Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of human glioma A172 cells with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), an alkylating antitumor agent the primary target of which has been thought to be DNA, resulted in elevated expression of mRNA for multidrug resistance-associated protein (MRP) within the first 2 h and then a decrease in expression 24 h after the treatment. Western blot analyses revealed that levels of MRP in these ACNU-treated cells paralleled mRNA levels. Membrane vesicles prepared from ACNU-treated cells also displayed elevated transport activities for leukotriene C4, a known substrate for MRP. Gamma-glutamylcysteine synthetase (gamma-GCS) mRNA expression was coinduced with MRP by ACNU. Because gamma-GCS is the rate-limiting enzyme involved in the de novo biosynthesis of glutathione, increases in glutathione were also transiently induced by ACNU. These results demonstrate for the first time that the expression of functional MRP and gamma-GCS can be transiently coinduced by ACNU. Multiple short exposures (1 h) of ACNU following a long duration (1 week) of drug-free conditions resulted in the development of an ACNU-resistant population (designated A172R) that overexpressed MRP/gamma-GCS mRNA and had elevated transport activities for leukotriene C4. A172R exhibited cross-resistance to the antitumor drug doxorubicin and heavy metal sodium arsenate but not to cisplatin. Our results also demonstrate that intermittent treatments of human glioma cells with ACNU can lead to the development of MRP-related multidrug resistance. These results, taken together, reveal a possible new mechanism of the development of drug resistance for the antitumor nitrosoureas.
Cancer Res 1997 Dec 01
PMID:Transient induction of the MRP/GS-X pump and gamma-glutamylcysteine synthetase by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea in human glioma cells. 939 52

Multidrug resistance is a major obstacle to the success of cancer chemotherapy. The multidrug resistance-associated protein (MRP) has been shown to confer multidrug resistance. To study MRP gene expression at the transcriptional level, we have fused the MRP gene promoter with the luciferase reporter gene and studied its regulation. Cotransfection of MRP promoter constructs with p53 expression plasmids in p53-null human H1299 and mouse (10)1 cells demonstrated that the wild-type (wt) p53 markedly suppressed MRP promoter activity, whereas mutant p53 had little inhibitory effect. Transfections using 5' deletion mutant constructs of the MRP promoter showed that inhibition of the promoter activity by wt p53 mainly resided in the region from -91 to +103 bp, where several Sp1 transcription factor binding sites are localized. Cotransfection of the MRP promoter into Drosophila SL2 cells with an Sp1 expression vector increased the promoter activity in a dose-related manner up to approximately 200-fold. The stimulation of MRP promoter activity by Sp1 was attenuated by the cotransfection of a wt p53-expression plasmid. Furthermore, we have determined that endogenous MRP mRNA levels were down-regulated by restoration of wt p53-expression in a human lung cancer cell line. The relevance of MRP regulation in drug resistance was studied in a drug-resistant cell line, CEM/VM-1-5, that is approximately 140-fold more resistant to the epipodophyllotoxin, teniposide (VM-26), than the parental CEM cells. CEM/VM-1-5 cells express a much higher amount of MRP mRNA and protein than CEM cells, indicating that the resistant phenotype is at least partly due to increased MRP production. Transient transfection of the promoter constructs revealed that CEM/VM-1-5 cells had higher (7-fold) MRP promoter activity than CEM cells. Cotransfection of a wt p53-expression plasmid caused a reduction of MRP promoter activity in both CEM and CEM/VM-1-5 cells, but the inhibition was more than double in CEM/VM-1-5 cells compared with CEM cells. Our results demonstrated that wt p53 acts as a negative regulator of MRP gene transcription, at least in part by diminishing the effect of a powerful transcription activator Sp1. Therefore, a loss of wt p53 function and/or an increase in Sp1 activity in tumor cells could contribute to an up-regulation of the MRP gene.
Cancer Res 1998 Dec 15
PMID:Transcriptional suppression of multidrug resistance-associated protein (MRP) gene expression by wild-type p53. 986 34

Advanced neuroblastoma and malignant liver tumor are representative childhood cancers for which combined chemotherapy including cisplatin and doxorubicin is routinely performed. The prognosis of patients with tumors which develop multiple drug resistance (MDR) is unfavorable. To elucidate the role of multidrug resistance-associated protein (MRP) and canalicular multispecific organic anion transporter (cMOAT) in the clinical behavior of the tumors, we examined 42 neuroblastomas and 10 malignant liver tumors for the expressions of MRP and cMOAT by quantitative RNA-polymerase chain reaction (PCR). The amplification and expression of N-myc oncogene in the neuroblastomas were also investigated. We found a close association between MRP and N-myc expression in each neuroblastoma sample but no significant relationship between MRP expression and the patients' outcome. The forced expression of N-myc failed to enhance the expression of MRP in N-myc transfected neuroblastoma cell lines. cMOAT was rarely expressed in the neuroblastomas, but was frequently expressed in the malignant liver tumors. The expression of MRP and cMOAT in the childhood liver tumors was more common and higher, especially in advanced cases with a poor outcome, than that observed in normal liver or in 9 hepatocellular carcinomas from adult patients. The enhanced expression of these genes might be characteristic of childhood malignant liver tumors and related to their clinical chemoresistance.
Jpn J Cancer Res 1998 Dec
PMID:Expression of MRP and cMOAT in childhood neuroblastomas and malignant liver tumors and its relevance to clinical behavior. 1008 88

In vitro resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL), but the underlying mechanisms are poorly understood. Using flow cytometry, we studied the contribution of daunorubicin (DNR) accumulation and retention, cell size, expression of the major vault protein/lung resistance protein (LRP), P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) to the cytotoxicity of DNR (by MTT assay) in childhood ALL. The accumulated and retained DNR content was not related to the degree of DNR resistance, nor did the content differ between 53 initial and 20 relapse ALL samples (P >0. 05), although the latter were median two-fold more resistant to DNR (P = 0.004). Leukemic cell volume correlated with resistance to the anthracyclines DNR (Rs 0.32, P = 0.012) and idarubicin (Rs 0.46, P = 0.011) but not to other classes of drugs such as prednisolone, vincristine, L-asparaginase and etoposide. Relapsed patients had 1. 5-fold larger cells than patients at initial diagnosis of ALL (P = 0. 001). After cell volume correction, the intracellular DNR concentration was lower in relapsed compared with initial ALL cells (eg 60 min accumulation, P = 0.003). Moreover, the intracellular DNR concentration inversely correlated with DNR resistance, both in the accumulation (Rs -0.44, P < 0.001) and retention (Rs -0.33, P = 0. 016) test condition. The accumulated DNR concentration inversely correlated with expression of LRP (Rs -0.36, P = 0.012) but not with P-gp and MRP. Expression of LRP, but not of P-gp and MRP, significantly correlated with DNR resistance in childhood ALL (Rs 0. 33, P = 0.03). In conclusion, the intracellular DNR concentration and the expression level of LRP may contribute to DNR resistance in childhood ALL. The strength of the correlations also indicates that resistance to anthracyclines can not be explained by one single mechanism.
Leukemia 1999 Dec
PMID:Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia. 1060 24

Intrinsic and acquired antineoplastic drug resistance remain a major problem for advanced prostate cancer treatment. In order to characterize mechanisms of anti-neoplastic drug resistance in human prostate cancer cell lines, resistant sublines of four of the commonly studied prostate cancer cell lines (DU 145, PC-3, PPC-1, and TSU-PR1) were selected following exposure to increasing concentrations of doxorubicin (from 10-1000 nM). Sensitivity patterns of the parent and doxorubicin-resistant sublines to various anti-neoplastic drugs, including adriamycin, amsacrine, etoposide, camptothecin, vinblastine, vincristine, fluorodeoxyuridine, and melphalan, were determined using a sulforhodamine B growth inhibition assay. The expression of three well-described antineoplastic drug resistance proteins, P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance protein (LRP), was assessed using reverse transcriptase-polymerase chain reaction (RT-PCR) assays specific for each of the mRNA species, and using immunocytochemical staining procedures specific for each of the polypeptides. All four of the doxorubicin-selected prostate cancer cell lines exhibited a multidrug resistance phenotype; administration of verapamil restored doxorubicin sensitivity for each of the drug resistant sublines. Although significant MDR1 expression was not detected in any of the parent cell lines before drug exposure by RT-PCR analysis or by immunocytochemistry, both MDR1 mRNA and P-gp protein were expressed by the TSU-PR1 Adr 1000 subline. In contrast, MRP mRNA and protein were present in each of the prostate cancer cell lines before doxorubicin-selection, and an increase in MRP expression appeared to accompany the acquisition of drug resistance in DU 145, PC-3, and PPC-1 doxorubicin-resistant sublines. LRP was variably expressed by each of the parent and resistant cell lines. These data suggest that drug resistance in human prostate cancer may be multifactorial, with MRP and LRP frequently expressed in prostate cancer cells before antineoplastic drug treatment and P-gp expression occasionally acquired after drug exposure.
Int J Oncol 2000 Dec
PMID:Doxorubicin-resistant variants of human prostate cancer cell lines DU 145, PC-3, PPC-1, and TSU-PR1: characterization of biochemical determinants of antineoplastic drug sensitivity. 1107 91

Malignant gliomas are largely resistant to current chemotherapeutic strategies often displaying a multidrug-resistant phenotype. Mechanisms involved in drug resistance are reduced cellular drug accumulation through membrane efflux pumps, drug detoxification as well as alterations in drug target specificity. In 27 primary and 17 secondary glioblastomas and their astrocytic precursor tumors, we studied the immunohistochemical expression profile of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), metallothionein, and topoisomerase II alpha. Glial tumor cells in all glioblastomas showed constant up-regulation of LRP, MRP, and topoisomerase II alpha. P-gp was found in 90% of the primary and 60% of the secondary glioblastomas. In precursor tumors, these drug resistance-related factors were expressed in varying proportions. Metallothionein, also found in normal and activated astrocytes, was retained in all neoplastic phenotypes. Furthermore, metallothionein, P-gp, LRP, and topoisomerase II alpha were strongly expressed by normal and neoplastic vessels which may confer to impaired penetration of therapeutic agents through the blood-brain and blood-tumor barrier. However, the expression profiles of drug resistance-related proteins neither differed between primary and secondary glioblastomas nor revealed any correlation to precursor or recurrent tumors. Nevertheless, inhibition of these factors may be promising approaches to the management of malignant gliomas.
J Neurooncol 2000 Dec
PMID:Drug resistance-associated factors in primary and secondary glioblastomas and their precursor tumors. 1126 2

In contrast to the parent triptycene (code name TT0), triptycene bisquinone (code name TT2) is cytostatic (IC50: 300 nM) and cytotoxic (IC50: 230 nM) in wild-type (WT), drug-sensitive HL-60 cells (HL-60-S) at day 4. Therefore, the effects of this new quinone antitumor drug were assessed and compared to those of daunorubicin (DAU, daunomycin) in the multidrug-resistant (MDR) HL-60-RV and HL-60-R8 sublines, which respectively overexpress P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP). In contrast to DAU, which loses its cytostatic [resistance factors (RFs): 22.9-35.7] and cytotoxic (RFs: 23.8-31.3) activities in MDR sublines, TT2 decreases tumor cell proliferation (RFs: 0.9-1.3) and viability (RFs: 0.9-1.5) as effectively in HL-60-S as in HL-60-RV and HL-60-R8 cells at days 2 and 4. Similarly, DAU inhibits the rate of DNA synthesis less effectively in MDR than in parental HL-60 cells (RFs: 8.1-11.9) but TT2 decreases the incorporation of 3[H]-thymidine into DNA to the same degree in HL-60-S, HL-60-RV and HL-60-R8 cells (RFs: 1.2). In contrast to DAU, which is inactive, the advantage of TT2 is its ability to block the cellular transport of purine and pyrimidine nucleosides in WT tumor cells, an effect which persists in both MDR sublines (RFs: 1.0-1.2). Moreover, the concentrations of DAU which induce maximal DNA cleavage in HL-60-S cells at 24 h lose all or most of their DNA-damaging activity in HL-60-RV and HL-60-R8 cells, whereas treatments with 4 microM TT2 produce similar peaks of DNA fragmentation in all WT and MDR cell lines. Since TT2 not only mimics the antitumor effects of DAU but also blocks nucleoside transport and retains its effectiveness in MDR cells that have already developed different mechanisms of resistance to DAU, this new quinone antitumor drug might be valuable to develop new means of polychemotherapy.
Int J Oncol 2001 Dec
PMID:A synthetic triptycene bisquinone, which blocks nucleoside transport and induces DNA fragmentation, retains its cytotoxic efficacy in daunorubicin-resistant HL-60 cell lines. 1171 86

In the present study, we have cloned the cDNA of ABCC13, a novel ABC transporter, from the cDNA library of adult human placenta. The ABCC13 gene spans approximately 70kb on human chromosome 21q11.2 and consists of 14 exons. The open reading frame of the ABCC13 cDNA encodes a peptide consisting of 325 amino acid residues. The amino acid sequence corresponding to putative membrane-spanning domains was remarkably similar to ABCC1, ABCC2, ABCC3, and ABCC6. The ABCC13 gene was expressed in the fetal liver at the highest level among the organs studied. While ABCC13 was expressed in the bone marrow, its expression in peripheral blood leukocytes of adult humans was much lower and no detectable levels were observed in differentiated hematopoietic cells. The expression of ABCC13 in K562 cells decreased during cell differentiation induced by TPA. These results suggest that the expression of human ABCC13 is related with hematopoiesis.
Biochem Biophys Res Commun 2002 Dec 06
PMID:ABCC13, an unusual truncated ABC transporter, is highly expressed in fetal human liver. 1244 16

Ycf1p is the prototypical member of the yeast multidrug resistance-associated protein (MRP) subfamily of ATP-binding cassette (ABC) transporters. Ycf1p resides in the vacuolar membrane and mediates glutathione-dependent transport processes that result in resistance to cadmium and other xenobiotics. A feature common to many MRP proteins that distinguishes them from other ABC transporters is the presence of a hydrophobic N-terminal extension (NTE), whose function is not clearly established. The NTE contains a membrane spanning domain (MSD0) with five transmembrane spans and a cytosolic linker region (L0). The goal of this study was to determine the functional significance of the NTE of Ycf1p by examining the localization and functional properties of Ycf1p partial molecules, expressed either singly or together. We show that MSD0 plays a critical role in the vacuolar membrane trafficking of Ycf1p, whereas L0 is dispensable for localization. On the other hand, L0 is required for transport function, as determined by monitoring cadmium resistance. We also examine an unusual aspect of Ycf1p biology, namely, the posttranslational proteolytic processing that occurs within a lumenal loop of Ycf1p. Processing is shown to be Pep4p dependent and thus serves as a convenient marker for proper vacuolar localization. The processed fragments associate with each other, suggesting that these natural cleavage products contribute together to Ycf1p function.
Mol Biol Cell 2002 Dec
PMID:Requirement of the N-terminal extension for vacuolar trafficking and transport activity of yeast Ycf1p, an ATP-binding cassette transporter. 1247 64

Multidrug-resistance-associated protein 1 (MRP1/ABCC1) is a human ATP-binding cassette transporter that confers cell resistance to antitumour drugs. Its NBDs (nucleotide-binding domains) bind/hydrolyse ATP, a key step in the activation of MRP1 function. To relate its intrinsic functional features to the mechanism of action of the full-size transporter, we expressed the N-terminal NBD1 domain (Asn(642) to Ser(871)) in Escherichia coli. NBD1 was highly purified under native conditions and was characterized as a soluble monomer. (15)N-labelling allowed recording of the first two-dimensional NMR spectra of this domain. The NMR study showed that NBD1 was folded, and that Trp(653) was a key residue in the NBD1-ATP interaction. Thus, interaction of NBD1 with ATP/ADP was studied by intrinsic tryptophan fluorescence. The affinity for ATP and ADP were in the same range (K (d(ATP))=118 microM and K (d(ADP))=139 microM). Binding of nucleotides did not influence the monomeric state of NBD1. The ATPase activity of NBD1 was magnesium-dependent and very low [V (max) and K (m) values of 5x10(-5) pmol of ATP x (pmol NBD1)(-1) x s(-1) and 833 microM ATP respectively]. The present study suggests that NBD1 has a low contribution to the ATPase activity of full-length MRP1 and/or that this activity requires NBD1-NBD2 heterodimer formation.
Biochem J 2003 Dec 15
PMID:Biochemical characterization and NMR studies of the nucleotide-binding domain 1 of multidrug-resistance-associated protein 1: evidence for interaction between ATP and Trp653. 1295 82


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