Abstract
Inactivation of the von Hippel–Lindau tumor suppressor protein (pVHL) has been linked to a variety of tumors such as renal cell carcinoma, pheochromocytomas, and cerebellar hemangioblastomas. The best characterized of its many proposed functions is the ability to downregulate hypoxia-inducible factor-α (HIFα) subunits. Inactivation of pVHL and its ubiquitin ligase activity result in the stabilization of HIFα subunits and the transactivation of HIF target genes. Therapeutic approaches that restore pVHL action or inhibit HIF transcriptional activity remain unrealized and will likely remain a therapeutic challenge. Several pVHL independent pathways that alter HIFα protein stability have recently been identified, and the availability of inhibitors in clinical trials makes these pathways attractive for further investigation.
Keywords
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Akiyama, H., T. Tanaka, et al (2004). “Inhibition of ocular angiogenesis by an adenovirus carrying the human von Hippel-Lindau tumor-suppressor gene in vivo”. Invest Ophthalmol Vis Sci 45(5): 1289–96.
Atkins, M.B., M. Hidalgo, et al (2004). “Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma”. J Clin Oncol 22(5): 909–18.
Bai, C., P. Sen, et al (1996). “SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box.” Cell 86(2): 263–74.
Benjamin, L.E., D. Golijanin, et al (1999). “Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal”. J Clin Invest 103(2): 159–65.
Bergers, G. and L.E. Benjamin (2003). “Tumorigenesis and the angiogenic switch”. Nat Rev Cancer 3(6): 401–10.
Bergers, G., S. Song, et al (2003). “Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors.” J Clin Invest 111(9): 1287–95.
Blankenship, C., J.G. Naglich, et al (1999). “Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity.” Oncogene 18(8): 1529–35.
Bolden, J.E., M.J. Peart, et al (2006). “Anticancer activities of histone deacetylase inhibitors.” Nat Rev Drug Discov 5(9): 769–84.
Brugarolas, J.B., F. Vazquez, et al (2003). “TSC2 regulates VEGF through mTOR-dependent and -independent pathways.” Cancer Cell 4(2): 147–58.
Bruick, R.K.and S.L. McKnight (2001). “A conserved family of prolyl-4-hydroxylases that modify HIF.” Science 294(5545): 1337–40.
Bukowski, R.M., F.F. Kabbinavar, et al (2007). “Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer.” J Clin Oncol 25(29): 4536–41.
Caldwell, M.C., C. Hough, et al (2002). “Serial analysis of gene expression in renal carcinoma cells reveals VHL-dependent sensitivity to TNFalpha cytotoxicity.” Oncogene 21(6): 929–36.
Castillo, M., A. Petit, et al (2004). “C-kit expression in sarcomatoid renal cell carcinoma: potential therapy with imatinib.” J Urol 171(6 Pt 1): 2176–80.
Cockman, M.E., N. Masson, et al (2000). “Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel–Lindau tumor suppressor protein.” J Biol Chem 275(33): 25733–41.
Costa, L.J.and H.A. Drabkin (2007). “Renal cell carcinoma: new developments in molecular biology and potential for targeted therapies.” Oncologist 12(12): 1404–15.
de Paulsen, N., A. Brychzy, et al (2001). “Role of transforming growth factor-alpha in von Hippel-Lindau (VHL) (−/−) clear cell renal carcinoma cell proliferation: a possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis.” Proc Natl Acad Sci U S A 98(4): 1387–92.
Dham, A.and A.Z. Dudek (2007). “Sequential therapy with sorafenib and sunitinib in renal cell carcinoma.” J Clin Oncol, ASCO Annual Meeting Proceedings Part I 25(No. 18S (June 20 Supplement)): 5106.
Duan, D.R., A. Pause, et al (1995). “Inhibition of transcription elongation by the VHL tumor suppressor protein.” Science 269(5229): 1402–6.
Epstein, A.C., J.M. Gleadle, et al (2001). “C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.” Cell 107(1): 43–54.
Escudier, B., T. Eisen, et al (2007). “Sorafenib in advanced clear-cell renal-cell carcinoma.” N Engl J Med 356(2): 125–34.
Escudier, B., A. Pluzanska, et al (2007). “Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial.” Lancet 370(9605): 2103–11.
Fox, S.B., H. Turley, et al (2004). “Phosphorylated KDR is expressed in the neoplastic and stromal elements of human renal tumours and shuttles from cell membrane to nucleus.” J Pathol 202(3): 313–20.
Galban, S., J. Fan, et al (2003). “von Hippel–Lindau protein-mediated repression of tumor necrosis factor alpha translation revealed through use of cDNA arrays.” Mol Cell Biol 23(7): 2316–28.
George, P., P. Bali, et al (2004). “Cotreatment with 17-allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3.” Cancer Res 64(10): 3645–52.
Gong, K., N. Zhang, et al (2006). “Coexpression of erythopoietin and erythopoietin receptor in sporadic clear cell renal cell carcinoma.” Cancer Biol Ther 5(6): 582–5.
Gradin, K., J. McGuire, et al (1996). “Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor.” Mol Cell Biol 16(10): 5221–31.
Gunaratnam, L., M. Morley, et al (2003). “Hypoxia inducible factor activates the transforming growth factor-alpha/epidermal growth factor receptor growth stimulatory pathway in VHL (−/−) renal cell carcinoma cells.” J Biol Chem 278(45): 44966–74.
Hacein-Bey-Abina, S., C. Von Kalle, et al (2003). “LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.” Science 302(5644): 415–9.
Hayashi, M., M. Sakata, et al (2005). “Up-regulation of c-met protooncogene product expression through hypoxia-inducible factor-1alpha is involved in trophoblast invasion under low-oxygen tension.” Endocrinology 146(11): 4682–9.
Hergovich, A., J. Lisztwan, et al (2003). “Regulation of microtubule stability by the von Hippel–Lindau tumour suppressor protein pVHL.” Nat Cell Biol 5(1): 64–70.
Hergovich, A., J. Lisztwan, et al (2006). “Priming-dependent phosphorylation and regulation of the tumor suppressor pVHL by glycogen synthase kinase 3.” Mol Cell Biol 26(15): 5784–96.
Hood, J.D., M. Bednarski, et al (2002). “Tumor regression by targeted gene delivery to the neovasculature.” Science 296(5577): 2404–7.
Huang, L.E., J. Gu, et al (1998). “Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway.” Proc Natl Acad Sci U S A 95(14): 7987–92.
Hudes, G., M. Carducci, et al (2007). “Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.” N Engl J Med 356(22): 2271–81.
Hudson, C.C., M. Liu, et al (2002). “Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin.” Mol Cell Biol 22(20): 7004–14.
Hutson, T.E., I.D. Davis, et al (2007). “Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): Interim results of a phase II randomized discontinuation trial (RDT).” J Clin Oncol, ASCO Annual Meeting Proceedings 25 (June 20 Supplement): 5031.
Iliopoulos, O., A. Kibel, et al (1995). “Tumour suppression by the human von Hippel–Lindau gene product.” Nat Med 1(8): 822–6.
Iliopoulos, O., A.P. Levy, et al (1996). “Negative regulation of hypoxia-inducible genes by the von Hippel–Lindau protein.” Proc Natl Acad Sci U S A 93(20): 10595–9.
Iliopoulos, O., M. Ohh, et al (1998). “pVHL19 is a biologically active product of the von Hippel–Lindau gene arising from internal translation initiation.” Proc Natl Acad Sci U S A 95(20): 11661–6.
Isaacs, J.S., Y.J. Jung, et al (2002). “Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway.” J Biol Chem 277(33): 29936–44.
Isaacs, J.S., W. Xu, et al (2003). “Heat shock protein 90 as a molecular target for cancer therapeutics.” Cancer Cell 3(3): 213–7.
Ivan, M., T. Haberberger, et al (2002). “Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor.” Proc Natl Acad Sci U S A 99(21): 13459–64.
Ivan, M., K. Kondo, et al (2001). “HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.” Science 292(5516): 464–8.
Jaakkola, P., D.R. Mole, et al (2001). “Targeting of HIF-alpha to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.” Science 292(5516): 468–72.
Jeong, J.W., M.K. Bae, et al (2002). “Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation.” Cell 111(5): 709–20.
Jiang, Y., W. Zhang, et al (2003). “Gene expression profiling in a renal cell carcinoma cell line: dissecting VHL and hypoxia-dependent pathways.” Mol Cancer Res 1(6): 453–62.
Kaelin, W.G. (2005). “von Hippel–Lindau-associated malignancies: Mechanisms and therapeutic opportunities.” Drug Discov Today 2(2): 225–31.
Kaelin, W.G., Jr. (2002). “Molecular basis of the VHL hereditary cancer syndrome.” Nat Rev Cancer 2(9): 673–82.
Kamura, T., M.N. Conrad, et al (1999). “The Rbx1 subunit of SCF and VHL E3 ubiquitin ligase activates Rub1 modification of cullins Cdc53 and Cul2.” Genes Dev 13(22): 2928–33.
Kamura, T., S. Sato, et al (2000). “Activation of HIF1alpha ubiquitination by a reconstituted von Hippel–Lindau (VHL) tumor suppressor complex.” Proc Natl Acad Sci U S A 97(19): 10430–5.
Kibel, A., O. Iliopoulos, et al (1995). “Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C.” Science 269(5229): 1444–6.
Kim, M.S., H.J. Kwon, et al (2001). “Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes.” Nat Med 7(4): 437–43.
Kim, W.Y. and W.G. Kaelin (2004). “Role of VHL gene mutation in human cancer.” J Clin Oncol 22(24): 4991–5004.
Kim, W.Y., M. Safran, et al (2006). “Failure to prolyl hydroxylate HIFalpha phenocopies VHL inactivation in vivo.” Embo J 25(19): 4650–62.
Kishida, T., T.M. Stackhouse, et al (1995). “Cellular proteins that bind the von Hippel-Lindau disease gene product: mapping of binding domains and the effect of missense mutations.” Cancer Res 55(20): 4544–8.
Knebelmann, B., S. Ananth, et al (1998). “Transforming growth factor alpha is a target for the von Hippel–Lindau tumor suppressor.” Cancer Res 58(2): 226–31.
Knudson, A.G., Jr. (1971). “Mutation and cancer: statistical study of retinoblastoma.” Proc Natl Acad Sci U S A 68(4): 820–3.
Kondo, K., W.Y. Kim, et al (2003). “Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth.” PLoS Biol 1(3): E83.
Kondo, K., J. Klco, et al (2002). “Inhibition of HIF is necessary for tumor suppression by the von Hippel–Lindau protein.” Cancer Cell 1(3): 237–46.
Kong, X., Z. Lin, et al (2006). “Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1{alpha}.” Mol Cell Biol 26(6): 2019–28.
Kourembanas, S., R.L. Hannan, et al (1990). “Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells.” J Clin Invest 86(2): 670–4.
Kruger, S., K. Sotlar, et al (2005). “Expression of KIT (CD117) in renal cell carcinoma and renal oncocytoma.” Oncology 68(2–3): 269–75.
Latif, F., K. Tory, et al (1993). “Identification of the von Hippel-Lindau disease tumor suppressor gene.” Science 260(5112): 1317–20.
Lee, S., D.Y. Chen, et al (1996). “Nuclear/cytoplasmic localization of the von Hippel-Lindau tumor suppressor gene product is determined by cell density.” Proc Natl Acad Sci U S A 93(5): 1770–5.
Lee, S., M. Neumann, et al (1999). “Transcription-dependent nuclear-cytoplasmic trafficking is required for the function of the von Hippel–Lindau tumor suppressor protein.” Mol Cell Biol 19(2): 1486–97.
Lee, Y.S., A.O. Vortmeyer, et al (2005). “Coexpression of erythropoietin and erythropoietin receptor in von Hippel–Lindau disease-associated renal cysts and renal cell carcinoma.” Clin Cancer Res 11(3): 1059–64.
Linehan, W.M., P.A. Pinto, et al (2007). “Identification of the genes for kidney cancer: opportunity for disease-specific targeted therapeutics.” Clin Cancer Res 13(2 Pt 2): 671s–679s.
Liu, Y.V., J.H. Baek, et al (2007). “RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha.” Mol Cell 25(2): 207–17.
Lolkema, M.P., M.L. Gervais, et al (2005). “Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain.” J Biol Chem 280(23): 22205–11.
Lonergan, K.M., O. Iliopoulos, et al (1998). “Regulation of hypoxia-inducible mRNAs by the von Hippel–Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2.” Mol Cell Biol 18(2): 732–41.
Lynch, T.J., D.W. Bell, et al (2004). “Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.” N Engl J Med 350(21): 2129–39.
Mabjeesh, N.J., D. Escuin, et al (2003). “2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF.” Cancer Cell 3(4): 363–75.
Mabjeesh, N.J., D.E. Post, et al (2002). “Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells.” Cancer Res 62(9): 2478–82.
Mandriota, S.J., K.J. Turner, et al (2002). “HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron.” Cancer Cell 1(5): 459–68.
Maranchie, J.K., J.R. Vasselli, et al (2002). “The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma.” Cancer Cell 1(3): 247–55.
Masson, N., C. Willam, et al (2001). “Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation.” Embo J 20(18): 5197–206.
Maxwell, P.H., M.S. Wiesener, et al (1999). “The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.” Nature 399(6733): 271–5.
Melillo, G. (2007). “Hypoxia-inducible factor 1 inhibitors.” Methods Enzymol 435: 385–402.
Mendez, R., M.G. Myers, Jr., et al (1996). “Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation, and PHAS-I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3-kinase.” Mol Cell Biol 16(6): 2857–64.
Meyuhas, O. (2000). “Synthesis of the translational apparatus is regulated at the translational level.” Eur J Biochem 267(21): 6321–30.
Motzer, R.J., R. Amato, et al (2003). “Phase II trial of antiepidermal growth factor receptor antibody C225 in patients with advanced renal cell carcinoma.” Invest New Drugs 21(1): 99–101.
Motzer, R.J., T.E. Hutson, et al (2007). “Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.” N Engl J Med 356(2): 115–24.
Nakaigawa, N., M. Yao, et al (2006). “Inactivation of von Hippel–Lindau gene induces constitutive phosphorylation of MET protein in clear cell renal carcinoma.” Cancer Res 66(7): 3699–705.
Nicol, D., S.I. Hii, et al (1997). “Vascular endothelial growth factor expression is increased in renal cell carcinoma.” J Urol 157(4): 1482–6.
Ohh, M., C.W. Park, et al (2000). “Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel–Lindau protein.” Nat Cell Biol 2(7): 423–7.
Paez, J.G., P.A. Janne, et al (2004). “EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.” Science 304(5676): 1497–500.
Pause, A., S. Lee, et al (1997). “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 U S A 94(6): 2156–61.
Pennacchietti, S., P. Michieli, et al (2003). “Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene.” Cancer Cell 3(4): 347–61.
Pisters, L.L., A.K. el-Naggar, et al (1997). “C-met proto-oncogene expression in benign and malignant human renal tissues.” J Urol 158(3 Pt 1): 724–8.
Qian, D.Z., S.K. Kachhap, et al (2006). “Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha.” Cancer Res 66(17): 8814–21.
Rahmani, M., C. Yu, et al (2003). “Coadministration of the heat shock protein 90 antagonist 17-allylamino-17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells.” Cancer Res 63(23): 8420–7.
Rankin, E.B., D.F. Higgins, et al (2005). “Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel–Lindau disease-associated vascular tumors in mice.” Mol Cell Biol 25(8): 3163–72.
Rankin, E.B., J.E. Tomaszewski, et al (2006). “Renal cyst development in mice with conditional inactivation of the von Hippel–Lindau tumor suppressor.” Cancer Res 66(5): 2576–83.
Rapisarda, A., B. Uranchimeg, et al (2004). “Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications.” Cancer Res 64(4): 1475–82.
Rixe, O., R.M. Bukowski, et al (2007). “Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study.” Lancet Oncol 8(11): 975–84.
Ronnen, E.A., G.V. Kondagunta, et al (2006). “A phase II trial of 17-(Allylamino)-17-demethoxygeldanamycin in patients with papillary and clear cell renal cell carcinoma.” Invest New Drugs 24(6): 543–6.
Rosenwald, I.B., R. Kaspar, et al (1995). “Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels.” J Biol Chem 270(36): 21176–80.
Rowinsky, E.K., G.H. Schwartz, et al (2004). “Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer.” J Clin Oncol 22(15): 3003–15.
Sakaeda, T., N. Okamura, et al (2005). “EGFR mRNA is upregulated, but somatic mutations of the gene are hardly found in renal cell carcinoma in Japanese patients.” Pharm Res 22(10): 1757–61.
Schmidt, L., F.M. Duh, et al (1997). “Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.” Nat Genet 16(1): 68–73.
Schoenfeld, A., E.J. Davidowitz, et al (1998). “A second major native von Hippel–Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor.” Proc Natl Acad Sci U S A 95(15): 8817–22.
Seizinger, B.R., G.A. Rouleau, et al (1988). “Von Hippel–Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma.” Nature 332(6161): 268–9.
Semenza, G.L. (2003). “Targeting HIF-1 for cancer therapy.” Nat Rev Cancer 3(10): 721–32.
Sengupta, S., J.C. Cheville, et al (2006). “Rare expression of KIT and absence of KIT mutations in high grade renal cell carcinoma.” J Urol 175(1): 53–6.
Shaw, R.J. and L.C. Cantley (2006). “Ras, PI(3)K and mTOR signalling controls tumour cell growth.” Nature 441(7092): 424–30.
Solit, D.B., S.P. Ivy, et al (2007). “Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.” Clin Cancer Res 13(6): 1775–82.
Stebbins, C.E., W.G. Kaelin, Jr., et al (1999). “Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function.” Science 284(5413): 455–61.
Takahashi, A., H. Sasaki, et al (1994). “Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis.” Cancer Res 54(15): 4233–7.
Tanimoto, K., Y. Makino, et al (2000). “Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel–Lindau tumor suppressor protein.” Embo J 19(16): 4298–309.
Thomas, G.V. (2006). “mTOR and cancer: Reason for dancing at the crossroads?” Curr Opin Genet Dev 16(1): 78–84.
Thomas, G.V., C. Tran, et al (2006). “Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer.” Nat Med 12(1): 122–7.
Treins, C., S. Giorgetti-Peraldi, et al (2002). “Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway.” J Biol Chem 277(31): 27975–81.
Vaishampayan, U., E. Sausville, et al (2007). “Phase I trial of intravenous 17-allylaminogeldanamycin (A) and oral sorafenib (B) in pretreated advanced malignancy: Plasma Hsp90α induction correlates with clinical benefit.” Am Soc Clin Oncol 25(185): 3531.
Vuky, J., C. Isacson, et al (2006). “Phase II trial of imatinib (Gleevec) in patients with metastatic renal cell carcinoma.” Invest New Drugs 24(1): 85–8.
Westenfelder, C. and R.L. Baranowski (2000). “Erythropoietin stimulates proliferation of human renal carcinoma cells.” Kidney Int 58(2): 647–57.
Wiesener, M.S., P. Munchenhagen, et al (2007). “Erythropoietin gene expression in renal carcinoma is considerably more frequent than paraneoplastic polycythemia.” Int J Cancer 121(11): 2434–42.
Yamauchi, M., H. Kataoka, et al (2004). “Hepatocyte growth factor activator inhibitor types 1 and 2 are expressed by tubular epithelium in kidney and down-regulated in renal cell carcinoma.” J Urol 171(2 Pt 1): 890–6.
Yang, J.C., L. Haworth, et al (2003). “A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.” N Engl J Med 349(5): 427–34.
Yu, F., S.B. White, et al (2001). “HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation.” Proc Natl Acad Sci U S A 98(17): 9630–5.
Zigeuner, R., M. Ratschek, et al (2005). “Kit (CD117) immunoreactivity is rare in renal cell and upper urinary tract transitional cell carcinomas.” BJU Int 95(3): 315–8.
Zimmer, M., D. Doucette, et al (2004). “Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL−/− tumors.” Mol Cancer Res 2(2): 89–95.
Author information
Authors and Affiliations
Corresponding author
Editor information
Rights and permissions
Copyright information
© 2009 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Kim, W.Y., Kaelin, W.G. (2009). Modulation of Protein Stability: Targeting the VHL Pathway. In: Rubin, E., Sakamoto, K. (eds) Modulation of Protein Stability in Cancer Therapy. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69147-3_4
Download citation
DOI: https://doi.org/10.1007/978-0-387-69147-3_4
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-69143-5
Online ISBN: 978-0-387-69147-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)