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

Multidrug resistance (MDR) in cancer cells is a major contributor to the failure of chemotherapy treatment. This paper describes a novel protein named the anthracycline resistance associated (ARA) protein. The ara gene is amplified in the MDR leukaemia line CCRF-CEM/E1000 and its mRNA is overexpressed. ARA belongs to the ATP binding cassette (ABC) family of proteins. Another ABC protein, the multidrug resistance-associated protein (MRP), has previously been reported to be overexpressed in the CEM/E1000 subline. The primary amino acid sequence of ARA indicates that it is 49.5 kDa without glycosylation, and that it has one potential glycosylation site. ARA has one ATP binding site and associated transmembrane regions. This is in contrast to MRP (190 kDa, 172 kDa deglycosylated) and most other higher eukaryote ABC proteins, which consist of two similar halves, each having one ATP binding site. In addition to ARA being coexpressed with MRP, comparison of amino acid sequences showed that, among known proteins, ARA is most similar to the C-terminal half of MRP.
 ...
PMID:The anthracycline resistance-associated (ara) gene, a novel gene associated with multidrug resistance in a human leukaemia cell line. 891 25

The protein encoded by the multidrug resistance-associated protein (MRP) gene was examined after infection of SF21 insect cells with recombinant baculovirus containing a full-length MRP cDNA. The time course of appearance of the protein as determined by western blot analysis revealed that maximum levels occurred 2 days postinfection. The amount of MRP made in this system was somewhat variable, but levels that were about 4-fold greater than that found in HL60/ADR cells could be achieved. The protein appeared to be full-length but was present in a highly deglycosylated form. The P170 (MRP) was phosphorylated and located exclusively in membranes of infected cells. P170 (MRP) synthesized in this system was capable of carrying out the ATP-dependent transport of leukotriene C4 into isolated membrane vesicles. The results thus indicate that MRP synthesized in insect cells is functional and has properties similar to the authentic protein found overexpressed in certain multidrug-resistant isolates.
 ...
PMID:Expression and characterization of the multidrug resistance-associated protein in insect cells infected with a recombinant baculovirus. 893 92

Glucuronides and mercapturates were examined as possible high-affinity substrates for a low-affinity ATP-dependent transport system for 2,4-dinitrophenyl S-glutathione (DNP-SG) in mouse L1210 cells. Initial inhibitor studies with inside-out vesicles revealed that the low-affinity transport of [3H]DNP-SG (Km 450 microM) exhibits a high sensitivity to N-acetyl 2,4-dinitrophenyl cysteine (NAc-DNP-Cys) (Ki 5.0 microM) and alpha-naphthyl beta-D-glucuronide (naphthyl glucuronide) (Ki 8.5 microM). Direct transport measurements showed the presence of ATP-dependent uptake activities for NAc-DNP-[35S]Cys and naphthyl [14C] glucuronide, and Km values for half-maximal transport were comparable to the Ki values of these compounds for inhibition of [3H]DNP-SG transport. Transport of [3H]DNP-SG, NAc-DNP-[35S]Cys and naphthyl [14C]glucuronide each showed the same sensitivity to various anions and anion conjugates. Inhibition was competitive and was most potent for bilirubin ditaurate, indoprofen, 4-biphenylacetic acid, 4-acridine 4 beta-D-glucuronide, N-acetyl leukotriene E4, 17 beta-oestradiol 3 beta-D-glucuronide and taurolithocholate 3-sulphate. Inside-out vesicles from human erythrocytes contain a comparable ATP-dependent transport system. These results show that NAc-DNP-Cys and naphthyl glucuronide are high-affinity substrates for a single system identified previously as a low-affinity transporter of DNP-SG. Substrate and inhibitor studies identify this system as a novel multispecific organic-anion transport system (MOAT4) that accommodates glucuronides and mercapturates and is distinct from other MOAT transporters. Human erythrocytes contain an additional ATP-dependent system for NAc-DNP-Cys (Km 33 microM) that does not transport monoglucuronides.
 ...
PMID:MOAT4, a novel multispecific organic-anion transporter for glucuronides and mercapturates in mouse L1210 cells and human erythrocytes. 894 98

Using cyclosporin A (CsA) to inhibit P-glycoprotein (P-gp) function we showed previously that there was a discordance between the ability of acute myeloid leukemic (AML) blast cells to accumulate daunorubicin and P-gp antigen expression (Xie et al, Leukemia 1995; 9:1882-1887). This discordance suggests that a CsA-sensitive drug efflux mechanism distinct from P-gp is expressed in many clinical samples. In the present study using the ATP depleting agents cyanide, azide, or dinitrophenol to inhibit energy dependent transport processes, we observed even larger increases in daunorubicin accumulation than were seen with CsA. Similar patterns were seen in a wide range of P-gp negative human cancer cell lines. Also the observed cyanide effect did not correlate with the expression of mRNA for multidrug resistance-associated protein (MRP), the only other member of the ABC family of membrane transporters that is known to be capable of effluxing daunorubicin. Thse results suggest that daunorubicin accumulation in many cases of AML is modulated by one or more novel energy-dependent processes that are distinct from P-gp or MRP. We speculate that this novel drug transport mechanism(s) may influence the response of AML patients to daunorubicin and other therapeutic agents.
 ...
PMID:A novel energy dependent mechanism reducing daunorubicin accumulation in acute myeloid leukemia. 900 18

A group of ATP-binding cassette (ABC) transporters, including the yeast cadmium transporter (YCF1), the mammalian multidrug resistance-associated protein (MRP), the multispecific organic anion transporter and its congener (MOAT and EBCR), as well as the sulfonylurea receptor (SUR), group into a subfamily by sequence comparison. We suggest that these MRP-related proteins are also characterized by a special, common membrane topology pattern. The most studied ABC transporters, the cystic fibrosis transmembrane conductance regulator (CFTR) and the multidrug resistance (MDR) proteins, were shown to contain a tandem repeat of six transmembrane helices, each set followed by an ATP-binding domain. According to the present study, in contrast to various membrane topology predictions proposed for the different MRP-related proteins, they all seem to have a CFTR/MDR-like core structure, and an additional, large, N-terminal hydrophobic region. This latter domain is predicted to contain 4-6 (most probably 5) transmembrane helices, and is occasionally glycosylated on the cell surface. Since all the MRP-related transporters were shown to interact with anionic compounds, the N-terminal membrane-bound domain may have a key role in these interactions.
 ...
PMID:Membrane topology distinguishes a subfamily of the ATP-binding cassette (ABC) transporters. 901 45

The multidrug resistance proteins, discovered as membrane transporters producing chemotherapy-resistance in cancer, are functioning as complex cellular defence systems through recognition and energy-dependent removal of a large variety of toxic agents. The multidrug transporters belong to the ATP-binding cassette (ABC) transporters, present both in prokaryotes and eukaryotes and built from a combination of characteristic membrane-spanning helices and cytoplasmic ATP-binding domains. In mammals the MDR1 (P-glycoprotein) extrudes large hydrophobic compounds and provides the basis of the blood-brain and the blood-testis barrier for such molecules. The multidrug resistance-associated protein (MRP) and its homologues have a major role in the cellular export of large organic anions, including e.g. conjugated bile salts and glutathione-conjugates. The substrate recognition, that is the self and non-self discrimination and the ATP-dependent foreign agent extrusion are directly coupled within the structure of these large plasma membrane proteins. Here we suggest that the multidrug transporters are essential parts of our immune-defence system, working as 'cellular antitoxic' mechanisms.
 ...
PMID:The multidrug transporters--proteins of an ancient immune system. 905 81

Three agents, verapamil, cepharanthine, and 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1, 3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-3-py ridinecarboxylate P-oxide (PAK-104P), that reverse drug resistance in P-glycoprotein (P-Gp)-mediated multidrug-resistant cells were examined for their activity to reverse drug resistance in multidrug resistance-associated protein (MRP)-mediated multidrug-resistant C-A120 cells. Agents other than PAK-104P could not reverse the resistance to doxorubicin in C-A120 cells. PAK-104P moderately reversed the doxorubicin resistance. In contrast, PAK-104P almost completely reversed the resistance to vincristine (VCR) in C-A120 cells as well as in KB-8-5 cells, and other agents moderately reversed the VCR resistance in C-A120 cells. PAK-104P at 10 microM enhanced the accumulation of VCR in C-A120 cells to the level of that in KB-3-1 cells without the agent. PAK-104P competitively inhibited the ATP-dependent [3H]leukotriene C4 uptake in membrane vesicles isolated from C-A120 cells. These findings demonstrate that PAK-104P can completely reverse the resistance to VCR in both P-Gp- and MRP-mediated multidrug-resistant cells and that PAK-104P directly interacts with MRP and inhibits the transporting activity of MRP.
 ...
PMID:Reversal of multidrug resistance-associated protein-mediated drug resistance by the pyridine analog PAK-104P. 905 94

P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) are members of the superfamily of ATP-binding cassette transporter proteins. Because the ATP-dependent export system has been implicated in the release of leukotriene C4 (LTC4), we examined the roles of P-gp and MRP in the release of LTC4 from normal murine mast cells (MC-9). We have previously shown that MC-9 cells express P-gp at the level of protein and mRNA. In the present study, MRP expression in MC-9 cells was examined at the protein level by anti-MRP Ab, using flow cytometry and at the level of mRNA by PCR and Northern blot analyses. MC-9 cells were stimulated with calcium ionophore A23187 for 15 min in the presence or the absence of various concentrations of cyclosporin A (CsA) and its nonimmunosuppressive analogue CsA-1, which are known to inhibit P-gp efflux function, or in the presence or the absence of probenecid, an organic ion transport inhibitor that appears to inhibit MRP-mediated transport function. Culture supernatants were collected, and LTC4 was measured by ELISA assay. CsA and CsA-1 had no effect on LTC4 secretion from MC-9 cells, suggesting that P-gp is not involved in LTC4 release from MC-9 cells. In contrast, probenecid, in a concentration-dependent manner, inhibited LTC4 secretion from MC-9 cells without inhibiting its synthesis. However, MC-9 lacked MRP at both the protein and mRNA levels. These data suggest that LTC4 is secreted by normal mast cells by a probenecid-sensitive mechanism that is independent of MRP.
 ...
PMID:Leukotriene C4 secretion from normal murine mast cells by a probenecid-sensitive and multidrug resistance-associated protein-independent mechanism. 914 9

An attempt was made to isolate resistant sublines of acute myelogenous leukemia (OCI/ AML-2) cells by chronic exposure to gradually increasing concentrations of daunorubicin in order to determine the mechanism of its resistance to this drug. Four daunorubicin-resistant sublines, AML-2/D100, /D250, /D500, and /D1,000 were isolated. The values of relative resistance of each daunorubicin-resistant AML subline were about 3, 6, 18, and 23-fold, respectively, as compared to the AML-2 line with an IC50 of 5 nM. The daunorubicin-resistant AML-2 sublines also showed cross resistance to various anticancer drugs including another anthracycline doxorubicin, a Vinca alkaloid vincristine, and an epipodophyllotoxin etoposide. A functional assay using flow cytometry showed decreased accumulation of daunorubicin in these sublines as compared to that of AML-2, which was reversed by cyclosporin A or cyanide. The development of the ATP-dependent multidrug resistant phenotype was due to low to high levels of expression of P-glycoprotein (PGP). The major mechanisms of increased PGP appears to be associated with gene amplification. In addition, other mechanisms such as increased stability of protein or mRNA might be involved depending on the concentration of daunorubicin used for selection. However, a multidrug resistance-associated protein (MRP) was not involved in these resistant sublines. These daunorubicin-resistant AML-2 sublines could provide a useful model for the study of multidrug resistance mediated by PGP.
 ...
PMID:Isolation and characterization of daunorubicin-resistant AML-2 sublines. 916 28

Human KB carcinoma C-A120 cells that express multidrug resistance-associated protein (MRP) were cross-resistant to trivalent and pentavalent antimonials and arsenicals. Intracellular glutathione (GSH) content was higher in C-A120 than its parental KB-3-1 cell line. Glutathione-S-transferase (GST) was similar in both cell lines. Depletion of cellular GSH by treatment of the cells with the inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS), buthione sulfoximine (BSO), significantly increased the sensitivity of both KB-3-1 and C-A120 cells to heavy metals. A pyridine analog, PAK-104P, almost completely reversed the resistance to antimonials and arsenicals in C-A120 cells. BSO at 100 microM or PAK-104P at 10 microM enhanced the accumulation of antimony potassium tartrate in C-A120 cells to the level of that in KB-3-1 cells without the agents. PAK-104P inhibited the ATP-dependent efflux of antimony potassium tartrate. These findings suggest that MRP transports antimony conjugated with GSH ATP-dependently outside the cells and PAK-104P inhibits the transporting activity of MRP.
 ...
PMID:Reversal of heavy metal resistance in multidrug-resistant human KB carcinoma cells. 924 93


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>