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)

A specific and quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay was developed for measuring the mRNA of the multidrug resistance-associated protein (MRP). A region corresponding to bp 3897-4471 of MRP cDNA is amplified, which encompasses approximately half of the second nucleotide-binding domain (NBD2). In two multidrug resistant (MDR) sublines of the HL-60 human acute myeloid leukemia (AML) cell line which overexpress MRP but not P-glycoprotein, the assay detects elevated levels of MRP mRNA (4- to 8-fold) relative to the drug-sensitive parental cells (designated HL-60/W). Blast cells from 24 patients with AML were also studied for MRP expression using this RT-PCR method. Expression of MRP was normalized for that of beta-actin in the blast cells, which was also determined by RT-PCR. All of these blast cell samples had MRP expression that was detectable after 35 PCR cycles. Eighteen of these patients samples had levels of expression of MRP mRNA equal to or less than that expressed by HL-60/W cells. In six patient blast cell specimens, the expression of MRP mRNA was up to 1.7-fold higher than that of HL-60/W cells. In 21 specimens, the steady-state intracellular accumulation of daunorubicin (1 microgram/ml, 3h) was also determined. The blast cells with MRP mRNA expression higher than HL-60/W had a lower median accumulation of daunorubicin compared to those whose MRP expression was less than HL-60/W, suggesting a functional defect in drug transport in the cells with higher MRP expression; a similar trend toward lower daunorubicin accumulation was also noted in the one-third of samples that displayed the highest expression of MDR1 mRNA (also determined by RT-PCR). These studies illustrate the range of expression of MRP in AML blast cell specimens. The identification of MRP overexpression in MDR AML cell lines and in some AML patient blast cells with low intracellular daunorubicin accumulation warrants further study of MRP as a component of clinical drug resistance in AML.
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PMID:Expression of multidrug resistance-associated protein (MRP) mRNA in blast cells from acute myeloid leukemia (AML) patients. 855 37

A human bladder cancer cell line resistant to adriamycin (ADM), T24/ADM9 has been established in vitro by exposing T24 parent cells to progressively higher concentrations of the drug over a period of 12 months. The T24/ADM9 cells were found to be 9 times more resistant to ADM than the T24 parent, and showed various degrees of cross-resistance to an ADM derivative, vinea alkaloids and a DNA topoisomerase II (Topo II)-targeting agent, etoposide. No significant differences was observed in the cellular accumulation of ADM between the T24/ADM9 and T24 parent cells. A Northern blot analysis showed an overexpression of multidrug resistance-associated protein (MRP) mRNA, but no overexpression of multidrug resistance-1 (MDR1) mRNA was observed in the T24/ADM9 cells. A flow cytometric analysis showed that the MDR1 gene product, P-glycoprotein (Pgp), is not expressed on the T24/ADM9 cells. T24/ADM9 showed approximately the parental level of DNA Topo II catalytic activity. In Western blot and Northern blot analyses, however, the cellular level of DNA topo II was apparently much lower in T24/ADM9 than in the T24 parent. Thus, these results suggest that a decreased cellular level of DNA Topo II and an overexpression of MRP gene may be responsible for the expression of an MDR phenotype in the T24/ADM9 cells and that such non-Pgp-mediated, atypical MDR may develop in bladder cancer treated with chemotherapy including ADM.
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PMID:Non-P-glycoprotein-mediated atypical multidrug resistance in a human bladder cancer cell line. 856 4

The efficacy of taxol against a wide range of sensitive and refractory solid tumors has prompted extensive investigation into the factors that influence its cytotoxicity. Our preliminary observations indicated that taxol had a superior antitumor effect against human cells (Daudi, K562, 2008, 2008/C13*, 2780 and C70) compared with its effect against rodent cells (WS, WR, NIH3T3, and CHO). Although verapamil, an inhibitor of P-glycoprotein function, markedly increased the efficacy of taxol against the rodent cells (WS, WR, and CHO), the expression of P-glycoprotein was found only at low levels in the WR cells. In addition, levels of the multidrug resistance-associated protein (MRP), as assessed by reverse transcriptase-polymerase chain reaction analysis, were found to be higher in the human than in the rodent cells, although MRP mRNA was not detected by northern blotting. Transport studies indicated that the reduced sensitivity of the rodent cells to taxol was due to decreased intracellular taxol levels and reduced intracellular binding. However, no correlation was found between the intracellular binding of taxol and the intracellular levels of alpha- and beta-tubulin, or the intracellular concentration of polymerized tubulin. These studies were extended further by assessing the binding of taxol to semi-purified microtubule proteins from WS, CHO and 2008/C13* cells in vitro. The microtubule protein preparations from WS, CHO and 2008/C13* cells, which have a 50-fold difference in their sensitivity to taxol, were found to bind equal amounts of radiolabeled taxol, and this binding was inhibited (80%) in the presence of unlabeled taxol. These results lead us to propose the presence in the rodent cells of an alternative taxol transport system that is distinct from the P-glycoprotein and MRP systems.
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PMID:Species-specific differences in taxol transport and cytotoxicity against human and rodent tumor cells. Evidence for an alternate transport system. 857 97

The human pancreatic tumour cell line PSN1/ADR, stepwise selected in 17-510 nM doxorubicin, displayed a multidrug resistance not conferred by P-glycoprotein (P-gp). Resistance to 17-51 nM doxorubicin was accompanied by overexpression of the vesicular marker lung resistance-related protein (LRP). Further selection in 170 nM doxorubicin led to the activation of multidrug resistance-associated protein (MRP) and to the development of drug accumulation/retention defects sensitive to verapamil. In addition, these defects were reversible by the vesicular traffic inhibitors brefeldin A, fluoroaluminate and nocodazole. In contrast, in human ovarian H134AD cells that are resistant to 1700 nM doxorubicin and used as P-gp-positive controls, the drug efflux was inhibited only by verapamil. The tyrosine kinase inhibitor genistein was a potent blocker of doxorubicin efflux in the PSN1/ADR cells but showed no activity in the H134 AD cells. The doxorubicin cytotoxicity in the PSN1/ADR cells was enhanced both by verapamil and brefeldin A, whereas in the parental PSN1 cells they demonstrated the opposite effects, being respectively sensitising and protecting. The P-gp-negative PSN1/ADR cells adapted to 510 nM doxorubicin retained brefeldin A-sensitive doxorubicin accumulation defects while MRP declined. The persistence of brefeldin A-responsive phenotype on the background of variable MRP expression suggests this agent as a useful functional probe for non-P-gp-mediated resistance to plasma-achievable doxorubicin concentrations.
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PMID:Low-level doxorubicin resistance in P-glycoprotein-negative human pancreatic tumour PSN1/ADR cells implicates a brefeldin A-sensitive mechanism of drug extrusion. 860 92

In this paper we demonstrate that the expression of the multidrug resistance-associated protein (MRP) in a variety of intact human tumour cells results in the ATP-dependent, mutually exclusive extrusion of both the acetoxymethyl ester and the free anion forms of the fluorescent dye calcein, as well as that of a fluorescent pyrenemaleimide-glutathione conjugate. The MRP-dependent transport of all these three model compounds closely correlates with the expression level of MRP and is cross-inhibited by hydrophobic anticancer drugs, by reversing agents for MDR1, and also by compounds not influencing MDR1, such as hydrophobic anions, alkylating agents, and inhibitors of organic anion transporters. Cellular glutathione depletion affects neither the MRP-dependent extrusion of calcein AM or free calcein, nor its modulation by most hydrophobic or anionic compounds, although eliminating the cross-inhibitory effect of glutathione conjugates. These results suggest that the outward pumping of both hydrophobic uncharged and water-soluble anionic compounds, including glutathione conjugates, is an inherent property of MRP, and offer sensitive methods for the functional diagnostics of this transport protein as well as for the rapid screening of drug-resistance modulating agents.
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PMID:Transport properties of the multidrug resistance-associated protein (MRP) in human tumour cells. 861 2

The multidrug resistance-associated protein (MRP) is a member of the ATP binding cassette superfamily of transporters which includes the mammalian P-glycoproteins (P-gp) family. In order to facilitate the biochemical and genetic analyses of MRP, we have expressed human MRP in the yeast Saccharomyces cerevisiae and have compared its functional properties to those of the mouse Mdr3 P-gp isoform. Expression of both MRP and Mdr3 in the anthracycline hypersensitive mutant VASY2563 restored cellular resistance to Adriamycin in this mutant. MRP and Mdr3 expression produced pleiotropic effects on drug resistance in this mutant, as corresponding VASY2563 transformants also acquired resistance to the anti-fungal agent FK506 and to the K+/H+ ionophore valinomycin. The appearance of increased cellular resistance to the toxic effect of Adriamycin (ADM) in MRP and Mdr3 transformants was concomitant with a reduced intracellular accumulation of [14C]ADM in spheroplasts prepared from these cells. Moreover, MRP and Mdr3, but not control spheroplasts, could mediate a time-dependent reduction in the overall cell-associated [14C]ADM from preloaded cells, suggesting the presence of an active ADM transport mechanism in MRP and Mdr3 transformants. Finally, human MRP was found to complement the biological activity of the yeast peptide pheromone transporter Ste6 and partially restored mating in a sterile ste6 null mutant. These findings suggest that despite their relatively low level of structural homology, MRP and P-gp share similar functional aspects, since both proteins can mediate transport of chemotherapeutic drugs and the a mating peptide pheromone in yeast.
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PMID:Functional expression of the multidrug resistance-associated protein in the yeast Saccharomyces cerevisiae. 1041 50

In previous studies, we have cloned and sequenced a 5'-end region of the multidrug resistance-associated protein (MRP) gene that contains promoter activity as assessed through transient transfections of constructs contained in a pCAT basic reporter plasmid. In the present study, using a series of deletion mutants, evidence was obtained that the SP1 binding sites contained in the promoter are essential for optimal MRP transcriptional activity. These results were supported by the finding that introduction of site-specific mutations into the wild-type SP1 sequence produced a major reduction in CAT activity. DNase I protection assays also demonstrated that SP1 sites are protected from hydrolysis with proteins from nuclei of a variety of cell lines. Gel mobility-shift assays with proteins extracted from CHO, HeLa, HL60, or HL60/ADR demonstrated the presence of a protein that bound to the wild-type SP1 sequence but not to an SP1 sequence containing site-specific mutations. The mobility shift with nuclear extracts was closely similar to that occurring after incubating purified SP1 protein with wild-type SP1 sequence. DNA supershift experiments with antibody to SP1 strongly suggest that the complexes formed with nuclear extracts contain the SP1 protein.
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PMID:Evidence that SP1 modulates transcriptional activity of the multidrug resistance-associated protein gene. 863 38

For investigation of relative differences in mRNA expression levels and of correlations in the expression of genes possibly involved in multidrug resistance (MDR) of acute myelogenous leukemias (AML), a complementary DNA polymerase chain reaction (cDNA-PCR) analysis was established for the genes encoding MDR1/P-glycoprotein, the multidrug resistance-associated protein (MRP), topoisomerase II alpha, topoisomerase II beta, topoisomerase I, glutathione S-transferase pi, protein kinase C (PKC) isozymes alpha, beta 1, beta 2, epsilon, eta, theta and cyclin A. In a first descriptive study comprising samples of childhood or adult AML we calculated the mean values from primary (n=14) or relapsed (n=23) states of the diseases, respectively. We found in the latter significant increases of MDR1, MRP, gst pi, and PKC theta gene expression. MDR1 and MRP gene expression levels were generally correlated (rs= +0.4128, P<0.02, n=37), as well as topoisomerase II alpha and cyclin A gene expression levels (rs= +0.8727, P<0.0001, n=35). Within the group of relapsed state AML a significant negative correlation between the gene expression levels of MDR1 and topoisomerase II alpha (rs= -0.5500, P<0.01, n=22) was observed. Remarkably, highly significant positive correlations were found for MDR1/PKC eta (rs= +0.5560, P<0.001, n=32), MRP/PKC theta (rs= +0.6573, P<0.0001, n=34) and MRP/PKC eta (rs= +0.5241, P<0.005, n=32).
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PMID:Expression of PKC isozyme and MDR-associated genes in primary and relapsed state AML. 864 57

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-regulated, cAMP-activated chloride channel located in the apical membrane of many epithelial secretory cells. Here we report cloning of a cAMP-activated epithelial basolateral chloride conductance regulator (EBCR) that appears to be a basolateral CFTR counterpart. This novel chloride channel or regulator shows 49% identity with multidrug resistance-associated protein (MRP) and 29% identity with CFTR. On expression in Xenopus oocytes, EBCR confers a cAMP-activated chloride conductance that is inhibited by the chloride channel blockers niflumic acid, 5-nitro-2-(3-phenylpropylamine)benzoic acid, and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid. Northern blot analysis reveals high expression in small intestine, kidney, and liver. In kidney, immunohistochemistry shows a conspicuous basolateral localization mainly in the thick ascending limb of Henle's loop, distal convoluted tubules and to a lesser extent connecting tubules. These data suggest that in the kidney EBCR is involved in hormone-regulated chloride reabsorption.
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PMID:Molecular cloning and expression of a cyclic AMP-activated chloride conductance regulator: a novel ATP-binding cassette transporter. 864 87

The multidrug resistance-associated protein (MRP), a new membrane transporter related to non-Pgp multidrug resistance, is overexpressed in some drug-selected cancer-cell lines. The role of MRP in unselected cell lines and in human cancer is unknown. MRP gene expression, determined by RNase protection assay and chemosensitivity to doxorubicin, etoposide and cisplatin, determined by MTT assay, were assessed in 18 non-drug-selected lung-cancer cell lines (10 small-cell lung cancer, 6 non-small-cell lung cancer, and 1 carcinoid). MRP gene expression was also investigated in normal lung tissue and primary non-small-cell lung cancer. All cell lines except one and all normal lung tissues and primary non-small-cell lung cancers expressed detectable levels of MRP. Expression was significantly lower in cell lines than in normal and neoplastic lung. MRP protein expression was also assessed by immunohistochemistry using the monoclonal antibody MRPr1; comparable levels of expression were observed between mRNA and protein in cell lines; however, in tumor samples intense staining was observed in tumor cells as well as in infiltrating normal cells in tumors, making the results less comparable to those obtained by RNase expression. MRP expression did not directly correlate with function in a calcein accumulation assay in 2 unselected cell lines. No gene amplification was observed by Southern-blot analysis, in the unselected cell lines or in tumor samples. In general, in cell lines, MRP gene expression was correlated with lower chemosensitivity to doxorubicin and etoposide, but not to cisplatin. However, MRP expression did not directly correlate with MRP function as assessed by a calcein accumulation assay in one of 2 unselected cell lines examined. Our results suggest that MRP may be implicated in drug resistance in unselected lung-cancer cell lines and its role in normal lung and primary lung cancer warrants further investigation in patients undergoing chemotherapy.
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PMID:MRP is frequently expressed in human lung-cancer cell lines, in non-small-cell lung cancer and in normal lungs. 864 46


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