Multidrug Resistance Transporter

  • Michael M. Gottesman
  • Suresh V. Ambudkar
  • Marilyn M. Cornwell
  • Ira Pastan
  • Ursula A. Germann


The mechanisms by which cells evade the lethal effects of cytotoxic drugs have been the subject of intense investigation by cell and molecular biologists for more than 20 years. Much of this work was stimulated by the initial success of cancer chemotherapy in disseminated childhood cancers such as leukemias, neuroblastoma, and sarcomas, in germ-cell tumors such as choriocarcinoma and testicular cancer, and in the responsiveness of other cancers such as lymphomas, breast, and ovarian cancers. These clinical successes suggested that metastatic cancer could be cured with chemotherapy, yet in many cases promising remissions were followed by regrowth of drug-resistant cancers. The possibility of cure, coupled with the hope that a defined set of reversible resistance mechanism could be delineated, led to the intense interest in studies of drug resistance.


ATPase Activity Multidrug Transporter Photoaffinity Label Multidrug Resistance Transporter Tidrug Resistance 
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  1. 1.
    Gottesman, M. M., and Pastan, I. (1993). Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62:385–427.PubMedCrossRefGoogle Scholar
  2. 2.
    Danø, K. (1972). Cross resistance between vinca alkaloids and anthracyclines in Ehrlich ascites tumor in vivo. Biochim. Biophys. Acta 323:466–483.Google Scholar
  3. 3.
    Ling, V., and Thompson, L. H. (1974). Reduced permeability in CHO cells as a mechanism of resistance to colchicine. J. Cell. Physiol. 83:103–116.PubMedCrossRefGoogle Scholar
  4. 4.
    Danø, K. (1973). Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochim. Biophys. Acta 323:466–483.PubMedCrossRefGoogle Scholar
  5. 5.
    Fojo, A., Akiyama, S.-i., Gottesman, M. M., and Pastan, I. (1985). Reduced drug accumulation in multiply drug-resistant human KB carcinoma cell lines. Cancer Res. 45:3002–3007.PubMedGoogle Scholar
  6. 6.
    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
  7. 7.
    Ueda, K., Cornwell, M. M., Gottesman, M. M., Pastan, I., Roninson, I. B., Ling, V., Riordan, J. R. (1986). The mdr1 gene, responsible for multidrug-resistance, codes for P-glycoprotein. Biochem. Biophys. Res. Commun. 141:956–962.PubMedCrossRefGoogle Scholar
  8. 8.
    Shen, D.-W., Fojo, A. T., Chin, J. E., Roninson, I. B., Richert, N., Pastan, I., and Gottesman, M. M. (1986). Human multidrug resistant cell lines: Increased mdr1expression can precede gene amplification. Science 232:643–645.PubMedCrossRefGoogle Scholar
  9. 9.
    Roninson, I. B., Chin, J. E., Choi, K., et al. (1986). Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells. Proc. Natl. Acad. Sci. USA 83:4538–4552.PubMedCrossRefGoogle Scholar
  10. 10.
    Ueda, K., Cardarelli, C, Gottesman, M. M., et al. (1987). Expression of a full-length cDNA for the human “MDR1” (P-glycoprotein) gene confers multidrug resistance to colchicine, doxorubicin, and vinblastine. Proc. Natl. Acad. Sci. USA 84:3004–3008.PubMedCrossRefGoogle Scholar
  11. 11.
    Pastan, I., Gottesman, M. M., Ueda, K., et al. (1988). A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells. Proc. Natl. Acad. Sci. USA 85:4486–4490.PubMedCrossRefGoogle Scholar
  12. 12.
    Gros, P., Ben Neriah, Y., Croop, J., et al. (1986). Isolation and characterization of a complementary DNA that confers multidrug resistance. Nature 323:728–731.PubMedCrossRefGoogle Scholar
  13. 13.
    Gros, P., Raymond, M., Bell, J., et al. (1988). Cloning and characterization of a second member of the mouse mdr gene family. Mol. Cell Biol. 8:2770–2778.PubMedGoogle Scholar
  14. 14.
    Scotto, K. W., Biedler, J. L., and Melera, P. W. (1986). The differential amplification and expression of genes associated with multidrug-resistance in mammalian cells. Science 232:751–755.PubMedCrossRefGoogle Scholar
  15. 15.
    Gerlach, J. H., Endicott, J. A., Juranka, P. R, et al. (1986). Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistance. Nature 324:485–489.PubMedCrossRefGoogle Scholar
  16. 16.
    Chen, C.-J., Chin, J. E., Ueda, K., Clark, D., Pastan, I., Gottesman, M. M., and Roninson, I. B. (1986). Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47:381–389.PubMedCrossRefGoogle Scholar
  17. 17.
    Ambudkar, S. V., Pastan, I., and Gottesman, M. M. (1995). Cellular and biochemical aspects of multidrug resistance. In Drug Transport in Antimicrobial and Anticancer Chemotherapy (N.H. Georgapapadakou, ed.), Dekker, New York, pp. 525–547.Google Scholar
  18. 18.
    Zhang, J.-T., and Ling, V. (1991). Study of membrane orientation and glycosylated extracellular loops of mouse P-glycoprotein by in vitro translation. J. Biol. Chem. 266:18224–18232.PubMedGoogle Scholar
  19. 19.
    Zhang, J. T., Duthie, M., and Ling, V. (1993). Membrane topology of the N-terminal half of the hamster P-glycoprotein molecule. J. Biol. Chem. 268:15101–15110.PubMedGoogle Scholar
  20. 20.
    Skach, W. R., Calayag, M. C, and Lingappa, V. R. (1993). Evidence for an alternate model of human P-glycoprotein structure and biogenesis. J. Biol. Chem. 268:6903–6908.PubMedGoogle Scholar
  21. 21.
    Germann, U. A., Pastan, I., and Gottesman, M. M. (1993). P-glycoproteins: Mediators of multidrug resistance. Semin. Cell Biol. 4:63–76.PubMedCrossRefGoogle Scholar
  22. 22.
    Germann, U. A. (1993). Molecular analysis of the multidrug transporter. Cytotechnology 12:33–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Hyde, S. C, Emsley, P., Hartshorn, M. J., et al. (1990). Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance, and bacterial transport. Nature 346:362–365.PubMedCrossRefGoogle Scholar
  24. 24.
    Mimura, C. S., Holbrook, S. R., and Ames, G. F.-L. (1991). Structural model of the nucleotide-binding conserved component of periplasmic permeases. Proc. Natl. Acad. Sci. USA 88:84–88.PubMedCrossRefGoogle Scholar
  25. 25.
    Ames, G. F.-L., Mimura, C. S., Holbrook, S. R., et al. (1992). Traffic ATPases: A superfamily of transport proteins operating from Escherichia coli to humans. Adv. Enzymol 65:1–47.PubMedGoogle Scholar
  26. 26.
    Ames, G. F.-L., and Lecar, H. (1992). ATP-dependent bacterial transporters and cystic fibrosis: Analogy between channels and transporters. FASEB J. 6:2660–2666.PubMedGoogle Scholar
  27. 27.
    Higgins, C. F. (1992). ABC transporters—from microorganisms to man. Annu. Rev. Cell Biol. 8:67–113.PubMedCrossRefGoogle Scholar
  28. 28.
    Smit, J. J. M., Schinkel, A. H., Oude Elferink, R. P. J., et al. (1993). Homozygous disruption of the murine mdr1 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75:451–462.PubMedCrossRefGoogle Scholar
  29. 29.
    Ruetz, S., and Gros, P. (1994). Phosphatidylcholine translocase: A physiological role for the mdr1 gene. Cell 77:1071–1081.PubMedCrossRefGoogle Scholar
  30. 30.
    Cole, S. P. C, Bhardwaj, G., Gerlach, J. H., et al. (1992). Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258:1650–1654.PubMedCrossRefGoogle Scholar
  31. 31.
    Riordan, J. R., Rommens, J. M., Kerem, B.-s., et al. (1989). Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science 245:1066–1073.PubMedCrossRefGoogle Scholar
  32. 32.
    Kamijo, K., Taketani, S., Yokota, S., et al. (1989). The 70-kDa peroxisomal membrane protein is a member of the Mdr (P-glycoprotein)-related ATP binding superfamily. J. Biol. Chem. 265:4534–4540.Google Scholar
  33. 33.
    Gärtner, J., Moser, H., and Valle, D. (1992). Mutations in the 70K peroxisomal membrane protein gene in Zellweger syndrome. Nature Genet 1:16–23.PubMedCrossRefGoogle Scholar
  34. 34.
    Mosser, J., Douar, A., Sarde, C, et al. (1993). Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 361:726–730.PubMedCrossRefGoogle Scholar
  35. 35.
    Valle, D., and Gärtner, J. (1993). Penetrating the peroxisome. Nature 361:682–683.PubMedCrossRefGoogle Scholar
  36. 36.
    Monaco, J. J. (1992). Major histocompatibility complex-linked transport proteins and antigen processing. Immunol. Res. 11:125–132.PubMedCrossRefGoogle Scholar
  37. 37.
    Van der Bliek, A. M., Baas, F., Ten Houte de Lange, T., et al. (1987). The human mdr3 gene encodes a novel P-glycoprotein homologue and gives rise to alternatively spliced mRNAs in liver. EMBO J. 6:3325–3331.PubMedGoogle Scholar
  38. 38.
    Van der Bliek, A. M., Kooiman, P. M., Schneider, C, et al. (1988). Sequence of mdr3 cDNA, encoding a human P-glycoprotein. Gene 71:401–411.PubMedCrossRefGoogle Scholar
  39. 39.
    McGrath, J. P., and Varshavsky, A. (1989). The yeast STE6 gene encodes a homologue of the mammalian multidrug resistance P-glycoprotein. Nature 340:400–404.PubMedCrossRefGoogle Scholar
  40. 40.
    Hess, J., Wels, W., Vogel, M., et al. (1986). Nucleotide sequence of a plasmid-encoded haemolysin determinant and its comparison with a corresponding chromosomal haemolysin sequence. FEMS Microbiol. Lett. 34:1–11.Google Scholar
  41. 41.
    Higgins, C. F., Haag, P. D., Nikaido, K., et al. (1982). Complete nucleotide sequence and identification of membrane components of the histidine transport operon of S. typhimurium. Nature 298:723–727.PubMedCrossRefGoogle Scholar
  42. 42.
    Hiles, I. D., Gallagher, M. P., Jamieson, D., et al. (1987). Molecular characterization of the oligopeptide permease of Salmonella typhimurium. J. Mol. Biol. 195:125–142.PubMedCrossRefGoogle Scholar
  43. 43.
    Bell, A. W., Buckel, S. D., Groarke, J. M., et al. (1986). The nucleotide sequence of the rbsD, rbsA and rbsC genes of Escherichia coli. J. Biol. Chem. 261:7652–7658.PubMedGoogle Scholar
  44. 44.
    Kostler, W., and Braun, V. (1986). Iron hydroxamate transport of Escherichia coli: Nucleotide sequence of the fhuB gene and identification of the protein. Mol. Gen. Genet. 204:435–442.CrossRefGoogle Scholar
  45. 45.
    Coulton, J. W., Mason, P., and Allatt, D. (1987). fhuC and fhuD genes for iron(III)-ferrichrome transport into Escherichia coli K-12. J. Bacteriol. 169:3844–3849.PubMedGoogle Scholar
  46. 46.
    Walker, J. E., Saraste, M., Runswick, M. J., et al. (1982). Distantly related sequences in the α- and ß-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1:945–951.PubMedGoogle Scholar
  47. 47.
    Shyamala, V, Baichwald, V, Beall, E., et al. (1991). Structure-function analysis of the histidine permease and comparison with cystic fibrosis mutations. J. Biol. Chem. 266:18714–18719.PubMedGoogle Scholar
  48. 48.
    Manavalan, P., Smith, A. E., and Mcpherson, J. M. (1993). Sequence and structural homology among membrane-associated domains of CFTR and certain transporter proteins. J. Protein Chem. 12:279–290.PubMedCrossRefGoogle Scholar
  49. 49.
    Tang-Wai, D. F., Brossi, A., Arnold, L. D., et al. (1993). The nitrogen of the acetamido group of colchicine modulates P-glycoprotein-mediated multidrug resistance. Biochemistry 32:6470–6476.PubMedCrossRefGoogle Scholar
  50. 50.
    Kessel, D. (1989). Exploring multidrug resistance by using rhodamine 123. Cancer Commun. 1:145–149.PubMedGoogle Scholar
  51. 51.
    Weaver, J. L., Ine, P. S., Aszalos, A., et al. (1991). Laser scanning and confocal microscopy of daunorubicin, doxorubicin and rhodamine 123 in multidrug-resistant cells. Exp. Cell Res. 196:323–329.PubMedCrossRefGoogle Scholar
  52. 52.
    Raviv, Y, Pollard, H. B., Bruggemann, E. P., et al. (1990). Photosensitized labeling of a functional multidrug transporter in living drugresistant tumor cells. J. Biol. Chem. 265:3975–3980.PubMedGoogle Scholar
  53. 53.
    Stein, W. D., Cardarelli, C. O., Pastan, I., et al. (1994). Kinetic evidence suggesting that the multidrug transporter differentially handies influx and efflux of its substrates. Mol. Pharmacol. 45:763–772.PubMedGoogle Scholar
  54. 54.
    Homolya, L., Hollo, Z., Germann, U. A., et al. (1993). Fluorescent cellular indicators are extruded by the multidrug resistance protein. J. Biol. Chem. 268:21493–21496.PubMedGoogle Scholar
  55. 55.
    Higgins, C. F., and Gottesman, M. M. (1992). Is the multidrug transporter a flippase? Trends Pharmacol. Sci. 17:18–21.Google Scholar
  56. 56.
    Gill, D. R., Hyde, S. C, Higgins, C. F, et al. (1992). Separation of drug transport and chloride channel functions of the human multidrug resistance P-glycoprotein. Cell 71:23–32.PubMedCrossRefGoogle Scholar
  57. 57.
    Valverde, M. A., Diâz, M., SepuTveda, F. V., et al. (1992). Volume-regulated chloride channels associated with the human multidrug resistance P-glycoprotein. Nature 355:830–833.PubMedCrossRefGoogle Scholar
  58. 58.
    Cornwell, M. M, Gottesman, M. M, and Pastan, I. (1986). Increased vinblastine binding to membrane vesicles from multidrug resistant KB cells. J. Biol. Chem. 262:7921–7928.Google Scholar
  59. 59.
    Cornwell, M. M., Safa, A. R., Felsted, R. L., et al. (1986). Membrane vesicles from multidrug-resistant human cancer cells contain a specific 150–170kDa protein detected by photoaffinity labeling. Proc. Natl. Acad. Sci. USA 83:3847–3850.PubMedCrossRefGoogle Scholar
  60. 60.
    Safa, A. R., Glover, C. J., Meyets, M. B., et al. (1986). Vinblastine photoaffinity labeling of a high-molecular-weight surface membrane glycoprotein specific for multidrug-resistant cells. J. Biol. Chem. 261:6137–6140.PubMedGoogle Scholar
  61. 61.
    Bruggemann, E. P., Germann, U. A., Gottesman, M. M., et al. (1989). Two different regions of P-glycoprotein are photoaffinity labeled by azidopine. J. Biol. Chem. 264:15483–15488.PubMedGoogle Scholar
  62. 62.
    Bruggemann, E. P., Currier, S. J., Gottesman, M. M., et al. (1992). Characterization of the azidopine and vinblastine binding site of P-glycoprotein. J. Biol. Chem. 267:21020–21026.PubMedGoogle Scholar
  63. 63.
    Greenberger, L. M., Lisanti, C. J., Silva, J. T., et al. (1991). Domain mapping of the photoaffinity drug-binding sites in P-glycoprotein encoded mouse mdr1b. J. Biol. Chem. 266:20744–20751.PubMedGoogle Scholar
  64. 64.
    Morris, D. I., Speicher, L. A., Ruoho, A. E., et al. (1991). Interaction of forskolin with the P-glycoprotein multidrug transporter. Biochemistry 30:8371–8379.PubMedCrossRefGoogle Scholar
  65. 65.
    Greenberger, L. M. (1993). Major photoaffinity drug labeling sites for iodoarylazidoprazosin in P-glycoprotein are within, or immediately C-terminal to, transmembrane domain-6 and domain-12. J. Biol. Chem. 268:11417–11425.PubMedGoogle Scholar
  66. 66.
    Tamai, I., and Safa, A. R. (1991). Azidopine noncompetitively interacts with vinblastine and cyclosporin A binding to P-glycoprotein in multidrug resistant cells. J. Biol. Chem. 266:16796–16800.PubMedGoogle Scholar
  67. 67.
    Buschman, E., and Gros, P. (1991). Functional analysis of chimeric genes obtained by exchanging homologous domains of the mouse mdr1 and mdr2genes. Mol. Cell. Biol. 11:595–603.PubMedGoogle Scholar
  68. 68.
    Dhir, R., and Gros, P. (1992). Functional analysis of chimeric proteins constructed by exchanging homologous domains of two P-glycoproteins conferring distinct drug resistance profiles. Biochemistry 31:6103–6110.PubMedCrossRefGoogle Scholar
  69. 69.
    Currier, S. J., Kane, S. E., Willingham, M. C, et al. (1992). Identification of residues in the first cytoplasmic loop of P-glycoprotein involved in the function of chimeric human MDR1-MDR2 transporters. J. Biol. Chem. 267:25153–25159.PubMedGoogle Scholar
  70. 70.
    Currier, S. J., Ueda, K., Willingham, M. C, et al. (1989). Deletion and insertion mutants of the multidrug transporter. J. Biol. Chem. 264:14376–14381.PubMedGoogle Scholar
  71. 71.
    Choi, K., Chen, C.-J., Kriegler, M., et al. (1989). An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1(P-glycoprotein) gene. Cell 53:519–529.CrossRefGoogle Scholar
  72. 72.
    Kioka, N., Tsubota, J., Kakehi, Y., et al. (1989). P-glycoprotein gene (MDR1) cDNA from human adrenal: Normal P-glycoprotein carries Gly185 with an altered pattern of multidrug resistance. Biochem. Biophys. Res. Commun. 162:224–231.PubMedCrossRefGoogle Scholar
  73. 73.
    Safa, A. R., Stern, R. K., Choi, K., et al. (1990). Molecular basis of preferential resistance to colchicine in multidrug-resistant human cells conferred by Gly to Val-185 substitution in P-glycoprotein. Proc. Natl. Acad. Sci. USA 87:7225–7229.PubMedCrossRefGoogle Scholar
  74. 74.
    Loo, T. W., and Clarke, D. M. (1993). Functional consequences of proline mutations in the predicted transmembrane domain of P-glycoprotein. J. Biol. Chem. 268:3143–3149.PubMedGoogle Scholar
  75. 75.
    Devine, S. E., Ling, V, and Melera, P. W. (1992). Amino acid substitutions in the 6th transmembrane domain of P-glycoprotein alter multidrug resistance. Proc. Natl. Acad. Sci. USA 89:4564–4568.PubMedCrossRefGoogle Scholar
  76. 76.
    Loo, T. W., and Clarke, D. M. (1993). Functional consequences of phenylalanine mutations in the predicted transmembrane domain of P-glycoprotein. J. Biol. Chem. 268:19965–19972.PubMedGoogle Scholar
  77. 77.
    Gros, P., Dhir, R., Croop, J., et al. (1991). A single amino acid substitution strongly modulates the activity and substrate specificity of the mouse mdr1 and mdr3 drug efflux pumps. Proc. Natl. Acad. Sci. USA 88:7289–7293.PubMedCrossRefGoogle Scholar
  78. 78.
    Kajiji, S., Talbot, F, Grizzuti, K., et al. (1993). Functional analysis of P-glycoprotein mutants identifies predicted transmembrane domain-11 as a putative drug binding site. Biochemistry 32:4185–4194.PubMedCrossRefGoogle Scholar
  79. 79.
    Kajiji, S., Dreslin, J. A., Grizzuti, K., et al. (1994). Structurally distinct MDR modulators show specific patterns of reversal against P-glycoproteins bearing unique mutations at serine 939/941. Biochemistry 33:5041–5048. PubMedCrossRefGoogle Scholar
  80. 80.
    Dhir, R., Grizzuti, K., Kajiji, S., et al. (1993). Modulatory effects on substrate specificity of independent mutations at the serine (939/941) position in predicted transmembrane domain-11 of P-glycoproteins. Biochemistry 32:9492–9499.PubMedCrossRefGoogle Scholar
  81. 81.
    Azzaria, M., Schurr, E., and Gros, P. (1989). Discrete mutations introduced in the predicted nucleotide-binding sites of the mdr1 gene abolish its ability to confer multidrug resistance. Mol. Cell. Biol. 9:5289–5297.PubMedGoogle Scholar
  82. 82.
    Shimabuku, A. M., Saeki, T., Ueda, K., et al.. (1991). Production of a site specifically cleavable P-glycoprotein-ß-galactosidase fusion protein. Agric. Biol. Chem. 55:1075–1080.PubMedCrossRefGoogle Scholar
  83. 83.
    Shimabuku, A. M., Nishimoto, T., Ueda, K., et al. (1992). P-glycoprotein—ATP hydrolysis by the N-terminal nucleotide-binding domain. J. Biol. Chem. 267:4308–4311.PubMedGoogle Scholar
  84. 84.
    Buschman, E., Arceci, R. J., Croop, J. M., et al. (1992). mdr1 encodes P-glycoprotein expressed in the bile canalicular membrane as determined by isoform-specific antibodies. J. Biol. Chem. 267:18093–18099.PubMedGoogle Scholar
  85. 85.
    Schinkel, A. H., Roelofs, M. E. M., and Borst, P. (1991). Characterization of the human MDR3 P-glycoprotein and its recognition by P-glycoprotein-specific monoclonal antibodies. Cancer Res. 51:2628–2635.PubMedGoogle Scholar
  86. 86.
    Sarkadi, B., Price, E. M., Boucher, R. C, et al. (1992). Expression of the human multidrug resistance cDNA in insect cells generates a high activity drug-stimulated membrane ATPase. J. Biol. Chem. 267:4854–4858.PubMedGoogle Scholar
  87. 87.
    Doige, C. A., Yu, X. H., and Sharom, F. J. (1992). ATPase activity of partially purified P-glycoprotein from multidrug-resistant Chinese hamster ovary cells. Biochim. Biophys. Acta 1109:149–160.PubMedCrossRefGoogle Scholar
  88. 88.
    Al-Shawi, M. K., and Senior, A. E. (1993). Characterization of the adenosine triphosphatase activity of Chinese hamster P-glycoprotein. J. Biol. Chem. 268:4197–4206.PubMedGoogle Scholar
  89. 89.
    Al-Shawi, M. K., Urbatsch, I. L., and Senior A. E. (1994). Covalent inhibitors of P-glycoprotein ATPase activity. J. Biol. Chem. 269:8986–8992.PubMedGoogle Scholar
  90. 90.
    Shapiro, A. B., and Ling, V (1994). ATPase activity of purified and reconstituted P-glycoprotein from Chinese hamster ovary cells. J. Biol. Chem. 269:3745–3754.PubMedGoogle Scholar
  91. 91.
    Ng, W. F., Sarangi, F., Zastawny, R. L., et al. (1989). Identification of members of the P-glycoprotein multigene family. Mol. Cell. Biol. 9:1224–1232.PubMedGoogle Scholar
  92. 92.
    Ambudkar, S. V., Lelong, I. H., Zhang, J. P., et al. (1992). Partial purification and reconstitution of the human multidrug-resistance pump—Characterization of the drug-stimulatable ATP hydrolysis. Proc. Natl. Acad. Sci. USA 89:8472–8476.PubMedCrossRefGoogle Scholar
  93. 93.
    Davidson, A. L., Shuman, H. A., and Nikaido, H. (1992). Mechanism of maltose transport in Escherichia coli: Transmembrane signaling by periplasmic binding proteins. Proc. Natl. Acad. Sci. USA 89:2360–2364.PubMedCrossRefGoogle Scholar
  94. 94.
    Bishop, L., Agbyani, R., Ambudkar, S. V., et al. (1989). Reconstitution of a bacterial periplasmic permease in proteoliposomes and demonstration of ATP hydrolysis concomitant with transport. Proc. Natl. Acad. Sci. USA 86:6953–6957.PubMedCrossRefGoogle Scholar
  95. 95.
    Horio, M., Gottesman, M. M., and Pastan, I. (1988). ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells. Proc. Natl. Acad. Sci. USA 85:3580–3584.PubMedCrossRefGoogle Scholar
  96. 96.
    Gros, P., Croop, J., and Housman, D. E. (1986). Mammalian multidrug resistance gene: Complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 47:371–380.PubMedCrossRefGoogle Scholar
  97. 97.
    Croop, J. M., Raymond, M., Haber, D., et al. (1989). The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Mol. Cell Biol. 9:1346–1350.PubMedGoogle Scholar
  98. 98.
    Chin, J. E., Chen, C.-J., Kriegler, M., et al. (1989). Structure and expression of the human MDR (P-glycoprotein) gene family. Mol. Cell. Biol. 9:3808–3820.PubMedGoogle Scholar
  99. 99.
    Cardon-Cardo, C, O’Brien, J. P., Boccia, C, et al. (1990). Expression of multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J. Histochem. Cytochem. 38:1277–1287.CrossRefGoogle Scholar
  100. 100.
    Gottesman, M. M., Willingham, M. C., Theibaut, F., et al. (1991). Expression of the MDR1 gene in normal human tissues. In Molecular and Cellular Biology of Multidrug Resistance in Tumors (I. B. Roninson, ed.), Plenum Press, New York, pp. 279–289.CrossRefGoogle Scholar
  101. 101.
    Chaudhary, P. M., and Roninson, I. B. (1991). Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66:85–94.PubMedCrossRefGoogle Scholar
  102. 102.
    Drach, D., Zhao, S. R., Drach, J., et al. (1992). Subpopulations of normal peripheral blood and bone marrow cells express a functional multidrug resistant phenotype. Blood 80:2729–2734.PubMedGoogle Scholar
  103. 103.
    Chaudhary, P. M., Mechetner, E. B., and Roninson, I. B. (1992). Expression and activity of the multidrug resistance P-glycoprotein in human peripheral blood lymphocytes. Blood 80:2735–2739.PubMedGoogle Scholar
  104. 104.
    Arceci, R. J., Croop, J. M., Horwitz, S. B., et al. (1988). The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus. Proc. Natl. Acad. Sci. USA 85:4350–4354.PubMedCrossRefGoogle Scholar
  105. 105.
    Arceci, R. J., Baas, F., Raponi, R., et al. (1990). Multidrug resistance gene expression is controlled by steroid hormones in the secretory epithelium of the uterus. Mol. Reprod. Dev. 25:101–109.PubMedCrossRefGoogle Scholar
  106. 106.
    Piekarz, R. L., Cohen, D., and Horwitz, S. B. (1993). Progesterone regulates the murine multidrug resistance mdr1b gene. J. Biol. Chem. 268:7613–7616.PubMedGoogle Scholar
  107. 107.
    Bates, S. E., Mickley, L. A., Chen, Y.-N., et al. (1989). Expression of a drug resistance gene in human neuroblastoma cell lines. Mol. Cell Biol. 9:4337–4344.PubMedGoogle Scholar
  108. 108.
    Mickley, L. A., Bates, S. E., Richert, N. D., et al. (1989). Modulation of the expression of a multidrug resistance gene by differentiating agents. J. Biol. Chem. 264:18031–18040.PubMedGoogle Scholar
  109. 109.
    Frommel, T. O., Coon, J. S., Tsuruo, T., et al. (1993). Variable effects of sodium butyrate on the expression and function of the MDR1(P-glycoprotein) gene in colon carcinoma cell lines. Int. J. Cancer 55:297–302.PubMedCrossRefGoogle Scholar
  110. 110.
    Burt, R. K., Garfield, S., Johnson, K., et al. (1988). Transformation of rat liver epithelial cells with v-Ha-ras or v-raf causes expression of MDR1, glutathione-S-transferase-P and increased resistance to cytotoxic chemicals. Carcinogenesis 9:2329–2332.PubMedCrossRefGoogle Scholar
  111. 111.
    Chin, K.-V., Ueda, K., Pastan, I., et al. (1992). Modulation of the activity of the promoter of the human MDR1 gene by Ras and p53. Science 255:459–462.PubMedCrossRefGoogle Scholar
  112. 112.
    Cornwell, M. M., and Smith, D. E. (1993). A signal transduction pathway for activation of the mdr1 promoter involves the proto-oncogene c-raf kinase. J. Biol. Chem. 268:15347–15350.PubMedGoogle Scholar
  113. 113.
    Thorgeirsson, S. S., Huber, B. E., Sorrell, S., et al. (1987). Expression of the multidrug-resistance gene in hepatocarcinogenesis and regenerating rat liver. Science 236:1120–1122.PubMedCrossRefGoogle Scholar
  114. 114.
    Fairchild, C, Ivy, S., Rushmore, T., et al. (1987). Carcinogen-induced mdr overexpression is associated with xenobiotic resistance in rat preneoplastic nodules and hepatocellular carcinomas. Proc. Natl. Acad. Sci. USA 84:7701–7705.PubMedCrossRefGoogle Scholar
  115. 115.
    Gant, T. W., Silverman, J. A., Bisgaard, H. C, et al. (1991). Regulation of 2-AAF and methylcholanthrene-mediated induction of multidrug resistance and cytochrome P450IA gene family expression in primary hepatocyte cultures and rat liver. Mol. Carcinogenesis 4:499–509.CrossRefGoogle Scholar
  116. 116.
    Chin, K.-V, Chauhan, S., Pastan, I., et al. (1990). Regulation of mdr gene expression in acute response to cytotoxic insults in rodent cells. Cell Growth Differ. 1:361–365.PubMedGoogle Scholar
  117. 117.
    Herzog, C. E., Tsokos, M., Bates, S. E., et al. (1993). Increased mdr-1/P-glycoprotein expression after treatment of human colon carcinoma cells with P-glycoprotein antagonists. J. Biol. Chem. 268:2946–2952.PubMedGoogle Scholar
  118. 118.
    Chin, K.-V, Tanaka, S., Darlington, G., et al. (1990). Heat shock and arsenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells. J. Biol. Chem. 265:221–226.PubMedGoogle Scholar
  119. 119.
    Kioka, N., Yamano, Y, Komano, T., et al. (1992). Heat-shock responsive elements in the induction of the multidrug resistance gene (MDR1). FEBS Lett. 301:37–40.PubMedCrossRefGoogle Scholar
  120. 120.
    Chin, K.-V, Pastan, I., and Gottesman, M. M. (1993). Function and regulation of the human multidrug resistance gene. Adv. Cancer Res. 60:157–180.PubMedCrossRefGoogle Scholar
  121. 121.
    Ueda, K., Clark, D. P., Chen, C.-j., et al. (1987). The human multidrug-resistance (mdr1) gene: cDNA cloning and transcription initiation. J. Biol. Chem. 262:505–508.PubMedGoogle Scholar
  122. 122.
    Hsu, S. I., Lothstein, L., and Horwitz, S. B. (1989). Differential overexpression of three mdr gene family members in multidrug-resistant J774.2 mouse cells. J. Biol. Chem. 264:12053–12062.PubMedGoogle Scholar
  123. 123.
    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
  124. 124.
    Raymond, M., and Gros, P. (1990). Cell-specific activity of cis-acting regulatory elements in the promoter of the mouse multidrug resistance gene mdr1. Mol. Cell Biol. 10:6036–6040.PubMedGoogle Scholar
  125. 125.
    Cohen, D., Piekarz, R. I., Hsu, S. I., et al. (1991). Structural and functional analysis of the mouse mdr1b gene promoter. J. Biol. Chem. 266:2239–2244.PubMedGoogle Scholar
  126. 126.
    Madden, M. J., Morrow, C. S., Nakagawa, M., et al. (1993). Identification of 5′ and 3′ sequences involved in the regulation of transcription of the human mdr1 gene in vivo. J. Biol. Chem. 268:8290–8297.PubMedGoogle Scholar
  127. 127.
    Cornwell, M. M., and Smith, D. E. (1993). SP1 activates the MDR1 promoter through one of two distinct G-rich regions that modulate promoter activity. J. Biol. Chem. 268:19505–19511.PubMedGoogle Scholar
  128. 128.
    Zastawny, R. L., and Ling, V (1993). Structural and functional analysis of 5′ flanking and intron-1 sequences of the hamster P-glycoprotein pgp1 and pgp2 genes. Biochim. Biophys. Acta 1173:303–313.PubMedGoogle Scholar
  129. 129.
    Silverman, J. A., Raunio, H., Gant, T. W., et al. (1991). Cloning and characterization of a member of the rat multidrug resistance (mdr) gene family. Gene 106:229–236.PubMedCrossRefGoogle Scholar
  130. 130.
    Ikeguchi, M., Teeter, L., Eckersberg, T., et al. (1991). Structural and functional analyses of the promoter of the murine multidrug resistance gene mdr3/mdr1a reveal a negative element containing the AP1-site. DNA Cell Biol. 10:639–649.Google Scholar
  131. 131.
    Teeter, L. D., Eekersberg, T., Tsai, Y., et al. (1991). Analysis of the Chinese hamster P-glycoprotein/multidrug resistance gene pgp1 reveals that the AP-1 site is essential for full promoter activity. Cell Growth Differ. 2:429–437.PubMedGoogle Scholar
  132. 132.
    Goldsmith, M. E., Madden, M. J., Morrow, C. S., et al. (1993). A y-box consensus sequence is required for basal expression of the human multidrug resistance (mdr1) gene. J. Biol. Chem. 268:5856–5860.PubMedGoogle Scholar
  133. 133.
    Ogura, M., Takatori, T., and Tsuruo, T. (1992). Purification and characterization of NF-R1 that regulates the expression of the human multidrug resistance (MDR1) gene. Nucleic Acids Res. 20:5811–5817.PubMedCrossRefGoogle Scholar
  134. 134.
    Cornwell, M. M. (1990). The human multidrug-resistance (MDR1) gene: Sequences upstream and downstream of the initiation site influence transcription. Cell Growth Differ. 1:607–615.PubMedGoogle Scholar
  135. 135.
    Van Groenigen, M., Valentijn, L. J., and Baas, F. (1993). Identification of a functional initiator sequence in the human MDR1 promoter. Biochim. Biophys. Acta 1172:138–146.PubMedGoogle Scholar
  136. 136.
    Schinkel, A. H., Kemp, S., Dolle, M., et al. (1993). N-glycosylation and deletion mutants of the human MDR1 P-glycoprotein. J. Biol. Chem. 268:7474–7481.PubMedGoogle Scholar
  137. 137.
    Beck, W. T, and Cirtain, M. (1982). Continued expression of Vinca alkaloid resistance by CCRF-CEM cells after treatment with tunicamycin or pronase. Cancer Res. 42:184–189.PubMedGoogle Scholar
  138. 138.
    Ling, V., Kartner, N., Sudo, T., et al. (1983). The multidrug resistance phenotype in Chinese hamster ovary cells. Cancer Treat. Rep. 67:869–874.PubMedGoogle Scholar
  139. 139.
    Center, M. S. (1985). Mechanisms regulating cell resistance to adriamycin: Evidence that drug accumulation in resistant cells is modulated by phosphorylation of a plasma membrane glycoprotein. Biochem. Pharmacol. 34:1471–1476.PubMedCrossRefGoogle Scholar
  140. 140.
    Mellado, W., and Horwitz, S. B. (1987). Phosphorylation of the multidrug resistance associated glycoprotein. Biochemistry 26:6900–6904.PubMedCrossRefGoogle Scholar
  141. 141.
    Hamada, H., Hagiwara, K.-I., Nakajima, T., et al. (1987). Phosphorylation of the Mr 170,000 to 180,000 glycoprotein specific to multidrug-resistant tumor cells: Effects of verapamil, trifluoperazine, and phorbol esters. Cancer Res. 47:2860–2865.PubMedGoogle Scholar
  142. 142.
    Fine, R. L., Patel, J., and Chabner, B. A. (1988). Phorbol esters induce multidrug resistance in human breast cancer cells. Proc. Natl. Acad. Sci. USA 85:582–586.PubMedCrossRefGoogle Scholar
  143. 143.
    Epand, R. M., and Stafford, A. R. (1993). Protein kinases and multidrug resistance. Cancer J. 6:154–158.Google Scholar
  144. 144.
    Chambers, T. C, McAvoy, E. M., Jacobs, J. W., et al. (1990). Protein kinase C phosphorylates P-glycoprotein in multidrug resistant human KB carcinoma cells. J. Biol. Chem. 265:7679–7686.PubMedGoogle Scholar
  145. 145.
    Ahmad, S., Trepel, J. B., Ohno, S., et al. (1992). Role of protein kinase-C in the modulation of multidrug resistance—Expression of the atypical gamma-isoform of protein kinase-C does not confer increased resistance to doxorubicin. Mol. Pharmacol. 42:1004–1009.PubMedGoogle Scholar
  146. 146.
    Ahmad, S., and Glazer, R. I. (1993). Expression of the antisense cDNA for protein kinase-C-alpha attenuates resistance in doxorubicin-resistant MCF-7 breast carcinoma cells. Mol. Pharmacol. 43:858–862.PubMedGoogle Scholar
  147. 147.
    Chaudhary, P. M., and Roninson, I. B. (1992). Activation of MDR1 (P-glycoprotein) gene expression in human cells by protein kinase-C agonists. Oncol. Res. 4:281–290.PubMedGoogle Scholar
  148. 148.
    Bates, S. E., Lee, J. S., Dickstein, B., et al. (1993). Differential modulation of P-glycoprotein transport by protein kinase inhibition. Biochemistry 32:9156–9164.PubMedCrossRefGoogle Scholar
  149. 149.
    Chambers, T. C, Pohl, J., Raynor, R. L., et al. (1993). Identification of specific sites in human P-glycoprotein phosphorylated by protein kinase-C. J. Biol. Chem. 268:4592–4595.PubMedGoogle Scholar
  150. 150.
    Orr, G. A., Han, E. K.-H., Browne, P. C, et al. (1993). Identification of the major phosphorylation domain of murine mdr1b P-glycoprotein. J. Biol. Chem. 268:25054–25062.PubMedGoogle Scholar
  151. 151.
    Riordan, J. R. (1993). The cystic fibrosis transmembrane conductance regulator. Annu. Rev. Physiol. 55:609–630.PubMedCrossRefGoogle Scholar
  152. 152.
    Gottesman, M. M. (1993). How cancer cells evade chemotherapy—Sixteenth Richard and Linda Rosenthal Foundation Award Lecture. Cancer Res. 53:747–754.PubMedGoogle Scholar
  153. 153.
    Galski, H., Sullivan, M., Willingham, M. C, et al. (1989). Expression of a human multidrug-resistance cDNA(MDR1) in the bone marrow of transgenic mice: Resistance to daunomycin-induced leukopenia. Mol. Cell. Biol. 9:4357–4363.PubMedGoogle Scholar
  154. 154.
    Mickisch, G., Merlino, G. T., Galski, H., et al. (1991). Transgenic mice that express the human multidrug resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance. Proc. Natl. Acad. Sci. USA 88:547–551.PubMedCrossRefGoogle Scholar
  155. 155.
    Mickisch, G. H., Aksentijevich, I., Schoenlein, P. V., et al. (1992). Transplantation of bone marrow cells from transgenic mice expressing the human MDR1 gene results in long-term protection against the myelosuppressive effect of chemotherapy in mice. Blood 79:1–7.Google Scholar
  156. 156.
    Sorrentino, B. P., Brandt, S. J., Bodine, D., et al. (1992). Retroviral transfer of the human MDR1 gene permits selection of drug resistant bone marrow cells in vivo. Science 257:99–103.PubMedCrossRefGoogle Scholar
  157. 157.
    Podda, S., Ward, M., Himelstein, A., et al. (1992). Transfer and expression of the human multiple drug resistance gene into live mice. Proc. Natl. Acad. Sci. USA 89:9676–9680.PubMedCrossRefGoogle Scholar
  158. 158.
    Cardarelli, C. O., Aksentijevich, I., Pastan I., et al. (1995). Differential effects of P-glycoprotein inhibitors on NIH3T3 cells transfected with wild-type (G185) or mutant (V185) multidrug transporters. Cancer Res. 55:1086–1091.PubMedGoogle Scholar
  159. 159.
    Germann, U. A., Chambers, T. C, Ambudkar, S. V., et al. (1996). Characterization of phosphorylation-defective mutants of human P-glycoprotein expressed in mammalian cells. J. Bio. Chem. 271:1708–1716.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1996

Authors and Affiliations

  • Michael M. Gottesman
    • 1
  • Suresh V. Ambudkar
    • 2
  • Marilyn M. Cornwell
    • 3
  • Ira Pastan
    • 4
  • Ursula A. Germann
    • 5
  1. 1.Laboratory of Cell BiologyNational Cancer Institute, National Institutes of HealthBethesdaUSA
  2. 2.Department of MedicineThe Johns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Fred Hutchinson Cancer Research CenterSeattleUSA
  4. 4.Laboratory of Molecular BiologyNational Cancer Institute, National Institutes of HealthBethesdaUSA
  5. 5.Vertex Pharmaceuticals IncorporatedCambridgeUSA

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