Oxygen sensing in cancer

Annals of Medicine

Volumn 35, Issue 6, 2003, Pages 380-390

  Pugh, Christopher W ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Angiogenesis; Cancer; Clonal selection; HIF; Hydroxylase; Hypoxia; Von Hippel Lindau

Indexed keywords

HYPOXIA INDUCIBLE FACTOR 1; OXYGEN; OXYGENASE; TUMOR SUPPRESSOR PROTEIN;

ANGIOGENESIS; CANCER; CARCINOGENESIS; ENERGY YIELD; GENE INDUCTION; GENE MUTATION; GENETIC REGULATION; GLYCOLYSIS; HYPOXIA; IRON METABOLISM; OXYGEN SUPPLY; PHENOTYPE; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; VON HIPPEL LINDAU DISEASE;

ANIMALS; CELL HYPOXIA; DNA-BINDING PROTEINS; GENES, TUMOR SUPPRESSOR; HIPPEL-LINDAU DISEASE; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; NEOPLASMS; NUCLEAR PROTEINS; OXYGEN; TRANSCRIPTION FACTORS; TUMOR SUPPRESSOR PROTEINS;

EID: 0141924556     PISSN: 07853890     EISSN: None     Source Type: Journal    
DOI: 10.1080/07853890310017062     Document Type: Review

References (109)

1. Raleigh JA, Chou S-C, Arteel GE, Horsman MR. Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. Radiat Res 1999; 151: 580-89.
2. Kennedy AS, Raleigh JA, Perez GM, Calkins DP, Thrall DE, Novotny DB, et al. Proliferation and hypoxia in human squamous cell carcinoma of the cervix: first report of combined immunohistochemical assays. Int J Radiat Oncol Biol Phys 1997; 37: 897-905.
3. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997; 38: 285-9.
4. Gatenby RA, Kessler HB, Rosenblum JS, Coia LR, Moldofsky PJ, Hartz WH, et al. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 1988; 14: 831-38.
5. Airley RE, Loncaster J, Raleigh JA, Harris AL, Davidson SE, Hunter RD, et al. GLUT-1 and CAIX as intrinsic markers of hypoxia in carinoma of the cervix: relationship to pimonidazole binding. Int J Cancer 2003; 104: 85-91.
6. Olive PL, Vikse CM, Durand RE. Hypoxic fractions measured in murine tumors and normal tissues using the comet assay. Int J Radiat Oncol Biol Phys 1994; 29: 487-91.
7. Warburg O. The metabolism of tumours London: Arnold Constable; 1930.
8. Warburg O. On the origin of cancer cells. Science 1956; 123: 309-14.
9. Wang GL, Semenza GL. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 1993; 268: 21513-18.
10. Wang GL, Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood 1993; 82: 3610-15.
11. Maxwell PH, Pugh CW, Ratcliffe PJ. Inducible operation of the erythropoietin 3′ enhancer in multiple cell lines: evidence for a widespread oxygen sensing mechanism. Proc Natl Acad Sci USA 1993; 90: 2423-27.
12. Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 1993; 90: 4304-08.
13. Firth JD, Ebert BL, Pugh CW, Ratcliffe PJ. Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoeitin 3' enhancer. Proc Natl Acad Sci USA 1994; 91: 6496-500.
14. Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev 2000; 14: 1983-91.
15. 2 tension. Proc Natl Acad Sci USA 1995; 92: 5510-14.
16. Reyes H, Reisz-Porszasz S, Hankinson O. Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. Science 1992; 256: 1193-95.
17. Drutel G, Kathmann M, Heron A, Schwartz J-C, Arrang J-M. Cloning and selective expression in brain and kidney of ARNT2 homologous to the Ah receptor nuclear translocator (ARNT). Biochem Biophys Res Commun 1996; 225: 333-39.
18. Tian H, McKnight SL, Russell DW. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively-expressed in endothelial cells. Genes Dev 1997; 11: 72-82.
19. Flamme I, Fröhlich T, von Reutern M, Kappel A, Damert A, Risau W. HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1a and developmentally expressed in blood vessels. Mech Dev 1997; 63: 51-60.
20. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1a regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 1997; 94: 4273-78.
21. Gu YZ, Moran SM, Hogenesch JB, Wartman L, Bradfield CA. Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. Gene Expr 1998; 7: 205-13.
22. Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 2001; 414: 550-54.
23. Gu Y-Z, Hogenesch JB, Bradfield CA. The PAS superfamily: sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol 2000; 40: 519-61.
24. Bacon NC, Wappner P, O'Rourke JF, Bartlett SM, Shilo B, Pugh CW, et al. Regulation of the Drosophila Basic helix-loop-helix PAS protein Sima by hypoxia: functional evidence for homology with mammalian HIF-1 alpha. Biochem Biophys Res Commun 1998; 249: 811-6.
25. Lavista-Llanos S, Centanin L, Irisarri M, Russo DM, Gleadle JM, Bocca SN, et al. Control of the hypoxic reponse in Drosophila melanogaster by the basic helix-loop-helix PAS protein Similar. Mol Cell Biol 2002; 22: 6842-53.
26. Sonnenfeld M, Ward M, Nystrom G, Mosher J, Stahl S, Crews S. The Drosophila tango gene ecodes a bHLH-PAS protein that is orthologous to mammalian Arnt and controls CNS midline and tracheal development. Development 1997; 124: 4571-82.
27. Powell-Coffman JA, Bradfield CA, Wood WB. Caenorhabditis elegans orthologs of the aryl hydrocarbon receptor and its heterodimerization partner the aryl hydrocarbon receptor nuclear translocator. Proc Natl Acad Sci USA 1998; 95: 2844-49.
28. Epstein ACR, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, et al. C. elegans EGL-9 and mammalian homologues define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001; 107: 43-54.
29. Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, et al. Hypoxia inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA 1997; 94: 8104-09.
30. Carmeliet P, Dor Y, Herbert J-M, Fukumura D, Brusselmans K, Dewerchin M, et al. Role of HIF-1a in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 1998; 394: 485-90.
31. Ryan HE, Lo J, Johnson RS. HIF-1a is required for solid tumor formation and embryonic vascularization. EMBO J 1998; 17: 3005-15.
32. Ryan HE, Poloni M, McNulty W, Elson D, Gassmann M, Arbeit JM, et al. Hypoxia-inducible factor-1a is a positive factor in solid tumor growth. Cancer Res 2000; 60: 4010-15.
33. Kung AL, Wang S, Klco JM, Kaelin WG, Livingston DM. Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med 2000; 6: 1335-40.
34. Hopfl G, Wenger RH, Ziegler U, Stallmach T, Gardelle O, Achermann R, et al. Rescue of hypoxia-inducible factor-1a-deficient tumor growth by wild-type cells is independent of vascular endothelial growth factor. Cancer Res 2002; 62: 2962-70.
35. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor la in common human cancers and their metastases. Cancer Res 1999; 59: 5830-5.
36. Talks K, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, et al. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 2000; 157: 411-21.
37. Dachs GU, Patterson AV, Firth JD, Ratcliffe PJ, Townsend KMS, Stratford IJ, et al. Targeting gene expression to Hypoxic tumour cells. Nat Med 1997; 3: 515-20.
38. Harris A. Hypoxia-a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2: 38-47.
39. Wenger RH. Mammalian oxygen sensing, signalling and gene regulation. J Exp Biol 2000; 203: 1253-63.
40. Zelzer E, Levy Y, Kahana C, Shilo B-Z, Rubinstein M, Cohen B. Insulin induces transcription of tatget genes through the hypoxia-inducible factor HIF-1a/ARNT. EMBO J 1998; 17: 5085-94.
41. Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 1999; 59: 3915-8.
42. Hellwig-Buergel T, Rutkowski T, Metzen E, Fandrey E, Jelkmann W. Interleukin-1b and tumor necrosis factor-a stimulate DNA binding of hypoxia inducible factor-1. Blood 1999; 94: 1561-67.
43. Richard DE, Berra E, Pouyssegur J. Non-hypoxic pathway mediates the induction of hypoxia inducible factor 1 alpha (HIF-1 {alpha}) in vascular smooth muscle cells. J Biol Chem 2000; 275: 26765-71.
44. Sogawa K, Numayama-Tsuruta K, Ema M, Abe M, Abe H, Fujii-Kuriyama Y. Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia. Proc Natl Acad Sci USA 1998; 95: 7368-73.
45. Huang LE, Willmore WG, Gu J, Goldberg MA, Bunn HF. Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide. J Biol Chem 1999; 274: 9038-44.
46. Sandau KB, Zhou J, Kietzmann T, Brune B. Regulation of the hypoxia-inducible factor 1a by the inflammatory mediators nitric oxide and tumor necrosis factor-a in contrast to desferroxamine and phenylarsine oxide. J Biol Chem 2001; 276: 39805-11.
47. Brusselmans K, Bono F, Maxwell P, Dor Y, Dewerchin M, Collen D, et al. Hypoxia-inducible factor-2a (HIF-2a) is involved in the apoptotic response to hypoglycemia but not to hypoxia. J Biol Chem 2001; 276: 39192-6.
48. Pugh CW, O'Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ. Activation of hypoxia inducible factor-1; definition of regulatory domains within the a subunit. J Biol Chem 1997; 272: 11205-14.
49. Jiang B-H, Zheng JZ, Leung SW, Roe R, Semenza GL. Transactivation and inhibitory domains of hypoxia-inducible factor 1a. Modulation of transcriptional activity by oxygen tension. J Biol Chem 1997; 272: 19253-60.
50. O'Rourke JF, Tian Y-M, Ratcliffe PJ, Pugh CW. Oxygen-regulated and transactivating domains in endothelial PAS protein 1: comparison with hypoxia inducible factor-1a. J Biol Chem 1999; 274: 2060-71.
51. Salceda S, Caro J. Hypoxia-inducible factor 1a (HIF-1a) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. J Biol Chem 1997; 272: 22642-47.
52. Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxia-inducible factor 1a is mediated by an oxygen-dependent domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 1998; 95: 7987-92.
53. Kallio PJ, Wilson WJ, O'Brien S, Makino Y, Poellinger L. Regulation of the hypoxia-inducible transcription factor 1a by the ubiquitin-proteasome pathway. J Biol Chem 1999; 274: 6519-25.
54. Srinivas V, Zhang LP, Zhu XH, Caro J. Characterization of an oxygen/redox-dependent degradation domain of hypoxia-inducible factor alpha (HIF-alpha) proteins. Biochem Biophys Res Commun 1999; 260: 557-61.
55. Richard DE, Berra E, Gothie E, Roux D, Pouysségur J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1a (HIF-1a) and enhance the transcriptional activity of HIF-1. J Biol Chem 1999; 274: 32631-37.
56. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu M-M, et al. Modulation of hypoxia-inducible factor 1a 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: 1541-45.
57. Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 2000; 14: 391-96.
58. Maxwell PH, Wiesener MS, Chang G-W, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399: 271-75.
59. Ohh M, Park CW, Ivan M, Huffman MA, Kim TY, Huang LE, 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: 423-27.
60. Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, et al. Hypoxia inducible factor-a binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 2000; 275: 25733-41.
61. 2 sensing. Science 2001; 292: 464-8.
62. 2-regulated prolyl hydroxylation. Science 2001; 292: 468-72.
63. Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. Independent function of two destruction domains in hypoxia-inducible factor-a chains activated by prolyl hydroxylation. EMBO J 2001; 20: 5197-206.
64. Min J-H, Yang H, Ivan M, Gertler F, Kaelin WGJ, Pavletich NP. Structure of an HIF-1a-pVHL complex: hydroxyproline recognition in signaling. Science 2002; 296: 1886-9.
65. Hon WC, Wilson MI, Harlos K, Claridge TD, Schofield CJ, Pugh CW, et al. Structural basis for the recognition of hydroxyproline in HIF-1a by pVHL. Nature 2002; 417: 975-78.
66. Myllyharju J, Kivirikko KI. Characterization of the iron-and 2-oxoglutarate-binding sites of human prolyl 4-hydroxylase. EMBO J 1997; 16: 1173-80.
67. Schofield CJ, Zhang Z. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Curr Opin Struct Biol 1999; 9: 722-31.
68. Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1a and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 2001; 15: 2675-86.
69. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 2002; 295: 858-61.
70. Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 2002; 16: 1466-71.
71. Hewitson KS, McNeill LA, M.V. R, Tian Y-M, Bullock AN, Welford RW, 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 2002; 277: 26351-55.
72. McNeill LA, Hewitson KS, Claridge TD, Seibel JF, Horsfall LE, Schofield CJ. Hypoxia-inducible factor asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at the b-carbon of asparagine-803. J Biochem 2002; 367: 571-75 [Research Communication].
73. Lee C, Kim SJ, Jeong DG, Lee SI, Ryu SE. Structure of human FIH-1 reveals a unique active site pocket and interaction sites for HIF-1 and von Hippel-Lindau. J Biol Chem 2003; 278: 7558-63.
74. Elkins JM, Hewitson KS, McNeill LA, Seibel JF, Schlemminger I, Pugh CW, et al. Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1a. J Biol Chem 2003; 278: 1802-06.
75. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000; 287: 848-51.
76. Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000; 26: 268-70.
77. Astuti D, Latif F, Dallol A, Dahia PLM, Douglas F, George E, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001; 69: 49-54.
78. Gimenez-Roqueplo A-P, Favier J, Rustin P, Mourad J-J, Plouin P-F, Corvol P, et al. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 2001; 69: 1186-97.
79. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002; 30: 406-10.
80. Le NTV, Richardson DR. The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim Biophys Acta 2002; 1603: 31-46.
81. Knowles HJ, Raval RR, Harris AL, Ratcliffe PJ. Effect of ascorbate on the activity of hypoxia inducible factor (HIF) in cancer cells. Cancer Res 2003; 63: 1764-68.
82. Kaelin WG, Maher ER. The VHL tumour-suppressor gene paradigm. Trends Genet 1998; 14: 423-26.
83. Knudson AG. Chasing the cancer demon. Annu Rev Genet 2000; 34: 1-19.
84. Latif F, Tory K, Gnarra J, Yao M, Duh F-M, Orcutt ML, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993; 260: 1317-20.
85. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet 1994; 7: 85-90.
86. 19 is a biologically active product of the von Hippel-Lindau gene arising from internal translation initiation. Proc Natl Acad Sci USA 1998; 95: 11661-66.
87. Schoenfeld A, Davidowitz EJ, Burk RD. 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 1998; 95: 8817-22.
88. Iliopoulos O, Levy AP, Jiang C, Kaelin WG, Jr, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci USA 1996; 93: 10595-99.
89. Kibel A, Iliopoulos O, DeCaprio JA, Kaelin WG, Jr. Binding of the von Hippel-Lindau tumor suppressor protein to elongin B and C. Science 1995; 269: 1444-46.
90. Lonergan KM, Iliopoulos O, Ohh M, Kamura T, Conaway RC, Weliky Conaway J, et al. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Molecular and Cell Biol 1998; 18: 732-41.
91. 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 1999; 96: 9533-38.
92. Ohta T, Michel JJ, Schottelius AJ, Xiong Y. ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Mol Cell 1999; 3: 535-41.
93. Ivan M, Kaelin WG. The von Hippel-Lindau tumor suppressor protein. Curr Opin Genet Dev 2001; 11: 27-34.
94. Huffman MA, Ohh M, Yang H, Klco JM, Ivan M, Kaelin WGJ. von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum Mol Genet 2001; 10: 1019-27.
95. Clifford SC, Cockman ME, Smallwood AC, Mole DR, Woodward ER, Maxwell PH, et al. Contrasting effects on HIF-1a regulation by disease-causing pVHL mutations correlate with patterns of tumpurigenesis in von Hippel-Lindau disease. Hum Mol Genet 2001; 10: 1029-38.
96. Kondo K, Kico J, Nakamura E, Lechpammer M, Kaelin WGJ. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002; 1: 237-46.
97. Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM, et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor funtion in the nephron. Cancer Cell 2002; 1: 459-68.
98. Wykoff CC, Pugh CW, Maxwell PH, Harris AL, Ratcliffe PJ. Identification of novel hypoxia-dependent and independent target genes of the von Hippel-Lindau (VHL) tumor suppressor by mRNA differential expression profiling. Oncogene 2000; 19: 6297-305.
99. Bruick RK. Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci USA 2000; 97: 9082-87.
100. Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res 2001; 61: 6669-73.
101. Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN, et al. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell 1998; 1: 959-68.
102. Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W. Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat Cell Biol 2002; 5: 64-70.
103. Kuznetsova AV, Meller J, Schnell PO, Nash JA, Ignacak ML, Sanchez Y, 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 USA 2003; 100: 2706-11.
104. 2 homeostasis by hypoxia-inducible factor 1a. Genes Dev 1997; 12: 149-62.
105. Kotch LE, Iyer NV, Laughner E, Semenza GL. Defective vascularization of HIF-1a-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Dev Biol 1999; 209: 254-67.
106. Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL. The hypoxia responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 1998; 12: 3320-24.
107. Peng J, Zhang L, Drysdale L, Fong GH. The transcription factor EPAS-1/hypoxia-inducible factor 2a plays an important role in vascular remodeling. Proc Natl Acad Sci USA Proceedings of the National Academy of Sciences, USA 2000; 97: 8386-91.
108. Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, et al. Loss of HIF-2a and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nature Medicine 2002; 8: 702-10.
109. Vaux EC, Wood SM, Cockman ME, Nicholls LG, Yeates KM, Pugh CW, et al. Selection of mutant CHO cells with constitutive activation of the HIF system and inactivation of the von Hippel-Lindau tumor suppressor. Journal of Biological Chemistry 2001; 276: 44323-30.