Biochemistry (Moscow)

, Volume 83, Issue 8, pp 907–929 | Cite as

Structure and Function of Multidrug Resistance Protein 1

  • E. N. Yakusheva
  • D. S. TitovEmail author


This review considers one of the most clinically relevant representatives of the ABC transporters–multidrug resistance protein 1 (P-glycoprotein 1 or Pgp). Data on the primary, secondary, and tertiary structure of the protein, its synthesis and degradation, and roles of its fragments in transporter activity are presented. Particular attention is given to the mechanism of functioning of Pgp. In view of the absence of a generally recognized mechanism of action of Pgp, several existing models of the protein transport cycle are discussed. Epigenetic regulation of the ABCB1 gene and modulation of Pgp expression by microRNAs are discussed.


multidrug resistance protein 1 P-glycoprotein 1 structure ABCB1 gene transport cycle 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Vasiliou, V., Vasiliou, K., and Nebert, D. W. (2009) Human ATP–binding cassette (ABC) transporter family, Hum. Genomics, 3, 281–290.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Higgins, C. F. (1992) ABC transporters: from microorganisms to man, Annu. Rev. Cell Biol., 8, 67–113.PubMedCrossRefGoogle Scholar
  3. 3.
    Dean, M., Hamon, Y., and Chimini, G. (2001) The human ATP–binding cassette (ABC) transporter superfamily, J. Lipid Res., 42, 1007–1017.PubMedGoogle Scholar
  4. 4.
    Fletcher, J. I., Haber, M., Henderson, M. J., and Norris, M. D. (2010) ABC transporters in cancer: more than just drug efflux pumps, Nat. Rev. Cancer, 10, 147–156.PubMedCrossRefGoogle Scholar
  5. 5.
    Fletcher, J. I., Williams, R. T., Henderson, M. J., Norris, M. D., and Haber, M. (2016) ABC transporters as mediators of drug resistance and contributors to cancer cell biology, Drug Resist. Updat., 26, 1–9.PubMedCrossRefGoogle Scholar
  6. 6.
    HGNC Database, HUGO Gene Nomenclature Committee (HGNC), European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK, URL,
  7. 7.
    The Universal Protein Resource (UniProt), URL,
  8. 8.
    Stavrovskaya, A. A., and Stromskaya, T. P. (2008) Transport proteins of the ABC family and multidrug resistance of tumor cells, Biochemistry (Moscow), 73, 592–604.CrossRefGoogle Scholar
  9. 9.
    Becker, J. P., Depret, G., Van Bambeke, F., Tulkens, P. M., and Prevost, M. (2009) Molecular models of human P–glycoprotein in two different catalytic states, BMC Struct. Biol., 9, 1.CrossRefGoogle Scholar
  10. 10.
    Quazi, F., Lenevich, S., and Molday, R. S. (2012) ABCA4 is an N–retinylidene–phosphatidylethanolamine and phosphatidylethanolamine importer, Nat. Commun., 3, 925.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Zheleznova, E. E., Markham, P. N., Neyfakh, A. A., and Brennan, R. G. (1999) Structural basis of multidrug recognition by BmrR, a transcription activator of a multidrug transporter, Cell, 96, 353–362.PubMedCrossRefGoogle Scholar
  12. 12.
    Neifakh, A. A. (2003) Multiple drug resistance: solution for the problem? Biol. Membr. Zh. Membr. Klet. Biol., 20, 206–212.Google Scholar
  13. 13.
    Callen, D. F., Baker, E., Simmers, R. N., Seshadri, R., and Roninson, I. B. (1987) Localisation of the human multiple drug resistance gene, MDR1, to 7q21.1, Hum. Genet., 77, 142–144.PubMedCrossRefGoogle Scholar
  14. 14.
    Brambila–Tapia, A. J. (2013) MDR1 (ABCB1) polymorphisms: functional effects and clinical implications, Rev. Invest. Clin., 65, 445–454.PubMedGoogle Scholar
  15. 15.
    Szollosi, D., Rose–Sperling, D., Hellmich, U. A., and Stockner, T. (2018) Comparison of mechanistic transport cycle models of ABC exporters, Biochim. Biophys. Acta, 1860, 818–832.PubMedCrossRefGoogle Scholar
  16. 16.
    Ruetz, S., and Gros, P. (1994) Phosphatidylcholine translocase: a physiological role for the mdr 2 gene, Cell, 77, 1071–1081.PubMedCrossRefGoogle Scholar
  17. 17.
    Van Helvoort, A., Smith, A. J., Sprong, H., Fritzsche, I., Schinkel, A. H., Borst, P., and van Meer, G. (1996) MDR1 P–glycoprotein is a lipid translocase of broad specificity, while MDR3 P–glycoprotein specifically translocates phosphatidylcholine, Cell, 87, 507–517.PubMedCrossRefGoogle Scholar
  18. 18.
    Lin, J. H., and Yamazaki, M. (2003) Role of P–glycoprotein in pharmacokinetics: clinical implications, Clin. Pharmacokinet., 42, 59–98.PubMedCrossRefGoogle Scholar
  19. 19.
    Smith, A. J., van Helvoort, A., van Meer, G., Szabo, K., Welker, E., Szakacs, G., Varadi, A., Sarkadi, B., and Borst, P. (2000) MDR3 P–glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping, J. Biol. Chem., 275, 23530–23539.PubMedCrossRefGoogle Scholar
  20. 20.
    Loo, T. W., and Clarke, D. M. (1999) Determining the structure and mechanism of the human multidrug resistance P–glycoprotein using cysteine–scanning mutagenesis and thiol–modification techniques, Biochim. Biophys. Acta, 1461, 315–325.PubMedCrossRefGoogle Scholar
  21. 21.
    Gribar, J. J., Ramachandra, M., Hrycyna, C. A., Dey, S., and Ambudkar, S. V. (2000) Functional characterization of glycosylation–deficient human P–glycoprotein using a vaccinia virus expression system, J. Membr. Biol., 173, 203–214.PubMedCrossRefGoogle Scholar
  22. 22.
    Tang, Y., Beuerlein, G., Pecht, G., Chilton, T., Huse, W. D., and Watkins, J. D. (1999) Use of a peptide mimotope to guide the humanization of MRK–16, an anti–P–glycoprotein monoclonal antibody, J. Biol. Chem., 274, 27371–27378.PubMedCrossRefGoogle Scholar
  23. 23.
    Germann, U. A. (1996) P–glycoprotein–a mediator of multidrug resistance in tumour cells, Eur. J. Cancer, 32, 927–944.CrossRefGoogle Scholar
  24. 24.
    Cohen, D., Yang, C.–P. H., and Horwitz, S. B. (1990) The products of the mdrla and mdrlb genes from multidrug resistant murine cells have similar degradation rates, Life Sci., 46, 489–495.PubMedCrossRefGoogle Scholar
  25. 25.
    Juliano, R. L., and Ling, V. (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants, Biochim. Biophys. Acta, 455, 152–162.PubMedCrossRefGoogle Scholar
  26. 26.
    Borst, P., and Elferink, R. O. (2002) Mammalian ABC transporters in health and disease, Annu. Rev. Biochem., 71, 537–592.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Shilling, R. A., Venter, H., Velamakanni, S., Bapna, A., Woebking, B., Shahi, S., and van Veen, H. W. (2006) New light on multidrug binding by an ATP–binding–cassette transporter, Trends Pharmacol. Sci., 27, 195–203.PubMedCrossRefGoogle Scholar
  28. 28.
    Li, Y., Yuan, H., Yang, K., Xu, W., Tang, W., and Li, X. (2010) The structure and functions of P–glycoprotein, Curr. Med. Chem., 17, 786–800.PubMedCrossRefGoogle Scholar
  29. 29.
    Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2005) The dileucine motif at the COOH terminus of human multidrug resistance P–glycoprotein is important for folding but not activity, J. Biol. Chem., 280, 2522–2528.PubMedCrossRefGoogle Scholar
  30. 30.
    Kim, Y., and Chen, J. (2018) Molecular structure of human P–glycoprotein in the ATP–bound, outward–facing confor–mation, Science, 359, 915–919.PubMedCrossRefGoogle Scholar
  31. 31.
    Kast, C., Canfield, V., Levenson, R., and Gros, P. (1995) Membrane topology of P–glycoprotein as determined by epitope insertion: transmembrane organization of the N–terminal domain of mdr3, Biochemistry, 34, 4402–4411.PubMedCrossRefGoogle Scholar
  32. 32.
    Loo, T. W., and Clarke, D. M. (1995) Membrane topology of a cysteine–less mutant of human P–glycoprotein, J. Biol. Chem., 270, 843–848.PubMedCrossRefGoogle Scholar
  33. 33.
    Loo, T. W., and Clarke, D. M. (2005) Do drug substrates enter the common drug–binding pocket of P–glycoprotein through gates? Biochem. Biophys. Res. Commun., 329, 419–422.PubMedCrossRefGoogle Scholar
  34. 34.
    Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2009) Identification of residues in the drug translocation pathway of the human multidrug resistance P–glycoprotein by arginine mutagenesis, J. Biol. Chem., 284, 24074–24087.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Dong, M., Ladaviere, L., Penin, F., Deleage, G., and Baggetto, L. G. (1998) Secondary structure of P–glycoprotein investigated by circular dichroism and amino acid sequence analysis, Biochim. Biophys. Acta, 1371, 317–334.PubMedCrossRefGoogle Scholar
  36. 36.
    Hennessy, M., and Spiers, J. P. (2007) A primer on the mechanics of P–glycoprotein the multidrug transporter, Pharmacol. Res., 55, 1–15.PubMedCrossRefGoogle Scholar
  37. 37.
    Nauck, M. A., El–Ouaghlidi, A., Gabrys, B., Hucking, K., Holst, J. J., Deacon, C. F., Gallwitz, B., Schmidt, W. E., and Meie, J. J. (2004) Secretion of incretin hormones (GIP and GLP–1) and incretin effect after oral glucose in first–degree relatives of patients with type 2 diabetes, Regul. Pept., 122, 209–217.PubMedCrossRefGoogle Scholar
  38. 38.
    Rosenberg, M. F., Callaghan, R., Ford, R. C., and Higgins, C. F. (1997) Structure of the multidrug resistance P–glyco–protein to 2.5 nm resolution determined by electron microscopy and image analysis, J. Biol. Chem., 272, 10685–10694.PubMedCrossRefGoogle Scholar
  39. 39.
    Rosenberg, M. F., Kamis, A. B., Callaghan, R., Higgins, C. F., and Ford, R. C. (2003) Three–dimensional structures of the mammalian multidrug resistance P–glycoprotein demonstrate major conformational changes in the trans–membrane domains upon nucleotide binding, J. Biol. Chem., 278, 8294–8299.PubMedCrossRefGoogle Scholar
  40. 40.
    Rosenberg, M. F., Callaghan, R., Modok, S., Higgins, C. F., and Ford, R. C. (2005) Three–dimensional structure of P–glycoprotein: the transmembrane regions adopt an asym–metric configuration in the nucleotide–bound state, J. Biol. Chem., 280, 2857–2862.PubMedCrossRefGoogle Scholar
  41. 41.
    Stenham, D. R., Campbell, J. D., Sansom, M. S., Higgins, C. F., Kerr, I. D., and Linton, K. J. (2003) An atomic detail model for the human ATP binding cassette transporter P–glycoprotein derived from disulfide cross–linking and homology modeling, Fed. Am. Soc. Exp. Biol., 17, 2287–2289.PubMedGoogle Scholar
  42. 42.
    Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2004) Disulfide cross–linking analysis shows that transmembrane segments 5 and 8 of human P–glycoprotein are close together on the cytoplasmic side of the membrane, J. Biol. Chem., 279, 7692–7697.PubMedCrossRefGoogle Scholar
  43. 43.
    Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2004) Val133 and Cys137 in transmembrane segment 2 are close to Arg935 and Gly939 in transmembrane segment 11 of human P–glycoprotein, J. Biol. Chem., 279, 18232–18238.PubMedCrossRefGoogle Scholar
  44. 44.
    Al–Shawi, M. K., and Omote, H. (2005) The remarkable transport mechanism of P–glycoprotein: a multidrug transporter, J. Bioenerg. Biomembr., 37, 489–496.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Pleban, K., Kopp, S., Csaszar, E., Peer, M., Hrebicek, T., Rizzi, A., Ecker, G. F., and Chiba, P. (2005) P–glycoprotein substrate binding domains are located at the transmembrane domain/transmembrane domain interfaces: a combined photoaffinity labeling–protein homology modeling approach, Mol. Pharmacol., 67, 365–374.PubMedCrossRefGoogle Scholar
  46. 46.
    Loo, T. W., and Clarke, D. M. (1999) Molecular dissection of the human multidrug resistance P–glycoprotein, Biochem. Cell Biol., 77, 11–23.PubMedCrossRefGoogle Scholar
  47. 47.
    Rothnie, A., Storm, J., McMahon, R., Taylor, A., Kerr, I. D., and Callaghan, R. (2005) The coupling mechanism of P–glycoprotein involves residue L339 in the sixth membrane spanning segment, FEBS Lett., 579, 3984–3990.PubMedCrossRefGoogle Scholar
  48. 48.
    Loo, T. W., and Clarke, D. M. (1998) Superfolding of the partially unfolded core–glycosylated intermediate of human P–glycoprotein into the mature enzyme is promoted by substrate–induced transmembrane domain interactions, J. Biol. Chem., 273, 14671–14674.PubMedCrossRefGoogle Scholar
  49. 49.
    Loo, T. W., and Clarke, D. M. (1999) The transmembrane domains of the human multidrug resistance P–glycoprotein are sufficient to mediate drug binding and trafficking to the cell surface, J. Biol. Chem., 274, 24759–24765.PubMedCrossRefGoogle Scholar
  50. 50.
    Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2005) ATP hydrolysis promotes interactions between the extracellular ends of transmembrane segments 1 and 11 of human multidrug resistance P–glycoprotein, Biochemistry, 44, 10250–10258.PubMedCrossRefGoogle Scholar
  51. 51.
    Vigano, C., Julien, M., Carrier, I., Gros, P., and Ruysschaert, J. M. (2002) Structural and functional asymmetry of the nucleotide–binding domains of P–glycoprotein investigated by attenuated total reflection Fourier transform infrared spectroscopy, J. Biol. Chem., 277, 5008–5016.PubMedCrossRefGoogle Scholar
  52. 52.
    Loo, T. W., and Clarke, D. M. (2001) Determining the dimensions of the drug–binding domain of human P–glyco–protein using thiol cross–linking compounds as molecular rulers, J. Biol. Chem., 276, 36877–36880.PubMedCrossRefGoogle Scholar
  53. 53.
    Ambudkar, S. V., Kim, I. W., and Sauna, Z. E. (2006) The power of the pump: mechanisms of action of P–glycoprotein (ABCB1), Eur. J. Pharm. Sci., 27, 392–400.PubMedCrossRefGoogle Scholar
  54. 54.
    Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2003) Simultaneous binding of two different drugs in the binding pocket of the human multidrug resistance P–glycoprotein, J. Biol. Chem., 278, 39706–39710.PubMedCrossRefGoogle Scholar
  55. 55.
    Loo, T. W., and Clarke, D. M. (2002) Location of the rhodamine–binding site in the human multidrug resistance P–glycoprotein, J. Biol. Chem., 277, 44332–44338.PubMedCrossRefGoogle Scholar
  56. 56.
    Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2003) Substrate–induced conformational changes in the transmembrane segments of human P–glycoprotein direct evidence for the substrate–induced fit mechanism for drug binding, J. Biol. Chem., 278, 13603–13606.PubMedCrossRefGoogle Scholar
  57. 57.
    Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2006) Transmembrane segment 1 of human P–glycoprotein contributes to the drug–binding pocket, Biochem. J., 396, 537–545.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Loo, T. W., and Clarke, D. M. (2001) Defining the drug–binding site in the human multidrug resistance P–glycoprotein using a methanethiosulfonate analog of verapamil, MTS–verapamil, J. Biol. Chem., 276, 14972–14979.PubMedCrossRefGoogle Scholar
  59. 59.
    Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2006) Transmembrane segment 7 of human P–glycoprotein forms part of the drug–binding pocket, Biochem. J., 399, 351–359.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Druley, T. E., Stein, W. D., Ruth, A., and Roninson, I. B. (2001) P–glycoprotein–mediated colchicine resistance in different cell lines correlates with the effects of colchicine on P–glycoprotein conformation, Biochemistry, 40, 4323–4331.PubMedCrossRefGoogle Scholar
  61. 61.
    Lugo, M. R., and Sharom, F. J. (2005) Interaction of LDS–751 with P–glycoprotein and mapping of the location of the R drug binding site, Biochemistry, 44, 643–655.PubMedCrossRefGoogle Scholar
  62. 62.
    Cianchetta, G., Singleton, R. W., Zhang, M., Wildgoose, M., Giesing, D., Fravolini, A., Cruciani, G., and Vaz, R. J. (2005) A pharmacophore hypothesis for P–glycoprotein substrate recognition using GRIND–based 3D–QSAR, J. Med. Chem., 48, 2927–2935.PubMedCrossRefGoogle Scholar
  63. 63.
    Frelet, A., and Klein, M. (2006) Insight in eukaryotic ABC transporter function by mutation analysis, FEBS Lett., 580, 1064–1084.PubMedCrossRefGoogle Scholar
  64. 64.
    Wan, C. K., Zhu, G. Y., Shen, X. L., Chattopadhyay, A., Dey, S., and Fong, W. F. (2006) Gomisin A alters substrate interaction and reverses P–glycoprotein–mediated mul–tidrug resistance in HepG2–DR cells, Biochem. Pharmacol., 72, 824–837.PubMedCrossRefGoogle Scholar
  65. 65.
    Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2002) The LSGGQ motif in each nucleotide–binding domain of human P–glycoprotein is adjacent to the opposing walker A sequence, J. Biol. Chem., 277, 41303–41306.PubMedCrossRefGoogle Scholar
  66. 66.
    Li, W., Zhang, H., Assaraf, Y. G., Zhao, K., Xu, X., Xie, J., Yang, D. H., and Chen, Z. S. (2016) Overcoming ABC transporter–mediated multidrug resistance: molecular mechanisms and novel therapeutic drug strategies, Drug Resist. Updat., 27, 14–29.PubMedCrossRefGoogle Scholar
  67. 67.
    Kim, I. W., Peng, X. H., Sauna, Z. E., FitzGerald, P. C., Xia, D., Muller, M., Nandigama, K., and Ambudkar, S. V. (2006) The conserved tyrosine residues 401 and 1044 in ATP sites of human P–glycoprotein are critical for ATP binding and hydrolysis: evidence for a conserved subdomain, the A–loop in the ATP–binding cassette, Biochemistry, 45, 7605–7616.PubMedCrossRefGoogle Scholar
  68. 68.
    Eytan, G. D., Regev, R., and Assaraf, Y. G. (1996) Functional reconstitution of P–glycoprotein reveals an apparent near stoichiometric drug transport to ATP hydrolysis, J. Biol. Chem., 271, 3172–3178.PubMedCrossRefGoogle Scholar
  69. 69.
    Gottesman, M. M., Pastan, I., and Ambudkar, S. V. (1996) P–glycoprotein and multidrug resistance, Curr. Opin. Genet. Dev., 6, 610–617.PubMedCrossRefGoogle Scholar
  70. 70.
    Sauna, Z. E., and Ambudkar, S. V. (2007) About a switch: how P–glycoprotein (ABCB1) harnesses the energy of ATP binding and hydrolysis to do mechanical work, Mol. Cancer Ther., 6, 13–23.PubMedCrossRefGoogle Scholar
  71. 71.
    Sauna, Z. E., Nandigama, K., and Ambudka, S. V. (2006) Exploiting reaction intermediates of the ATPase reaction to elucidate the mechanism of transport by P–glycoprotein (ABCB1), J. Biol. Chem., 281, 26501–26511.PubMedCrossRefGoogle Scholar
  72. 72.
    Tombline, G., Muharemagic, A., White, L. B., and Senior, A. F. (2005) Involvement of the occluded nucleotide conformation of P–glycoprotein in the catalytic pathway, Biochemistry, 44, 12879–12886.PubMedCrossRefGoogle Scholar
  73. 73.
    Loo, T. W., and Clarke, D. M. (2001) Cross–linking of human multidrug resistance P–glycoprotein by the substrate, tris–(2–maleimidoethyl) amine, is altered by ATP hydrolysis evidence for rotation of a transmembrane helix, J. Biol. Chem., 276, 31800–31805.PubMedCrossRefGoogle Scholar
  74. 74.
    Druley, T. E., Stein, W. D., Ruth, A., and Roninson, I. B. (2001) P–glycoprotein–mediated colchicine resistance in different cell lines correlates with the effects of colchicine on P–glycoprotein conformation, Biochemistry, 40, 4323–4331.PubMedCrossRefGoogle Scholar
  75. 75.
    Ferte, J. (2000) Analysis of the tangled relationships between P–glycoprotein–mediated multidrug resistance and the lipid phase of the cell membrane, Eur. J. Biochem., 267, 277–294.PubMedCrossRefGoogle Scholar
  76. 76.
    Hrycyna, C. A., Airan, L. E., Germann, U. A., Ambudkar, S. V., Pastan, I., and Gottesman, M. M. (1998) Structural flexibility of the linker region of human P–glycoprotein permits ATP hydrolysis and drug transport, Biochemistry, 37, 13660–13673.PubMedCrossRefGoogle Scholar
  77. 77.
    Sharom, F. J., Yu, X., and Doige, C. A. (1993) Functional reconstitution of drug transport and ATPase activity in proteoliposomes containing partially purified P–glycoprotein, J. Biol. Chem., 268, 24197–24202.PubMedGoogle Scholar
  78. 78.
    Ambudkar, S. V., Cardarelli, C. O., Pashinsky, I., and Stein, W. D. (1997) Relation between the turnover number for vinblastine transport and for vinblastine–stimulated ATP hydrolysis by human P–glycoprotein, J. Biol. Chem., 272, 21160–21166.PubMedCrossRefGoogle Scholar
  79. 79.
    Shapiro, A. B., and Ling, V. (1998) Stoichiometry of cou–pling of rhodamine 123 transport to ATP hydrolysis by P–glycoprotein, Eur. J. Biochem., 254, 189–193.PubMedCrossRefGoogle Scholar
  80. 80.
    Delannoy, S., Urbatsch, I. L., Tombline, G., Senior, A. E., and Vogel, P. D. (2005) Nucleotide binding to the mul–tidrug resistance P–glycoprotein as studied by ESR spectroscopy, Biochemistry, 44, 14010–14019.PubMedCrossRefGoogle Scholar
  81. 81.
    Senior, A. E., Al–Shawi, M. K., and Urbatsch, I. L. (1995) The catalytic cycle of P–glycoprotein, FEBS Lett., 377, 285–289.PubMedCrossRefGoogle Scholar
  82. 82.
    Urbatsch, I. L., Sankaran, B., Weber, J., and Senior, A. E. (1995) P–glycoprotein is stably inhibited by vanadate–induced trapping of nucleotide at a single catalytic site, J. Biol. Chem., 270, 19383–19390.PubMedCrossRefGoogle Scholar
  83. 83.
    Urbatsch, I. L., Beaudet, L., Carrier, I., and Gros, P. (1998) Mutations in either nucleotide–binding site of P–glycoprotein (Mdr3) prevent vanadate trapping of nucleotide at both sites, Biochemistry, 37, 4592–4602.PubMedCrossRefGoogle Scholar
  84. 84.
    Qu, Q., Russell, P. L., and Sharom, F. J. (2003) Stoichiometry and affinity of nucleotide binding to P–glycoprotein during the catalytic cycle, Biochemistry, 42, 1170–1177.PubMedCrossRefGoogle Scholar
  85. 85.
    Wang, G., Pincheira, R., and Zhang, J. T. (1998) Dissection of drug–binding–induced conformational changes in P–glycoprotein, Eur. J. Biochem., 255, 383–390.PubMedCrossRefGoogle Scholar
  86. 86.
    Julien, M., and Gros, P. (2000) Nucleotide–induced conformational changes in P–glycoprotein and in nucleotide binding site mutants monitored by trypsin sensitivity, Biochemistry, 39, 4559–4568.PubMedCrossRefGoogle Scholar
  87. 87.
    Druley, T. E., Stein, W. D., and Roninson, I. B. (2001) Analysis of MDR1 P–glycoprotein conformational changes in permeabilized cells using differential immunoreactivity, Biochemistry, 40, 4312–4322.PubMedCrossRefGoogle Scholar
  88. 88.
    Ruth, A., Stein, W. D., Rose, E., and Roninson, I. B. (2001) Coordinate changes in drug resistance and drug–induced conformational transitions in altered–function mutants of the multidrug transporter P–glycoprotein, Biochemistry, 40, 4332–4339.PubMedCrossRefGoogle Scholar
  89. 89.
    Loo, T. W., Bartlett, M. C., and Clarke, D. M. (2003) Drug binding in human P–glycoprotein causes conformational changes in both nucleotide–binding domains, J. Biol. Chem., 278, 1575–1578.PubMedCrossRefGoogle Scholar
  90. 90.
    Callaghan, R., Ford, R. C., and Kerr, I. D. (2006) The translocation mechanism of P–glycoprotein, FEBS Lett., 580, 1056–1063.PubMedCrossRefGoogle Scholar
  91. 91.
    Ambudkar, S. V., Kim, I. W., and Sauna, Z. E. (2006) The power of the pump: mechanisms of action of P–glycoprotein (ABCB1), Eur. J. Pharm. Sci., 27, 392–400.PubMedCrossRefGoogle Scholar
  92. 92.
    Subramanian, N., Condic–Jurkic, K., and O’Mara, M. L. (2016) Structural and dynamic perspectives on the promis–cuous transport activity of P–glycoprotein, Neurochem. Int., 98, 146–152.PubMedCrossRefGoogle Scholar
  93. 93.
    Martin, C., Higgins, C. F., and Callaghan, R. (2001) The vinblastine binding site adopts high–and low–affinity conformations during a transport cycle of P–glycoprotein, Biochemistry, 40, 15733–15742.PubMedCrossRefGoogle Scholar
  94. 94.
    Rosenberg, M. F., Velarde, G., Ford, R. C., Martin, C., Berridge, G., Kerr, I. D., Callaghan, R., Schmidlin, A., Wooding, C., Linton, K. J., and Higgins, C. F. (2001) Repacking of the transmembrane domains of P–glycoprotein during the transport ATPase cycle, EMBO J., 20, 5615–5625.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Higgins, C. F., and Linton, K. J. (2004) The ATP switch model for ABC transporters, Nat. Struct. Mol. Biol., 11, 918–926.PubMedCrossRefGoogle Scholar
  96. 96.
    Hyde, S. C., Emsley, P., Hartshorn, M. J., Mimmack, M. M., Gileadi, U., Pearce, S. R., Gallagher, M. P., Gill, D. R., Hubbard, R. E., and Higgins, C. F. (1990) Structural model of ATP–binding protein associated with cystic fibrosis, multidrug resistance and bacterial transport, Nature, 26, 362–365.CrossRefGoogle Scholar
  97. 97.
    Mimura, C. S., Holbrook, S. R., and Ames, G. F. (1991) Structural model of the nucleotide–binding conserved component of periplasmic permeases, Proc. Natl. Acad. Sci. USA, 88, 84–88.PubMedCrossRefGoogle Scholar
  98. 98.
    Senior, A. E., Al–Shawi, M. K., and Urbatsch, I. L. (1995) The catalytic cycle of P–glycoprotein, FEBS Lett., 377, 285–289.PubMedCrossRefGoogle Scholar
  99. 99.
    Al–Shawi, M. K., Polar, M. K., Omote, H., and Figler, R. A. (2003) Transition state analysis of the coupling of drug transport to ATP hydrolysis by P–glycoprotein, J. Biol. Chem., 278, 52629–52640.PubMedCrossRefGoogle Scholar
  100. 100.
    Omote, H., and Al–Shawi, M. K. (2006) Interaction of transported drugs with the lipid bilayer and P–glycoprotein through a solvation exchange mechanism, Biophys. J., 90, 4046–4059.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Baker, E. K., Johnstone, R. W., Zalcberg, J. R., and El–Osta, A. (2005) Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs, Oncogene, 24, 8061–8075.PubMedCrossRefGoogle Scholar
  102. 102.
    Chen, K. G., Wang, Y. C., Schaner, M. E., Francisco, B., Duran, G. E., Juric, D., Huff, L. M., Padilla–Nash, H., Ried, T., Fojo, T., and Sikic, B. I. (2005) Genetic and epigenetic modeling of the origins of multidrug–resistant cells in a human sarcoma cell line, Cancer Res., 65, 9388–9397.PubMedCrossRefGoogle Scholar
  103. 103.
    Scotto, K. W. (2003) Transcriptional regulation of ABC drug transporters, Oncogene, 22, 7496–7511.PubMedCrossRefGoogle Scholar
  104. 104.
    Ueda, K., Pastan, I., and Gottesman, M. M. (1987) Isolation and sequence of the promoter region of the human multidrug–resistance (P–glycoprotein) gene, J. Biol. Chem., 262, 17432–17436.PubMedGoogle Scholar
  105. 105.
    Arrigoni, E., Galimberti, S., Petrini, M., Danesi, R., and Di Paolo, A. (2016) ATP–binding cassette transmembrane transporters and their epigenetic control in cancer: an overview, Expert Opin. Drug Metab. Toxicol., 12, 1419–1432.PubMedCrossRefGoogle Scholar
  106. 106.
    Dejeux, E., Ronneberg, J. A., Solvang, H., Bukholm, I., Geisler, S., Aas, T., Gut, I. G., Borresen–Dale, A. L., Lonning, P. E., Kristensen, V. N., and Tost, J. (2010) DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response, Mol. Cancer, 9, 68.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Mencalha, A. L., Rodrigues, E. F., Abdelhay, E., and Fernandez, T. S. (2013) Accurate monitoring of promoter gene methylation with high–resolution melting polymerase chain reaction using the ABCB1 gene as a model, Genet. Mol. Res., 12, 714–722.PubMedCrossRefGoogle Scholar
  108. 108.
    Reed, K., Hembruff, S. L., Sprowl, J. A., and Parissenti, A. M. (2010) The temporal relationship between ABCB1 promoter hypomethylation, ABCB1 expression and acqui–sition of drug resistance, Pharmacogenomics J., 10, 489–504.PubMedGoogle Scholar
  109. 109.
    Nakayama, M., Wada, M., Harada, T., Nagayama, J., Kusaba, H., Ohshima, K., Kozuru, M., Komatsu, H., Ueda, R., and Kuwano, M. (1998) Hypomethylation status of CpG sites at the promoter region and overexpression of the human MDR1 gene in acute myeloid leukemias, Blood, 92, 4296–4307.PubMedGoogle Scholar
  110. 110.
    Tada, Y., Wada, M., Kuroiwa, K., Kinugawa, N., Harada, T., Nagayama, J., Nakagawa, M., Naito, S., and Kuwano, M. (2000) MDR1 gene overexpression and altered degree of methylation at the promoter region in bladder cancer during chemotherapeutic treatment, Clin. Cancer Res., 6, 4618–4627.PubMedGoogle Scholar
  111. 111.
    Reed, K., Hembruff, S. L., Laberge, M. L., Villeneuve, D. J., Cote, G. B., and Parissenti, A. M. (2008) Hypermethylation of the ABCB1 downstream gene promoter accompanies ABCB1 gene amplification and increased expression in docetaxel–resistant MCF–7 breast tumor cells, Epigenetics, 3, 270–280.PubMedCrossRefGoogle Scholar
  112. 112.
    El–Osta, A., Kantharidis, P., Zalcberg, J. R., and Wolffe, A. P. (2002) Precipitous release of methyl–CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation, Mol. Cell. Biol., 22, 1844–1857.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Henrique, R., Oliveira, A. I., Costa, V. L., Baptista, T., Martins, A. T., Morais, A., Oliveira, J., and Jeronimo, C. (2013) Epigenetic regulation of MDR1 gene through post–translational histone modifications in prostate cancer, BMC Genomics, 14, 898.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Huo, H., Magro, P. G., Pietsch, E. C., Patel, B. B., and Scotto, K. W. (2010) Histone methyltransferase MLL1 regulates MDR1 transcription and chemoresistance, Cancer Res., 70, 8726–8735.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Baker, E. K., Johnstone, R. W., Zalcberg, J. R., and El–Osta, A. (2005) Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs, Oncogene, 24, 8061–8075.PubMedCrossRefGoogle Scholar
  116. 116.
    Jin, S., and Scotto, K. W. (1998) Transcriptional regulation of the MDR1 gene by histone acetyltransferase and deacetylase is mediated by NF–Y, Mol. Cell. Biol., 18, 4377–4384.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    El–Khoury, V., Breuzard, G., Fourre, N., and Dufer, J. (2007) The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription–dependent mechanism in a drug–resistant small cell lung carcinoma cell line model, Br. J. Cancer, 97, 562–573.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Balaguer, T. M., Gomez–Martinez, A., Garcia–Morales, P., Lacueva, J., Calpena, R., Reverte, L. R., Riquelme, N. L., Martinez–Lacaci, I., Ferragut, J. A., and Saceda, M. (2012) Dual regulation of P–glycoprotein expression by trichostatin A in cancer cell lines, BMC Mol. Biol., 13, 25.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Blandino, G., Fazi, F., Donzelli, S., Kedmi, M., Sas–Chen, A., Muti, P., Strano, S., and Yarden, Y. (2014) Tumor suppressor microRNAs: a novel non–coding alliance against cancer, FEBS Lett., 588, 2639–2652.PubMedCrossRefGoogle Scholar
  120. 120.
    Garofalo, M., and Croce, C. M. (2013) MicroRNAs as therapeutic targets in chemoresistance, Drug Resist. Updat., 16, 47–59.PubMedCrossRefGoogle Scholar
  121. 121.
    Li, W., Zhang, H., Assaraf, Y. G., Zhao, K., Xu, X., Xie, J., Yang, D. H., and Chen, Z. S. (2016) Overcoming ABC transporter–mediated multidrug resistance: molecular mechanisms and novel therapeutic drug strategies, Drug Resist. Updat., 27, 14–29.PubMedCrossRefGoogle Scholar
  122. 122.
    Livney, Y. D., and Assaraf, Y. G. (2013) Rationally designed nanovehicles to overcome cancer chemoresis–tance, Adv. Drug Deliv. Rev., 65, 1716–1730.PubMedCrossRefGoogle Scholar
  123. 123.
    Wijdeven, R. H., Pang, B., Assaraf, Y. G., and Neefjes, J. (2016) Old drugs, novel ways out: drug resistance toward cytotoxic chemotherapeutics, Drug Resist. Updat., 28, 65–81.PubMedCrossRefGoogle Scholar
  124. 124.
    Geretto, M., Pulliero, A., Rosano, C., Zhabayeva, D., Bersimbaev, R., and Izzotti, A. (2017) Resistance to cancer chemotherapeutic drugs is determined by pivotal microRNA regulators, Am. J. Cancer Res., 7, 1350–1371.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Bruhn, O., Drerup, K., Kaehler, M., Haenisch, S., Roder, C., and Cascorbi, I. (2016) Length variants of the ABCB1 3′–UTR and loss of miRNA binding sites: possible conse–quences in regulation and pharmacotherapy resistance, Pharmacogenomics, 17, 327–340.PubMedCrossRefGoogle Scholar
  126. 126.
    Ikemura, K., Yamamoto, M., Miyazaki, S., Mizutani, H., Iwamoto, T., and Okuda, M. (2013) MicroRNA–145 post–transcriptionally regulates the expression and function of P glycoprotein in intestinal epithelial cells, Mol. Pharmacol., 83, 399–405.PubMedCrossRefGoogle Scholar
  127. 127.
    Li, N., Yang, L., Wang, H., Yi, T., Jia, X., Chen, C., and Xu, P. (2015) MiR–130a and miR–374a function as novel regulators of cisplatin resistance in human ovarian cancer A2780Cells, PLoS One, 10, e0128886.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Bourguignon, L. Y., Spevak, C. C., Wong, G., Xia, W., and Gilad, E. (2009) Hyaluronan–CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the production of microRNA–21, leading to downregulation of the tumor suppressor protein PDCD4, anti–apoptosis, and chemotherapy resistance in breast tumor cells, J. Biol. Chem., 284, 26533–26546.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Wu, D. D., Li, X. S., Meng, X. N., Yan, J., and Zong, Z. H. (2016) MicroRNA–873 mediates multidrug resistance in ovarian cancer cells by targeting ABCB1, Tumour Biol., 37, 10499–10506.PubMedCrossRefGoogle Scholar
  130. 130.
    Tian, S., Zhang, M., Chen, X., Liu, Y., and Lou, G. (2016) MicroRNA–595 sensitizes ovarian cancer cells to cisplatin by targeting ABCB1, Oncotarget, 7, 87091–87099.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Zhu, H., Wu, H., Liu, X., Evans, B. R., Medina, D. J., Liu, C. G., and Yang, J. M. (2008) Role of microRNA miR–27a and miR–451 in the regulation of MDR1/P–glycoprotein expression in human cancer cells, Biochem. Pharmacol., 76, 582–588.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Bitarte, N., Bandres, E., Boni, V., Zarate, R., Rodriguez, J., Gonzalez–Huarriz, M., Lopez, I., Javier Sola, J., Alonso, M. M., Fortes, P., and Garcia–Foncillas, J. (2011) MicroRNA–451 is involved in the self–renewal, tumori–genicity, and chemoresistance of colorectal cancer stem cells, Stem Cells, 29, 1661–1671.PubMedCrossRefGoogle Scholar
  133. 133.
    Chen, Z., Ma, T., Huang, C., Zhang, L., Lv, X., Xu, T., Hu, T., and Li, J. (2013) MiR–27a modulates the MDR1/P–glycoprotein expression by inhibiting FZD7/beta–catenin pathway in hepatocellular carcinoma cells, Cell. Signal., 25, 2693–2701.PubMedCrossRefGoogle Scholar
  134. 134.
    Kovalchuk, O., Filkowski, J., Meservy, J., Ilnytskyy, Y., Tryndyak, V. P., Chekhun, V. F., and Pogribny, I. P. (2008) Involvement of microRNA–451 in resistance of the MCF–7 breast cancer cells to chemotherapeutic drug doxorubicin, Mol. Cancer Ther., 7, 2152–2159.PubMedCrossRefGoogle Scholar
  135. 135.
    Zhao, Y., Qi, X., Chen, J., Wei, W., Yu, C., Yan, H., Pu, M., Li, Y., Miao, L., Li, C., and Ren, J. (2017) The miR–/ Sp3/ABCB1 axis attenuates multidrug resistance of hepatocellular carcinoma, Cancer Lett., 408, 102–111.PubMedCrossRefGoogle Scholar
  136. 136.
    Shang, Y., Zhang, Z., Liu, Z., Feng, B., Ren, G., Li, K., Zhou, L., Sun, Y., Li, M., Zhou, J., An, Y., Wu, K., Nie, Y., and Fan, D. (2014) miR–508–5p regulates multidrug resistance of gastric cancer by targeting ABCB1 and ZNRD1, Oncogene, 33, 3267–3276.PubMedCrossRefGoogle Scholar
  137. 137.
    Takwi, A. A., Wang, Y. M., Wu, J., Michaelis, M., Cinatl, J., and Chen, T. (2014) miR–137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin–resistant neuroblastoma cells, Oncogene, 33, 3717–3729.PubMedCrossRefGoogle Scholar
  138. 138.
    Lu, C., Shan, Z., Li, C., and Yang, L. (2017) MiR–129 regulates cisplatin–resistance in human gastric cancer cells by targeting P–gp, Biomed. Pharmacother., 86, 450–456.PubMedCrossRefGoogle Scholar
  139. 139.
    Bao, L., Hazari, S., Mehra, S., Kaushal, D., Moroz, K., and Dash, S. (2012) Increased expression of P–glycoprotein and doxorubicin chemoresistance of metastatic breast cancer is regulated by miR–298, Am. J. Pathol., 180, 2490–2503.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Wang, H., Zhan, M., Xu, S. W., Chen, W., Long, M. M., Shi, Y. H., Liu, Q., Mohan, M., and Wang, J. (2017) MiR–218–5p restores sensitivity to gemcitabine through PRKCE/MDR1 axis in gallbladder cancer, Cell Death Dis., 8, e2770.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Genovese, I., Ilari, A., Assaraf, Y. G., Fazi, F., and Colotti, G. (2017) Not only P–glycoprotein: amplification of the ABCB1–containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance–related protein, Drug Resist. Updat., 32, 23–46.PubMedCrossRefGoogle Scholar
  142. 142.
    Yakusheva, E. N., Titov, D. S., and Nikiforov, A. A. (2016) Effect of combined action of vildagliptin and gliquidone on the functional activity and expression of P–glycoprotein in the norm and in experimental alloxan–induced type 2 diabetes, Ros. Med.–Biol. Vest. im. Akad. I. P. Pavlova, 3, 53–66.Google Scholar
  143. 143.
    Yakusheva, E. N., and Titov, D. S. (2017) Effect of gliq–uidone on P–glycoprotein expression in the norm and in experimental alloxan–induced type 2 diabetes, Nauka Molodykh (Eruditio Juvenium), 5, 208–224.CrossRefGoogle Scholar
  144. 144.
    Yakusheva, E. N., Titov, D. S., and Pravkin, S. K. (2017) Localization, model of functioning, and physiological functions of P–glycoprotein, Usp. Fiziol. Nauk, 48, 70–87.Google Scholar

Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  1. 1.Ryazan State Medical UniversityRyazanRussia

Personalised recommendations