rak J, Jothy S, Iliopoulos O, Kaelin W, Kerbel R. von Hippel-Lindau gene-mediated growth suppression and induction of differentiation in renal cell carcinoma cells grown as multicellular tumor spheroids. Cancer Res 1998;58:4957–62.

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 2001;21:865–74.

Krishnamachary B, Zagzag D, Nagasawa H, et al. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, ZFHX1B. Cancer Res 2006;66:2725–31.

Calzada MJ, Esteban MA, Feijoo-Cuaresma M, et al. von Hippel-Lindau tumor suppressor protein regulates the assembly of intercellular junctions in renal cancer cells through hypoxia-inducible factor-independent mechanisms. Cancer Res 2006;66:1553–60.

Kurban G, Hudon V, Duplan E, Ohh M, Pause A. Characterization of a von Hippel-Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res 2006;66:1313–9.

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 U S A 2001;98:1583–8.

Ma W, Tessarollo L, Hong SB, et al. Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene. Cancer Res 2003;63:5320–8.

Rankin EB, Higgins DF, Walisser JA, Johnson RS, Bradfield CA, Haase VH. Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Mol Cell Biol 2005;25:3163–72.

Kim WY, Safran M, Buckley MR, et al. Failure to prolyl hydroxylate hypoxia-inducible factor α phenocopies VHL inactivation in vivo. EMBO J 2006;25:4650–62.

Gnarra J, Ward J, Porter F, et al. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci U S A 1997;94:9102–7.

Rankin EB, Tomaszewski JE, Haase VH. Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res 2006;66:2576–83.

Kondo K, Kim WY, Lechpammer M, Kaelin WG, Jr. Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 2003;1:E83.

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

Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002;1:237–46.

Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM, Klausner RD. The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 2002;1:247–55.

Raval RR, Lau KW, Tran MG, et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol 2005;25:5675–86.

Knauth K, Bex C, Jemth P, Buchberger A. Renal cell carcinoma risk in type 2 von Hippel-Lindau disease correlates with defects in pVHL stability and HIF-1α interactions. Oncogene 2006;25:370–7.

de Paulsen N, Brychzy A, Fournier M-C, 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 U S A 2001;13:1387–92.

Bindra RS, Vasselli JR, Stearman R, Linehan WM, Klausner RD. VHL-mediated hypoxia regulation of cyclin D1 in renal carcinoma cells. Cancer Res 2002;62:3014–9.

Zatyka M, da Silva NF, Clifford SC, et al. Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. Cancer Res 2002;62:3803–11.

Baba M, Hirai S, Yamada-Okabe H, et al. Loss of von Hippel-Lindau protein causes cell density dependent deregulation of cyclin D1 expression through hypoxia-inducible factor. Oncogene 2003;22:2728–38.

Brezis M, Rosen S. Hypoxia of the renal medulla-its implications for disease. N Engl J Med 1995;332:647–55.

Oya M, Ohtsubo M, Takayanagi A, Tachibana M, Shimizu N, Murai M. Constitutive activation of nuclear factor-κB prevents TRAIL-induced apoptosis in renal cancer cells. Oncogene 2001;20:3888–96.

Oya M, Takayanagi A, Horiguchi A, et al. Increased nuclear factor-κB activation is related to the tumor development of renal cell carcinoma. Carcinogenesis 2003;24:377–84.

An J, Fisher M, Rettig MB. VHL expression in renal cell carcinoma sensitizes to bortezomib (PS-341) through an NF-κB-dependent mechanism. Oncogene 2005;24:1563–70.

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

An J, Rettig MB. Mechanism of von Hippel-Lindau protein-mediated suppression of nuclear factor κB activity. Mol Cell Biol 2005;25:7546–56.

Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002;22:7004–14.

Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000;60:1541–5.

Arsham AM, Howell JJ, Simon MC. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J Biol Chem 2003;278:29655–60.

Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG, Jr. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 2003;4:147–58.

Thomas GV, Tran C, Mellinghoff IK, et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 2006;12:122–7.

Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway. J Biol Chem 2002;277:29936–44.

Neckers L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 2002;8:S55–61.

Kim MS, Kwon HJ, Lee YM, et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 2001;7:437–43.

Hudes G, Carducci M, Tomczak J, et al. A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-α (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma (adv RCC). JCO 2006 ASCO Annual Meetings Proceedings Part I 2006;24:LBA4.

Hara S, Nakashiro KI, Klosek SK, Ishikawa T, Shintani S, Hamakawa H. Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1α in human salivary gland cancer cells. Oral Oncol 2006;42:593–8.

Hayashi M, Sakata M, Takeda T, et al. Up-regulation of c-met protooncogene product expression through hypoxia-inducible factor-1α is involved in trophoblast invasion under low-oxygen tension. Endocrinology 2005;146:4682–9.

Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 2003;3:347–61.

Knebelmann B, Ananth S, Cohen H, Sukhatme V. Transforming growth factor α is a target for the von Hippel-Lindau tumor suppressor. Cancer Res 1998;58:226–31.

Smith K, Gunaratnam L, Morley M, Franovic A, Mekhail K, Lee S. Silencing of epidermal growth factor receptor suppresses hypoxia-inducible factor-2-driven VHL−/− renal cancer. Cancer Res 2005;65:5221–30.

Ananth S, Knebelmann B, Gruning W, et al. Transforming growth factor β1 is a target for the von Hippel-Lindau tumor suppressor and a critical growth factor for clear cell renal carcinoma. Cancer Res 1999;59:2210–6.

Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 2003;425:307–11.

Zagzag D, Krishnamachary B, Yee H, et al. Stromal cell-derived factor-1α and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res 2005;65:6178–88.

Koochekpour S, Jeffers M, Wang P, 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 1999;19:5902–12.

Petrella BL, Lohi J, Brinckerhoff CE. Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2α in von Hippel-Lindau renal cell carcinoma. Oncogene 2005;24:1043–52.

Zhuang Z, Bertheau P, Emmert-Buck M, et al. A microscopic dissection technique for archival DNA analysis of specific cell populations in lesions <1 mm in size. Am J Pathol 1995;146:620–5.

Lubensky IA, Gnarra JR, Bertheau P, Walther MM, Linehan WM, Zhuang Z. Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel-Lindau disease patients. Am J Pathol 1996;149:2089–94.

Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 1999;103:159–65.

Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003;111:1287–95.