Document Detail


Single amino acid substitutions in the transmembrane domains of breast cancer resistance protein (BCRP) alter cross resistance patterns in transfectants.
MedLine Citation:
PMID:  14566825     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Breast cancer resistance protein (BCRP) is a member of ATP-binding cassette transporters that has an N-terminal ATP binding domain and a C-terminal transmembrane domain (TM). Expression of wild-type BCRP confers resistance to multiple chemotherapeutic agents such as mitoxantrone, SN-38 and topotecan, but not to doxorubicin. We made 32 BCRP mutants with an amino acid substitution in the TMs (7 E446-mutants in TM2, 15 R482-mutants in TM3, 4 N557-mutants in TM5 and 6 H630-mutants in TM6) and examined the effect of the substitutions on cellular drug resistance. PA317 cells transfected with any one of the 7 E446-mutant BCRP cDNAs did not show drug resistance. Cells transfected with any one of the 13 R482X2-BCRP cDNAs (X2 = N, C, M, S, T, V, A, G, E, W, D, Q and H, but not Y and K) showed higher resistance to mitoxantrone and doxorubicin than the wild-type BCRP-transfected cells. Cells transfected with N557D-BCRP cDNA showed similar resistance to mitoxantrone but lower resistance to SN-38 than the wild-type BCRP-transfected cells. Cells transfected with N557E-, H630E- or H630L-BCRP cDNA showed similar degrees of resistance to mitoxantrone and SN-38. Estrone and fumitremorgin C reversed the drug resistance of cells transfected with R482-, N557- or H630-mutant BCRP cDNA. Cells transfected with R482G- or R482S-BCRP cDNA showed less intracellular accumulation of [3H]mitoxantrone than the wild-type BCRP-transfected cells. These results suggest that E446 in TM2, R482 in TM3, N557 in TM5 and H630 in TM6 play important roles in drug recognition of BCRP.
Authors:
Miyu Miwa; Satomi Tsukahara; Etsuko Ishikawa; Sakiyo Asada; Yasuo Imai; Yoshikazu Sugimoto
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  107     ISSN:  0020-7136     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2003 Dec 
Date Detail:
Created Date:  2003-10-20     Completed Date:  2004-02-18     Revised Date:  2007-09-25    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  757-63     Citation Subset:  IM    
Copyright Information:
Copyright 2003 Wiley-Liss, Inc.
Affiliation:
Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / chemistry,  genetics*,  metabolism*
Amino Acid Substitution
Animals
Antineoplastic Agents, Phytogenic / pharmacokinetics
Biological Transport
Camptothecin / analogs & derivatives*,  pharmacokinetics
Cell Line
Cell Membrane / chemistry
DNA, Complementary / genetics
Drug Resistance, Multiple / genetics*
Fibroblasts
Humans
Kinetics
Mice
Mitoxantrone / pharmacokinetics*
Neoplasm Proteins / chemistry,  genetics*,  metabolism*
Recombinant Proteins / chemistry
Transfection
Chemical
Reg. No./Substance:
0/ABCG2 protein, human; 0/ATP-Binding Cassette Transporters; 0/Antineoplastic Agents, Phytogenic; 0/DNA, Complementary; 0/Neoplasm Proteins; 0/Recombinant Proteins; 100286-90-6/irinotecan; 65271-80-9/Mitoxantrone; 7689-03-4/Camptothecin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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