This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Honjo, Y. Articles by Bates, S. E. Search for Related Content PubMed PubMed Citation Articles by Honjo, Y. Articles by Bates, S. E.

Acquired Mutations in the MXR/BCRP/ABCP Gene Alter Substrate Specificity in MXR/BCRP/ABCP-overexpressing Cells

Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892 [Y. H., Q-W. Y., W. Y. M-P., R. W. R., A. v. d. L., S. E. B.]; Department of Chemistry, Purdue University, West Lafayette, Indiana 47907-1393 [C. A. H.]; Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark [T. L.]; and Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland 21702 [M. D.]

A disparity was noted in the transport of rhodamine 123 among nine MXR/BCRP/ABCP-overexpressing cells studied; all demonstrated mitoxantrone transport, whereas only two effluxed rhodamine 123. When the MXR/BCRP/ABCP gene was sequenced in the cell lines studied, differences were noted at amino acid 482, predicted to be at the start of the third transmembrane domain. Sequencing genomic DNA revealed wild-type MXR/BCRP/ABCP to have an arginine at position 482. Cells having a threonine or glycine at position 482 were able to efflux rhodamine 123, whereas cells having an arginine were not. A vaccinia virus expression system confirmed that rhodamine as well as doxorubicin efflux is observed with R482T or R482G but not with the wild-type R482; all three MXR/BCRP/ABCP forms transported mitoxantrone. Cross-resistance studies suggest that, compared with wild-type MXR/BCRP/ABCP, cells having an R482T mutation have higher anthracycline resistance, whereas an R482G mutation seems to confer relatively less resistance to SN-38 and topotecan. These results suggest that amino acid 482 has a crucial role in MXR/BCRP/ABCP function and that mutation of a single amino acid residue significantly changes substrate specificity, thus altering the drug resistance phenotype.

This article has been cited by other articles:

				M. Solazzo, O. Fantappie, M. D'Amico, C. Sassoli, A. Tani, G. Cipriani, C. Bogani, L. Formigli, and R. Mazzanti Mitochondrial Expression and Functional Activity of Breast Cancer Resistance Protein in Different Multiple Drug-Resistant Cell Lines Cancer Res., September 15, 2009; 69(18): 7235 - 7242. [Abstract] [Full Text] [PDF]

				M. Huls, F. G. M. Russel, and R. Masereeuw The Role of ATP Binding Cassette Transporters in Tissue Defense and Organ Regeneration J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 3 - 9. [Abstract] [Full Text] [PDF]

				C.-l. Dai, A. K. Tiwari, C.-P. Wu, X.-d. Su, S.-R. Wang, D.-g. Liu, C. R. Ashby Jr., Y. Huang, R. W. Robey, Y.-j. Liang, et al. Lapatinib (Tykerb, GW572016) Reverses Multidrug Resistance in Cancer Cells by Inhibiting the Activity of ATP-Binding Cassette Subfamily B Member 1 and G Member 2 Cancer Res., October 1, 2008; 68(19): 7905 - 7914. [Abstract] [Full Text] [PDF]

				J. Mishra, Q. Zhang, J. L. Rosson, J. Moran, J. M. Dopp, and B. L. Neudeck Lipopolysaccharide Increases Cell Surface P-glycoprotein That Exhibits Diminished Activity in Intestinal Epithelial Cells Drug Metab. Dispos., October 1, 2008; 36(10): 2145 - 2149. [Abstract] [Full Text] [PDF]

				D. K. Hiwase, V. Saunders, D. Hewett, A. Frede, S. Zrim, P. Dang, L. Eadie, L. B. To, J. Melo, S. Kumar, et al. Dasatinib Cellular Uptake and Efflux in Chronic Myeloid Leukemia Cells: Therapeutic Implications Clin. Cancer Res., June 15, 2008; 14(12): 3881 - 3888. [Abstract] [Full Text] [PDF]

				S. Velamakanni, T. Janvilisri, S. Shahi, and H. W. van Veen A Functional Steroid-Binding Element in an ATP-Binding Cassette Multidrug Transporter Mol. Pharmacol., January 1, 2008; 73(1): 12 - 17. [Abstract] [Full Text] [PDF]

				C.-P. Wu, S. Shukla, A. M. Calcagno, M. D. Hall, M. M. Gottesman, and S. V. Ambudkar Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance linked ABCG2 transporter Mol. Cancer Ther., December 1, 2007; 6(12): 3287 - 3296. [Abstract] [Full Text] [PDF]

				Z. Shi, X.-X. Peng, I.-W. Kim, S. Shukla, Q.-S. Si, R. W. Robey, S. E. Bates, T. Shen, C. R. Ashby Jr., L.-W. Fu, et al. Erlotinib (Tarceva, OSI-774) Antagonizes ATP-Binding Cassette Subfamily B Member 1 and ATP-Binding Cassette Subfamily G Member 2 Mediated Drug Resistance Cancer Res., November 15, 2007; 67(22): 11012 - 11020. [Abstract] [Full Text] [PDF]

				H. Glavinas, E. Kis, A. Pal, R. Kovacs, M. Jani, E. Vagi, E. Molnar, S. Bansaghi, Z. Kele, T. Janaky, et al. ABCG2 (Breast Cancer Resistance Protein/Mitoxantrone Resistance-Associated Protein) ATPase Assay: A Useful Tool to Detect Drug-Transporter Interactions Drug Metab. Dispos., September 1, 2007; 35(9): 1533 - 1542. [Abstract] [Full Text] [PDF]

				A. Pal, D. Mehn, E. Molnar, S. Gedey, P. Meszaros, T. Nagy, H. Glavinas, T. Janaky, O. von Richter, G. Bathori, et al. Cholesterol Potentiates ABCG2 Activity in a Heterologous Expression System: Improved in Vitro Model to Study Function of Human ABCG2 J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1085 - 1094. [Abstract] [Full Text] [PDF]

				C. Q. Xia, N. Liu, G. T. Miwa, and L.-S. Gan Interactions of Cyclosporin A with Breast Cancer Resistance Protein Drug Metab. Dispos., April 1, 2007; 35(4): 576 - 582. [Abstract] [Full Text] [PDF]

				S. S. Lee, H.-E. Jeong, J.-M. Yi, H.-J. Jung, J.-E. Jang, E.-Y. Kim, S.-J. Lee, and J.-G. Shin Identification and Functional Assessment of BCRP Polymorphisms in a Korean Population Drug Metab. Dispos., April 1, 2007; 35(4): 623 - 632. [Abstract] [Full Text] [PDF]

				P. Breedveld, D. Pluim, G. Cipriani, F. Dahlhaus, M. A. J. van Eijndhoven, C. J. F. de Wolf, A. Kuil, J. H. Beijnen, G. L. Scheffer, G. Jansen, et al. The Effect of Low pH on Breast Cancer Resistance Protein (ABCG2)-Mediated Transport of Methotrexate, 7-Hydroxymethotrexate, Methotrexate Diglutamate, Folic Acid, Mitoxantrone, Topotecan, and Resveratrol in In Vitro Drug Transport Models Mol. Pharmacol., January 1, 2007; 71(1): 240 - 249. [Abstract] [Full Text] [PDF]

				J. G. Turner, J. L. Gump, C. Zhang, J. M. Cook, D. Marchion, L. Hazlehurst, P. Munster, M. J. Schell, W. S. Dalton, and D. M. Sullivan ABCG2 expression, function, and promoter methylation in human multiple myeloma Blood, December 1, 2006; 108(12): 3881 - 3889. [Abstract] [Full Text] [PDF]

				B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System. Physiol Rev, October 1, 2006; 86(4): 1179 - 1236. [Abstract] [Full Text] [PDF]

				J. A. Seamon, C. A. Rugg, S. Emanuel, A. M. Calcagno, S. V. Ambudkar, S. A. Middleton, J. Butler, V. Borowski, and L. M. Greenberger Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor. Mol. Cancer Ther., October 1, 2006; 5(10): 2459 - 2467. [Abstract] [Full Text] [PDF]

				W. Chearwae, S. Shukla, P. Limtrakul, and S. V. Ambudkar Modulation of the function of the multidrug resistance-linked ATP-binding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin. Mol. Cancer Ther., August 1, 2006; 5(8): 1995 - 2006. [Abstract] [Full Text] [PDF]

				S. Choudhuri and C. D. Klaassen Structure, Function, Expression, Genomic Organization, and Single Nucleotide Polymorphisms of Human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) Efflux Transporters International Journal of Toxicology, July 1, 2006; 25(4): 231 - 259. [Abstract] [Full Text] [PDF]

				H. E. M. zu Schwabedissen, M. Grube, A. Dreisbach, G. Jedlitschky, K. Meissner, K. Linnemann, C. Fusch, C. A. Ritter, U. Volker, and H. K. Kroemer EPIDERMAL GROWTH FACTOR-MEDIATED ACTIVATION OF THE MAP KINASE CASCADE RESULTS IN ALTERED EXPRESSION AND FUNCTION OF ABCG2 (BCRP) Drug Metab. Dispos., April 1, 2006; 34(4): 524 - 533. [Abstract] [Full Text] [PDF]

				K. Meissner, B. Heydrich, G. Jedlitschky, H. Meyer zu Schwabedissen, I. Mosyagin, P. Dazert, L. Eckel, S. Vogelgesang, R. W. Warzok, M. Bohm, et al. The ATP-binding Cassette Transporter ABCG2 (BCRP), a Marker for Side Population Stem Cells, Is Expressed in Human Heart J. Histochem. Cytochem., February 1, 2006; 54(2): 215 - 221. [Abstract] [Full Text] [PDF]

				Z. Benderra, A. M. Faussat, L. Sayada, J.-Y. Perrot, R. Tang, D. Chaoui, H. Morjani, C. Marzac, J.-P. Marie, and O. Legrand MRP3, BCRP, and P-Glycoprotein Activities are Prognostic Factors in Adult Acute Myeloid Leukemia Clin. Cancer Res., November 1, 2005; 11(21): 7764 - 7772. [Abstract] [Full Text] [PDF]

				A. Shafran, I. Ifergan, E. Bram, G. Jansen, I. Kathmann, G. J. Peters, R. W. Robey, S. E. Bates, and Y. G. Assaraf ABCG2 Harboring the Gly482 Mutation Confers High-Level Resistance to Various Hydrophilic Antifolates Cancer Res., September 15, 2005; 65(18): 8414 - 8422. [Abstract] [Full Text] [PDF]

				C.-H. Yang, C.-J. Huang, C.-S. Yang, Y.-C. Chu, A.-L. Cheng, J. Whang-Peng, and P.-C. Yang Gefitinib Reverses Chemotherapy Resistance in Gefitinib-Insensitive Multidrug Resistant Cancer Cells Expressing ATP-Binding Cassette Family Protein Cancer Res., August 1, 2005; 65(15): 6943 - 6949. [Abstract] [Full Text] [PDF]

				Y. Liu, H. Peng, and J.-T. Zhang Expression Profiling of ABC Transporters in a Drug-Resistant Breast Cancer Cell Line Using AmpArray Mol. Pharmacol., August 1, 2005; 68(2): 430 - 438. [Abstract] [Full Text] [PDF]

				C. Q. Xia, N. Liu, D. Yang, G. Miwa, and L.-S. Gan EXPRESSION, LOCALIZATION, AND FUNCTIONAL CHARACTERISTICS OF BREAST CANCER RESISTANCE PROTEIN IN CACO-2 CELLS Drug Metab. Dispos., May 1, 2005; 33(5): 637 - 643. [Abstract] [Full Text] [PDF]

				Y. Adachi, H. Suzuki, A. H. Schinkel, and Y. Sugiyama Role of Breast Cancer Resistance Protein (Bcrp1/Abcg2) in the Extrusion of Glucuronide and Sulfate Conjugates from Enterocytes to Intestinal Lumen Mol. Pharmacol., March 1, 2005; 67(3): 923 - 928. [Abstract] [Full Text] [PDF]

				K. F. K. Ejendal and C. A. Hrycyna Differential Sensitivities of the Human ATP-Binding Cassette Transporters ABCG2 and P-Glycoprotein to Cyclosporin A Mol. Pharmacol., March 1, 2005; 67(3): 902 - 911. [Abstract] [Full Text] [PDF]

				Y. Nakamura, M. Oka, H. Soda, K. Shiozawa, M. Yoshikawa, A. Itoh, Y. Ikegami, J. Tsurutani, K. Nakatomi, T. Kitazaki, et al. Gefitinib ("Iressa", ZD1839), an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Reverses Breast Cancer Resistance Protein/ABCG2-Mediated Drug Resistance Cancer Res., February 15, 2005; 65(4): 1541 - 1546. [Abstract] [Full Text] [PDF]

				D. Kobayashi, I. Ieiri, T. Hirota, H. Takane, S. Maegawa, J. Kigawa, H. Suzuki, E. Nanba, M. Oshimura, N. Terakawa, et al. FUNCTIONAL ASSESSMENT OF ABCG2 (BCRP) GENE POLYMORPHISMS TO PROTEIN EXPRESSION IN HUMAN PLACENTA Drug Metab. Dispos., January 1, 2005; 33(1): 94 - 101. [Abstract] [Full Text] [PDF]

				P. Pavek, G. Merino, E. Wagenaar, E. Bolscher, M. Novotna, J. W. Jonker, and A. H. Schinkel Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 144 - 152. [Abstract] [Full Text] [PDF]

				P.L. R. Ee, X. He, D. D. Ross, and W. T. Beck Modulation of breast cancer resistance protein (BCRP/ABCG2) gene expression using RNA interference Mol. Cancer Ther., December 1, 2004; 3(12): 1577 - 1584. [Abstract] [Full Text] [PDF]

				H. Burger, H. van Tol, A. W. M. Boersma, M. Brok, E. A. C. Wiemer, G. Stoter, and K. Nooter Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump Blood, November 1, 2004; 104(9): 2940 - 2942. [Abstract] [Full Text] [PDF]

				S. E. Bates, W. Y. Medina-Perez, G. Kohlhagen, S. Antony, T. Nadjem, R. W. Robey, and Y. Pommier ABCG2 Mediates Differential Resistance to SN-38 (7-Ethyl-10-hydroxycamptothecin) and Homocamptothecins J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 836 - 842. [Abstract] [Full Text] [PDF]

				A. Gupta, Y. Zhang, J. D. Unadkat, and Q. Mao HIV Protease Inhibitors Are Inhibitors but Not Substrates of the Human Breast Cancer Resistance Protein (BCRP/ABCG2) J. Pharmacol. Exp. Ther., July 1, 2004; 310(1): 334 - 341. [Abstract] [Full Text] [PDF]

				H. Minderman, K. L. O'Loughlin, L. Pendyala, and M. R. Baer VX-710 (Biricodar) Increases Drug Retention and Enhances Chemosensitivity in Resistant Cells Overexpressing P-Glycoprotein, Multidrug Resistance Protein, and Breast Cancer Resistance Protein Clin. Cancer Res., March 1, 2004; 10(5): 1826 - 1834. [Abstract] [Full Text] [PDF]

				R. W. Robey, K. Steadman, O. Polgar, K. Morisaki, M. Blayney, P. Mistry, and S. E. Bates Pheophorbide a Is a Specific Probe for ABCG2 Function and Inhibition Cancer Res., February 15, 2004; 64(4): 1242 - 1246. [Abstract] [Full Text] [PDF]

				C G Dietrich, A Geier, and R P J Oude Elferink ABC of oral bioavailability: transporters as gatekeepers in the gut Gut, December 1, 2003; 52(12): 1788 - 1795. [Full Text] [PDF]

				T. Nakanishi, L. A. Doyle, B. Hassel, Y. Wei, K. S. Bauer, S. Wu, D. W. Pumplin, H.-B. Fang, and D. D. Ross Functional Characterization of Human Breast Cancer Resistance Protein (BCRP, ABCG2) Expressed in the Oocytes of Xenopus laevis Mol. Pharmacol., December 1, 2003; 64(6): 1452 - 1462. [Abstract] [Full Text] [PDF]

				S. L. A. Plasschaert, D. M. van der Kolk, E. S. J. M. de Bont, W. A. Kamps, K. Morisaki, S. E. Bates, G. L. Scheffer, R. J. Scheper, E. Vellenga, and E. G. E. de Vries The Role of Breast Cancer Resistance Protein in Acute Lymphoblastic Leukemia Clin. Cancer Res., November 1, 2003; 9(14): 5171 - 5177. [Abstract] [Full Text] [PDF]

				T. Brooks, H. Minderman, K. L. O'Loughlin, P. Pera, I. Ojima, M. R. Baer, and R. J. Bernacki Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein Mol. Cancer Ther., November 1, 2003; 2(11): 1195 - 1205. [Abstract] [Full Text] [PDF]

				E. L. Volk and E. Schneider Wild-Type Breast Cancer Resistance Protein (BCRP/ABCG2) is a Methotrexate Polyglutamate Transporter Cancer Res., September 1, 2003; 63(17): 5538 - 5543. [Abstract] [Full Text] [PDF]

				Y. Imai, S. Asada, S. Tsukahara, E. Ishikawa, T. Tsuruo, and Y. Sugimoto Breast Cancer Resistance Protein Exports Sulfated Estrogens but Not Free Estrogens Mol. Pharmacol., September 1, 2003; 64(3): 610 - 618. [Abstract] [Full Text] [PDF]

				M. Wierdl, A. Wall, C. L. Morton, J. Sampath, M. K. Danks, J. D. Schuetz, and P. M. Potter Carboxylesterase-Mediated Sensitization of Human Tumor Cells to CPT-11 Cannot Override ABCG2-Mediated Drug Resistance Mol. Pharmacol., August 1, 2003; 64(2): 279 - 288. [Abstract] [Full Text] [PDF]

				T. Nakanishi, J. E. Karp, M. Tan, L. A. Doyle, T. Peters, W. Yang, D. Wei, and D. D. Ross Quantitative Analysis of Breast Cancer Resistance Protein and Cellular Resistance to Flavopiridol in Acute Leukemia Patients Clin. Cancer Res., August 1, 2003; 9(9): 3320 - 3328. [Abstract] [Full Text] [PDF]

				Z.-S. Chen, R. W. Robey, M. G. Belinsky, I. Shchaveleva, X.-Q. Ren, Y. Sugimoto, D. D. Ross, S. E. Bates, and G. D. Kruh Transport of Methotrexate, Methotrexate Polyglutamates, and 17{beta}-Estradiol 17-({beta}-D-glucuronide) by ABCG2: Effects of Acquired Mutations at R482 on Methotrexate Transport Cancer Res., July 15, 2003; 63(14): 4048 - 4054. [Abstract] [Full Text] [PDF]

				A. C. Lockhart, R. G. Tirona, and R. B. Kim Pharmacogenetics of ATP-binding Cassette Transporters in Cancer and Chemotherapy Mol. Cancer Ther., July 1, 2003; 2(7): 685 - 698. [Abstract] [Full Text] [PDF]

				R. Rajendra, M. K. Gounder, A. Saleem, J. H. M. Schellens, D. D. Ross, S. E. Bates, P. Sinko, and E. H. Rubin Differential Effects of the Breast Cancer Resistance Protein on the Cellular Accumulation and Cytotoxicity of 9-Aminocamptothecin and 9-Nitrocamptothecin Cancer Res., June 15, 2003; 63(12): 3228 - 3233. [Abstract] [Full Text] [PDF]

				M. Suzuki, H. Suzuki, Y. Sugimoto, and Y. Sugiyama ABCG2 Transports Sulfated Conjugates of Steroids and Xenobiotics J. Biol. Chem., June 13, 2003; 278(25): 22644 - 22649. [Abstract] [Full Text] [PDF]

				J. D. Allen, S. C. van Dort, M. Buitelaar, O. van Tellingen, and A. H. Schinkel Mouse Breast Cancer Resistance Protein (Bcrp1/Abcg2) Mediates Etoposide Resistance and Transport, but Etoposide Oral Availability Is Limited Primarily by P-glycoprotein Cancer Res., March 15, 2003; 63(6): 1339 - 1344. [Abstract] [Full Text] [PDF]

				X. Wang, T. Furukawa, T. Nitanda, M. Okamoto, Y. Sugimoto, S.-I. Akiyama, and M. Baba Breast Cancer Resistance Protein (BCRP/ABCG2) Induces Cellular Resistance to HIV-1 Nucleoside Reverse Transcriptase Inhibitors Mol. Pharmacol., January 1, 2003; 63(1): 65 - 72. [Abstract] [Full Text] [PDF]

				B. L. Abbott, A.-M. Colapietro, Y. Barnes, F. Marini, M. Andreeff, and B. P. Sorrentino Low levels of ABCG2 expression in adult AML blast samples Blood, December 15, 2002; 100(13): 4594 - 4601. [Abstract] [Full Text] [PDF]

				C. Ozvegy, A. Varadi, and B. Sarkadi Characterization of Drug Transport, ATP Hydrolysis, and Nucleotide Trapping by the Human ABCG2 Multidrug Transporter. MODULATION OF SUBSTRATE SPECIFICITY BY A POINT MUTATION J. Biol. Chem., December 6, 2002; 277(50): 47980 - 47990. [Abstract] [Full Text] [PDF]

				E. L. Volk, K. M. Farley, Y. Wu, F. Li, R. W. Robey, and E. Schneider Overexpression of Wild-Type Breast Cancer Resistance Protein Mediates Methotrexate Resistance Cancer Res., September 1, 2002; 62(17): 5035 - 5040. [Abstract] [Full Text] [PDF]

				J. D. Allen, S. C. Jackson, and A. H. Schinkel A Mutation Hot Spot in the Bcrp1 (Abcg2) Multidrug Transporter in Mouse Cell Lines Selected for Doxorubicin Resistance Cancer Res., April 1, 2002; 62(8): 2294 - 2299. [Abstract] [Full Text] [PDF]

				J. D. Allen and A. H. Schinkel Multidrug Resistance and Pharmacological Protection Mediated by the Breast Cancer Resistance Protein (BCRP/ABCG2) Mol. Cancer Ther., April 1, 2002; 1(6): 427 - 434. [Full Text] [PDF]

				I. F. Faneyte, P. M. P. Kristel, M. Maliepaard, G. L. Scheffer, R. J. Scheper, J. H. M. Schellens, and M. J. van de Vijver Expression of the Breast Cancer Resistance Protein in Breast Cancer Clin. Cancer Res., April 1, 2002; 8(4): 1068 - 1074. [Abstract] [Full Text] [PDF]