Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Generating specificity and diversity in the transcriptional response to hypoxia

Nature Reviews Genetics volume 10, pages 821–832 (2009)Cite this article

Key Points

  • Hypoxia and the cellular hypoxic response have key roles in homeostasis and physiological adaptations, as well as in pathophysiological conditions.

  • The cellular hypoxic response can generate both diversity and specificity in the downstream signalling output, despite a relatively simple core signalling pathway.

  • Hypoxia-inducible factor-α proteins constitute key transcriptional regulators in the cellular hypoxic response, and are subject to various different post-translational modifications.

  • Analysis of the hypoxia transcriptional response has begun to reveal a core hypoxic transcriptional signature in addition to cell type-specific gene activation events.

  • The transcriptional responses to acute and chronic hypoxia are distinct. Likewise, hypoxia-mimicking chemical compounds have a substantially broader transcriptional output than hypoxia.

  • Intersections with other signalling mechanisms, such as Myc and Notch signalling, contribute to modulation of the hypoxic response.

Abstract

The sensing of oxygen levels and maintenance of oxygen homeostasis is crucial for cells. The hypoxic-sensitive regulation of gene expression allows information about the oxygen status to be converted into appropriate cellular responses. Although there is a core transcriptional pathway, the signalling cascade can be modified to allow diversity and specificity in the transcriptional output. In this Review, we discuss recent advances in our understanding of the mechanisms and factors that contribute to the observed diversity and specificity. A deeper knowledge about how hypoxic signalling is tuned will further our understanding of the cellular hypoxic response in normal physiology and how it becomes derailed in disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The core cellular hypoxic response pathway.
Figure 2: The hypoxia transcriptome.
Figure 3: Distinct roles for HIF1α, HIF2α and HIF3α.
Figure 4: Distinct effects of post-translational modifications of HIFα and ARNT proteins.
Figure 5: Functional integration between the HIF and Myc regulatory pathways.
Figure 6: Notch and hypoxia signalling pathways and their intersection.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003).

    CAS  Google Scholar 

  2. Smith, T. G., Robbins, P. A. & Ratcliffe, P. J. The human side of hypoxia-inducible factor. Br. J. Haematol. 141, 325–334 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Weidemann, A. & Johnson, R. S. Biology of HIF-1α. Cell Death Differ. 15, 621–727 (2008).

    CAS  PubMed  Google Scholar 

  4. Simon, M. C., Liu, L., Barnhart, B. C. & Young, R. M. Hypoxia-induced signaling in the cardiovascular system. Annu. Rev. Physiol. 70, 51–71 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Chan, D. A., Krieg, A. J., Turcotte, S. & Giaccia, A. J. HIF gene expression in cancer therapy. Methods Enzymol. 435, 323–345 (2007).

    CAS  PubMed  Google Scholar 

  6. Harris, A. L. Hypoxia — a key regulatory factor in tumour growth. Nature Rev. Cancer 2, 38–47 (2002).

    CAS  Google Scholar 

  7. Denko, N. C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nature Rev. Cancer 8, 705–713 (2008).

    CAS  Google Scholar 

  8. 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. USA 92, 5510–5514 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen, K. F., Lai, Y. Y., Sun, H. S. & Tsai, S. J. Transcriptional repression of human cad gene by hypoxia inducible factor-1α. Nucleic Acids Res. 33, 5190–5198 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Mazure, N. M. et al. Repression of α-fetoprotein gene expression under hypoxic conditions in human hepatoma cells: characterization of a negative hypoxia response element that mediates opposite effects of hypoxia inducible factor-1 and c-Myc. Cancer Res. 62, 1158–1165 (2002).

    CAS  PubMed  Google Scholar 

  11. Peyssonnaux, C. et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J. Clin. Invest. 117, 1926–1932 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Mole, D. R. et al. Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF-2α DNA binding with expression profiling of hypoxia-inducible transcripts. J. Biol. Chem. 284, 16767–16775 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wenger, R. H., Stiehl, D. P. & Camenisch, G. Integration of oxygen signaling at the consensus HRE. Sci. STKE 2005, re12 (2005).

    PubMed  Google Scholar 

  14. Antonsson, C., Arulampalam, V., Whitelaw, M. L., Pettersson, S. & Poellinger, L. Constitutive function of the basic helix–loop–helix/PAS factor Arnt. Regulation of target promoters via the E box motif. J. Biol. Chem. 270, 13968–13972 (1995).

    CAS  PubMed  Google Scholar 

  15. Sogawa, K. et al. Possible function of Ah receptor nuclear translocator (Arnt) homodimer in transcriptional regulation. Proc. Natl Acad. Sci. USA 92, 1936–1940 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lindebro, M. C., Poellinger, L. & Whitelaw M. L. Protein–protein interaction via PAS domains: role of the PAS domain in positive and negative regulation of the bHLH/PAS dioxin receptor–Arnt transcription factor complex. EMBO J. 14, 3528–3539 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Pongratz, I., Antonsson, C., Whitelaw, M. L. & Poellinger, L. Role of the PAS domain in regulation of dimerization and DNA binding specificity of the dioxin receptor. Mol. Cell. Biol. 18, 4079–4088 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ruas, J. L., Poellinger, L. & Pereira, T. Role of CBP in regulating HIF-1-mediated activation of transcription. J. Cell Sci. 118, 301–311 (2005).

    CAS  PubMed  Google Scholar 

  19. Carrero, P. et al. Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1α. Mol. Cell. Biol. 20, 402–415 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kato, H., Tamamizu-Kato, S. & Shibasaki, F. Histone deacetylase 7 associates with hypoxia-inducible factor 1α and increases transcriptional activity. J. Biol. Chem. 279, 41966–41974 (2004).

    CAS  PubMed  Google Scholar 

  21. Mahon, P. C., Hirota, K. & Semenza, G. L. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 15, 2675–2686 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kallio, P. J., Pongratz, I., Gradin, K., McGuire, J. & Poellinger, L. Activation of hypoxia-inducible factor 1α: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc. Natl Acad. Sci. USA 94, 5667–5672 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Salceda, S. & Caro, J. Hypoxia-inducible factor 1α (HIF-1α) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J. Biol. Chem. 272, 22642–22647 (1997).

    CAS  PubMed  Google Scholar 

  24. Huang, L. E., Gu, J., Schau, M. & Bunn, H. F. Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc. Natl Acad. Sci. USA 95, 7987–7992 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kallio, P. J. et al. Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1α. EMBO J. 17, 6573–6586 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kallio, P. J., Wilson, W. J., O'Brien, S., Makino, Y. & Poellinger, L. Regulation of the hypoxia-inducible transcription factor 1α by the ubiquitin-proteasome pathway. J. Biol. Chem. 274, 6519–6525 (1999).

    CAS  PubMed  Google Scholar 

  27. Stebbins, C. E., Kaelin, W. G. Jr & Pavletich, N. P. Structure of the VHL–ElonginC–ElonginB complex: implications for VHL tumor suppressor function. Science 284, 455–461 (1999).

    CAS  PubMed  Google Scholar 

  28. 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. 19, 4298–4309 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ohh, M. et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein. Nature Cell Biol. 2, 423–427 (2000).

    CAS  PubMed  Google Scholar 

  30. Cockman, M. E. et al. Hypoxia inducible factor-α binding and ubiquitylation by the von Hippel–Lindau tumor suppressor protein. J. Biol. Chem. 275, 25733–25741 (2000).

    CAS  PubMed  Google Scholar 

  31. Ivan, M. et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468 (2001).

    CAS  PubMed  Google Scholar 

  32. Jaakkola, P. et al. Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292, 468–472 (2001).

    CAS  PubMed  Google Scholar 

  33. Epstein A. C. et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001).

    CAS  PubMed  Google Scholar 

  34. Bruick, R. K. & McKnight, S. L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294, 1337–1340 (2001).

    CAS  PubMed  Google Scholar 

  35. Lando, D. et al. Asparagine hydroxylation of the HIF transactivation domain: a hypoxic switch. Science 295, 858–861 (2002).

    CAS  PubMed  Google Scholar 

  36. Lando, D. et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 16, 1466–1471 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hewitson, K. S. 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. 277, 26351–26355 (2002).

    CAS  PubMed  Google Scholar 

  38. Carbia-Nagashima, A. et al. RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1α during hypoxia. Cell 131, 309–323 (2007).

    CAS  PubMed  Google Scholar 

  39. Cheng, J., Kang, X., Zhang, S. & Yeh, E. T. SUMO-specific protease 1 is essential for stabilization of HIF1α during hypoxia. Cell 131, 584–595 (2007). This paper describes the discovery of a new mechanism for the regulation of VHL–HIFα interaction.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. André, H. & Pereira, T. S. Identification of an alternative mechanism of degradation of the hypoxia-inducible factor-1α. J. Biol. Chem. 283, 29375–29384 (2008).

    PubMed  PubMed Central  Google Scholar 

  41. Tojo, M. et al. The aryl hydrocarbon receptor nuclear transporter is modulated by the SUMO-1 conjugation system. J. Biol. Chem. 277, 46576–46585 (2002).

    CAS  PubMed  Google Scholar 

  42. Cardone, L. et al. Circadian clock control by SUMOylation of BMAL1. Science 309, 1390–1394 (2005).

    CAS  PubMed  Google Scholar 

  43. Li, F. et al. Regulation of HIF-1α stability through S-nitrosylation. Mol. Cell 26, 63–74 (2007).

    PubMed  PubMed Central  Google Scholar 

  44. Gradin, K. et al. Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor. Mol. Cell. Biol. 16, 5221–5231 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu, Y. V. et al. RACK1 competes with HSP90 for binding to HIF-1α and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1α. Mol. Cell 25, 207–217 (2007).

    PubMed  PubMed Central  Google Scholar 

  46. Yun, Z., Maecker, H. L., Johnson, R. S. & Giaccia, A. J. Inhibition of PPAR γ 2 expression by the HIF-1-regulated gene DEC1/Stra13. Dev. Cell 2, 331–341 (2002).

    CAS  PubMed  Google Scholar 

  47. Boutin, A. T. et al. Epidermal sensing of oxygen is essential for systemic hypoxic response. Cell 132, 223–234 (2008). This paper indicates a role of the skin as a mediator of systemic responses to environmental oxygen.

    Google Scholar 

  48. Botusan, I. R. et al. Stabilization of HIF-1α is critical to improve wound healing in diabetic mice. Proc. Natl Acad. Sci. USA 105, 19426–19431 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Iyer, N. V. et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev. 12, 149–162 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ryan, H. E., Lo, J. & Johnson, R. S. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J. 17, 3005–3015 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Carmeliet, P. et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).

    CAS  PubMed  Google Scholar 

  52. Maltepe, E., Schmidt, J. V., Baunoch, D., Bradfield, C. A. & Simon, M. C. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature 386, 403–407.

  53. Tian, H., Hammer, R. E., Matsumoto, A. M., Russell, D. W. & McKnight, S. L. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev. 12, 3320–3324 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Peng, J., Zhang, L. Y., Drysdale L. & Fong, G. H. The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling. Proc. Natl Acad. Sci. USA 97, 8386–8391 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Compernolle, V. et al. Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nature Med. 8, 702–710 (2002).

    CAS  PubMed  Google Scholar 

  56. Scortegagna, M. et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice. Nature Genet. 35, 331–340 (2003).

    CAS  PubMed  Google Scholar 

  57. Morita, M. et al. HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin. EMBO J. 22, 1134–1146 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003). Myeloid-specific gene targeting identifies an essential role for HIF1α in regulating inflammatory responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Rius, J. et al. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453, 807–811 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Yamashita, T. et al. Abnormal heart development and lung remodeling in mice lacking the hypoxia-inducible factor-related basic helix–loop–helix PAS protein NEPAS. Mol. Cell. Biol. 28, 1285–1297 (2008).

    CAS  PubMed  Google Scholar 

  61. Krishnan, J. et al. Activation of a HIF1α–PPARγ axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab. 9, 512–524 (2009).

    CAS  PubMed  Google Scholar 

  62. Percy, M. J. et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc. Natl Acad. Sci. USA 103, 654–659 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Percy, M. J. et al. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N. Engl. J. Med. 358, 162–168 (2008). This study provides evidence that HIF2α is a transcription factor that regulates EPO levels in humans.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Ang, S. O. et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nature Genet. 32, 614–621 (2002).

    CAS  PubMed  Google Scholar 

  65. Schofield, C. J. & Ratcliffe, P. J. Oxygen sensing by HIF hydroxylases. Nature Rev. Mol. Cell Biol. 5, 343–354 (2004).

    CAS  Google Scholar 

  66. Cao, R., Jensen, L. D., Soll, I., Hauptmann, G. & Cao, Y. Hypoxia-induced retinal angiogenesis in zebrafish as a model to study retinopathy. PLoS ONE 3, e2748 (2008).

    PubMed  PubMed Central  Google Scholar 

  67. Marques, I. J. et al. Transcriptome analysis of the response to chronic constant hypoxia in zebrafish hearts. J. Comp. Physiol. B 178, 77–92 (2008).

    CAS  PubMed  Google Scholar 

  68. Ton, C., Stamatiou, D. & Liew, C. C. Gene expression profile of zebrafish exposed to hypoxia during development. Physiol. Genomics 13, 97–106 (2003).

    CAS  PubMed  Google Scholar 

  69. van Rooijen, E. et al. Zebrafish mutants in the von Hippel–Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia. Blood 113, 6449–6460 (2009).

    CAS  PubMed  Google Scholar 

  70. Azad, P., Zhou, D., Russo, E. & Haddad, G. G. Distinct mechanisms underlying tolerance to intermittent and constant hypoxia in Drosophila melanogaster. PLoS ONE 4, e5371 (2009).

    PubMed  PubMed Central  Google Scholar 

  71. Zhou, D. et al. Mechanisms underlying hypoxia tolerance in Drosophila melanogaster: hairy as a metabolic switch. PLoS Genet. 4, e1000221 (2008).

    PubMed  PubMed Central  Google Scholar 

  72. Zhou, D. et al. Experimental selection for Drosophila survival in extremely low O2 environment. PLoS ONE 2, e490 (2007).

    PubMed  PubMed Central  Google Scholar 

  73. Shen, C., Nettleton, D., Jiang, M., Kim, S. K. & Powell-Coffman, J. A. Roles of the HIF-1 hypoxia-inducible factor during hypoxia response in Caenorhabditis elegans. J. Biol. Chem. 280, 20580–20588 (2005).

    CAS  PubMed  Google Scholar 

  74. Bishop, T. et al. Genetic analysis of pathways regulated by the von Hippel–Lindau tumor suppressor in Caenorhabditis elegans. PLoS Biol. 2, e289 (2004).

    PubMed  PubMed Central  Google Scholar 

  75. Kundaje, A. et al. A predictive model of the oxygen and heme regulatory network in yeast. PLoS Comput. Biol. 4, e1000224 (2008).

    PubMed  PubMed Central  Google Scholar 

  76. Hickman, M. J. & Winston, F. Heme levels switch the function of Hap1 of Saccharomyces cerevisiae between transcriptional activator and transcriptional repressor. Mol. Cell. Biol. 27, 7414–7424 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Rustad, T. R., Harrell, M. I., Liao, R. & Sherman, D. R. The enduring hypoxic response of Mycobacterium tuberculosis. PLoS ONE 3, e1502 (2008).

    PubMed  PubMed Central  Google Scholar 

  78. Park, H. D. et al. Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis. Mol. Microbiol. 48, 833–843 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Sherman, D. R. et al. Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding α-crystallin. Proc. Natl Acad. Sci. USA 98, 7534–7539 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Baena-Gonzalez, E., Rolland, F., Thevelein, J. M. & Sheen, J. A central integrator of transcription networks in plant stress and energy signalling. Nature 448, 938–942 (2007).

    CAS  PubMed  Google Scholar 

  81. Loreti, E., Poggi, A., Novi, G., Alpi, A. & Perata, P. A genome-wide analysis of the effects of sucrose on gene expression in Arabidopsis seedlings under anoxia. Plant Physiol. 137, 1130–1138 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Chi, J. T. et al. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med. 3, e47 (2006).

    PubMed  PubMed Central  Google Scholar 

  83. Benita, Y. et al. An integrative genomics approach identifies hypoxia inducible factor-1 (HIF-1)-target genes that form the core response to hypoxia. Nucleic Acids Res. 37, 4587–4602 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Chua, S.-W. et al. A novel normalization method for effective removal of systematic variation in microarray data. Nucleic Acids Res. 34, e38 (2006).

    PubMed  PubMed Central  Google Scholar 

  85. Xia, X. et al. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc. Natl Acad. Sci. USA 106, 4260–4265 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Pollard, P. J. et al. Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1α. Biochem. J. 416, 387–394 (2008).

    CAS  PubMed  Google Scholar 

  87. Beyer, S., Kristensen, M. M., Jensen, K. S., Johansen, J. V. & Staller, P. The histone demethylases JMJD1A and JMJD2B are transcriptional targets of hypoxia-inducible factor HIF. J. Biol. Chem. 283, 36542–3 6552.

    Google Scholar 

  88. Vengellur, A., Phillips, J. M., Hogenesch, J. B. & LaPres, J. J. Gene expression profiling of hypoxia signaling in human hepatocellular carcinoma cells. Physiol. Genomics 22, 308–318 (2005).

    CAS  PubMed  Google Scholar 

  89. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    CAS  PubMed  Google Scholar 

  90. Farh, K. K. The widespread impact of mammalian microRNAs on mRNA repression and evolution. Science 310, 1817–1821 (2005).

    CAS  PubMed  Google Scholar 

  91. He, L. & Hannon, G. J. MicroRNAs: small RNAs with a big role in gene regulation. Nature Rev. Genet. 5, 522–531 (2004).

    CAS  PubMed  Google Scholar 

  92. Kulshreshtha, R. et al. A microRNA signature of hypoxia. Mol. Cell. Biol. 27, 1859–1867 (2006).

    PubMed  Google Scholar 

  93. Hua, Z. et al. MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia. PLoS ONE 1, e116 (2006).

    PubMed  PubMed Central  Google Scholar 

  94. Crosby, M. E., Kulshreshtha, R., Ivan, M. & Glazer, P. M. MicroRNA regulation of DNA repair gene expression in hypoxic stress. Cancer Res. 69, 1221–1229 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Goldberg, A. D., Allis, C. D. & Bernstein, E. Epigenetics: a landscape takes shape. Cell 128, 635–638 (2007).

    CAS  PubMed  Google Scholar 

  96. Ruthenburg, A. J., Li, H., Patel, D. J. & Allis, C. D. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nature Struct. Mol. Biol. 14, 1025–1040 (2007).

    Google Scholar 

  97. Cloos, P. A. et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307–311 (2006).

    CAS  PubMed  Google Scholar 

  98. Whetstine, J. R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).

    CAS  PubMed  Google Scholar 

  99. Yamane, K. et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125, 483–495 (2006).

    CAS  PubMed  Google Scholar 

  100. Loenarz, C. & Schofield, C. J. Expanding chemical biology of 2-oxoglutarate oxygenases. Nature Chem. Biol. 4, 152–156 (2008).

    CAS  Google Scholar 

  101. Holmquist-Mengelbier, L. et al. Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype. Cancer Cell 10, 413–423 (2006). This paper shows distinct properties of HIF1α and HIF2α in acute and chronic hypoxia, respectively, and links HIF2α to tumour malignancy.

    CAS  PubMed  Google Scholar 

  102. Raval, R. R. 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. 25, 5675–5686 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Koshiji, M. et al. HIF-1α induces cell cycle arrest by functionally counteracting Myc. EMBO J. 23, 1949–1956 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Gordan, J. D., Bertout, J. A., Hu, C. J., Diehl, J. A. & Simon, M. C. HIF-2α promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11, 335–347 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Covello, K. L. et al. HIF-2α regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 21, 1037–1049 (2006).

    Google Scholar 

  106. Gu, Y. Z., Moran, S. M., Hogenesch, J. B., Wartman, L. & Bradfield, C. A. Molecular characterization and chromosomal localization of a third α-class hypoxia inducible factor subunit, HIF3α. Gene Expr. 7, 205–213 (1998).

    CAS  PubMed  Google Scholar 

  107. Makino, Y. et al. Transcriptional up-regulation of inhibitory PAS domain protein gene expression by hypoxia-inducible factor 1 (HIF-1): a negative feedback regulatory circuit in HIF-1-mediated signaling in hypoxic cells. J. Biol. Chem. 282, 14073–14082 (2007).

    CAS  PubMed  Google Scholar 

  108. Tanaka, T., Wiesener, M. S., Bernhardt, W., Eckardt, K. U. & Warnecke, C. The human hypoxia-inducible factor (HIF)-3α gene is a HIF-1 target and may modulate hypoxic gene induction. Biochem. J. 21 Aug 2009 (doi:10.1042/BJ20090120).

    CAS  Google Scholar 

  109. Makino, Y., Kanopka, A., Wilson, W. J., 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. 277, 32405–3 2408.

    Google Scholar 

  110. Makino, Y. et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414, 550–554 (2001).

    CAS  PubMed  Google Scholar 

  111. Webby, C. J. et al. Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science 325, 90–93 (2009). This study establishes a role of a Jumonji-domain dioxygenase in regulation of splicing and provides a possible mode by which oxygen regulates this process.

    CAS  PubMed  Google Scholar 

  112. Bilton, R., Trottier, E., Pouysségur, J. & Brahimi-Horn, M. C. ARDent about acetylation and deacetylation in hypoxia signalling. Trends Cell Biol. 16, 616–621 (2006).

    CAS  PubMed  Google Scholar 

  113. Dioum, E. M. et al. Regulation of hypoxia-inducible factor 2α signaling by the stress-responsive deacetylase sirtuin 1. Science 324, 1289–1293 (2009). This paper identifies a role of the environmental stress-inducible deacetylase SIRT1 in the regulation of HIFα function.

    CAS  PubMed  Google Scholar 

  114. Yamamoto, H., Schoonjans, K. & Auwerx, J. Sirtuin functions in health and disease. Mol. Endocrinol. 21, 1745–1755 (2007).

    CAS  PubMed  Google Scholar 

  115. Yang, X. J. & Seto, E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nature Rev. Mol. Cell Biol. 9, 206–218 (2008).

    CAS  Google Scholar 

  116. Hurlbut, G. D., Kankel, M. W., Lake, R. J. & Artavanis-Tsakonas, S. Crossing paths with Notch in the hyper-network. Curr. Opin. Cell Biol. 19, 166–175 (2007).

    CAS  PubMed  Google Scholar 

  117. Chitalia, V. C. et al. Jade-1 inhibits Wnt signalling by ubiquitylating β-catenin and mediates Wnt pathway inhibition by pVHL. Nature Cell Biol. 10, 1208–1216.

  118. Wouters, B. G. & Koritzinsky, M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nature Rev. Cancer 8, 851–864 (2008).

    CAS  Google Scholar 

  119. Ao, A., Wang, H., Kamarajugadda, S. & Lu, J. Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors. Proc. Natl Acad. Sci. USA 105, 7821–7826 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Arany Z. et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature 451, 1008–1012 (2008). This study describes the surprising finding that PGC1α induces VEGFA expression and angiogenesis not via the canonical hypoxia response pathway but via the orphan nuclear receptor ERRα.

    CAS  PubMed  Google Scholar 

  121. Adhikary, S. & Eilers, M. Transcriptional regulation and transformation by Myc proteins. Nature Rev. Mol. Cell Biol. 6, 635–645 (2005).

    CAS  Google Scholar 

  122. Koshiji, M. et al. HIF-1α induces genetic instability by transcriptionally downregulating MutSα expression. Mol. Cell 17, 793–803 (2005).

    CAS  PubMed  Google Scholar 

  123. Zhang, H. et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11, 407–420 (2007).

    CAS  PubMed  Google Scholar 

  124. Löfstedt, T. et al. HIF-1α induces MXI1 by alternate promoter usage in human neuroblastoma cells. Exp. Cell Res. 315, 1924–1936 (2009).

    PubMed  Google Scholar 

  125. Schreiber-Agus, N. et al. An amino-terminal domain of Mxi1 mediates anti-Myc oncogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3. Cell 80, 777–786 (1995).

    CAS  PubMed  Google Scholar 

  126. Gordan, J. D. et al. HIF-α effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14, 435–446 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Li, J. L. et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res. 67, 11244–11253 (2007).

    CAS  PubMed  Google Scholar 

  128. Diez, H. et al. Hypoxia-mediated activation of Dll4–Notch–Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Exp. Cell Res. 313, 1–9 (2007).

    CAS  PubMed  Google Scholar 

  129. Sahlgren, C., Gustafsson, M. V., Jin, S., Poellinger, L. & Lendahl, U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc. Natl Acad. Sci USA 105, 6392–6397 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Gustafsson, M. V. et al. Hypoxia requires Notch signaling to maintain the undifferentiated cell state. Dev. Cell 9, 617–628 (2005). This paper provides a mechanism for how hypoxia impacts differentiation.

    CAS  PubMed  Google Scholar 

  131. Bertout, J. A. et al. Heterozygosity for hypoxia inducible factor 1α decreases the incidence of thymic lymphomas in a p53 mutant mouse model. Cancer Res. 69, 3213–3220 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Coleman, M. L. et al. Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor. J. Biol. Chem. 282, 24027–24038 (2007).

    CAS  PubMed  Google Scholar 

  133. Zheng, X. et al. Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways. Proc. Natl Acad. Sci. USA 105, 3368–3373 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Wilkins, S. E. et al. Differences in hydroxylation and binding of Notch and HIF-1α demonstrate substrate selectivity for factor inhibiting HIF-1 (FIH-1). Int. J. Biochem. Cell Biol. 41, 1563–1571 (2009).

    CAS  PubMed  Google Scholar 

  135. Cockman, M. E., Webb, J. D., Kramer, H. B., Kessler, B. M. & Ratcliffe, P. J. Proteomics-based identification of novel factor inhibiting hypoxia-inducible factor (FIH) substrates indicates widespread asparaginyl hydroxylation of ankyrin repeat domain-containing proteins. Mol. Cell. Proteomics 8, 535–546 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Tien, A. C. et al. Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12–Notch repeats in Drosophila melanogaster. J. Cell Biol. 182, 1113–1125 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Prasad, S. M. et al. Continuous hypoxic culturing maintains activation of Notch and allows long-term propagation of human embryonic stem cells without spontaneous differentiation. Cell Prolif. 42, 63–74 (2009).

    CAS  PubMed  Google Scholar 

  138. Jögi, A. et al. Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc. Natl Acad. Sci. USA 99, 7021–7026 (2002).

    PubMed  PubMed Central  Google Scholar 

  139. Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).

    CAS  PubMed  Google Scholar 

  140. Xie, L. et al. Oxygen-regulated β2-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. Sci. Signal. 2, ra33 (2009). This study identifies a substrate for PHDs that is distinct from the HIFα proteins.

    PubMed  PubMed Central  Google Scholar 

  141. Cook, K. M. et al. Epidithiodiketopiperazines block the interaction between hypoxia inducible factor-1α (HIF-1α) and p300 by a zinc ejection mechanism. J. Biol. Chem. 284, 26831–26838 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize that we are unable to discuss all observations that are relevant to the modulation of HIF function owing to space limitations. This work was supported by the Swedish Research Council, the Swedish Cancer Society, the European Union, the Singapore National Research Foundation and the Singapore Ministry of Education under the Research Center of Excellence Programme.

Author information

Authors and Affiliations

  1. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, SE-171 77, Sweden

    Urban Lendahl & Lorenz Poellinger

  2. The Cancer Science Institute of Singapore, The National University of Singapore, 117456, Singapore

    Kian Leong Lee & Lorenz Poellinger

  3. The Singapore Immunology Network, Agency for Science, Technology and Research, 138648, Singapore

    Henry Yang

Authors
  1. Urban Lendahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kian Leong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henry Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lorenz Poellinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lorenz Poellinger.

Related links

Related links

DATABASES

OMIM

Chuvash polycythaemia

FURTHER INFORMATION

NCBI Gene Expression Omnibus database

European Bioinformatics Institute ArrayExpress database

Glossary

Oxidative phosphorylation

An aerobic, oxygen-dependent process in which electrons are transferred from electron donors to acceptors through a series of redox reactions in mitochondria. The resulting proton gradient across the inner mitochondrial membrane is used to make ATP from NADH produced, for example, by the citric acid cycle or glycolysis.

Glycolysis

The metabolic pathway that converts glucose to pyruvate, which is accompanied by energy generation in the form of ATP and NADH. Monosaccharides, such as fructose and galactose, can also be metabolized in the glycolytic pathway. Under anaerobic conditions, pyruvate can be further processed to lactate. Glycolysis produces considerably less ATP per metabolized glucose molecule than oxidative phosphorylation.

Familial erythrocytosis

Erythrocytosis is an increase in the number of red blood cells caused, for example, by emphysema, heart failure or respiratory diseases. The familial form is a rare inherited disorder in which the increase in red blood cells is not accompanied by an increase in white blood cells.

Chuvash polycythaemia

A disease in which excess numbers of red blood cells are formed, which is often associated with elevated haematocrit levels. Some forms of polycythaemia are caused by defects in the bone marrow or increased erythropoietin production, whereas the familial form, Chuvash polycythaemia, is caused by mutations in the von Hippel–Lindau protein.

Gluconeogenesis

A metabolic pathway that is used to maintain cellular or blood glucose levels and to avoid hypoglycaemia. In gluconeogenesis, glucose is generated from non-carbohydrates, such as lactate, glycerol and amino acids.

Warburg effect

The observation by Warburg in the 1920s that, in contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate energy, tumour cells exhibit increased aerobic glycolysis and use of glucose. Although aerobic glycolysis was initially proposed by Warburg to be due to mitochondrial impairment, recent studies have shown a preferential switch to glycolysis in tumour cells with functional mitochondria.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lendahl, U., Lee, K., Yang, H. et al. Generating specificity and diversity in the transcriptional response to hypoxia. Nat Rev Genet 10, 821–832 (2009). https://doi.org/10.1038/nrg2665

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2665

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing