Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1996 Nov;74(9):1331–1335. doi: 10.1038/bjc.1996.545

The anthracycline resistance-associated (ara) gene, a novel gene associated with multidrug resistance in a human leukaemia cell line.

T J Longhurst 1, G M O'Neill 1, R M Harvie 1, R A Davey 1
PMCID: PMC2074757  PMID: 8912525

Abstract

Multidrug resistance (MDR) in cancer cells is a major contributor to the failure of chemotherapy treatment. This paper describes a novel protein named the anthracycline resistance associated (ARA) protein. The ara gene is amplified in the MDR leukaemia line CCRF-CEM/E1000 and its mRNA is overexpressed. ARA belongs to the ATP binding cassette (ABC) family of proteins. Another ABC protein, the multidrug resistance-associated protein (MRP), has previously been reported to be overexpressed in the CEM/E1000 subline. The primary amino acid sequence of ARA indicates that it is 49.5 kDa without glycosylation, and that it has one potential glycosylation site. ARA has one ATP binding site and associated transmembrane regions. This is in contrast to MRP (190 kDa, 172 kDa deglycosylated) and most other higher eukaryote ABC proteins, which consist of two similar halves, each having one ATP binding site. In addition to ARA being coexpressed with MRP, comparison of amino acid sequences showed that, among known proteins, ARA is most similar to the C-terminal half of MRP.

Full text

PDF
1331

Images in this article

1332Figure 1
on p.1332
1332Figure 2
on p.1332

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Almquist K. C., Loe D. W., Hipfner D. R., Mackie J. E., Cole S. P., Deeley R. G. Characterization of the M(r) 190,000 multidrug resistance protein (MRP) in drug-selected and transfected human tumor cell. Cancer Res. 1995 Jan 1;55(1):102–110. [PubMed] [Google Scholar]
  2. Barrand M. A., Heppell-Parton A. C., Wright K. A., Rabbitts P. H., Twentyman P. R. A 190-kilodalton protein overexpressed in non-P-glycoprotein-containing multidrug-resistant cells and its relationship to the MRP gene. J Natl Cancer Inst. 1994 Jan 19;86(2):110–117. doi: 10.1093/jnci/86.2.110. [DOI] [PubMed] [Google Scholar]
  3. Barrand M. A., Rhodes T., Center M. S., Twentyman P. R. Chemosensitisation and drug accumulation effects of cyclosporin A, PSC-833 and verapamil in human MDR large cell lung cancer cells expressing a 190k membrane protein distinct from P-glycoprotein. Eur J Cancer. 1993;29A(3):408–415. doi: 10.1016/0959-8049(93)90397-x. [DOI] [PubMed] [Google Scholar]
  4. Beck S., Kelly A., Radley E., Khurshid F., Alderton R. P., Trowsdale J. DNA sequence analysis of 66 kb of the human MHC class II region encoding a cluster of genes for antigen processing. J Mol Biol. 1992 Nov 20;228(2):433–441. doi: 10.1016/0022-2836(92)90832-5. [DOI] [PubMed] [Google Scholar]
  5. Binaschi M., Supino R., Gambetta R. A., Giaccone G., Prosperi E., Capranico G., Cataldo I., Zunino F. MRP gene overexpression in a human doxorubicin-resistant SCLC cell line: alterations in cellular pharmacokinetics and in pattern of cross-resistance. Int J Cancer. 1995 Jul 4;62(1):84–89. doi: 10.1002/ijc.2910620116. [DOI] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Coblenz A., Wolf K. The role of glutathione biosynthesis in heavy metal resistance in the fission yeast Schizosaccharomyces pombe. FEMS Microbiol Rev. 1994 Aug;14(4):303–308. doi: 10.1111/j.1574-6976.1994.tb00103.x. [DOI] [PubMed] [Google Scholar]
  8. Cole S. P., Bhardwaj G., Gerlach J. H., Mackie J. E., Grant C. E., Almquist K. C., Stewart A. J., Kurz E. U., Duncan A. M., Deeley R. G. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 1992 Dec 4;258(5088):1650–1654. doi: 10.1126/science.1360704. [DOI] [PubMed] [Google Scholar]
  9. Cole S. P., Sparks K. E., Fraser K., Loe D. W., Grant C. E., Wilson G. M., Deeley R. G. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res. 1994 Nov 15;54(22):5902–5910. [PubMed] [Google Scholar]
  10. Davey R. A., Longhurst T. J., Davey M. W., Belov L., Harvie R. M., Hancox D., Wheeler H. Drug resistance mechanisms and MRP expression in response to epirubicin treatment in a human leukaemia cell line. Leuk Res. 1995 Apr;19(4):275–282. doi: 10.1016/0145-2126(94)00159-8. [DOI] [PubMed] [Google Scholar]
  11. FOLEY G. E., LAZARUS H., FARBER S., UZMAN B. G., BOONE B. A., MCCARTHY R. E. CONTINUOUS CULTURE OF HUMAN LYMPHOBLASTS FROM PERIPHERAL BLOOD OF A CHILD WITH ACUTE LEUKEMIA. Cancer. 1965 Apr;18:522–529. doi: 10.1002/1097-0142(196504)18:4<522::aid-cncr2820180418>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  12. Flens M. J., Izquierdo M. A., Scheffer G. L., Fritz J. M., Meijer C. J., Scheper R. J., Zaman G. J. Immunochemical detection of the multidrug resistance-associated protein MRP in human multidrug-resistant tumor cells by monoclonal antibodies. Cancer Res. 1994 Sep 1;54(17):4557–4563. [PubMed] [Google Scholar]
  13. Gekeler V., Ise W., Sanders K. H., Ulrich W. R., Beck J. The leukotriene LTD4 receptor antagonist MK571 specifically modulates MRP associated multidrug resistance. Biochem Biophys Res Commun. 1995 Mar 8;208(1):345–352. doi: 10.1006/bbrc.1995.1344. [DOI] [PubMed] [Google Scholar]
  14. Germann U. A., Pastan I., Gottesman M. M. P-glycoproteins: mediators of multidrug resistance. Semin Cell Biol. 1993 Feb;4(1):63–76. doi: 10.1006/scel.1993.1008. [DOI] [PubMed] [Google Scholar]
  15. Higgins C. F. ABC transporters: from microorganisms to man. Annu Rev Cell Biol. 1992;8:67–113. doi: 10.1146/annurev.cb.08.110192.000435. [DOI] [PubMed] [Google Scholar]
  16. Higgins C. F., Hyde S. C., Mimmack M. M., Gileadi U., Gill D. R., Gallagher M. P. Binding protein-dependent transport systems. J Bioenerg Biomembr. 1990 Aug;22(4):571–592. doi: 10.1007/BF00762962. [DOI] [PubMed] [Google Scholar]
  17. Jedlitschky G., Leier I., Buchholz U., Center M., Keppler D. ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res. 1994 Sep 15;54(18):4833–4836. [PubMed] [Google Scholar]
  18. Kamijo K., Kamijo T., Ueno I., Osumi T., Hashimoto T. Nucleotide sequence of the human 70 kDa peroxisomal membrane protein: a member of ATP-binding cassette transporters. Biochim Biophys Acta. 1992 Feb 11;1129(3):323–327. doi: 10.1016/0167-4781(92)90510-7. [DOI] [PubMed] [Google Scholar]
  19. Kelly A., Powis S. H., Kerr L. A., Mockridge I., Elliott T., Bastin J., Uchanska-Ziegler B., Ziegler A., Trowsdale J., Townsend A. Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex. Nature. 1992 Feb 13;355(6361):641–644. doi: 10.1038/355641a0. [DOI] [PubMed] [Google Scholar]
  20. Krishnamachary N., Center M. S. The MRP gene associated with a non-P-glycoprotein multidrug resistance encodes a 190-kDa membrane bound glycoprotein. Cancer Res. 1993 Aug 15;53(16):3658–3661. [PubMed] [Google Scholar]
  21. Krishnamachary N., Ma L., Zheng L., Safa A. R., Center M. S. Analysis of MRP gene expression and function in HL60 cells isolated for resistance to adriamycin. Oncol Res. 1994;6(3):119–127. [PubMed] [Google Scholar]
  22. Leier I., Jedlitschky G., Buchholz U., Cole S. P., Deeley R. G., Keppler D. The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J Biol Chem. 1994 Nov 11;269(45):27807–27810. [PubMed] [Google Scholar]
  23. Mosser J., Douar A. M., Sarde C. O., Kioschis P., Feil R., Moser H., Poustka A. M., Mandel J. L., Aubourg P. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. 1993 Feb 25;361(6414):726–730. doi: 10.1038/361726a0. [DOI] [PubMed] [Google Scholar]
  24. Müller M., Meijer C., Zaman G. J., Borst P., Scheper R. J., Mulder N. H., de Vries E. G., Jansen P. L. Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):13033–13037. doi: 10.1073/pnas.91.26.13033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nielsen D., Skovsgaard T. P-glycoprotein as multidrug transporter: a critical review of current multidrug resistant cell lines. Biochim Biophys Acta. 1992 Jul 7;1139(3):169–183. doi: 10.1016/0925-4439(92)90131-6. [DOI] [PubMed] [Google Scholar]
  26. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Schneider E., Yamazaki H., Sinha B. K., Cowan K. H. Buthionine sulphoximine-mediated sensitisation of etoposide-resistant human breast cancer MCF7 cells overexpressing the multidrug resistance-associated protein involves increased drug accumulation. Br J Cancer. 1995 Apr;71(4):738–743. doi: 10.1038/bjc.1995.144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Szczypka M. S., Wemmie J. A., Moye-Rowley W. S., Thiele D. J. A yeast metal resistance protein similar to human cystic fibrosis transmembrane conductance regulator (CFTR) and multidrug resistance-associated protein. J Biol Chem. 1994 Sep 9;269(36):22853–22857. [PubMed] [Google Scholar]
  29. Turi T. G., Rose J. K. Characterization of a novel Schizosaccharomyces pombe multidrug resistance transporter conferring brefeldin A resistance. Biochem Biophys Res Commun. 1995 Aug 15;213(2):410–418. doi: 10.1006/bbrc.1995.2147. [DOI] [PubMed] [Google Scholar]
  30. Versantvoort C. H., Broxterman H. J., Lankelma J., Feller N., Pinedo H. M. Competitive inhibition by genistein and ATP dependence of daunorubicin transport in intact MRP overexpressing human small cell lung cancer cells. Biochem Pharmacol. 1994 Sep 15;48(6):1129–1136. doi: 10.1016/0006-2952(94)90149-x. [DOI] [PubMed] [Google Scholar]
  31. Walker J. E., Saraste M., Runswick M. J., Gay N. J. Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1982;1(8):945–951. doi: 10.1002/j.1460-2075.1982.tb01276.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wilkinson M. RNA isolation: a mini-prep method. Nucleic Acids Res. 1988 Nov 25;16(22):10933–10933. doi: 10.1093/nar/16.22.10933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zaman G. J., Versantvoort C. H., Smit J. J., Eijdems E. W., de Haas M., Smith A. J., Broxterman H. J., Mulder N. H., de Vries E. G., Baas F. Analysis of the expression of MRP, the gene for a new putative transmembrane drug transporter, in human multidrug resistant lung cancer cell lines. Cancer Res. 1993 Apr 15;53(8):1747–1750. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES