Eukaryotic Mdr1/P-Glycoprotein Homologues: Unconventional Secretion Processes Mediated by a Growing Family of ATP-Dependent Membrane Translocators

  • Mikael Göransson
  • Jeremy Thorner
Conference paper
Part of the NATO ASI Series book series (volume 71)


Mdr1/P-glycoprotein, when overexpressed, can confer resistance of human tumor cells to multiple lipophilic cytotoxic drugs and this resistance is a major problem in cancer chemotherapy. When mouse and human mdr cDNAs were cloned and sequenced (10,17), one of the intriguing findings was that they showed homology to a family of bacterial active transport systems, including for example the E. coli hlyB gene, whose product is a membrane protein involved in the export of a hemolysin. This observation was the start of what has since been a very active and fruitful area of research, and in the past few years many Mdr/P-glycoprotein homologues have been identified in eukaryotes.


Cystic Fibrosis Transmembrane Conductance Regulator Multiple Drug Resistance Chloroquine Resistance Major Histocompatibility Class Mating Pheromone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Anderegg RJ, Betz R, Carr SA, Crabb JW, Duntze W (1988) Structure of Saccha-romyces cerevisiae mating hormone a-factor. Identification of S-farnesyl cysteine as a structural component. J Biol Chem 263: 18236–18240PubMedGoogle Scholar
  2. 2.
    Auron PE, Webb AC, Rosenwasser LJ, Mucci SF, Rich A, Wolff SM, Dinarello CA (1984) Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci USA 81: 7907–7911PubMedCrossRefGoogle Scholar
  3. 3.
    Azzaria M, Schurr E, 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: 5289–5297PubMedGoogle Scholar
  4. 4.
    Barnes DA, Foote SJ, Galatis D, Kemp DJ, Cowman AF (1992) Selection for high-level chloroquine resistance results in deamplification of the pfmdr1 gene and increased sensitivity to mefloquine in Plasmodium falciparum. EMBO J 11: 3067–3075PubMedGoogle Scholar
  5. 5.
    Bear CE, Li C, Kartner N, Bridges RJ, Jensen TJ, Ramjeesingh M, Riordan JR (1992) Purification and functional reconstitution of the cystic fibrosis trans-membrane conductance regulator (CFTR). Cell 68: 809–818PubMedCrossRefGoogle Scholar
  6. 6.
    Berkower C, Michaelis S (1991) Mutational analysis of the yeast a-factor transporter STE6, a member of the ATP binding cassette (ABC) protein superfamily. EMBO J 10: 3777–3785PubMedGoogle Scholar
  7. 7.
    Bradbury NA, Jilling T, Berta G, Sorscher EJ, Bridges RJ, Kirk KL (1992) Regulation of plasma membrane recycling by CFTR. Science 256: 530–532PubMedCrossRefGoogle Scholar
  8. 8.
    Brake AJ, Brenner C, Najarian R, Laybourn P, Merryweather J (1985) Structure of genes encoding precursors of the yeast peptide mating pheromone a-factor. In Gething MJ (ed) Protein Transport and Secretion. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 103–108Google Scholar
  9. 9.
    Bursten SL, Locksley RM, Ryan JL, Lovett DH (1988) Acylation of monocyte and glomerular mesangial cell proteins. Myristyl acylation of the interleukin 1 precursors. J Clin Invest 82: 1479–1488PubMedCrossRefGoogle Scholar
  10. 10.
    Chen C, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM, Roninson IB (1986) Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47: 381–389PubMedCrossRefGoogle Scholar
  11. 11.
    Cowman AF, Karcz S, Galatis D, Culvenor JG (1991) A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole. J Cell Biol 113: 1033–1042PubMedCrossRefGoogle Scholar
  12. 12.
    Devault A, Gros P (1990) Two members of the mouse mdr gene family confer multidrug resistance with overlapping but distinct drug specificities. Mol Cell Biol 10: 1652–1663PubMedGoogle Scholar
  13. 13.
    Dreesen TM, Johnson DH, Henikoff S (1988) The Brown protein of Drosophila melanogaster is similar to the White protein and to components of active transport complexes. Mol Cell Biol 8: 5206–5215PubMedGoogle Scholar
  14. 14.
    Egan M, Flotte T, Afione S, Solow R, Zeitlin PL, Carter BJ, Guggino WB (1992) Defective regulation of outwardly rectifying Cl¯ channels by protein kinase A corrected by insertion of CFTR. Nature 358: 581–584PubMedCrossRefGoogle Scholar
  15. 15.
    Foote SJ, Kyle DE, Martin RK, Oduola AMJ, Forsyth K, Kemp DJ, Cowman AF (1990) Several alleles of the multidrug-resistance gene are closely linked to chloro-quine resistance in Plasmodium falciparum. Nature 345: 255–258PubMedCrossRefGoogle Scholar
  16. 16.
    Fuller RS, Sterne RE, Thorner J (1988) Enzymes required for yeast prohormone processing. Ann Rev Physiol 50: 345–362CrossRefGoogle Scholar
  17. 17.
    Gros P, Croop J, Housman D (1986) Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 47: 371–380PubMedCrossRefGoogle Scholar
  18. 18.
    Hamada H, Tsuruo T (1988) Purification of the 170-to 180-kilodalton membrane glycoprotein associated with multidrug resistance. 170-to 180-kilodalton membrane glycoprotein is an ATPase. J Biol Chem 263: 1454–1458PubMedGoogle Scholar
  19. 19.
    Henderson DM, Sifri CD, Rodgers M, Wirth DF, Hendrickson N, Ullman B (1992) Multidrug resistance in Leishmania donovani is conferred by amplification of a gene homologous to the mammalian mdr1 gene. Mol Cell Biol 12: 2855–2865PubMedGoogle Scholar
  20. 20.
    Higgins CF, Hyde SC, Mimmack MM, Gileadi U, Gill DR, Gallagher MP (1990) Binding protein-dependent transport systems. J Bioenerg Biomembr 22: 571–592PubMedCrossRefGoogle Scholar
  21. 21.
    Horio M, Gottesman MM, Pastan I (1988) ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells. Proc Natl Acad Sci USA 85: 3580–3584PubMedCrossRefGoogle Scholar
  22. 22.
    Kamijo K, Taketani S, Yokota S, Osumi T, Hashimoto T (1990) The 70-kDa peroxi-somal membrane protein is a member of the Mdr (P-glycoprotein)-related ATP-binding protein superfamily. J Biol Chem 265: 4534–4540PubMedGoogle Scholar
  23. 23.
    Kelly A, Powis SH, Kerr LA, Mockridge I, Elliott T, Bastin J, Uchanska-Ziegler B, Ziegler A, Trowsdale J, Townsend A (1992) Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex. Nature 355: 641–644PubMedCrossRefGoogle Scholar
  24. 24.
    Kuchler K, Sterne RE, Thorner J (1989) Saccharomyces cerevisiae STE6 gene product: a novel pathway for protein export in eukaryotic cells. EMBO J 8: 3973–3984PubMedGoogle Scholar
  25. 25.
    Kuchler K, Thorner J (1992) Functional expression of human mdrl in the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci USA 89: 2302–2306PubMedCrossRefGoogle Scholar
  26. 26.
    Kuchler K, Thorner J (1992) Secretion of peptides and proteins lacking hydrophobic signal sequences: The role of adenosine triphosphate-driven membrane transloca-tors. Endocrine Reviews 13: in pressGoogle Scholar
  27. 27.
    Kuchler K, Thorner J (1992) The a-factor transporter (STE6 gene product) and cell polarity in the yeast Saccharomyces cerevisiae. J Cell Biol: in pressGoogle Scholar
  28. 28.
    Leppert G, McDevitt R, Falco SC, Van Dyk TK, Ficke MB, Golin J (1990) Cloning by gene amplification of two loci conferring multiple drug resistance in Saccha-romyces. Genetics 125: 13–20PubMedGoogle Scholar
  29. 29.
    March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, Gillis S, Henney CS, Kronheim SR, Grabstein K, Conlon PJ, Hopp TP, Cosman D (1985) Cloning, sequence, and expression of two distinct human interleukin-1 complementary DNAs. Nature 315: 641–647PubMedCrossRefGoogle Scholar
  30. 30.
    Monaco JJ, Cho S, Attaya M (1990) Transport protein genes in the murine MHC: possible implications for antigen processing. Science 250: 1723–1726PubMedCrossRefGoogle Scholar
  31. 31.
    Ouellette M, Fase-Fowler F, Borst P (1990) The amplified H circle of methotrexate-resistant Leishmania tarentolae contains a novel P-glycoprotein gene. EMBO J 9: 1027–1033PubMedGoogle Scholar
  32. 32.
    Purnelle B, Skala J, Goffeau A (1991) The product of the YCR105 gene located on the chromosome III from Saccharomyces cerevisiae presents homologies to ATP-dependent permeases. Yeast 7: 867–872PubMedCrossRefGoogle Scholar
  33. 33.
    Raymond M, Gros P, Whiteway M, Thomas DY (1992) Functional complementation of yeast ste6 by a mammalian multidrug resistance mdr gene. Science 256: 232–234PubMedCrossRefGoogle Scholar
  34. 34.
    Riordan JR, Rommens JM, Kerem B-S, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou J-L, Drumm ML, Iannuzzi MC, Collins FS, Tsui L-C (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245: 1066–1073PubMedCrossRefGoogle Scholar
  35. 35.
    Rubartelli A, Cozzolino F, Talio M, Sitia R (1990) A novel secretory pathway for interleukin-lß, a protein lacking a signal sequence. EMBO J 9: 1503–1510PubMedGoogle Scholar
  36. 36.
    Sharma RC, Inoue S, Roitelman J, Schimke RT, Simoni RD (1992) Peptide transport by the multidrug resistance pump. J Biol Chem 267: 5731–5734PubMedGoogle Scholar
  37. 37.
    Spies T, Cerundolo V, Colonna M, Cresswell P, Townsend A, DeMars R (1992) Presentation of viral antigen by MHC class I molecules is dependent on a putative peptide transporter heterodimer. Nature 355: 644–646PubMedCrossRefGoogle Scholar
  38. 38.
    Sterne RE (1989) A novel pathway for peptide hormone biogenesis: processing and secretion of the mating pheromone, a-factor, by Saccharomyces cerevisiae. ph D Thesis, University of California, BerkeleyGoogle Scholar
  39. 39.
    Valverde MA, Diaz M, Sepúlveda FV, Gill DR, Hyde SC, Higgins CF (1992) Volume-regulated chloride channels associated with the human multidrug-resis-tance P-glycoprotein. Nature 355: 830–833PubMedCrossRefGoogle Scholar
  40. 40.
    Wang M, Balzi E, Van Dyck L, Golin J, Goffeau A (1992) Sequencing of the yeast multidrug resistance PDR5 gene encoding a putative pump for arug efflux. Abstract, 16th Int. Conf. on Yeast Genetics and Molecular BiologyGoogle Scholar
  41. 41.
    Wellems TE, Panton LJ, Gluzman IY, Rosario VE, Gwadz RW, Walker-Jonah A, Krogstad DJ (1990) Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross. Nature 345: 253–255PubMedCrossRefGoogle Scholar
  42. 42.
    Wilson CM, Serrano AE, Wasley A, Bogenschutz MP, Shankar AH, Wirth DF (1989) Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science 244: 1184–1186PubMedCrossRefGoogle Scholar
  43. 43.
    Wu C-T, Budding M, Griffin MS, Croop JM (1991) Isolation and characterization of Drosophila multidrug resistance gene homologs. Mol Cell Biol 11: 3940–3948PubMedGoogle Scholar
  44. 44.
    Yoshimura A, Kuwazuru Y, Sumizawa T, Ichikawa M, Ikeda S, Uda T, Akiyama S (1989) Cytoplasmic orientation and two-domain structure of the multidrug transporter, P-glycoprotein, demonstrated with sequence-specific antibodies. J Biol Chem 264: 16282–16291PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • Mikael Göransson
    • 1
  • Jeremy Thorner
    • 1
  1. 1.Division of Biochemistry and Molecular Biology Department of Molecular and Cell BiologyUniversity of CaliforniaBerkeleyUSA

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