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. 1996 Jul;27:S126–S132.

The molecular response of mammalian cells to hypoxia and the potential for exploitation in cancer therapy.

G U Dachs 1, I J Stratford 1
PMCID: PMC2150030  PMID: 8763864

Abstract

In this review, reports of the increased expression of selected genes in response to hypoxia have been summarised. The best studied mammalian hypoxia response systems are those of the erythropoietin (Epo) and the vascular endothelial growth factor (VEGF) genes, which will be described in some detail. Other genes discussed here include those encoding growth factors, cytokines, transcription factors, metabolic enzymes and DNA repair enzymes. Short DNA sequences (hypoxia response elements) governing the increased gene expression in response to hypoxia have been discovered in the vicinity of most of these genes. The review will end by analysing the possibility of exploiting tumour hypoxia via the use of hypoxia response elements for gene therapy of cancer.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ausserer W. A., Bourrat-Floeck B., Green C. J., Laderoute K. R., Sutherland R. M. Regulation of c-jun expression during hypoxic and low-glucose stress. Mol Cell Biol. 1994 Aug;14(8):5032–5042. doi: 10.1128/mcb.14.8.5032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Balla J., Nath K. A., Balla G., Juckett M. B., Jacob H. S., Vercellotti G. M. Endothelial cell heme oxygenase and ferritin induction in rat lung by hemoglobin in vivo. Am J Physiol. 1995 Feb;268(2 Pt 1):L321–L327. doi: 10.1152/ajplung.1995.268.2.L321. [DOI] [PubMed] [Google Scholar]
  3. Beck I., Weinmann R., Caro J. Characterization of hypoxia-responsive enhancer in the human erythropoietin gene shows presence of hypoxia-inducible 120-Kd nuclear DNA-binding protein in erythropoietin-producing and nonproducing cells. Blood. 1993 Aug 1;82(3):704–711. [PubMed] [Google Scholar]
  4. Benjamin I. J., Kröger B., Williams R. S. Activation of the heat shock transcription factor by hypoxia in mammalian cells. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6263–6267. doi: 10.1073/pnas.87.16.6263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bicknell R., Harris A. L. Novel growth regulatory factors and tumour angiogenesis. Eur J Cancer. 1991;27(6):781–785. doi: 10.1016/0277-5379(91)90189-k. [DOI] [PubMed] [Google Scholar]
  6. Binienda Z., Scallet A. C. The effects of reduced perfusion and reperfusion on c-fos and HSP-72 protein immunohistochemistry in gestational day 21 rat brains. Int J Dev Neurosci. 1994 Nov;12(7):605–610. doi: 10.1016/0736-5748(94)90012-4. [DOI] [PubMed] [Google Scholar]
  7. Colotta F., Polentarutti N., Staffico M., Fincato G., Mantovani A. Heat shock induces the transcriptional activation of c-fos protooncogene. Biochem Biophys Res Commun. 1990 May 16;168(3):1013–1019. doi: 10.1016/0006-291x(90)91130-k. [DOI] [PubMed] [Google Scholar]
  8. DiSalvo J., Bayne M. L., Conn G., Kwok P. W., Trivedi P. G., Soderman D. D., Palisi T. M., Sullivan K. A., Thomas K. A. Purification and characterization of a naturally occurring vascular endothelial growth factor.placenta growth factor heterodimer. J Biol Chem. 1995 Mar 31;270(13):7717–7723. doi: 10.1074/jbc.270.13.7717. [DOI] [PubMed] [Google Scholar]
  9. Fandrey J., Frede S., Jelkmann W. Role of hydrogen peroxide in hypoxia-induced erythropoietin production. Biochem J. 1994 Oct 15;303(Pt 2):507–510. doi: 10.1042/bj3030507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Finkenzeller G., Technau A., Marmé D. Hypoxia-induced transcription of the vascular endothelial growth factor gene is independent of functional AP-1 transcription factor. Biochem Biophys Res Commun. 1995 Mar 8;208(1):432–439. doi: 10.1006/bbrc.1995.1356. [DOI] [PubMed] [Google Scholar]
  11. Firth J. D., Ebert B. L., Pugh C. W., Ratcliffe P. J. Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3' enhancer. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6496–6500. doi: 10.1073/pnas.91.14.6496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Galson D. L., Tsuchiya T., Tendler D. S., Huang L. E., Ren Y., Ogura T., Bunn H. F. The orphan receptor hepatic nuclear factor 4 functions as a transcriptional activator for tissue-specific and hypoxia-specific erythropoietin gene expression and is antagonized by EAR3/COUP-TF1. Mol Cell Biol. 1995 Apr;15(4):2135–2144. doi: 10.1128/mcb.15.4.2135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Giaccia A. J., Auger E. A., Koong A., Terris D. J., Minchinton A. I., Hahn G. M., Brown J. M. Activation of the heat shock transcription factor by hypoxia in normal and tumor cell lines in vivo and in vitro. Int J Radiat Oncol Biol Phys. 1992;23(4):891–897. doi: 10.1016/0360-3016(92)90667-7. [DOI] [PubMed] [Google Scholar]
  14. Gleadle J. M., Ebert B. L., Firth J. D., Ratcliffe P. J. Regulation of angiogenic growth factor expression by hypoxia, transition metals, and chelating agents. Am J Physiol. 1995 Jun;268(6 Pt 1):C1362–C1368. doi: 10.1152/ajpcell.1995.268.6.C1362. [DOI] [PubMed] [Google Scholar]
  15. Goldberg M. A., Dunning S. P., Bunn H. F. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science. 1988 Dec 9;242(4884):1412–1415. doi: 10.1126/science.2849206. [DOI] [PubMed] [Google Scholar]
  16. Goldberg M. A., Gaut C. C., Bunn H. F. Erythropoietin mRNA levels are governed by both the rate of gene transcription and posttranscriptional events. Blood. 1991 Jan 15;77(2):271–277. [PubMed] [Google Scholar]
  17. Goldberg M. A., Glass G. A., Cunningham J. M., Bunn H. F. The regulated expression of erythropoietin by two human hepatoma cell lines. Proc Natl Acad Sci U S A. 1987 Nov;84(22):7972–7976. doi: 10.1073/pnas.84.22.7972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Goldberg M. A., Schneider T. J. Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. J Biol Chem. 1994 Feb 11;269(6):4355–4359. [PubMed] [Google Scholar]
  19. Graeber T. G., Peterson J. F., Tsai M., Monica K., Fornace A. J., Jr, Giaccia A. J. Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol. 1994 Sep;14(9):6264–6277. doi: 10.1128/mcb.14.9.6264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Graven K. K., Troxler R. F., Kornfeld H., Panchenko M. V., Farber H. W. Regulation of endothelial cell glyceraldehyde-3-phosphate dehydrogenase expression by hypoxia. J Biol Chem. 1994 Sep 30;269(39):24446–24453. [PubMed] [Google Scholar]
  21. Gustafson D. L., Pritsos C. A. Bioactivation of mitomycin C by xanthine dehydrogenase from EMT6 mouse mammary carcinoma tumors. J Natl Cancer Inst. 1992 Aug 5;84(15):1180–1185. doi: 10.1093/jnci/84.15.1180. [DOI] [PubMed] [Google Scholar]
  22. Harrison L., Ascione A. G., Wilson D. M., 3rd, Demple B. Characterization of the promoter region of the human apurinic endonuclease gene (APE). J Biol Chem. 1995 Mar 10;270(10):5556–5564. doi: 10.1074/jbc.270.10.5556. [DOI] [PubMed] [Google Scholar]
  23. Hasan N. M., Cundall R. B., Adams G. E. Effects of hypoxia and reoxygenation on the conversion of xanthine dehydrogenase to oxidase in Chinese hamster V79 cells. Free Radic Biol Med. 1991;11(2):179–185. doi: 10.1016/0891-5849(91)90169-4. [DOI] [PubMed] [Google Scholar]
  24. Hassoun P. M., Yu F. S., Shedd A. L., Zulueta J. J., Thannickal V. J., Lanzillo J. J., Fanburg B. L. Regulation of endothelial cell xanthine dehydrogenase xanthine oxidase gene expression by oxygen tension. Am J Physiol. 1994 Feb;266(2 Pt 1):L163–L171. doi: 10.1152/ajplung.1994.266.2.L163. [DOI] [PubMed] [Google Scholar]
  25. Heacock C. S., Sutherland R. M. Induction characteristics of oxygen regulated proteins. Int J Radiat Oncol Biol Phys. 1986 Aug;12(8):1287–1290. doi: 10.1016/0360-3016(86)90155-0. [DOI] [PubMed] [Google Scholar]
  26. Hwang S. M., Wilson P. D., Laskin J. D., Denhardt D. T. Age and development-related changes in osteopontin and nitric oxide synthase mRNA levels in human kidney proximal tubule epithelial cells: contrasting responses to hypoxia and reoxygenation. J Cell Physiol. 1994 Jul;160(1):61–68. doi: 10.1002/jcp.1041600108. [DOI] [PubMed] [Google Scholar]
  27. Joannidis M., Cantley L. G., Spokes K., Medina R., Pullman J., Rosen S., Epstein F. H. Induction of heat-shock proteins does not prevent renal tubular injury following ischemia. Kidney Int. 1995 Jun;47(6):1752–1759. doi: 10.1038/ki.1995.242. [DOI] [PubMed] [Google Scholar]
  28. Keyse S. M., Tyrrell R. M. Induction of the heme oxygenase gene in human skin fibroblasts by hydrogen peroxide and UVA (365 nm) radiation: evidence for the involvement of the hydroxyl radical. Carcinogenesis. 1990 May;11(5):787–791. doi: 10.1093/carcin/11.5.787. [DOI] [PubMed] [Google Scholar]
  29. Klatt P., Schmidt K., Mayer B. Brain nitric oxide synthase is a haemoprotein. Biochem J. 1992 Nov 15;288(Pt 1):15–17. doi: 10.1042/bj2880015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Klempt N. D., Sirimanne E., Gunn A. J., Klempt M., Singh K., Williams C., Gluckman P. D. Hypoxia-ischemia induces transforming growth factor beta 1 mRNA in the infant rat brain. Brain Res Mol Brain Res. 1992 Mar;13(1-2):93–101. doi: 10.1016/0169-328x(92)90048-g. [DOI] [PubMed] [Google Scholar]
  31. Koong A. C., Chen E. Y., Giaccia A. J. Hypoxia causes the activation of nuclear factor kappa B through the phosphorylation of I kappa B alpha on tyrosine residues. Cancer Res. 1994 Mar 15;54(6):1425–1430. [PubMed] [Google Scholar]
  32. Kuwabara K., Ogawa S., Matsumoto M., Koga S., Clauss M., Pinsky D. J., Lyn P., Leavy J., Witte L., Joseph-Silverstein J. Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4606–4610. doi: 10.1073/pnas.92.10.4606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Laderoute K. R., Grant T. D., Murphy B. J., Sutherland R. M. Enhanced epidermal growth factor receptor synthesis in human squamous carcinoma cells exposed to low levels of oxygen. Int J Cancer. 1992 Sep 30;52(3):428–432. doi: 10.1002/ijc.2910520317. [DOI] [PubMed] [Google Scholar]
  34. Laderoute K. R., Murphy B. J., Short S. M., Grant T. D., Knapp A. M., Sutherland R. M. Enhancement of transforming growth factor-alpha synthesis in multicellular tumour spheroids of A431 squamous carcinoma cells. Br J Cancer. 1992 Feb;65(2):157–162. doi: 10.1038/bjc.1992.34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ladoux A., Frelin C. Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem Biophys Res Commun. 1993 Sep 15;195(2):1005–1010. doi: 10.1006/bbrc.1993.2144. [DOI] [PubMed] [Google Scholar]
  36. Lavrovsky Y., Schwartzman M. L., Levere R. D., Kappas A., Abraham N. G. Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5987–5991. doi: 10.1073/pnas.91.13.5987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Lee-Huang S., Lin J. J., Kung H. F., Huan P. L., Lee L., Huang P. L. The 3' flanking region of the human erythropoietin-encoding gene contains nitrogen-regulatory/oxygen-sensing consensus sequences and tissue-specific transcriptional regulatory elements. Gene. 1993 Dec 31;137(2):203–210. doi: 10.1016/0378-1119(93)90007-p. [DOI] [PubMed] [Google Scholar]
  38. Lefebvre V., Buc-Calderon P. Desferal prevents against cell lysis induced by hydrogen peroxide to hypoxic hepatocytes: a role for free iron in hypoxia-mediated cellular injury. Chem Biol Interact. 1995 Jan;94(1):37–48. doi: 10.1016/0009-2797(94)03319-4. [DOI] [PubMed] [Google Scholar]
  39. Madan A., Curtin P. T. A 24-base-pair sequence 3' to the human erythropoietin gene contains a hypoxia-responsive transcriptional enhancer. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3928–3932. doi: 10.1073/pnas.90.9.3928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Madan A., Lin C., Hatch S. L., 2nd, Curtin P. T. Regulated basal, inducible, and tissue-specific human erythropoietin gene expression in transgenic mice requires multiple cis DNA sequences. Blood. 1995 May 15;85(10):2735–2741. [PubMed] [Google Scholar]
  41. Minchenko A., Salceda S., Bauer T., Caro J. Hypoxia regulatory elements of the human vascular endothelial growth factor gene. Cell Mol Biol Res. 1994;40(1):35–39. [PubMed] [Google Scholar]
  42. Mukhopadhyay D., Tsiokas L., Zhou X. M., Foster D., Brugge J. S., Sukhatme V. P. Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature. 1995 Jun 15;375(6532):577–581. doi: 10.1038/375577a0. [DOI] [PubMed] [Google Scholar]
  43. Murphy B. J., Laderoute K. R., Short S. M., Sutherland R. M. The identification of heme oxygenase as a major hypoxic stress protein in Chinese hamster ovary cells. Br J Cancer. 1991 Jul;64(1):69–73. doi: 10.1038/bjc.1991.241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Ohigashi T., Brookins J., Fisher J. W. Interaction of nitric oxide and cyclic guanosine 3',5'-monophosphate in erythropoietin production. J Clin Invest. 1993 Sep;92(3):1587–1591. doi: 10.1172/JCI116740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Ohkawa F., Ikeda U., Kawasaki K., Kusano E., Igarashi M., Shimada K. Inhibitory effect of interleukin-6 on vascular smooth muscle contraction. Am J Physiol. 1994 Mar;266(3 Pt 2):H898–H902. doi: 10.1152/ajpheart.1994.266.3.H898. [DOI] [PubMed] [Google Scholar]
  46. Paller M. S., Hedlund B. E. Extracellular iron chelators protect kidney cells from hypoxia/reoxygenation. Free Radic Biol Med. 1994 Dec;17(6):597–603. doi: 10.1016/0891-5849(94)90099-x. [DOI] [PubMed] [Google Scholar]
  47. Patterson A. V., Barham H. M., Chinje E. C., Adams G. E., Harris A. L., Stratford I. J. Importance of P450 reductase activity in determining sensitivity of breast tumour cells to the bioreductive drug, tirapazamine (SR 4233). Br J Cancer. 1995 Nov;72(5):1144–1150. doi: 10.1038/bjc.1995.478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Perkins N. D., Edwards N. L., Duckett C. S., Agranoff A. B., Schmid R. M., Nabel G. J. A cooperative interaction between NF-kappa B and Sp1 is required for HIV-1 enhancer activation. EMBO J. 1993 Sep;12(9):3551–3558. doi: 10.1002/j.1460-2075.1993.tb06029.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Perkins N. D., Schmid R. M., Duckett C. S., Leung K., Rice N. R., Nabel G. J. Distinct combinations of NF-kappa B subunits determine the specificity of transcriptional activation. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1529–1533. doi: 10.1073/pnas.89.5.1529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Plate K. H., Breier G., Farrell C. L., Risau W. Platelet-derived growth factor receptor-beta is induced during tumor development and upregulated during tumor progression in endothelial cells in human gliomas. Lab Invest. 1992 Oct;67(4):529–534. [PubMed] [Google Scholar]
  51. Plate K. H., Breier G., Millauer B., Ullrich A., Risau W. Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. Cancer Res. 1993 Dec 1;53(23):5822–5827. [PubMed] [Google Scholar]
  52. Plate K. H., Breier G., Weich H. A., Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992 Oct 29;359(6398):845–848. doi: 10.1038/359845a0. [DOI] [PubMed] [Google Scholar]
  53. Pohl U., Busse R. Hypoxia stimulates release of endothelium-derived relaxant factor. Am J Physiol. 1989 Jun;256(6 Pt 2):H1595–H1600. doi: 10.1152/ajpheart.1989.256.6.H1595. [DOI] [PubMed] [Google Scholar]
  54. Price B. D., Calderwood S. K. Heat-induced transcription from RNA polymerases II and III and HSF binding activity are co-ordinately regulated by the products of the heat shock genes. J Cell Physiol. 1992 Nov;153(2):392–401. doi: 10.1002/jcp.1041530219. [DOI] [PubMed] [Google Scholar]
  55. Pugh C. W., Ebert B. L., Ebrahim O., Ratcliffe P. J. Characterisation of functional domains within the mouse erythropoietin 3' enhancer conveying oxygen-regulated responses in different cell lines. Biochim Biophys Acta. 1994 Apr 6;1217(3):297–306. doi: 10.1016/0167-4781(94)90289-5. [DOI] [PubMed] [Google Scholar]
  56. Qi Y., Jamindar T. M., Dawson G. Hypoxia alters iron homeostasis and induces ferritin synthesis in oligodendrocytes. J Neurochem. 1995 Jun;64(6):2458–2464. doi: 10.1046/j.1471-4159.1995.64062458.x. [DOI] [PubMed] [Google Scholar]
  57. Robertson N., Haigh A., Adams G. E., Stratford I. J. Factors affecting sensitivity to EO9 in rodent and human tumour cells in vitro: DT-diaphorase activity and hypoxia. Eur J Cancer. 1994;30A(7):1013–1019. doi: 10.1016/0959-8049(94)90134-1. [DOI] [PubMed] [Google Scholar]
  58. Semenza G. L., Roth P. H., Fang H. M., Wang G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994 Sep 23;269(38):23757–23763. [PubMed] [Google Scholar]
  59. Shibahara S., Müller R. M., Taguchi H. Transcriptional control of rat heme oxygenase by heat shock. J Biol Chem. 1987 Sep 25;262(27):12889–12892. [PubMed] [Google Scholar]
  60. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
  61. Shweiki D., Neeman M., Itin A., Keshet E. Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):768–772. doi: 10.1073/pnas.92.3.768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Stavri G. T., Zachary I. C., Baskerville P. A., Martin J. F., Erusalimsky J. D. Basic fibroblast growth factor upregulates the expression of vascular endothelial growth factor in vascular smooth muscle cells. Synergistic interaction with hypoxia. Circulation. 1995 Jul 1;92(1):11–14. doi: 10.1161/01.cir.92.1.11. [DOI] [PubMed] [Google Scholar]
  63. Stoler D. L., Anderson G. R., Russo C. A., Spina A. M., Beerman T. A. Anoxia-inducible endonuclease activity as a potential basis of the genomic instability of cancer cells. Cancer Res. 1992 Aug 15;52(16):4372–4378. [PubMed] [Google Scholar]
  64. Storch T. G., Talley G. D. Oxygen concentration regulates the proliferative response of human fibroblasts to serum and growth factors. Exp Cell Res. 1988 Apr;175(2):317–325. doi: 10.1016/0014-4827(88)90195-4. [DOI] [PubMed] [Google Scholar]
  65. Tischer E., Mitchell R., Hartman T., Silva M., Gospodarowicz D., Fiddes J. C., Abraham J. A. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991 Jun 25;266(18):11947–11954. [PubMed] [Google Scholar]
  66. Tuder R. M., Flook B. E., Voelkel N. F. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J Clin Invest. 1995 Apr;95(4):1798–1807. doi: 10.1172/JCI117858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Ullrich A., Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990 Apr 20;61(2):203–212. doi: 10.1016/0092-8674(90)90801-k. [DOI] [PubMed] [Google Scholar]
  68. Walker L. J., Craig R. B., Harris A. L., Hickson I. D. A role for the human DNA repair enzyme HAP1 in cellular protection against DNA damaging agents and hypoxic stress. Nucleic Acids Res. 1994 Nov 25;22(23):4884–4889. doi: 10.1093/nar/22.23.4884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Wang G. L., Jiang B. H., Rue E. A., Semenza G. L. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510–5514. doi: 10.1073/pnas.92.12.5510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Wang G. L., Semenza G. L. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood. 1993 Dec 15;82(12):3610–3615. [PubMed] [Google Scholar]
  71. Wang G. L., Semenza G. L. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4304–4308. doi: 10.1073/pnas.90.9.4304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Wang G. L., Semenza G. L. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995 Jan 20;270(3):1230–1237. doi: 10.1074/jbc.270.3.1230. [DOI] [PubMed] [Google Scholar]
  73. Xue C., Rengasamy A., Le Cras T. D., Koberna P. A., Dailey G. C., Johns R. A. Distribution of NOS in normoxic vs. hypoxic rat lung: upregulation of NOS by chronic hypoxia. Am J Physiol. 1994 Dec;267(6 Pt 1):L667–L678. doi: 10.1152/ajplung.1994.267.6.L667. [DOI] [PubMed] [Google Scholar]
  74. Yan S. F., Tritto I., Pinsky D., Liao H., Huang J., Fuller G., Brett J., May L., Stern D. Induction of interleukin 6 (IL-6) by hypoxia in vascular cells. Central role of the binding site for nuclear factor-IL-6. J Biol Chem. 1995 May 12;270(19):11463–11471. doi: 10.1074/jbc.270.19.11463. [DOI] [PubMed] [Google Scholar]
  75. Yao K. S., Clayton M., O'Dwyer P. J. Interaction of heat and hypoxia in modulating transcription of DT diaphorase in human colon adenocarcinoma cells. Cell Growth Differ. 1994 Feb;5(2):125–131. [PubMed] [Google Scholar]
  76. Yao K. S., O'Dwyer P. J. Involvement of NF-kappa B in the induction of NAD(P)H:quinone oxidoreductase (DT-diaphorase) by hypoxia, oltipraz and mitomycin C. Biochem Pharmacol. 1995 Jan 31;49(3):275–282. doi: 10.1016/0006-2952(94)00544-v. [DOI] [PubMed] [Google Scholar]
  77. Yao K. S., Xanthoudakis S., Curran T., O'Dwyer P. J. Activation of AP-1 and of a nuclear redox factor, Ref-1, in the response of HT29 colon cancer cells to hypoxia. Mol Cell Biol. 1994 Sep;14(9):5997–6003. doi: 10.1128/mcb.14.9.5997. [DOI] [PMC free article] [PubMed] [Google Scholar]

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