Overexpression of a Transporter Gene in a Multidrug-Resistant Human Lung Cancer Cell Line
10.1126/science.1360704
Crossref journal-article
American Association for the Advancement of Science (AAAS)
Science (221)
Abstract

The doxorubicin-selected lung cancer cell line H69AR is resistant to many chemotherapeutic agents. However, like most tumor samples from individuals with this disease, it does not overexpress P-glycoprotein, a transmembrane transport protein that is dependent on adenosine triphosphate (ATP) and is associated with multidrug resistance. Complementary DNA (cDNA) clones corresponding to messenger RNAs (mRNAs) overexpressed in H69AR cells were isolated. One cDNA hybridized to an mRNA of 7.8 to 8.2 kilobases that was 100- to 200-fold more expressed in H69AR cells relative to drug-sensitive parental H69 cells. Overexpression was associated with amplification of the cognate gene located on chromosome 16 at band p13.1. Reversion to drug sensitivity was associated with loss of gene amplification and a marked decrease in mRNA expression. The mRNA encodes a member of the ATP-binding cassette transmembrane transporter superfamily.

Bibliography

Cole, S. P. C., Bhardwaj, G., Gerlach, J. H., Mackie, J. E., Grant, C. E., Almquist, K. C., Stewart, A. J., Kurz, E. U., Duncan, A. M. V., & Deeley, R. G. (1992). Overexpression of a Transporter Gene in a Multidrug-Resistant Human Lung Cancer Cell Line. Science, 258(5088), 1650–1654.

Authors 10
  1. S. P. C. Cole (first)
  2. G. Bhardwaj (additional)
  3. J. H. Gerlach (additional)
  4. J. E. Mackie (additional)
  5. C. E. Grant (additional)
  6. K. C. Almquist (additional)
  7. A. J. Stewart (additional)
  8. E. U. Kurz (additional)
  9. A. M. V. Duncan (additional)
  10. R. G. Deeley (additional)
References 52 Referenced 2,332
  1. ARCECI, R.J., THE GENE ENCODING MULTIDRUG RESISTANCE IS INDUCED AND EXPRESSED AT HIGH-LEVELS DURING PREGNANCY IN THE SECRETORY EPITHELIUM OF THE UTERUS, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 85: 4350 (1988). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1988)
  2. Bairoch A. PROSITE: A dictionary of protein sites and patterns (1989).
  3. BRAMBILLA, E, CYTOTOXIC CHEMOTHERAPY INDUCES CELL-DIFFERENTIATION IN SMALL-CELL LUNG-CARCINOMA, JOURNAL OF CLINICAL ONCOLOGY 9: 50 (1991). (10.1200/JCO.1991.9.1.50) / JOURNAL OF CLINICAL ONCOLOGY (1991)
  4. CALLAHAN, H.L., HEAVY-METAL RESISTANCE - A NEW ROLE FOR P-GLYCOPROTEINS IN LEISHMANIA, JOURNAL OF BIOLOGICAL CHEMISTRY 266: 18427 (1991). (10.1016/S0021-9258(18)55077-8) / JOURNAL OF BIOLOGICAL CHEMISTRY (1991)
  5. CALLEN, D.F., LOCALIZATION OF THE HUMAN MULTIPLE-DRUG RESISTANCE GENE, MDR1, TO 7Q21.1, HUMAN GENETICS 77: 142 (1987). (10.1007/BF00272381) / HUMAN GENETICS (1987)
  6. CHEN, C.J., INTERNAL DUPLICATION AND HOMOLOGY WITH BACTERIAL TRANSPORT PROTEINS IN THE MDR1 (P-GLYCOPROTEIN) GENE FROM MULTIDRUG-RESISTANT HUMAN-CELLS, CELL 47: 381 (1986). (10.1016/0092-8674(86)90595-7) / CELL (1986)
  7. COLE, SPC, EFFECT OF CALCIUM-ANTAGONISTS ON THE CHEMOSENSITIVITY OF 2 MULTIDRUG-RESISTANT HUMAN-TUMOR CELL-LINES WHICH DO NOT OVEREXPRESS P-GLYCOPROTEIN, BRITISH JOURNAL OF CANCER 59: 42 (1989). (10.1038/bjc.1989.9) / BRITISH JOURNAL OF CANCER (1989)
  8. COLE, SPC, ELEVATED EXPRESSION OF ANNEXIN-II (LIPOCORTIN-II, P36) IN A MULTIDRUG RESISTANT SMALL-CELL LUNG-CANCER CELL-LINE, BRITISH JOURNAL OF CANCER 65: 498 (1992). (10.1038/bjc.1992.103) / BRITISH JOURNAL OF CANCER (1992)
  9. COLE, SPC, THE 1991 MERCK FROSST AWARD - MULTIDRUG RESISTANCE IN SMALL-CELL LUNG-CANCER, CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 70: 313 (1992). (10.1139/y92-040) / CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY (1992)
  10. COLE, SPC, PATTERNS OF CROSS-RESISTANCE IN A MULTIDRUG-RESISTANT SMALL-CELL LUNG-CARCINOMA CELL-LINE, CANCER CHEMOTHERAPY AND PHARMACOLOGY 26: 250 (1990). (10.1007/BF02897225) / CANCER CHEMOTHERAPY AND PHARMACOLOGY (1990)
  11. COLE, SPC, NON-P-GLYCOPROTEIN-MEDIATED MULTIDRUG RESISTANCE IN A SMALL-CELL LUNG-CANCER CELL-LINE - EVIDENCE FOR DECREASED SUSCEPTIBILITY TO DRUG-INDUCED DNA DAMAGE AND REDUCED LEVELS OF TOPOISOMERASE-II, CANCER RESEARCH 51: 3345 (1991). / CANCER RESEARCH (1991)
  12. COLE SPC unpublished data.
  13. CORDONCARDO, C, MULTIDRUG-RESISTANCE GENE (P-GLYCOPROTEIN) IS EXPRESSED BY ENDOTHELIAL-CELLS AT BLOOD-BRAIN BARRIER SITES, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 86: 695 (1989). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1989)
  14. 10.1093/nar/12.1Part1.387
  15. DUDLER, R, STRUCTURE OF AN MDR-LIKE GENE FROM ARABIDOPSIS-THALIANA - EVOLUTIONARY IMPLICATIONS, JOURNAL OF BIOLOGICAL CHEMISTRY 267: 5882 (1992). (10.1016/S0021-9258(18)42636-1) / JOURNAL OF BIOLOGICAL CHEMISTRY (1992)
  16. DUNCAN, AMV, INSITU HYBRIDIZATION OF 2 CLONED CHROMOSOME-7 SEQUENCES TIGHTLY LINKED TO THE CYSTIC-FIBROSIS LOCUS, CYTOGENETICS AND CELL GENETICS 49: 309 (1988). (10.1159/000132684) / CYTOGENETICS AND CELL GENETICS (1988)
  17. 10.1016/0003-2697(83)90418-9
  18. FENG, D.F., PROGRESSIVE SEQUENCE ALIGNMENT AS A PREREQUISITE TO CORRECT PHYLOGENETIC TREES, JOURNAL OF MOLECULAR EVOLUTION 25: 351 (1987). (10.1007/BF02603120) / JOURNAL OF MOLECULAR EVOLUTION (1987)
  19. GAZDAR, A.F., ESTABLISHMENT OF CONTINUOUS, CLONABLE CULTURES OF SMALL-CELL CARCINOMA OF THE LUNG WHICH HAVE AMINE PRECURSOR UPTAKE AND DECARBOXYLATION CELL PROPERTIES, CANCER RESEARCH 40: 3502 (1980). / CANCER RESEARCH (1980)
  20. GERLACH, J.H., MULTIDRUG RESISTANCE, CANCER SURVEYS 5: 25 (1986). / CANCER SURVEYS (1986)
  21. GERLACH, J.H., HOMOLOGY BETWEEN P-GLYCOPROTEIN AND A BACTERIAL HEMOLYSIN TRANSPORT PROTEIN SUGGESTS A MODEL FOR MULTIDRUG RESISTANCE, NATURE 324: 485 (1986). (10.1038/324485a0) / NATURE (1986)
  22. GERVASONI, J.E., SUBCELLULAR-DISTRIBUTION OF DAUNORUBICIN IN P-GLYCOPROTEIN-POSITIVE AND P-GLYCOPROTEIN-NEGATIVE DRUG-RESISTANT CELL-LINES USING LASER-ASSISTED CONFOCAL MICROSCOPY, CANCER RESEARCH 51: 4955 (1991). / CANCER RESEARCH (1991)
  23. GOLDSTEIN, L.J., EXPRESSION OF A MULTIDRUG RESISTANCE GENE IN HUMAN CANCERS, JOURNAL OF THE NATIONAL CANCER INSTITUTE 81: 116 (1989). (10.1093/jnci/81.2.116) / JOURNAL OF THE NATIONAL CANCER INSTITUTE (1989)
  24. GROS, P, ISOLATION AND EXPRESSION OF A COMPLEMENTARY-DNA THAT CONFERS MULTIDRUG RESISTANCE, NATURE 323: 728 (1986). (10.1038/323728a0) / NATURE (1986)
  25. HARPER, M.E., LOCALIZATION OF SINGLE COPY DNA-SEQUENCES ON G-BANDED HUMAN-CHROMOSOMES BY INSITU HYBRIDIZATION, CHROMOSOMA 83: 431 (1981). (10.1007/BF00327364) / CHROMOSOMA (1981)
  26. HIGGINS, C.F., A FAMILY OF RELATED ATP-BINDING SUBUNITS COUPLED TO MANY DISTINCT BIOLOGICAL PROCESSES IN BACTERIA, NATURE 323: 448 (1986). (10.1038/323448a0) / NATURE (1986)
  27. HINDENBURG, A.A., INTRACELLULAR-DISTRIBUTION AND PHARMACOKINETICS OF DAUNORUBICIN IN ANTHRACYCLINE-SENSITIVE AND ANTHRACYCLINE-RESISTANT HL-60 CELLS, CANCER RESEARCH 49: 4607 (1989). / CANCER RESEARCH (1989)
  28. HYDE, S.C., STRUCTURAL MODEL OF ATP-BINDING PROTEINS ASSOCIATED WITH CYSTIC-FIBROSIS, MULTIDRUG RESISTANCE AND BACTERIAL TRANSPORT, NATURE 346: 362 (1990). (10.1038/346362a0) / NATURE (1990)
  29. KEIZER, H.G., CORRELATION OF MULTIDRUG RESISTANCE WITH DECREASED DRUG ACCUMULATION, ALTERED SUBCELLULAR DRUG DISTRIBUTION, AND INCREASED P-GLYCOPROTEIN EXPRESSION IN CULTURED SW-1573 HUMAN-LUNG TUMOR-CELLS, CANCER RESEARCH 49: 2988 (1989). / CANCER RESEARCH (1989)
  30. KING, C.R., CHARACTERIZATION OF THE ESTROGEN-RESPONSIVE DOMAIN OF AVIAN LIVER AND CLONING OF DOUBLE-STRANDED CDNA DERIVED FROM ESTROGEN-INDUCIBLE RNA SPECIES, JOURNAL OF BIOLOGICAL CHEMISTRY 254: 6781 (1979). (10.1016/S0021-9258(18)50436-1) / JOURNAL OF BIOLOGICAL CHEMISTRY (1979)
  31. KLEIN, P, THE DETECTION AND CLASSIFICATION OF MEMBRANE-SPANNING PROTEINS, BIOCHIMICA ET BIOPHYSICA ACTA 815: 468 (1985). (10.1016/0005-2736(85)90375-X) / BIOCHIMICA ET BIOPHYSICA ACTA (1985)
  32. LAI, S.L., MDR1 GENE-EXPRESSION IN LUNG-CANCER, JOURNAL OF THE NATIONAL CANCER INSTITUTE 81: 1144 (1989). (10.1093/jnci/81.15.1144) / JOURNAL OF THE NATIONAL CANCER INSTITUTE (1989)
  33. LIN, C.C., HIGH-RESOLUTION CHROMOSOMAL LOCALIZATION OF THE BETA-GENE OF THE HUMAN BETA-GLOBIN GENE-COMPLEX BY INSITU HYBRIDIZATION, CYTOGENETICS AND CELL GENETICS 39: 269 (1985). (10.1159/000132156) / CYTOGENETICS AND CELL GENETICS (1985)
  34. MARQUARDT, D, INVOLVEMENT OF VACUOLAR H+-ADENOSINE TRIPHOSPHATASE-ACTIVITY IN MULTIDRUG RESISTANCE IN HL-60 CELLS, JOURNAL OF THE NATIONAL CANCER INSTITUTE 83: 1098 (1991). (10.1093/jnci/83.15.1098) / JOURNAL OF THE NATIONAL CANCER INSTITUTE (1991)
  35. MILROY, R, LACK OF EXPRESSION OF P-GLYCOPROTEIN IN 7 SMALL-CELL LUNG-CANCER CELL-LINES ESTABLISHED BOTH FROM UNTREATED AND FROM TREATED PATIENTS, ANTICANCER RESEARCH 12: 193 (1992). / ANTICANCER RESEARCH (1992)
  36. MIRSKI, SEL, MULTIDRUG RESISTANCE IN A HUMAN SMALL-CELL LUNG-CANCER CELL-LINE SELECTED IN ADRIAMYCIN, CANCER RESEARCH 47: 2594 (1987). / CANCER RESEARCH (1987)
  37. NOONAN, K.E., QUANTITATIVE-ANALYSIS OF MDR1 (MULTIDRUG RESISTANCE) GENE-EXPRESSION IN HUMAN TUMORS BY POLYMERASE CHAIN-REACTION, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 87: 7160 (1990). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1990)
  38. OUELLETTE, M, THE AMPLIFIED H-CIRCLE OF METHOTREXATE-RESISTANT LEISHMANIA-TARENTOLAE CONTAINS A NOVEL P-GLYCOPROTEIN GENE, EMBO JOURNAL 9: 1027 (1990). (10.1002/j.1460-2075.1990.tb08206.x) / EMBO JOURNAL (1990)
  39. PEARSON, W.R., IMPROVED TOOLS FOR BIOLOGICAL SEQUENCE COMPARISON, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 85: 2444 (1988). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1988)
  40. 10.1126/science.2475911
  41. 10.1073/pnas.74.12.5463
  42. SCHLAIFER, D, IMMUNOHISTOCHEMICAL DETECTION OF MULTIDRUG RESISTANCE ASSOCIATED P-GLYCOPROTEIN IN TUMOR AND STROMAL CELLS OF HUMAN CANCERS, BRITISH JOURNAL OF CANCER 62: 177 (1990). (10.1038/bjc.1990.256) / BRITISH JOURNAL OF CANCER (1990)
  43. SCHUURHUIS, G.J., EARLY MULTIDRUG RESISTANCE, DEFINED BY CHANGES IN INTRACELLULAR DOXORUBICIN DISTRIBUTION, INDEPENDENT OF P-GLYCOPROTEIN, BRITISH JOURNAL OF CANCER 64: 857 (1991). (10.1038/bjc.1991.413) / BRITISH JOURNAL OF CANCER (1991)
  44. SCHUURHUIS, G.J., QUANTITATIVE-DETERMINATION OF FACTORS CONTRIBUTING TO DOXORUBICIN RESISTANCE IN MULTIDRUG-RESISTANT CELLS, JOURNAL OF THE NATIONAL CANCER INSTITUTE 81: 1887 (1989). (10.1093/jnci/81.24.1887) / JOURNAL OF THE NATIONAL CANCER INSTITUTE (1989)
  45. SUGAWARA, I, PRIMER-DEPENDENT AMPLIFICATION OF MDR1 MESSENGER-RNA BY POLYMERASE CHAIN-REACTION, JAPANESE JOURNAL OF CANCER RESEARCH 83: 131 (1992). / JAPANESE JOURNAL OF CANCER RESEARCH (1992)
  46. THIEBAUT, F, CELLULAR-LOCALIZATION OF THE MULTIDRUG-RESISTANCE GENE-PRODUCT P-GLYCOPROTEIN IN NORMAL HUMAN-TISSUES, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 84: 7735 (1987). / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (1987)
  47. UEYAMA, H, STRUCTURE OF A HUMAN SMOOTH-MUSCLE ACTIN GENE (AORTIC TYPE) WITH A UNIQUE INTRON SITE, MOLECULAR AND CELLULAR BIOLOGY 4: 1073 (1984). / MOLECULAR AND CELLULAR BIOLOGY (1984)
  48. VANDERBLIEK, A.M., OVEREXPRESSION AND AMPLIFICATION OF 5 GENES IN A MULTIDRUG-RESISTANT CHINESE-HAMSTER OVARY CELL-LINE, MOLECULAR AND CELLULAR BIOLOGY 6: 1671 (1986). / MOLECULAR AND CELLULAR BIOLOGY (1986)
  49. WALKER, J.E., DISTANTLY RELATED SEQUENCES IN THE ALPHA-SUBUNITS AND BETA-SUBUNITS OF ATP SYNTHASE, MYOSIN, KINASES AND OTHER ATP-REQUIRING ENZYMES AND A COMMON NUCLEOTIDE BINDING FOLD, EMBO JOURNAL 1: 945 (1982). (10.1002/j.1460-2075.1982.tb01276.x) / EMBO JOURNAL (1982)
  50. WEAVER, J.L., LASER SCANNING AND CONFOCAL MICROSCOPY OF DAUNORUBICIN, DOXORUBICIN, AND RHODAMINE-123 IN MULTIDRUG-RESISTANT CELLS, EXPERIMENTAL CELL RESEARCH 196: 323 (1991). (10.1016/0014-4827(91)90267-X) / EXPERIMENTAL CELL RESEARCH (1991)
  51. WEINSTEIN, R.S., P-GLYCOPROTEINS IN PATHOLOGY - THE MULTIDRUG RESISTANCE GENE FAMILY IN HUMANS, HUMAN PATHOLOGY 21: 34 (1990). (10.1016/0046-8177(90)90073-E) / HUMAN PATHOLOGY (1990)
  52. WILLINGHAM, M.C., SINGLE CELL ANALYSIS OF DAUNOMYCIN UPTAKE AND EFFLUX IN MULTIDRUG-RESISTANT AND MULTIDRUG-SENSITIVE KB CELLS - EFFECTS OF VERAPAMIL AND OTHER DRUGS, CANCER RESEARCH 46: 5941 (1986). / CANCER RESEARCH (1986)
Dates
Type When
Created 18 years, 10 months ago (Oct. 5, 2006, 7:03 p.m.)
Deposited 1 year, 7 months ago (Jan. 10, 2024, 9:58 p.m.)
Indexed 5 hours, 49 minutes ago (Aug. 30, 2025, 12:25 p.m.)
Issued 32 years, 8 months ago (Dec. 4, 1992)
Published 32 years, 8 months ago (Dec. 4, 1992)
Published Print 32 years, 8 months ago (Dec. 4, 1992)
Funders 0

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@article{Cole_1992, title={Overexpression of a Transporter Gene in a Multidrug-Resistant Human Lung Cancer Cell Line}, volume={258}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1360704}, DOI={10.1126/science.1360704}, number={5088}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Cole, S. P. C. and Bhardwaj, G. and Gerlach, J. H. and Mackie, J. E. and Grant, C. E. and Almquist, K. C. and Stewart, A. J. and Kurz, E. U. and Duncan, A. M. V. and Deeley, R. G.}, year={1992}, month=dec, pages={1650–1654} }