HYPOXIA-INDUCIBLE FACTOR (HIF): STRUCTURE, FUNCTION AND GENETIC POLYMORPHISM

Cover Page

Cite item

Full Text

Abstract

Introduction. The review presents data on the structure and functions of hypoxia-inducible transcription factor – HIF. In today’s world, a person is constantly exposed to harmful damaging factors, the response of the body to which, depending on the state of adaptive systems leads either to the development of diseases or increase resistance. Important importance in the adaptation of the body to damaging effects belongs to the transcription factor, denoted as a hypoxia-inducible factor (HIF). There were identified more than 100 genes activated by HIF and therefore mediated by this transcription factor affecting the regulation of iron homeostasis, energy metabolism, the balance of Pro - and antioxidants in the cells, the activation of inhibitors of apoptosis and the formation of new blood vessels.

The structure of HIF and its isoforms. The data on isoforms of HIF-α and organ-specific features of the distribution of HIF-1α, HIF-2α, and HIF-3α. Increased expression of α-subunits of transcription factor occurs in response to hypoxic effects, both acute and adaptive, psycho-emotional stress, under the action of toxic production-related factors. The increase in the level of HIF-α isoforms provides an expression of genes involved in the implementation of compensatory-adaptive responses to various harmful effects.

Genetic polymorphism of the HIF. The data on the HIF-1α gene polymorphism and its association with various diseases are presented. It is shown that the most studied polymorphisms are rs11549465 C > T and rs11549467 T > C identified in the domain of oxygen-dependent degradation of the DNA sequence of the HIF-1α gene. Carriers of the C/T genotype have increased expression of HIF-1α transcription factor for rs11549465 C > T and rs11549467 T > C polymorphisms, Association with the risk of coronary heart disease and myocardial infarction is shown. The study of HIF-1α gene polymorphism can be promising for the diagnosis and prognosis of occupationally caused diseases, as well as the development of effective ways of their correction and prevention.

About the authors

Anna G. Zhukova

Research Institute for Complex Problems of Hygiene and Occupational Diseases; Novokuznetsk Institute (Branch Campus) of the Kemerovo State University

Author for correspondence.
Email: nyura_g@mail.ru
ORCID iD: 0000-0002-4797-7842

MD, Ph.D., DSci., head of the Laboratory of molecular-genetic and experimental researches, Research Institute for Complex Problems of Hygiene and Occupational Diseases, Novokuznetsk, 654041, Russian Federation.

e-mail: nyura_g@mail.ru

Russian Federation

A. S. Kazitskaya

Research Institute for Complex Problems of Hygiene and Occupational Diseases

Email: noemail@neicon.ru
ORCID iD: 0000-0001-8292-4810
Russian Federation

T. G. Sazontova

Lomonosov Moscow State University

Email: noemail@neicon.ru
Russian Federation

N. N. Mikhailova

Research Institute for Complex Problems of Hygiene and Occupational Diseases; Novokuznetsk Institute (Branch Campus) of the Kemerovo State University

Email: noemail@neicon.ru
Russian Federation

References

  1. Izmerov N.F., Shirokov Y.G., Lebedeva N.V. Epidemiologic research in occupational medicine and industrial ecology. Atomnaya energiya. 1994; 77(6): 1-7. (in Russian)
  2. Oktyabrsky O.N., Smirnova G.V. Redox regulation of cellular functions. Biokhimiya. 2007; 72(2): 158-74. (in Russian)
  3. Turpaev K.T. Reactive oxygen species and regulation of gene expression. Biokhimiya. 2002; 61(3): 339-52. (in Russian)
  4. Maulik N., Yoshida T., Das D.K. Regulation of cardiomyocyte apoptosis in ischemic reperfused mouse heart by glutathione peroxidase. Mol. Cell Biochem. 1999; 196: 13-21.
  5. Semenza G.L. HIF1: mediator of physiological and pathophysiological responses to hypoxia. J. Appl. Physiol. 2000; 88: 1474-80.
  6. Semenza G.L. Signal transduction to hypoxia-factor 1. Biochem. Pharmacol. 2002; 64: 993-8.
  7. Yang S-Li, Wu C., Xiong Z-F., Fang X. Progress on hypoxia-inducible factor-3: Its structure, gen regulation and biological function (Review). Molecular Medicine Reports. 2015; 12: 2411-16. https://doi.org/10.3892/mmr.2015.3689
  8. Ravenna L., Salvatori L., Russo M. HIF3α: the little know. FEBS Journal. 2016; 283: 993-1003. https://doi.org/10.1111/febs.13572
  9. Purdom-Dickinson S.E., Sheveleva E.V., Sun H., Chen Q.M. Translational control of Nrf2 protein in activation of antioxidant response by oxidants. Mol. Pharmacol. 2007; 72(4): 1074-81. https://doi.org/10.1124/mol.107.035360
  10. Sazontova T.G., Anchishkina N.A., Zhukova A.G. et al. Reactive oxygen species and redox-signaling during adaptation to changes of oxygen level. Fiziologichniy zhurnal. 2008; 54(2):18-32. (in Russian)
  11. Pugha C.W., Ratcliffe P.J. New horizons in hypoxia signaling pathways. Experimental Cell Research. 2017; 356: 116-21. https://doi.org/10.1016/j.yexcr.2017.03.008
  12. Alekhina D.A., Zhukova A.G., Sazontova T.G. Low dose of fluoride influences to free radical oxidation and intracellular protective systems in heart, lung and liver. Tekhnologii zhivykh sistem. 2016; 13(6): 49-56. (in Russian)
  13. Zhukova A.G., Sazontova T.G. Hypoxia inducible factor-1α: function and biological role. Hypoxia Medical Journal. 2005; 13 (3-4): 34-41.
  14. Zakharenkov V.V., Mikhailova N.N., Zhdanova N.N.et al. Experimental study of the mechanisms of intracellular defense in cardiomyocytes associated with stages of anthracosilicosis development. Bulletin of Experimental Biology and Medicine. 2015; 159 (4): 431-5. https://doi.org/10.1007/s10517-015-2983-9
  15. Ban J.J., Ruthenborg R.J., Cho K.W., Kim J.W. Regulation of obesity and resistance by hypoxia-inducible factors. Hypoxia (Auckl). 2014; 2: 171-83. https://doi.org/10.2147/HP.S68771
  16. Zhukova A.G. Molecular mechanisms of adaptation to changes in the level of oxygen (The role of free radical oxidation). [Molekulyarnyye mekhanizmy adaptatsii k izmeneniyu urovnya kisloroda (Rol’ svobodnoradikal’nogo okisleniya)]. Saarbrücken: Palmarium academic publishing; 2012. (in Russian)
  17. Novikov V.Ye., Levchenkova O.S. Hypoxia-inducible factor as a pharmacological target. Obzory po klinicheskoy farmakologii i lekarstvennoy terapii. 2013; 11(2): 8-16. (in Russian)
  18. Semenza G.L. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda). 2004; 19: 176-82. https://doi.org/10.1152/physiol.00001.2004
  19. Koshkin S.A., Tolkunova E.N. Role of aryl hydrocarbon receptor in cancerogenesis and maintenance of cancer stem cells of colon cancer. Tsitologiya. 2017; 59(12): 820-5. (in Russian)
  20. Popravka E.S., Linkova N.S., Trofimova S.V., Khavinson V.Kh. HIF-1 is a marker of age-related diseases associated with tissue hypoxia. Uspekhi sovremennoy biologii. 2018; 138(3): 259-72. https://doi.org/10.7868/S0042132418030043 (in Russian)
  21. Vorrink S.U., Domann F.E. Regulatory crosstalk and interference between the xenobiotic and hypoxia sensing pathways at the AhR-ARNT-HIF1α signaling node. Chem. Biol. Interact. 2014; 218: 82-8. https://doi.org/10.1016/j.cbi.2014.05.001
  22. Prabhakar N.R., Semenza G.L. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev. 2012; 92: 967-1003. https://doi.org/10.1152/physrev.00030.2011
  23. Zhukova A.G., Kisichenko N.V., Gorokhova L.G. Molecular biology: a textbook with exercises and problems. [Molekulyarnaya biologiya: uchebnik s uprazhneniyami i zadachami]. Moscow-Berlin: Direkt-Media; 2018. https://doi.org/10.23681/488606 (in Russian)
  24. Lee J.-W., Bae S.-H., Jeong J.-W., Kim S.H., Kim K.W. et al. Hypoxia-inducible factor (HIF-1) α: its protein stability and biological functions. Exp. Mol. Med. 2004; 36(1): 1-12. https://doi.org/10.1038/emm.2004.1
  25. Forristal C.E., Wright K.L., Hanley N.A., Oreffo R.O.C., Houghton F.D. Hypoxia inducible factors regulate pluripotency and proliferation in human embryonic stem cells cultured at reduced oxygen tensions. Reproduction. 2010; 139(1): 85-97. https://doi.org/10.1530/REP-09-0300
  26. Baranova K.A., Rybnikova E.A., Samoilov M.O. The dynamics of HIF-1α expression in the rat brain at different stages of experimental posttraumatic stress disorder and its correction with moderate hypoxia. Neyrokhimiya. 2017; 34(2): 137-45. https://doi.org/10.7868/S1027813317020029 (in Russian)
  27. Stroka D.M., Burkhardt T., Desbaillets I., Wenger R.H., Neil D.A.H., Bauer C. et al. HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia. FASEB J. 2001; 15(13): 2445-53. doi: 10.1096/fj.01-0125com.
  28. Pasanen A., Heikkilä M., Rautavuoma K. et al. Hypoxia-inducible factor (HIF)-3alfa is subject to extensive alternative splicing in human tissues and cancer cells and is regulated by HIF-1 but not HIF-2. Int. J. Biochem. Cell. Biol. 2010; 42(7): 1189-1200. https://doi.org/10.1016/j.biocel.2010.04.008
  29. Sazontova T.G., Bolotova A.V., Bedareva I.V., Kostina N.V., Yurasov A.R., Arkhipenko Y.V. Hypoxia-inducible factor (HIF-1α), HSPs, antioxidant enzymes and membrane resistanceto ROS in endurance exercise performance after adaptive hypoxic preconditioning. In: Wang P., Kuo C.-H., Takeda N., Singal P.K., eds. Adaptation Biology and Medicine. New Delhi: Narosa Publishing House; 2011: 161-79.
  30. Sazontova T.G., Glazachev O.S., Bolotova A.V., Dudnik E.N., Stryapko N.V., Bedareva I.V. et al. Adaptation to hypoxia and hyperoxia improves physical endurance: the role of reactive oxygen species and redox-signaling (Experimental and applied study). Rossiyskiy fiziologicheskiy zhurnal im. I.M. Sechenova. 2012; 98(6): 793-807. (in Russian)
  31. Chacaroun S., Borowik A., MorrisonS.A., Baillieul S., Flore P., Doutreleau S. et al. Physiological responses to two hypoxic conditioning strategies in healthy subjects. Front. Physiol. 2017; 7:675. https://doi.org/10.3389/fphys.2016.00675
  32. Balykin M.V., Sagidova S.A., Zharkov A.S., Ayzyatulova E.D., Pavlov D.A., Antipov I.V. Effect of intermittent hypobaric hypoxia on HIF-1Α expression and morphofunctional changes in the myocardium. Ul’yanovskiy mediko-biologicheskiy zhurnal. 2017; (2): 125-34. https://doi.org/10.23648/UMBJ.2017.26.6227 (in Russian)
  33. Belkina L.M., Lakomkin V.L., ZhukovaA.G., Kirillina T.N., Sazontova T.G., Kapelko V.I. Heart resistance to oxidative stress in rats of different genetic strains. Byulleten’ eksperimental’noi biologii i meditsiny. 2004; 138(9): 250-3. (in Russian)
  34. Zhukova A.G., Alekhina D.A., Sazontova T.G., Prokopyev Yu.A., Gorokhova L.G., Stryapko N.V. et al. The mechanisms of intracellular protection and the activity of free radical oxidation in the myocardium of rats in the dynamics of chronic fluoride intoxication. Byulleten’ eksperimental’noi biologii i meditsiny. 2013; 156(8): 190-4. (in Russian)
  35. Stryapko N.V., Sazontova T.G., Kostin A.I., Vdovina I.B., Bedareva I.V., Arkhipenko Y.V. Effect of adaptation to changes in the level of oxygen, hypoxia and hyperoxia on redox signaling and physical endurance under low dose intoxication. Vestnik Sankt-Peterburgskogo universiteta. Seriya 11. Meditsina. 2013; (2): 195-200. (in Russian)
  36. Ke Q., Costa M. Hypoxia-Inducible factor-1 (HIF-1). Mol. Pharmacol. 2006; 70(5): 1469-80. https://doi.org/10.1124/mol.106.027029
  37. Safran M., Kaelin Jr. W.G. HIF hydroxylation and the mammalian oxygen-sensing pathway. J. Clin. Invest. 2003; 111(6): 779-83. https://doi.org/10.1172/JCI18181
  38. Nakayama K., Gazdoiu S., Abraham R., Pan Zh.-Q., Ronai Z. Hypoxia-induced assembly of prolyl hydroxylase PHD3 into complexes: implications for its activity and susceptibility for degradation by the E3 ligase Siah2. Biochem. J. 2007; 401(Pt 1): 217-26. https://doi.org/10.1042/BJ20061135
  39. Patten D.A., Lafleur V.N., Robitaille G.A., Chan D.A., Giaccia A.J., Richard D.E. Hypoxia-inducible factor-1 activation in nonhypoxic conditions: the essential role of mitochondrial-derived reactive oxygen species. Mol. Biol. Cell. 2010; 21(18): 3247-57. https://doi.org/10.1091/mbc.E10-01-0025
  40. Koh M.Y., Darnay B.G., Powis G. Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1 alpha, leading to its oxygen-independent degradation. Mol. Cell. Biol. 2008; 28(23): 7081-95. https://doi.org/10.1128/MCB.00773-08
  41. Formenti F., Constantin-Teodosiu D., Emmanuel Y., Cheeseman J., Dorrington K.L., Edwards L.M. et al. Regulation of human metabolism by hypoxia-inducible factor. Proc. Natl Acad. Sci. USA. 2010; 107(28): 12722-27. https://doi.org/10.1073/pnas.1002339107
  42. Liu B., Liu Q., Song Y., Li X., Wang Y., Wan S. et al. Polymorphisms of HIF1A gene are associated with prognosis of early stage non-small-cell lung cancer patients after surgery. Med. Oncol. 2014; 31(4): 877. https://doi.org/10.1007/s12032-014-0877-8
  43. Guo X., Li D., Chen Y., An J., Wang K., Xu Zh. et al. SNP rs2057482 in HIF1A gene predicts clinical outcome of aggressive hepatocellular carcinoma patients after surgery. Sci. Rep. 2015; 5: 11846. https://doi.org/10.1038/srep11846
  44. Gladek I., Ferdin J., Horvat S., Calin G.A., Kunej T. HIF1A gene polymorphisms and human diseases: graphical review of 97 association studies. Genes Chromosomes and Cancer. 2017; 56(6): 439-52. https://doi.org/10.1002/gcc.22449
  45. Akhmetov I.I., Khakimullina A.M., Lyubaeva E.V., Vinogradova O.L., Rogozkin V.A. Effect of HIF1A gene polymorphism on human muscle activity. Byulleten’ eksperimental’noi biologii i meditsiny. 2008; 146(9): 327-9. (in Russian)
  46. Zhur K.V., Kundas L.A., Byshnev N.I., Marozik P., Mosse I. HIF1A gene as a genetic marker of athlete’s resistance to exercises. Vestnik Bashkirskogo gosudarstvennogo agrarnogo universiteta. 2013; (3): 58-60. (in Russian)
  47. McPhee J.S., Perez-Schindler J., Degenes H., Tomlinson D., Hennis P., Baar K. et al. HIF1A P582S gene association with endurance training responses in young women. Eur. J. Appl. Physiol. 2011; 111(9): 2339-47. https://doi.org/10.1007/s00421-011-1869-4
  48. Li Y., Wang S., Zhang D., Xu X., Yu B., Zhang Y. The association of functional polymorphisms in genes expressed in endothelial cells and smooth muscle cells with the myocardial infarction. Hum. Genomics. 2019; 13(1): 5. https://doi.org/10.1186/s40246-018-0189-8
  49. Betel D., Wilson M., Gabow A., Marks D.S., Sander C. The microRNA.org resource: targets and expression. Nucleic Acids Res. 2008; 36: D149-53. https://doi.org/10.1093/nar/gkm995
  50. Bartel D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116(2): 281-97.
  51. Lopez-Reyes A., Rodriguez-Perez J.M., Fernandez-Torres J., Martínez-Rodríguez N., Pérez-Hernández N., Fuentes-Gómez A.J. et al. The HIF1A rs2057482 polymorphism is associated with risk of developing premature coronaryartery disease and with some metabolic and cardiovascular risk factors. The Genetics of Atherosclerotic Disease (GEA) Mexican Study. Exp. Mol. Pathol. 2014; 96(3): 405-10. https://doi.org/10.1016/j.yexmp.2014.04.010
  52. Zhukova A.G., Gorokhova L.G., Kiseleva A.V., Sazontova T.G., Mikhailova N.N. Experimental study of the impact of low fuorine concentrations on the tissue level of HSP family proteins. Gigiena i sanitariya [Hygiene and Sanitation, Russian journal]. 2018; 97(7): 604-8. https://doi.org/10.18821/0016-9900-2018-97-7-604-608 (in Russian)

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2019 Zhukova A.G., Kazitskaya A.S., Sazontova T.G., Mikhailova N.N.


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 37884 от 02.10.2009.