Skip to main content
SpringerLink
Log in

Modelling HIF-PHD Dynamics and Related Downstream Pathways

  • Conference paper
  • First Online:
Mathematical Models and Computer Simulations for Biomedical Applications (MCHBS 2021)

Part of the book series: SEMA SIMAI Springer Series ((SEMA SIMAI,volume 33))

  • 160 Accesses

Abstract

Hypoxia can represent a challenging condition for survival at different biological scales, from cells to organisms. The efficiency of the response to decreased oxygen availability is importantly related to the Hypoxia-Inducible Factors (HIFs) that regulate the transcription of hundreds of genes whose proteins are responsible for changes in metabolism, cell cycle, vascularisation. All these downstream responses are aimed, on one side, to optimise the consumption of oxygen and, on the other side, to change the microenvironment in order to potentially create the conditions to favor oxygen delivery. In this chapter we firstly develop a mathematical model that focuses on the oxygen-dependent regulation of HIFs, on the basis of available biological experiments, we secondly use the model to mathematically investigate the role of HIFs and hypoxia on inflammation and we finally discuss the biological background of the main responses regulated by HIFs and the mathematical models that focused explicitly on HIF action.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Aik, W.S., Chowdhury, R., Clifton, I.J., Hopkinson, R.J., Leissing, T., McDonough, M.A., Nowak, R., Schofield, C.J., Walport, L.J.: Introduction to structural studies on 2-oxoglutarate-dependent oxygenases and related enzymes. In: 2-Oxoglutarate-Dependent Oxygenases, pp. 59–94. Royal Society of Chemistry Cambridge, Cambridge (2015)

    Google Scholar 

  2. Appelhoff, R.J., Tian, Y.-M., Raval, R.R., Turley, H., Harris, A.L., Pugh, C.W., Ratcliffe, P.J., Gleadle, J.M.: Differential function of the prolyl hydroxylases phd1, phd2, and phd3 in the regulation of hypoxia-inducible factor. J. Biol. Chem. 279(37), 38458–38465 (2004)

    Article  Google Scholar 

  3. Arocena, M., Landeira, M., Di Paolo, A., Silva, A., Sotelo-Silveira, J., Fernández, A., Alonso, J.: Using a variant of coverslip hypoxia to visualize tumor cell alterations at increasing distances from an oxygen source. J. Cell. Physiol. 234(10), 16671–16678 (2019)

    Article  Google Scholar 

  4. Bagnall, J., Leedale, J., Taylor, S.E., Spiller, D.G., White, M.R.H., Sharkey, K.J., Bearon, R.N., Sée, V.: Tight control of hypoxia-inducible factor-\(\alpha \) transient dynamics is essential for cell survival in hypoxia. J. Biol. Chem. 289(9), 5549–5564 (2014)

    Google Scholar 

  5. Bartsch, P., Gibbs, J.S.R.: Effect of altitude on the heart and the lungs. Circulation 116(19), 2191–2202 (2007)

    Article  Google Scholar 

  6. Beall, C.M., Cavalleri, G.L., Deng, L., Elston, R.C., Gao, Y., Knight, J., Li, C., Li, J.C., Liang, Y., McCormack, M., et al.: Natural selection on epas1 (hif2\(\alpha \)) associated with low hemoglobin concentration in tibetan highlanders. Proc. Nat. Acad. Sci. USA 107(25), 11459–11464 (2010)

    Google Scholar 

  7. Bedessem, B., Stéphanou, A.: A mathematical model of hif-1\(\alpha \)-mediated response to hypoxia on the g1/s transition. J. Math. Biosci. 248, 31–39 (2014)

    Google Scholar 

  8. Berra, E., Benizri, E., Ginouvès, A., Volmat, V., Roux, D., Pouysségur, J.: Hif prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of hif-1\(\alpha \) in normoxia. EMBO J. 22(16), 4082–4090 (2003)

    Google Scholar 

  9. Bertout, J.A., Majmundar, A.J., Gordan, J.D., Lam, J.C., Ditsworth, D., Keith, B., Brown, E.J., Nathanson, K.L., Simon, M.C.: Hif2\(\alpha \) inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc. Nat. Acad. Sci. USA 106(34), 14391–14396 (2009)

    Google Scholar 

  10. Bocharov, G., Jäger, W., Knoch, J., Neuss-Radu, M., Thiel, M.: A mathematical model of hif-1 regulated cellular energy metabolism. Vietnam J. Math. 49(1), 119–141 (2021)

    Article  MathSciNet  MATH  Google Scholar 

  11. Brand, A., Singer, K., Koehl, G.E., Kolitzus, M., Schoenhammer, G., Thiel, A., Matos, C., Bruss, C., Klobuch, S., Peter, K., et al.: Ldha-associated lactic acid production blunts tumor immunosurveillance by t and nk cells. Cell Metab. 24(5), 657–671 (2016)

    Article  Google Scholar 

  12. Butcher, D.T., Alliston, T., Weaver, V.M.: A tense situation: forcing tumour progression. Nature Rev. Cancer 9(2), 108–122 (2009)

    Article  Google Scholar 

  13. Chen, E.P., Song, R.S., Chen, X.: Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition. BMC Bioinf. 20(1), 1–15 (2019)

    Article  Google Scholar 

  14. Cogo, A.: The lung at high altitude. Multidisc. Resp. Med. 6(1), 1–2 (2011)

    Google Scholar 

  15. Corbet, C., Feron, O.: Tumour acidosis: From the passenger to the driver’s seat. Nature Rev. Cancer 17(10), 577–593 (2017)

    Article  Google Scholar 

  16. Coulibaly, A., Bettendorf, A., Kostina, E., Figueiredo, A.S., Velasquez Giraldo, S.Y., Bock, H.-G., Thiel, M., Lindner, H.A., Barbarossa, M.V.: Interleukin-15 signaling in hif-1\(\alpha \) regulation in natural killer cells, insights through mathematical models. Front. Immunol. 10(1), 2401 (2019)

    Google Scholar 

  17. Druker, J., Wilson, J.W., Child, F., Shakir, D., Fasanya, T., Rocha, S.: Role of hypoxia in the control of the cell cycle. Int. J. Molec. Sci. 22(9), 4874 (2021)

    Article  Google Scholar 

  18. Ehrismann, D., Flashman, E., Genn, D.N., Mathioudakis, N., Hewitson, K.S., Ratcliffe, P.J., Schofield, C.J.: Studies on the activity of the hypoxia-inducible-factor hydroxylases using an oxygen consumption assay. Biochem. J. 401(1), 227–234 (2007)

    Article  Google Scholar 

  19. Eltzschig, H.K., Carmeliet, P.: Hypoxia and inflammation. New Eng. J. Med. 364(7), 656–665 (2011)

    Article  Google Scholar 

  20. Ferrante, P., Preziosi, L., Scianna, M.: Modelling hypoxia-related inflammation scenarios in tumors. Math. Biosci. 355, 108952 (2023)

    Article  MATH  Google Scholar 

  21. Filatova, A., Seidel, S., Böğürcü, N., Gräf, S., Garvalov, B.K., Acker, T.: Acidosis acts through hsp90 in a phd/vhl-independent manner to promote hif function and stem cell maintenance in glioma acidosis promotes hif and glioma stem cells. Cancer Res. 76(19), 5845–5856 (2016)

    Article  Google Scholar 

  22. Gilkes, D.M., Semenza, G.L., Wirtz, D.: Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nature Rev. Cancer 14(6), 430–439 (2014)

    Article  Google Scholar 

  23. Grivennikov, S.I., Greten, F.R., Karin, M.: Immunity, inflammation, and cancer. Cell 140(6), 883–899 (2010)

    Article  Google Scholar 

  24. Hashemzadeh, S., Shahmorad, S., Rafii-Tabar, H., Omidi, Y.: Computational modeling to determine key regulators of hypoxia effects on the lactate production in the glycolysis pathway. Sci. Rep. 10(1), 1–8 (2020)

    Article  Google Scholar 

  25. Hikage, F., Atkins, S., Kahana, A., Smith, T.J., Chun, T.-H.: Hif2\(\alpha \)–lox pathway promotes fibrotic tissue remodeling in thyroid-associated orbitopathy. Endocrinology 160(1), 20–35 (2019)

    Google Scholar 

  26. Holmquist-Mengelbier, L., Fredlund, E., Löfstedt, T., Noguera, R., Navarro, S., Nilsson, H., Pietras, A., Vallon-Christersson, J., Borg, Å, Gradin, K., Poellinger, L., Pahlman, S.: Recruitment of hif-1\(\alpha \) and hif-2\(\alpha \) to common target genes is differentially regulated in neuroblastoma: Hif-2\(\alpha \) promotes an aggressive phenotype. Cancer Cell 10(5), 413–423 (2006)

    Google Scholar 

  27. Honda, T., Hirakawa, Y., Mizukami, K., Yoshihara, T., Tanaka, T., Tobita, S., Nangaku, M.: A distinctive distribution of hypoxia-inducible factor-1\(\alpha \) in cultured renal tubular cells with hypoperfusion simulated by coverslip placement. Physiol. Rep. 9(1), e14689 (2021)

    Google Scholar 

  28. Ji, F., Wang, Y., Qiu, L., Li, S., Zhu, J., Liang, Z., Wan, Y., Di, W.: Hypoxia inducible factor 1\(\alpha \)-mediated lox expression correlates with migration and invasion in epithelial ovarian cancer. Int. J. Oncol. 42(5), 1578–1588 (2013)

    Google Scholar 

  29. Jiang, B.-H., Rue, E., Wang, G.L., Roe, R., Semenza, G.L.: Dimerization, dna binding, and transactivation properties of hypoxia-inducible factor 1. J. Biol. Chem. 271(30), 17771–17778 (1996)

    Article  Google Scholar 

  30. Jiang, B.-H., Semenza, G.L., Bauer, C., Marti, H.H.: Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of o2 tension. Am. J. Physiol. Cell Physiol. 271(4):C1172–C1180 (1996)

    Article  Google Scholar 

  31. Kaelin, W.G., Ratcliffe, P.J.: Oxygen sensing by metazoans: the central role of the hif hydroxylase pathway. Molec. Cell 30(4), 393–402 (2008)

    Article  Google Scholar 

  32. Kass, L., Erler, J.T., Dembo, M., Weaver, V.M.: Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis. Int. J. Biochem. Cell Biol. 39(11), 1987–1994 (2007)

    Article  Google Scholar 

  33. Kazyken, D., Lentz, S.I., Fingar, D.C.: Alkaline intracellular ph (phi) activates ampk–mtorc2 signaling to promote cell survival during growth factor limitation. J. Biol. Chem. 297(4) (2021)

    Google Scholar 

  34. Kim, J.-W., Tchernyshyov, I., Semenza G.L., Dang, C.V.: Hif-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3(3), 177–185 (2006)

    Article  Google Scholar 

  35. Koh, M.Y., Powis, G.: Passing the baton: the hif switch. Trends Biochem. Sci. 37(9) 364–372 (2012)

    Article  Google Scholar 

  36. Koivunen, P., Hirsila, M., Kari, I.K., Myllyharju, J.: The length of peptide substrates has a marked effect on hydroxylation by the hypoxia-inducible factor prolyl 4-hydroxylases. J. Biol. Chem. 281(39), 28712–28720 (2006)

    Article  Google Scholar 

  37. Korbecki, J., Simińska, D., Gassowska-Dobrowolska, M., Listos, J., Gutowska, I., Chlubek, D., Baranowska-Bosiacka, I.: Chronic and cycling hypoxia: drivers of cancer chronic inflammation through hif-1 and nf-\(\kappa \)b activation: A review of the molecular mechanisms. Int. J. Molec. Sci. 22(19), 10701 (2021)

    Google Scholar 

  38. Lanikova, L., Reading, N.S., Hu, H., Tashi, T., Burjanivova, T., Shestakova, A., Siwakoti, B., Thakur, B.K., Pun, C.B., Sapkota, A., et al.: Evolutionary selected tibetan variants of hif pathway and risk of lung cancer. Oncotarget 8(7), 11739 (2017)

    Article  Google Scholar 

  39. Leedale, J., Herrmann, A., Bagnall, J., Fercher, A., Papkovsky, D., Sée, V., Bearon, R.N.: Modeling the dynamics of hypoxia inducible factor-1\(\alpha \) (hif-1\(\alpha \)) within single cells and 3d cell culture systems. Math. Biosci. 258, 33–43 (2014)

    Google Scholar 

  40. Liberti, M.V., Locasale, J.W.: The warburg effect: How does it benefit cancer cells? Trends Biochem. Sci. 41(3), 211–218 (2016)

    Article  Google Scholar 

  41. Lin, Q., Yun, Z.: The hypoxia-inducible factor pathway in adipocytes: the role of hif-2 in adipose inflammation and hypertrophic cardiomyopathy. Front. Endocr. 6, 39 (2015)

    Article  Google Scholar 

  42. Lorenzo, F.R., Huff, C., Myllymäki, M., Olenchock, B., Swierczek, S., Tashi, T., Gordeuk, V., Wuren, T., Ri-Li, G., Khan, T.M. McClain, D.A., Koul, P.A., Guchhait, P., Salama, M.E., Xing, J., Semenza, G.L., Liberzon, E., Wilson, A., Simonson, T.S., Jorde, L.B., Kaelin, W.G., Koivunen, P., Prchal, J.T.: A genetic mechanism for tibetan high-altitude adaptation. Nature Genet. 46(9), 951–956 (2014)

    Article  Google Scholar 

  43. Luks, A.M., Swenson, E.R., Bärtsch, P.: Acute high-altitude sickness. Eur. Resp. Rev. 26(143) (2017)

    Google Scholar 

  44. Maheshwari, R., Weis, E.: Thyroid associated orbitopathy. Indian J. Opht. 60(2), 87 (2012)

    Article  Google Scholar 

  45. McKeown, S.R.: Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response. Brit. J. Radiol. 87(1035), 20130676 (2014)

    Article  Google Scholar 

  46. Metzen, E., Berchner-Pfannschmidt, U., Stengel, P., Marxsen, J., Stolze, I., Klinger, M., Huang, W.Q., Wotzlaw, C., Hellwig-Burgel, T., Jelkmann, W., Acker, H., Fandreyothers, J.: Intracellular localisation of human hif-1\(\alpha \) hydroxylases: implications for oxygen sensing. J. Cell Sci. 116(7), 1319–1326 (2003)

    Google Scholar 

  47. Miller, A.E., Hu, P., Barker, T.H.: Feeling things out: bidirectional signaling of the cell–ecm interface, implications in the mechanobiology of cell spreading, migration, proliferation, and differentiation. Adv. Healthcare Mat. 9(8), 1901445 (2020)

    Article  Google Scholar 

  48. Mu, X., Shi, W., Xu, Y., Xu, C., Zhao, T., Geng, B., Yang, J., Pan, J., Hu, S., Zhang, C., Zhang, J., Wang, C., Shen, J., Che, Y., Liu, Z., Lv, Z., Wen, H., You, Q.: Tumor-derived lactate induces m2 macrophage polarization via the activation of the erk/stat3 signaling pathway in breast cancer. Cell Cycle 17(4), 428–438 (2018)

    Article  Google Scholar 

  49. Nguyen, L.K., Cavadas, M.A.S., Scholz, C.C., Fitzpatrick, S.F., Bruning, U., Cummins, E.P., Tambuwala, M.M., Manresa, M.C., Kholodenko, B.N., Taylor, C.T., Cheong, A.: A dynamic model of the hypoxia-inducible factor 1\(\alpha \) (hif-1\(\alpha \)) network. J. Cell Sci. 126(6), 1454–1463 (2013)

    Google Scholar 

  50. Nishi, H., Sasaki, T., Nagamitsu, Y., Terauchi, F., Nagai, T., Nagao, T., Isaka, K.: Hypoxia inducible factor-1 mediates upregulation of urokinase-type plasminogen activator receptor gene transcription during hypoxia in cervical cancer cells. Oncol. Rep. 35(2), 992–998 (2016)

    Article  Google Scholar 

  51. Papale, M., Buccarelli, M., Mollinari, C., Russo, M.A., Pallini, R., Ricci-Vitiani, L., Tafani, M.: Hypoxia, inflammation and necrosis as determinants of glioblastoma cancer stem cells progression. Int. J. Molec. Sci. 21(8), 2660 (2020)

    Article  Google Scholar 

  52. Paradise, R.K., Lauffenburger, D.A., Van Vliet, K.J.: Acidic extracellular ph promotes activation of integrin \(\alpha \)v\(\beta \)3. PLoS One 6(1), e15746 (2011)

    Google Scholar 

  53. Pektas, S., Knapp, M.J.: Substrate preference of the hif-prolyl hydroxylase-2 (phd2) and substrate-induced conformational change. J. Inorg. Biochem. 126, 55–60 (2013)

    Article  Google Scholar 

  54. Piasentin, N., Milotti, E., Chignola, R.: The control of acidity in tumor cells: A biophysical model. Sci. Rep. 10(1), 1–14 (2020)

    Article  Google Scholar 

  55. Pichiule, P., Chavez, J.C., Schmidt, A.M., Vannucci, S.J.: Hypoxia-inducible factor-1 mediates neuronal expression of the receptor for advanced glycation end products following hypoxia/ischemia. J. Biol. Chem. 282(50), 36330–36340 (2007)

    Article  Google Scholar 

  56. Pressley, M., Gallaher, J.A., Brown, J.S., Tomaszewski, M.R., Borad, P., Damaghi, M., Gillies, R.J., Whelan, C.J.: Cycling hypoxia selects for constitutive hif stabilization. Sci. Rep. 11(1), 1–14 (2021)

    Article  Google Scholar 

  57. Qutub, A.A., Popel, A.S.: Three autocrine feedback loops determine hif1\(\alpha \) expression in chronic hypoxia. J. Biochim. Biophys. Acta Molec. Cell Res. 1773(10), 1511–1525 (2007)

    Google Scholar 

  58. Robey, I.F., Lien, A.D., Welsh, S.J., Baggett, B.K., Gillies, R.J.: Hypoxia-inducible factor-1\(\alpha \) and the glycolytic phenotype in tumors. Neoplasia 7(4), 324–330 (2005)

    Google Scholar 

  59. Robinson, P.J., Hack, C.E.: Mathematical model of hif-1\(\alpha \) pathway, oxygen transport and hypoxia. Internal Report U.S. Army, AFRL-RH-WP-TR-2017-0080 (2017)

    Google Scholar 

  60. Ronen, R., Zhou, D., Bafna, V., Haddad, G.G.: The genetic basis of chronic mountain sickness. Physiology 29(6), 403–412 (2014)

    Article  Google Scholar 

  61. Salmond, R.J.: mtor regulation of glycolytic metabolism in t cells. Front. Cell Dev. Biol. 6, 122 (2018)

    Google Scholar 

  62. Schmierer, B., Novák, B., Schofield, C.J.: Hypoxia-dependent sequestration of an oxygen sensor by a widespread structural motif can shape the hypoxic response - a predictive kinetic model. BMC Syst. Biol. 4(1), 139 (2010)

    Article  Google Scholar 

  63. Semenza, G.L.: Hydroxylation of hif-1: oxygen sensing at the molecular level. Physiology 19(4), 176–182 (2004)

    Article  Google Scholar 

  64. Semenza, G.L., Jiang, B.-H., Leung, S.W., Passantino, R., Concordet, J.-P., Maire, P., Giallongo, A.: Hypoxia response elements in the aldolase a, enolase 1, and lactate dehydrogenase a gene promoters contain essential binding sites for hypoxia-inducible factor 1. J. Biol. Chem. 271(51), 32529–32537 (1996)

    Article  Google Scholar 

  65. Stiehl, D.P., Bordoli, M.R., Abreu-Rodriguez, I., Wollenick, K., Schraml, P., Gradin, K., Poellinger, L., Kristiansen, G., Wenger, R.H.: Non-canonical hif-2\(\alpha \) function drives autonomous breast cancer cell growth via an areg–egfr/erbb4 autocrine loop. Oncogene 31(18), 2283–2297 (2012)

    Google Scholar 

  66. Stiehl, D.P., Wirthner, R., Koditz, J., Spielmann, P., Camenisch, G., Wenger, R.H.: Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels: evidence for an autoregulatory oxygen-sensing system. J. Biol. Chem. 281(33), 23482–23491 (2006)

    Article  Google Scholar 

  67. Tafani, M., Schito, L., Pellegrini, L., Villanova, L., Marfe, G., Anwar, T., Rosa, R., Indelicato, M., Fini, M., Pucci, B., Russo, M.A.: Hypoxia-increased rage and p2x7r expression regulates tumor cell invasion through phosphorylation of erk1/2 and akt and nuclear translocation of nf-\(\kappa \)b. Carcinogenesis 32(8), 1167–1175 (2011)

    Google Scholar 

  68. Taneja, S., Vetter S.W., Leclerc, E.: Hypoxia and the receptor for advanced glycation end products (rage) signaling in cancer. Int. J. Mol. Sci. 22(15), 8153 (2021)

    Article  Google Scholar 

  69. Tay, S., Hughey, J.J., Lee, T.K., Lipniacki, T., Quake, S.R., Covert, M.W.: Single-cell nf-\(\kappa \)b dynamics reveal digital activation and analogue information processing. Nature 466(7303), 267–271 (2010)

    Google Scholar 

  70. Trayhurn, P.: Hypoxia and adipose tissue function and dysfunction in obesity. Physiol. Rev. 93(1), 1–21 (2013)

    Article  Google Scholar 

  71. Tuckerman, J.R., Zhao, Y., Hewitson, K.S., Tian, Y.-M., Pugh, C.W., Ratcliffe, P.J., Mole, D.R.: Determination and comparison of specific activity of the hif-prolyl hydroxylases. FEBS Lett. 576(1–2), 145–150 (2004)

    Article  Google Scholar 

  72. Vaupel, P.: Tumor microenvironmental physiology and its implications for radiation oncology. In: Seminars in Radiation Oncology, vol. 14, pp. 198–206. Elsevier, Amsterdam (2004)

    Google Scholar 

  73. Villafuerte, F.C., Corante, N.: Chronic mountain sickness: clinical aspects, etiology, management, and treatment. High Alt. Med Biol. 17(2), 61–69 (2016)

    Article  Google Scholar 

  74. Warburg, O.: On the origin of cancer cells. Science 123(3191), 309–314 (1956)

    Article  Google Scholar 

  75. Webb, B.A., Chimenti, M., Jacobson, M.P., Barber, D.L.: Dysregulated ph: A perfect storm for cancer progression. Nature Rev. Cancer 11(9), 671–677 (2011)

    Article  Google Scholar 

  76. Xiang, K., Peng, Y., Yang, Z., Zhang, X., Cui, C., Zhang, H., Li, M., Zhang, Y., Wu, T., Chen, H., et al.: Identification of a tibetan-specific mutation in the hypoxic gene egln1 and its contribution to high-altitude adaptation. Molec. Biol. Evol. 30(8), 1889–1898 (2013)

    Article  Google Scholar 

  77. Xiao, Q., Ge, G.: Lysyl oxidase, extracellular matrix remodeling and cancer metastasis. Cancer Microenv. 5(3), 261–273 (2012)

    Article  Google Scholar 

  78. Xu, L., Fukumura, D., Jain, R.K.: Acidic extracellular ph induces vascular endothelial growth factor (vegf) in human glioblastoma cells via erk1/2 mapk signaling pathway: Mechanism of low ph-induced vegf. J. Biol. Chem. 277(13), 11368–11374 (2002)

    Article  Google Scholar 

  79. Yu, Y., Wang, G., Simha, R., Peng, W., Turano, F., Zeng, C.: Pathway switching explains the sharp response characteristic of hypoxia response network. PLOS Comput. 3(8), e171 (2007)

    Article  MathSciNet  Google Scholar 

  80. Zatterale, F., Longo, M., Naderi, J., Raciti, G.A., Desiderio, A., Miele, C., Beguinot, F.: Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Front. Physiol. 10, 1607 (2020)

    Article  Google Scholar 

  81. Zhang, N., Fu, Z., Linke, S., Chicher, J., Gorman, J.J., Visk, D., Haddad, G.G., Poellinger, L., Peet, D.J., Powell, F., Johnson, R.S.: The asparaginyl hydroxylase factor inhibiting hif-1\(\alpha \) is an essential regulator of metabolism. Cell Metab. 11(5), 364–378 (2010)

    Google Scholar 

  82. Zhang, B., Ye, H., Yang, A.: Mathematical modelling of interacting mechanisms for hypoxia mediated cell cycle commitment for mesenchymal stromal cells. BMC Syst. Biol. 12, 35 (2018)

    Article  Google Scholar 

  83. Zhao, T., Zhu, Y., Morinibu, A., Kobayashi, M., Shinomiya, K., Itasaka, S., Yoshimura, M., Guo, G., Hiraoka, M., Harada, H.: Hif-1-mediated metabolic reprogramming reduces ros levels and facilitates the metastatic colonization of cancers in lungs. Sci. Rep. 4(1), 1–7 (2014)

    Google Scholar 

  84. Zimna, A., Kurpisz, M.: Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. BioMed. Res. Int. 2015 (2015)

    Google Scholar 

Download references

Acknowledgements

The Authors thank the Medical Student Isabella Ferrante for stimulating and fruitful discussions and for her contribution on the graphics of HIF-related reaction networks.

Author information

Authors and Affiliations

  1. Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy

    Patrizia Ferrante

  2. Department of Mathematical Sciences, Politecnico di Torino, Torino, Italy

    Luigi Preziosi

Authors
  1. Patrizia Ferrante
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luigi Preziosi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luigi Preziosi .

Editor information

Editors and Affiliations

  1. Istituto per le Applicazioni del Calcolo (IAC) “M. Picone”, Consiglio Nazionale delle Ricerche (CNR - National Research Council), Roma, Italy

    Gabriella Bretti

  2. Istituto per le Applicazioni del Calcolo (IAC) “M. Picone”, Consiglio Nazionale delle Ricerche (CNR - National Research Council), Roma, Italy

    Roberto Natalini

  3. Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy

    Pasquale Palumbo

  4. Department of Mathematical Sciences, Politecnico di Torino, Torino, Italy

    Luigi Preziosi

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this paper

Check for updates. Verify currency and authenticity via CrossMark

Cite this paper

Ferrante, P., Preziosi, L. (2023). Modelling HIF-PHD Dynamics and Related Downstream Pathways. In: Bretti, G., Natalini, R., Palumbo, P., Preziosi, L. (eds) Mathematical Models and Computer Simulations for Biomedical Applications. MCHBS 2021. SEMA SIMAI Springer Series, vol 33. Springer, Cham. https://doi.org/10.1007/978-3-031-35715-2_4

Download citation

Publish with us

Policies and ethics

Search

Navigation