Beyond the hypoxia-inducible factor-centric tumour suppressor model of von Hippel-Lindau

Current Opinion in Oncology

Volumn 20, Issue 1, 2008, Pages 83-89

  Roberts, Andrew M ^a   Ohh, Michael ^a  

^a UNIVERSITY OF TORONTO   (Canada)

Author keywords

Ciliogenesis; E cadherin; Extracellular matrix; Hypoxia inducible factor; Von Hippel Lindau

Indexed keywords

BETA CATENIN; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 2ALPHA; UBIQUITIN PROTEIN LIGASE E3; UVOMORULIN; VON HIPPEL LINDAU PROTEIN;

CANCER; CANCER INHIBITION; CELL ADHESION; DEREGULATION; EXTRACELLULAR MATRIX; HUMAN; MOLECULAR MECHANICS; NONHUMAN; OXYGEN SENSING; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; THEORETICAL STUDY; TUMOR SUPPRESSOR GENE; VON HIPPEL LINDAU DISEASE;

CADHERINS; CATENINS; EXTRACELLULAR MATRIX; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1; MODELS, BIOLOGICAL; VON HIPPEL-LINDAU DISEASE; VON HIPPEL-LINDAU TUMOR SUPPRESSOR PROTEIN;

EID: 36549044524     PISSN: 10408746     EISSN: None     Source Type: Journal    
DOI: 10.1097/CCO.0b013e3282f310de     Document Type: Review

References (52)

1. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993; 260:1317-1320.
2. Maxwell P, Weisner M, Chang G-W, et al. The von Hippel-Lindau gene product is necessary for oxgyen-dependent proteolysis of hypoxia-inducible factor α subunits. Nature 1999; 399:271-275.
3. Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2002; 2:673-682.
4. Ohh M. Ubiquitin pathway in VHL cancer syndrome. Neoplasia 2006; 8:623-630.
5. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68:820-823.
6. Cockman ME, Masson N, Mole DR, et al. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 2000; 275:25733-25741.
7. Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000; 2:423-427.
8. Okuda H, Hirai S, Takaki Y, et al. Direct interaction of the beta-domain of VHL tumor suppressor protein with the regulatory domain of atypical PKC isotypes. Biochem Biophys Res Commun 1999; 263:491-497.
9. Kuznetsova AV, Meller J, Schnell PO, et al. von Hippel-Lindau protein binds hyperphosphorylated large subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination. Proc Natl Acad Sci U S A 2003; 100:2706-2711.
10. Na X, Duan HO, Messing EM, et al. Identification of the RNA polymerase II subunit hsRPB7 as a novel target of the von Hippel-Lindau protein. EMBO J 2003; 22:4249-4259.
11. Li Z, Na X, Wang D, et al. Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein. J Biol Chem 2002; 277:4656-4662.
12. Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001; 292:464-468.
13. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292:468-472.
14. Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. [see comments]. Cell 2001; 107:43-54.
15. Sufan RI, Ohh M. Role of the NEDD8 modification of Cul2 in the sequential activation of ECV complex. Neoplasia 2006; 8:956-963. This study demonstrated that the oxygen-dependent recognition of HIFα substrates by VHL triggers Rbx1-mediated neddylation of Cul2, which recruits the E2 ubiquitin-conjugating enzyme UbcH5a. This work sheds light on the temporal mechanism by which the ECV degrades HIFα substrates and reveals a critical role for NEDD8 modification of Cul2 in the regulation of the oncogenic HIF pathway.
16. Kondo K, Klco J, Nakamura E, et al. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002; 1:237-246.
17. Maranchie JK, Vasselli JR, Riss J, et al. The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 2002; 1:247-255.
18. Kondo K, Kim WY, Lechpammer M, Kaelin WG Jr. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 2003; 1:E83.
19. Turner KJ, Moore JW, Jones A, et al. Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation. Cancer Res 2002; 62:2957-2961.
20. Li L, Zhang L, Zhang X, et al. Hypoxia-inducible factor linked to differential kidney cancer risk seen with Type 2A and Type 2B VHL Mutations. Mol Cell Biol 2007; 27:5381-5392. This study found that although both Type 2A and Type 2B VHL mutants have a diminished capacity to regulate HIF1α/ HIF2α compared to wild-type VHL, the defect is greater for Type 2B mutants. The resulting increase in stabilized HIF2α in Type 2B mutant-expressing cells as compared to Type 2A mutant-expressing cells accounts for the elevated incidence of RCC caused by Type 2B as compared to Type 2A VHL mutants.
21. 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; 94:9102-9107.
22. Rankin EB, Tomaszewski JE, Haase VH. Renal cyst development in mice with conditional inactivation of the von Hippel-Lindau tumor suppressor. Cancer Res 2006; 66:2576-2583. This work provided a mouse model for the study of VHL disease in the kidney and demonstrated that conditional inactivation of VHL in mice leads to the development of renal cysts but not RCC, suggesting that additional genetic events are required for malignant transformation. In addition, it was observed that inactivation of ARNT, but not HIF1α is sufficient to suppress renal cyst formation, suggesting that another ARNT-binding partner, such as HIF2α, is critical for driving VHL-associated neoplasia.
23. Lubensky IA, Gnarra JR, Bertheau P, 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 1996; 149:2089-2094.
24. 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; 1:459-468.
25. Rankin EB, Higgins DF, Walisser JA, et al. Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Mol Cell Biol 2005; 25:3163-3172.
26. Kim WY, Safran M, Buckley MR, et al. Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo. EMBO J 2006; 25:4650-4662. This work with transgenic mice showed that overexpression of constitutively stable HIFα subunits phenocopies VHL inactivation in vivo, further emphasizing the importance of HIF dysregulation to the pathogenesis of VHL-associated tumours. It was observed that overexpression of both HIF1α and HIF2α phenocopied VHL inactivation to a greater extent than overexpression of HIF2α alone, suggesting that although HIF1α may be dispensable for tumorigenesis, it does contribute to the phenotype of VHL-associated tumours.
27. Maynard MA, Evans AJ, Hosomi T, et al. Human HIF-3alpha4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma. FASEB J 2005; 19:1396-1406.
28. Maynard MA, Qi H, Chung J, et al. Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem 2003; 278:11032-11040.
29. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 2004; 303:1483-1487.
30. Esteban MA, Tran MG, Harten SK, et al. Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res 2006; 66:3567-3575. It was found that loss of VHL function results in downregulated expression of E-cadherin, a critical tumour suppressor of the epithelium, by a mechanism dependent on both HIF1α and HIF2α. This study lends support to the notion that promotion of E-cadherin expression may be critical for VHL-mediated tumour suppression.
31. Evans AJ, Russell RC, Roche O, et al. VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol 2007; 27:157-169. This work found that loss of VHL function results in downregulated expression of E-cadherin, a critical tumour suppressor of the epithelium, via HIF2α-mediated upregulation of SIP1 and Snail, transcriptional repressors of E-cadherin expression. It was shown by immunohistochemical staining of patient tumour samples that loss of VHL correlates with the loss of E-cadherin, suggesting that promotion of E-cadherin expression may be critical for VHL-mediated tumour suppression.
32. 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, and ZFHX1B. Cancer Res 2006; 66:2725-2731. This group found that loss of VHL function results in downregulated expression of E-cadherin, a critical tumour suppressor of the epithelium, via HIF1a-mediated upregulation of TCF3, ZFHX1A and SIP1, transcriptional repressors of E-cadherin expression. This work suggests a role for the promotion of E-cadherin expression in the tumour suppressor function of VHL.
33. Strathdee G. Epigenetic versus genetic alterations in the inactivation of E-cadherin. Semin Cancer Biol 2002; 12:373-379.
34. Brembeck FH, Rosario M, Birchmeier W. Balancing cell adhesion and Wnt signaling, the key role of beta-catenin. Curr Opin Genet Dev 2006; 16:51-59.
35. Nakaigawa N, Yao M, Baba M, et al. Inactivation of von Hippel-Lindau gene induces constitutive phosphorylation of MET protein in clear cell renal carcinoma. Cancer Res 2006; 66:3699-3705. This study revealed that loss of VHL function leads to constitutive activation of MET, which accounts for modified intercellular adherence associated with N-cadherin and β-catenin, as well as increased proliferation in vitro and increased tumorigenesis in vivo in nude mice. These results implicate downregulation of the oncogenic MET signalling pathway as a critical facet of the tumour suppressor mechanism of VHL and identify MET as a possible therapeutic target for the treatment of RCC.
36. Peruzzi B, Athauda G, Bottaro DP. The von Hippel-Lindau tumor suppressor gene product represses oncogenic beta-catenin signaling in renal carcinoma cells. Proc Natl Acad Sci U S A 2006; 103:14531-14536. This study demonstrated that the loss of VHL results in increased HGF-stimulated signalling through the oncogenic β-catenin pathway, leading to altered adherens junctions and increased in-vitro invasiveness of RCC cells, suggesting a critical role for the negative regulation of β-catenin signalling in VHL-mediated tumour suppression.
37. Kaidi A, Williams AC, Paraskeva C. Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol 2007; 9:210-217. This study revealed that stabilization of HIF1α induced by regions of hypoxia in colorectal tumours leads to an association with β-catenin that enhances transcription by HIF1α leading to increased adaptive cell survival under hypoxia.
38. Peruzzi B, Bottaro DP. Beta-catenin signaling: linking renal cell carcinoma and polycystic kidney disease. Cell Cycle 2006; 5:2839-2841.
39. Esteban MA, Harten SK, Tran MG, Maxwell PH. Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein. J Am Soc Nephrol 2006; 17:1801-1806. This work showed that loss of VHL function results in the defect in ciliogenesis and loss of cilia seen in premalignant renal cysts and subsequent malignant RCC tumours by a HIF-dependent mechanism, suggesting a possible role for proper ciliogenesis in VHL-mediated tumour suppression.
40. Lutz MS, Burk RD. Primary cilium formation requires von hippel-lindau gene function in renal-derived cells. Cancer Res 2006; 66:6903-6907. It was found that loss of VHL function results in the defect in ciliogenesis by a HIF-independent mechanism. This study suggests a role for proper ciliogenesis in VHL-mediated tumour suppression.
41. Schermer B, Ghenoiu C, Bartram M, et al. The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. J Cell Biol 2006; 175:547-554. This study suggests a mechanism whereby VHL promotes ciliogenesis and proper cilia function through binding to the Par3-Par6-atypical PKC polarity complex.
42. Thoma CR, Frew IJ, Hoerner CR, et al. pVHL and GSK3beta are components of a primary cilium-maintenance signalling network. Nat Cell Biol 2007; 9:588-595. This study demonstrates that loss of VHL function results in deregulated ciliogenesis by an HIF-independent and GSK3β-dependent mechanism.
43. Mukhopadhyay D, Knebelmann B, Cohen HT, et al. The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol Cell Biol 1997; 17:5629-5639.
44. Li Z, Wang D, Na X, et al. The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity. EMBO J 2003; 22:1857-1867.
45. Hergovich A, Lisztwan J, Barry R, et al. Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat Cell Biol 2003; 5:64-70.
46. Ohh M, Yauch RL, Lonergan KM, et al. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell 1998; 1:959-968.
47. Clifford SC, Cockman ME, Smallwood AC, et al. Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum Mol Genet 2001; 10:1029-1038.
48. Hoffman MA, Ohh M, Yang H, et al. von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 2001; 10:1019-1027.
49. Stickle NH, Chung J, Klco JM, et al. pVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development. Mol Cell Biol 2004; 24:3251-3261.
50. Kurban G, Hudon V, Duplan E, et al. Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res 2006; 66:1313-1319. This work revealed that the increase in microvessel density observed in VHL-associated RCC is primarily due to the lack of extracellular matrix integrity, rather than the aberrant overexpression of HIF-regulated pro-angiogenic factors. It was also shown that the lack of a structured ECM accounts for the elevated capacity of RCC for migration and invasion to a much greater extent than HIF dysregulation.
51. Tang N, Mack F, Haase VH, et al. pVHL function is essential for endothelial extracellular matrix deposition. Mol Cell Biol 2006; 26:2519-2530. This study found that the conditional inactivation of VHL in the endothelium of mice leads to defective vascular fibronectin matrix assembly and results in extensive vascular defects, which likely account for the observed embryonic lethality of the conditional knockout similar to VHL-knockout mice. This work suggests that VHL-mediated promotion of extracellular matrix integrity is important not only for tumour suppression, but also development and maintenance of vascular integrity.
52. Grosfeld A, Stolze IP, Cockman ME, et al. Interaction of hydroxylated collagen IV with the von hippel-lindau tumor suppressor. J Biol Chem 2007; 282:13264-13269. This study characterized a novel interaction between VHL and collagen IV, an integral extracellular matrix component. All tumour-causing VHL mutants tested displayed reduced collagen IV-binding ability compared to wild-type VHL, suggesting a role for this interaction in the tumour suppressor function of VHL.