Cellular and Molecular Life Sciences

, Volume 71, Issue 4, pp 699–710 | Cite as

The HIF-1 transcription complex is essential for translational control of myeloid hematopoietic cell function by maintaining mTOR phosphorylation

  • Inna M. Yasinska
  • Bernhard F. Gibbs
  • Gurprit S. Lall
  • Vadim V. SumbayevEmail author
Research Article


Mammalian myeloid cells are crucial effectors of host innate immune defense. Normal and pathological responses of these cells require adaptation to signaling stress through the hypoxia-inducible factor 1 (HIF-1) transcription complex. Adapted cells activate the mammalian target of rapamycin (mTOR), via S2448 phosphorylation, which induces de novo translation of vital signaling proteins. However, the molecular mechanisms underlying this signaling dogma remain unclear. Here, we demonstrate for the first time that inactivation of HIF-1, by silencing its inducible alpha subunit, significantly decreases mTOR S2448 phosphorylation caused by ligand-dependent activation of human myeloid leukemia cells. This shows that HIF-1 is essential for the activation of mTOR and serves at a crucial juncture of myeloid cell function in both in vitro and in vivo systems.


Myeloid cells Inflammation HIF-1 transcription complex mTOR (mammalian target of rapamycin) 

Supplementary material

18_2013_1421_MOESM1_ESM.pdf (534 kb)
Supplementary material 1 (PDF 533 kb)


  1. 1.
    Broudy VC (1997) Stem cell factor and hematopoiesis. Blood 90:1345–1364PubMedGoogle Scholar
  2. 2.
    Lee SJ, Yoon JH, Song KS (2007) Chrysin inhibited stem cell factor (SCF)/c-Kit complex-induced cell proliferation in human myeloid leukemia cells. Biochem Pharmacol 74:215–225PubMedCrossRefGoogle Scholar
  3. 3.
    Welker P, Grabbe J, Henz BM (2004) Differential expression of mast cell characteristics in human myeloid cell lines. Exp Dermatol 13:535–542PubMedCrossRefGoogle Scholar
  4. 4.
    Medzhitov R, Janeway C Jr (2000) Innate immunity. N Engl J Med 343:338–344PubMedCrossRefGoogle Scholar
  5. 5.
    Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511PubMedCrossRefGoogle Scholar
  6. 6.
    Kagan JC, Medzhitov R (2006) Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signalling. Cell 125:943–955PubMedCrossRefGoogle Scholar
  7. 7.
    Gibbs BF, Yasinska IM, Oniku AE, Sumbayev VV (2011) Effects of stem cell factor on hypoxia-inducible factor 1 alpha accumulation in human acute myeloid leukaemia and LAD2 mast cells. PLoS One 6:e22502PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Lopez-Pelaez M, Soria-Castro I, Bosca L, Fernandez M, Alemany S (2011) Cot/tpl2 activity is required for TLR-induced activation of the Akt p70 S6k pathway in macrophages: implications for NO synthase 2 expression. Eur J Immunol 41:1733–1741PubMedCrossRefGoogle Scholar
  9. 9.
    Dazert E, Hall MN (2011) mTOR signalling in disease. Curr Opin Cell Biol 23:744–755PubMedCrossRefGoogle Scholar
  10. 10.
    Walmsley SR, Cadwallader KA, Chilvers ER (2005) The role of HIF-1alpha in myeloid cell inflammation. Trends Immunol 26:434–439PubMedCrossRefGoogle Scholar
  11. 11.
    Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, De Berardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG, Pearce EJ (2010) Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115:4742–4749PubMedCrossRefGoogle Scholar
  12. 12.
    Dzeja P, Terzic A (2009) Adenylate kinase and AMP signalling networks: metabolic monitoring, signal communication and body energy sensing. Int J Mol Sci 10:1729–1772PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Cheng SW, Fryer LG, Carling D, Shepherd PR (2004) Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status. J Biol Chem 279:15719–15722PubMedCrossRefGoogle Scholar
  14. 14.
    Grimaldi C, Chiarini F, Tabellini G, Ricci F, Tazzari PL, Battistelli M, Falcieri E, Bortul R, Melchionda F, Iacobucci I (2012) AMP-dependent kinase/mammalian target of rapamycin complex 1 signalling in T cell acute lymphoblastic leukemia: therapeutic implications. Leukemia 26:91–100PubMedCrossRefGoogle Scholar
  15. 15.
    Hanze J, Eul BG, Savai R, Krick S, Goyal P, Grimminger F, Seeger W, Rose F (2003) RNA interference for HIF-1alpha inhibits its downstream signalling and affects cellular proliferation. Biochem Biophys Res Commun 312:571–577PubMedCrossRefGoogle Scholar
  16. 16.
    Yu EZ, Li YY, Liu XH, Kagan E, McCarron RM (2004) Antiapoptotic action of hypoxia-inducible factor-1alpha in human endothelial cells. Lab Investig 84:553–561PubMedCrossRefGoogle Scholar
  17. 17.
    Olsson T, Gulliksson H, Palmeborn M, Bergstrom K, Thore A (1983) Leakage of adenylate kinase from stored blood cells. J Appl Biochem 5:437–445PubMedGoogle Scholar
  18. 18.
    Kennedy JF, Kay IM (1975) Effects of titanium compounds on a d-glucose-d-glucose oxidase assay system. Carbohydr Res 44:291–300PubMedCrossRefGoogle Scholar
  19. 19.
    Georgescu P, Paunescu E (1960) Metode biochimie de diagnostic si cercetare. Medicala, pp 415Google Scholar
  20. 20.
    Nicholas SA, Bubnov VV, Yasinska IM, Sumbayev VV (2011) Involvement of xanthine oxidase and hypoxia-inducible factor 1 in Toll-like receptor 7/8-mediated activation of caspase 1 and interleukin-1beta. Cell Mol Life Sci 68:151–158PubMedCrossRefGoogle Scholar
  21. 21.
    Sumbayev VV, Yasinska IM, Oniku AE, Streatfield CL, Gibbs BF (2012) Involvement of hypoxia-inducible factor-1 in the inflammatory responses of human LAD2 mast cells and basophils. PLoS One 7:e34259PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Nicholas SA, Sumbayev VV (2009) The involvement of hypoxia-inducible factor 1 alpha in Toll-like receptor 7/8-mediated inflammatory response. Cell Res 19:973–983PubMedCrossRefGoogle Scholar
  23. 23.
    Spirig R, Djafarzadeh S, Regueira T, Shaw SG, von Garnier C, Takala J, Jakob SM, Rieben R, Lepper PM (2010) Effects of TLR agonists on the hypoxia-regulated transcription factor HIF-1alpha and dendritic cell maturation under normoxic conditions. PLoS One 5:e0010983PubMedCrossRefGoogle Scholar
  24. 24.
    Sumbayev VV, Nicholas SA (2010) Hypoxia-inducible factor 1 as one of the “signalling drivers” of Toll-like receptor-dependent and allergic inflammation. Arch Immunol Ther Exp (Warsz) 58:287–294CrossRefGoogle Scholar
  25. 25.
    Gaidhu MP, Fediuc S, Anthony NM, So M, Mirpourian M, Perry RLS, Ceddia RB (2009) Prolonged AICAR-induced AMP-kinase activation promotes energy dissipation in white adipocytes: novel mechanisms integrating HSL and ATGL. J Lipid Res 50:704–715PubMedCrossRefGoogle Scholar
  26. 26.
    Agani F, Jiang BH (2013) Oxygen-independent regulation of HIF-1: novel involvement of PI3K/AKT/mTOR pathway in cancer. Curr Cancer Drug Targets 13:245–251PubMedCrossRefGoogle Scholar
  27. 27.
    Liu Z, Yuan Q, Zhang X, Xiong C, Xue P, Ruan J (2012) RY10-4, a novel anti-tumor compound, exhibited its anti-angiogenesis activity by down-regulation of the HIF-1alpha and inhibition phosphorylation of AKT and mTOR. Cancer Chemother Pharmacol 69:1633–1640PubMedCrossRefGoogle Scholar
  28. 28.
    Finlay DK, Rosenzweig E, Sinclair LV, Feijoo-Carnero C, Hukelmann JL, Rolf J, Panteleyev AA, Okkenhaug K, Cantrell DA (2012) PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med 209:2441–2453PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery M, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of Raptor mediates a metabolic checkpoint. Mol Cell 30:214–226PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Inna M. Yasinska
    • 1
  • Bernhard F. Gibbs
    • 1
  • Gurprit S. Lall
    • 1
  • Vadim V. Sumbayev
    • 1
    Email author
  1. 1.Medway School of PharmacyUniversity of KentKentUK

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