Journal of Molecular Medicine

, Volume 93, Issue 6, pp 599–608 | Cite as

Nuclear-cytoplasmatic shuttling of proteins in control of cellular oxygen sensing

  • Reinhard DeppingEmail author
  • Wolfgang Jelkmann
  • Friederike Katharina Kosyna


In order to pass through the nuclear pore complex, proteins larger than ∼40 kDa require specific nuclear transport receptors. Defects in nuclear-cytoplasmatic transport affect fundamental processes such as development, inflammation and oxygen sensing. The transcriptional response to O2 deficiency is controlled by hypoxia-inducible factors (HIFs). These are heterodimeric transcription factors of each ∼100–120 kDa proteins, consisting of one out of three different O2-labile α subunits (primarily HIF-1α) and a more constitutive 1β subunit. In the presence of O2, the α subunits are hydroxylated by specific prolyl-4-hydroxylase domain proteins (PHD1, PHD2, and PHD3) and an asparaginyl hydroxylase (factor inhibiting HIF-1, FIH-1). The prolyl hydroxylation causes recognition by von Hippel-Lindau tumor suppressor protein (pVHL), ubiquitination, and proteasomal degradation. The activity of the oxygen sensing machinery depends on dynamic intracellular trafficking. Nuclear import of HIF-1α and HIF-1β is mainly mediated by importins α and β (α/β). HIF-1α can shuttle between nucleus and cytoplasm, while HIF-1β is permanently inside the nucleus. pVHL is localized to both compartments. Nuclear import of PHD1 relies on a nuclear localization signal (NLS) and uses the classical import pathway involving importin α/β receptors. PHD2 shows an atypical NLS, and its nuclear import does not occur via the classical pathway. PHD2-mediated hydroxylation of HIF-1α occurs predominantly in the cell nucleus. Nuclear export of PHD2 involves a nuclear export signal (NES) in the N-terminus and depends on the export receptor chromosome region maintenance 1 (CRM1). Nuclear import of PHD3 is mediated by importin α/β receptors and depends on a non-classical NLS. Specific modification of the nuclear translocation of the three PHD isoforms could provide a promising strategy for the development of new therapeutic substances to tackle major diseases.


Hypoxia-inducible factors (HIF) Importin Nuclear export Nuclear import HIF prolyl hydroxylases (PHD) 



The authors gratefully acknowledge financial support by the “Werner and Klara Kreitz-Stiftung” and the “Sektion Medizin an der Universität zu Lübeck J19-2015”. The authors wish to thank G. Fletschinger for preparing the artwork.


  1. 1.
    Görlich D, Kutay U (1999) Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol 15:607–660PubMedGoogle Scholar
  2. 2.
    Tran EJ, King MC, Corbett AH (2014) Macromolecular transport between the nucleus and the cytoplasm: advances in mechanism and emerging links to disease. Biochim Biophys Acta 1843:2784–2795PubMedGoogle Scholar
  3. 3.
    Lange A, Mills RE, Lange CJ, Stewart M, Devine SE, Corbett AH (2007) Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem 282:5101–5105PubMedGoogle Scholar
  4. 4.
    Conti E, Uy M, Leighton L, Blobel G, Kuriyan J (1998) Crystallographic analysis of the recognition of a nuclear localization signal by the nuclear import factor karyopherin alpha. Cell 94:193–204PubMedGoogle Scholar
  5. 5.
    Fontes MR, Teh T, Kobe B (2000) Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-alpha. J Mol Biol 297:1183–1194PubMedGoogle Scholar
  6. 6.
    Friedrich B, Quensel C, Sommer T, Hartmann E, Kohler M (2006) Nuclear localization signal and protein context both mediate importin alpha specificity of nuclear import substrates. Mol Cell Biol 26:8697–8709PubMedCentralPubMedGoogle Scholar
  7. 7.
    Fagerlund R, Melen K, Cao X, Julkunen I (2008) NF-kappaB p52, RelB and c-Rel are transported into the nucleus via a subset of importin alpha molecules. Cell Signal 20:1442–1451PubMedGoogle Scholar
  8. 8.
    Riddick G, Macara IG (2007) The adapter importin-alpha provides flexible control of nuclear import at the expense of efficiency. Mol Syst Biol 3:118PubMedCentralPubMedGoogle Scholar
  9. 9.
    Kimura M, Imamoto N (2014) Biological significance of the importin-beta family-dependent nucleocytoplasmic transport pathways. Traffic 15:727–748PubMedGoogle Scholar
  10. 10.
    Flores K, Seger R (2013) Stimulated nuclear import by beta-like importins. F1000Prime Rep 5:41PubMedCentralPubMedGoogle Scholar
  11. 11.
    Chook YM, Suel KE (2011) Nuclear import by karyopherin-betas: recognition and inhibition. Biochim Biophys Acta 1813:1593–1606PubMedCentralPubMedGoogle Scholar
  12. 12.
    Magnani M, Crinelli R, Bianchi M, Antonelli A (2000) The ubiquitin-dependent proteolytic system and other potential targets for the modulation of nuclear factor-kB (NF-kB). Curr Drug Targets 1:387–399PubMedGoogle Scholar
  13. 13.
    la Cour T, Kiemer L, Molgaard A, Gupta R, Skriver K, Brunak S (2004) Analysis and prediction of leucine-rich nuclear export signals. Protein Eng Des Sel 17:527–536PubMedGoogle Scholar
  14. 14.
    Kutay U, Guttinger S (2005) Leucine-rich nuclear-export signals: born to be weak. Trends Cell Biol 15:121–124PubMedGoogle Scholar
  15. 15.
    Hutten S, Kehlenbach RH (2007) CRM1-mediated nuclear export: to the pore and beyond. Trends Cell Biol 17:193–201PubMedGoogle Scholar
  16. 16.
    Semenza GL (2013) HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest 123:3664–3671PubMedCentralPubMedGoogle Scholar
  17. 17.
    Huenniger K, Kramer A, Soom M, Chang I, Kohler M, Depping R, Kehlenbach RH, Kaether C (2010) Notch1 signaling is mediated by importins alpha 3, 4, and 7. Cell Mol Life Sci 67:3187–3196PubMedCentralPubMedGoogle Scholar
  18. 18.
    Jang AR, Moravcevic K, Saez L, Young MW, Sehgal A (2015) Drosophila TIM binds importin alpha1, and acts as an adapter to transport PER to the nucleus. PLoS Genet 11:e1004974PubMedCentralPubMedGoogle Scholar
  19. 19.
    Depping R, Steinhoff A, Schindler SG, Friedrich B, Fagerlund R, Metzen E, Hartmann E, Kohler M (2008) Nuclear translocation of hypoxia-inducible factors (HIFs): Involvement of the classical importin alpha/beta pathway. Biochim Biophys Acta 1783:394–404PubMedGoogle Scholar
  20. 20.
    Suarez-Sanchez R, Aguilar A, Wagstaff KM, Velez G, Zuara-Medina PM, Gomez P, Vasquez-Limeta A, Hernandez-Hernandez O, Lieu KG, Jans DA et al (2014) Nucleocytoplasmic shuttling of the Duchenne muscular dystrophy gene product dystrophin Dp71d is dependent on the importin alpha/beta and CRM1 nuclear transporters and microtubule motor dynein. Biochim Biophys Acta 1843:985–1001PubMedGoogle Scholar
  21. 21.
    Takeda E, Murakami T, Matsuda G, Murakami H, Zako T, Maeda M, Aida Y (2011) Nuclear exportin receptor CAS regulates the NPI-1-mediated nuclear import of HIV-1 Vpr. PLoS One 6:e27815PubMedCentralPubMedGoogle Scholar
  22. 22.
    Ao Z, Danappa JK, Wang B, Zheng Y, Kung S, Rassart E, Depping R, Kohler M, Cohen EA, Yao X (2010) Importin alpha3 interacts with HIV-1 integrase and contributes to HIV-1 nuclear import and replication. J Virol 84:8650–8663PubMedCentralPubMedGoogle Scholar
  23. 23.
    Panchal M, Rawat K, Kumar G, Kibria KM, Singh S, Kalamuddin M, Mohmmed A, Malhotra P, Tuteja R (2014) Plasmodium falciparum signal recognition particle components and anti-parasitic effect of ivermectin in blocking nucleo-cytoplasmic shuttling of SRP. Cell Death Dis 5:e994PubMedCentralPubMedGoogle Scholar
  24. 24.
    Fagerlund R, Kinnunen L, Kohler M, Julkunen I, Melen K (2005) NF-{kappa}B is transported into the nucleus by importin {alpha}3 and importin {alpha}4. J Biol Chem 280:15942–15951PubMedGoogle Scholar
  25. 25.
    Kim IS, Kim DH, Han SM, Chin MU, Nam HJ, Cho HP, Choi SY, Song BJ, Kim ER, Bae YS et al (2000) Truncated form of importin alpha identified in breast cancer cell inhibits nuclear import of p53. J Biol Chem 275:23139–23145PubMedGoogle Scholar
  26. 26.
    Depping R, Schindler SG, Jacobi C, Kirschner KM, Scholz H (2012) Nuclear transport of Wilms’ tumour protein Wt1 involves importins alpha and beta. Cell Physiol Biochem 29:223–232PubMedGoogle Scholar
  27. 27.
    Nagara Y, Tateishi T, Yamasaki R, Hayashi S, Kawamura M, Kikuchi H, Iinuma KM, Tanaka M, Iwaki T, Matsushita T et al (2013) Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1alpha in amyotrophic lateral sclerosis. Brain Pathol 23:534–546PubMedGoogle Scholar
  28. 28.
    Kose S, Imamoto N (2014) Nucleocytoplasmic transport under stress conditions and its role in HSP70 chaperone systems. Biochim Biophys Acta 1840:2953–2960PubMedGoogle Scholar
  29. 29.
    Jo S, Kallo I, Bardoczi Z, Drigo A e, Drigo A e, Zeold A, Liposits Z, Oliva A, Lemmon VP, Bixby JL et al (2012) Neuronal hypoxia induces Hsp40-mediated nuclear import of type 3 deiodinase as an adaptive mechanism to reduce cellular metabolism. J Neurosci 32:8491–8500PubMedCentralPubMedGoogle Scholar
  30. 30.
    Crampton N, Kodiha M, Shrivastava S, Umar R, Stochaj U (2009) Oxidative stress inhibits nuclear protein export by multiple mechanisms that target FG nucleoporins and Crm1. Mol Biol Cell 20:5106–5116PubMedCentralPubMedGoogle Scholar
  31. 31.
    Ho JJ, Metcalf JL, Yan MS, Turgeon PJ, Wang JJ, Chalsev M, Petruzziello-Pellegrini TN, Tsui AK, He JZ, Dhamko H et al (2012) Functional importance of Dicer protein in the adaptive cellular response to hypoxia. J Biol Chem 287:29003–29020PubMedCentralPubMedGoogle Scholar
  32. 32.
    Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–634PubMedCentralPubMedGoogle Scholar
  33. 33.
    Mandl M, Kapeller B, Lieber R, Macfelda K (2013) Hypoxia-inducible factor-1beta (HIF-1beta) is upregulated in a HIF-1alpha-dependent manner in 518A2 human melanoma cells under hypoxic conditions. Biochem Biophys Res Commun 434:166–172PubMedGoogle Scholar
  34. 34.
    Mandl M, Depping R (2014) Hypoxia-inducible aryl hydrocarbon receptor nuclear translocator (ARNT) (HIF-1beta): is it a rare exception? Mol Med 20:215–220PubMedCentralPubMedGoogle Scholar
  35. 35.
    Epstein ACR, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A et al (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54PubMedGoogle Scholar
  36. 36.
    Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK (2002) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16:1466–1471PubMedCentralPubMedGoogle Scholar
  37. 37.
    Hon WC, Wilson MI, Harlos K, Claridge TD, Schofield CJ, Pugh CW, Maxwell PH, Ratcliffe PJ, Stuart DI, Jones EY (2002) Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature 417:975–978PubMedGoogle Scholar
  38. 38.
    Jiang BH, Semenza GL, Bauer C, Marti HH (1996) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol 271:C1172–C1180PubMedGoogle Scholar
  39. 39.
    Wang GL, Semenza GL (1995) Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270:1230–1237PubMedGoogle Scholar
  40. 40.
    Kallio PJ, Okamoto K, O'Brien S, Carrero P, Makino Y, Tanaka H, Poellinger L (1998) Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha. EMBO J 17:6573–6586PubMedCentralPubMedGoogle Scholar
  41. 41.
    Luo JC, Shibuya M (2001) A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (1alpha, 2alpha and 3alpha). Oncogene 20:1435–1444PubMedGoogle Scholar
  42. 42.
    Chachami G, Paraskeva E, Mingot JM, Braliou GG, Gorlich D, Simos G (2009) Transport of hypoxia-inducible factor HIF-1alpha into the nucleus involves importins 4 and 7. Biochem Biophys Res Commun 390:235–240PubMedGoogle Scholar
  43. 43.
    Mylonis I, Chachami G, Paraskeva E, Simos G (2008) Atypical CRM1-dependent nuclear export signal mediates regulation of hypoxia-inducible factor-1alpha by MAPK. J Biol Chem 283:27620–27627PubMedGoogle Scholar
  44. 44.
    Tian H, McKnight SL, Russell DW (1997) Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11:72–82PubMedGoogle Scholar
  45. 45.
    Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii KY (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A 94:4273–4278PubMedCentralPubMedGoogle Scholar
  46. 46.
    Flamme I, Frohlich T, von Reutern M, Kappel A, Damert A, Risau W (1997) HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1α and developmentally expressed in blood vessels. Mech Dev 63:51–60PubMedGoogle Scholar
  47. 47.
    O'Rourke JF, Tian YM, Ratcliffe PJ, Pugh CW (1999) Oxygen-regulated and transactivating domains in endothelial PAS protein 1: comparison with hypoxia-inducible factor-1alpha. J Biol Chem 274:2060–2071PubMedGoogle Scholar
  48. 48.
    Zhao J, Du F, Shen G, Zheng F, Xu B (2015) The role of hypoxia-inducible factor-2 in digestive system cancers. Cell Death Dis 6:e1600PubMedGoogle Scholar
  49. 49.
    Keith B, Johnson RS, Simon MC (2011) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22PubMedCentralPubMedGoogle Scholar
  50. 50.
    Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC (2003) Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 23:9361–9374PubMedCentralPubMedGoogle Scholar
  51. 51.
    Warnecke C, Zaborowska Z, Kurreck J, Erdmann VA, Frei U, Wiesener M, Eckardt KU (2004) Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. FASEB J 18:1462–1464PubMedGoogle Scholar
  52. 52.
    Makino Y, Kanopka A, Wilson WJ, Tanaka H, Poellinger L (2002) Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3α locus. J Biol Chem 277:32405–32408PubMedGoogle Scholar
  53. 53.
    Heikkila M, Pasanen A, Kivirikko KI, Myllyharju J (2011) Roles of the human hypoxia-inducible factor (HIF)-3alpha variants in the hypoxia response. Cell Mol Life Sci 68:3885–3901PubMedGoogle Scholar
  54. 54.
    Yamashita T, Ohneda O, Nagano M, Iemitsu M, Makino Y, Tanaka H, Miyauchi T, Goto K, Ohneda K, Fujii-Kuriyama Y et al (2008) Abnormal heart development and lung remodeling in mice lacking the hypoxia-inducible factor-related basic helix-loop-helix PAS protein NEPAS. Mol Cell Biol 28:1285–1297PubMedCentralPubMedGoogle Scholar
  55. 55.
    Hara S, Hamada J, Kobayashi C, Kondo Y, Imura N (2001) Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: suppression of HIF-mediated gene expression by HIF-3alpha. Biochem Biophys Res Commun 287:808–813PubMedGoogle Scholar
  56. 56.
    Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414:550–554PubMedGoogle Scholar
  57. 57.
    Maynard MA, Evans AJ, Hosomi T, Hara S, Jewett MA, Ohh M (2005) Human HIF-3alpha4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma. FASEB J 19:1396–1406PubMedGoogle Scholar
  58. 58.
    Torii S, Goto Y, Ishizawa T, Hoshi H, Goryo K, Yasumoto K, Fukumura H, Sogawa K (2011) Pro-apoptotic activity of inhibitory PAS domain protein (IPAS), a negative regulator of HIF-1, through binding to pro-survival Bcl-2 family proteins. Cell Death Differ 18:1711–1725PubMedCentralPubMedGoogle Scholar
  59. 59.
    Myllyharju J (2013) Prolyl 4-hydroxylases, master regulators of the hypoxia response. Acta Physiol (Oxf) 208:148–165Google Scholar
  60. 60.
    Katschinski DM (2009) In vivo functions of the prolyl-4-hydroxylase domain oxygen sensors: direct route to the treatment of anaemia and the protection of ischaemic tissues. Acta Physiol (Oxf) 195:407–414Google Scholar
  61. 61.
    Oehme F, Ellinghaus P, Kolkhof P, Smith TJ, Ramakrishnan S, Hütter J, Schramm M, Flamme I (2002) Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem Biophys Res Commun 296:343–349PubMedGoogle Scholar
  62. 62.
    Cioffi CL, Liu XQ, Kosinski PA, Garay M, Bowen BR (2003) Differential regulation of HIF-1α prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells. Biochem Biophys Res Commun 303:947–953PubMedGoogle Scholar
  63. 63.
    Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM (2004) Differential function of the prolyl hydroxylases, PHD1, 2 and 3 in the regulation of hypoxia inducible factor (HIF). J Biol Chem 279:38458–38465PubMedGoogle Scholar
  64. 64.
    Koivunen P, Tiainen P, Hyvarinen J, Williams KE, Sormunen R, Klaus SJ, Kivirikko KI, Myllyharju J (2007) An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor alpha. J Biol Chem 282:30544–30552PubMedGoogle Scholar
  65. 65.
    Mylonis I, Chachami G, Samiotaki M, Panayotou G, Paraskeva E, Kalousi A, Georgatsou E, Bonanou S, Simos G (2006) Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor 1α. J Biol Chem 281:33095–33106PubMedGoogle Scholar
  66. 66.
    Carbonaro M, Escuin D, O'Brate A, Thadani-Mulero M, Giannakakou P (2012) Microtubules regulate hypoxia-inducible factor-1alpha protein trafficking and activity: implications for taxane therapy. J Biol Chem 287:11859–11869PubMedCentralPubMedGoogle Scholar
  67. 67.
    Vandromme M, Gauthier-Rouviere C, Lamb N, Fernandez A (1996) Regulation of transcription factor localization: fine-tuning of gene expression. Trends Biochem Sci 21:59–64PubMedGoogle Scholar
  68. 68.
    Ahluwalia A, Narula J, Jones MK, Deng X, Tarnawski AS (2010) Impaired angiogenesis in aging myocardial microvascular endothelial cells is associated with reduced importin alpha and decreased nuclear transport of HIF1 alpha: mechanistic implications. J Physiol Pharmacol 61:133–139PubMedGoogle Scholar
  69. 69.
    Nardozzi JD, Lott K, Cingolani G (2010) Phosphorylation meets nuclear import: a review. Cell Commun Signal 8:32PubMedCentralPubMedGoogle Scholar
  70. 70.
    Pichler A, Melchior F (2002) Ubiquitin-related modifier SUMO1 and nucleocytoplasmic transport. Traffic 3:381–387PubMedGoogle Scholar
  71. 71.
    Golan M, Mabjeesh NJ (2013) SEPT9_i1 is required for the association between HIF-1alpha and importin-alpha to promote efficient nuclear translocation. Cell Cycle 12:2297–2308PubMedCentralPubMedGoogle Scholar
  72. 72.
    Torii S, Sakaki K, Otomo M, Saka K, Yasumoto K, Sogawa K (2013) Nucleocytoplasmic shuttling of IPAS by its unique nuclear import and export signals unshared with other HIF-3alpha splice variants. J Biochem 154:561–567PubMedGoogle Scholar
  73. 73.
    Eguchi H, Ikuta T, Tachibana T, Yoneda Y, Kawajiri K (1997) A nuclear localization signal of human aryl hydrocarbon receptor nuclear translocator/hypoxia-inducible factor 1beta is a novel bipartite type recognized by the two components of nuclear pore-targeting complex. J Biol Chem 272:17640–17647PubMedGoogle Scholar
  74. 74.
    Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92:5510–5514PubMedCentralPubMedGoogle Scholar
  75. 75.
    Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L (1997) Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc Natl Acad Sci U S A 94:5667–5672PubMedCentralPubMedGoogle Scholar
  76. 76.
    Mandl M, Depping R (2014) Hypoxia-inducible ARNT (HIF-1beta): a rare exception? Mol Med 10Google Scholar
  77. 77.
    Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, Huang WQ, Wotzlaw C, Hellwig-Buergel T, Jelkmann W et al (2003) Intracellular localisation of human HIF-1α hydroxylases: implications for oxygen sensing. J Cell Sci 116:1319–1326PubMedGoogle Scholar
  78. 78.
    Steinhoff A, Pientka FK, Mockel S, Kettelhake A, Hartmann E, Kohler M, Depping R (2009) Cellular oxygen sensing: Importins and exportins are mediators of intracellular localisation of prolyl-4-hydroxylases PHD1 and PHD2. Biochem Biophys Res Commun 387:705–711PubMedGoogle Scholar
  79. 79.
    Wotzlaw C, Gneuss S, Konietzny R, Fandrey J (2010) Nanoscopy of the cellular response to hypoxia by means of fluorescence resonance energy transfer (FRET) and new FRET software. PMC Biophys 3:5PubMedCentralPubMedGoogle Scholar
  80. 80.
    Yasumoto K, Kowata Y, Yoshida A, Torii S, Sogawa K (2009) Role of the intracellular localization of HIF-prolyl hydroxylases. Biochim Biophys Acta 1793:792–797PubMedGoogle Scholar
  81. 81.
    Berchner-Pfannschmidt U, Tug S, Trinidad B, Oehme F, Yamac H, Wotzlaw C, Flamme I, Fandrey J (2008) Nuclear oxygen sensing: induction of endogenous prolyl-hydroxylase 2 activity by hypoxia and nitric oxide. J Biol Chem 283:31745–31753PubMedGoogle Scholar
  82. 82.
    Berra E, Roux D, Richard DE, Pouyssegur J (2001) Hypoxia-inducible factor-1α (HIF-1α) escapes O2-driven proteasomal degradation irrespective of its subcellular localization: nucleus or cytoplasm. EMBO J 2:615–620Google Scholar
  83. 83.
    Jokilehto T, Rantanen K, Luukkaa M, Heikkinen P, Grenman R, Minn H, Kronqvist P, Jaakkola PM (2006) Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness. Clin Cancer Res 12:1080–1087PubMedGoogle Scholar
  84. 84.
    Soilleux EJ, Turley H, Tian YM, Pugh CW, Gatter KC, Harris AL (2005) Use of novel monoclonal antibodies to determine the expression and distribution of the hypoxia regulatory factors PHD-1, PHD-2, PHD-3 and FIH in normal and neoplastic human tissues. Histopathology 47:602–610PubMedGoogle Scholar
  85. 85.
    Pientka FK, Hu J, Schindler S, Brix B, Johren O, Fandrey J, Berchner-Pfannschmidt U, Depping R (2012) Oxygen sensing by prolyl-4-hydroxylase PHD2 within the nuclear compartment and the influence of compartimentalization on HIF-1 signaling. J Cell Sci 125:5168–5176PubMedGoogle Scholar
  86. 86.
    McDonough MA, Li V, Flashman E, Chowdhury R, Mohr C, Lienard BM, Zondlo J, Oldham NJ, Clifton IJ, Lewis J et al (2006) Cellular oxygen sensing: crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). Proc Natl Acad Sci U S A 103:9814–9819PubMedCentralPubMedGoogle Scholar
  87. 87.
    Groulx I, Lee S (2002) Oxygen-dependent ubiquitination and degradation of hypoxia-inducible factor requires nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor protein. Mol Cell Biol 22:5319–5336PubMedCentralPubMedGoogle Scholar
  88. 88.
    Takeda K, Ho VC, Takeda H, Duan LJ, Nagy A, Fong GH (2006) Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2. Mol Cell Biol 26:8336–8346PubMedCentralPubMedGoogle Scholar
  89. 89.
    Takeda K, Cowan A, Fong GH (2007) Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system. Circulation 116:774–781PubMedGoogle Scholar
  90. 90.
    Takeda K, Aguila HL, Parikh NS, Li X, Lamothe K, Duan LJ, Takeda H, Lee FS, Fong GH (2008) Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood 111:3229–3235PubMedCentralPubMedGoogle Scholar
  91. 91.
    Shin D, Jeon JH, Jeong M, Suh HW, Kim S, Kim HC, Moon OS, Kim YS, Chung JW, Yoon SR et al (2008) VDUP1 mediates nuclear export of HIF1alpha via CRM1-dependent pathway. Biochim Biophys Acta 1783:838–848PubMedGoogle Scholar
  92. 92.
    Huang J, Zhao Q, Mooney SM, Lee FS (2002) Sequence determinants in hypoxia inducible factor-1α for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J Biol Chem 277:39792–39800PubMedCentralPubMedGoogle Scholar
  93. 93.
    Hilz A, Schillinger T, Schindler S, Köster M, Depping R (2007) Characterisation of NLS in human PHD1 and PHD3. FEBS J 274Google Scholar
  94. 94.
    Linke S, Stojkoski C, Kewley RJ, Booker GW, Whitelaw ML, Peet DJ (2004) Substrate requirements of the oxygen-sensing asparaginyl hydroxylase factor-inhibiting hypoxia-inducible factor. J Biol Chem 279:14391–14397PubMedGoogle Scholar
  95. 95.
    Groulx I, Lee S (2002) Oxygen-dependent ubiquitination and degradation of hypoxia-inducible factor requires nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor protein. Mol Cell Biol 22:5319–5336PubMedCentralPubMedGoogle Scholar
  96. 96.
    Khacho M, Mekhail K, Pilon-Larose K, Payette J, Lee S (2008) Cancer-causing mutations in a novel transcription-dependent nuclear export motif of VHL abrogate oxygen-dependent degradation of hypoxia-inducible factor. Mol Cell Biol 28:302–314PubMedCentralPubMedGoogle Scholar
  97. 97.
    Khacho M, Lee S (2009) Subcellular dynamics of the VHL tumor suppressor: on the move for HIF degradation. Future Oncol 5:85–95PubMedGoogle Scholar
  98. 98.
    Cai Q, Robertson ES (2010) Ubiquitin/SUMO modification regulates VHL protein stability and nucleocytoplasmic localization. PLoS One 5:e12636PubMedCentralPubMedGoogle Scholar
  99. 99.
    Jokilehto T, Hogel H, Heikkinen P, Rantanen K, Elenius K, Sundstrom J, Jaakkola PM (2010) Retention of prolyl hydroxylase PHD2 in the cytoplasm prevents PHD2-induced anchorage-independent carcinoma cell growth. Exp Cell Res 316:1169–1178PubMedGoogle Scholar
  100. 100.
    Jokilehto T, Jaakkola PM (2010) The role of HIF prolyl hydroxylases in tumour growth. J Cell Mol Med 14:758–770PubMedCentralPubMedGoogle Scholar
  101. 101.
    Luukkaa M, Jokilehto T, Kronqvist P, Vahlberg T, Grenman R, Jaakkola P, Minn H (2009) Expression of the cellular oxygen sensor PHD2 (EGLN-1) predicts radiation sensitivity in squamous cell cancer of the head and neck. Int J Radiat Biol 85:900–908PubMedGoogle Scholar
  102. 102.
    Couvelard A, Deschamps L, Rebours V, Sauvanet A, Gatter K, Pezzella F, Ruszniewski P, Bedossa P (2008) Overexpression of the oxygen sensors PHD-1, PHD-2, PHD-3, and FIH Is associated with tumor aggressiveness in pancreatic endocrine tumors. Clin Cancer Res 14:6634–6639PubMedGoogle Scholar
  103. 103.
    Chan DA, Sutphin PD, Yen SE, Giaccia AJ (2005) Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1 alpha. Mol Cell Biol 25:6415–6426PubMedCentralPubMedGoogle Scholar
  104. 104.
    Ozer A, Wu LC, Bruick RK (2005) The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci U S A 102:7481–7486PubMedCentralPubMedGoogle Scholar
  105. 105.
    Ranganathan P, Yu X, Na C, Santhanam R, Shacham S, Kauffman M, Walker A, Klisovic R, Blum W, Caligiuri M et al (2012) Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood 120:1765–1773PubMedCentralPubMedGoogle Scholar
  106. 106.
    Mallavia B, Recio C, Oguiza A, Ortiz-Munoz G, Lazaro I, Lopez-Parra V, Lopez-Franco O, Schindler S, Depping R, Egido J et al (2013) Peptide inhibitor of NF-kappaB translocation ameliorates experimental atherosclerosis. Am J Pathol 182:1910–1921PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Reinhard Depping
    • 1
    Email author
  • Wolfgang Jelkmann
    • 1
  • Friederike Katharina Kosyna
    • 1
  1. 1.Institute of Physiology, Centre for Structural and Cell Biology in MedicineUniversity of LübeckLübeckGermany

Personalised recommendations