Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P-glycoprotein, a 170-kd glycoprotein encoded by the MDR 1 gene, is a member of a highly conserved superfamily of ATP-binding cassette (ABC) transport proteins. It shares extensive homology with numerous bacterial and eukaryotic ABC transport proteins. P-glycoprotein acts as an energy-dependent efflux pump that appears to transport structurally diverse agents ranging from ions to peptides. P-glycoprotein (P-gP) has been implicated as playing a role in multidrug (MDR) resistance in cancer, chloroquine-resistant Plasmodium falciparum infection, and possibly human immunodeficiency virus-1 (HIV-1) resistance to nucleoside compounds. A number of normal tissues in humans and rodents have been shown to express high levels of P-gp. The expression and function of P-gp in cells of the immune system have been explored in the past 2 years. This review presents a state of the art regarding the expression, regulation, and function of Pgp in cells of the immune system. In addition, its alteration in aging and HIV-1 infection is reviewed. A possible physiologic role of P-gp in cytokine secretion, antigen processing/presentation, and effector functions is also discussed.
 ...
PMID:P-glycoprotein (MDR 1 gene product) in cells of the immune system: its possible physiologic role and alteration in aging and human immunodeficiency virus-1 (HIV-1) infection. 790 61

Using degenerate oligodeoxyribonucleotides from conserved regions of the gene family encoding ATP-binding domain of the active transporter, two new Escherichia coli genes were identified. The first of the genes, named mdl (multidrug resistance-like), is located at min 10.2 of the E. coli chromosome and encodes two ATP-binding motifs and two hydrophobic (transmembrane) domains. The ATP-binding domains of mdl show 35-38% amino acid (aa) identity with members of the eukaryotic P-glycoprotein/multidrug resistance family. To date, 25 members of the ATP-transporter/permease gene family have been characterized in E. coli. Comparison of the ATP-binding domains from this family indicates that mdl is part of a distinct subfamily of sequences that includes hlyB, msbA, and cvaB. Gene-disruption studies revealed that mdl is not essential for cell growth. The second open reading frame, named abc (ATP-binding cassette), is located at min 4.9 of the chromosome, encodes a single ATP-binding domain, and is most homologous to ftsE, a cell division control gene of E. coli. The abc gene product also shows aa sequence homology to several E. coli permeases.
 ...
PMID:Cloning and organization of the abc and mdl genes of Escherichia coli: relationship to eukaryotic multidrug resistance. 790 73

ATP-binding cassette (ABC) transporters share significant sequence identity within their ATP-binding domains. Degenerate oligonucleotides based on highly conserved portions of the ATP-binding domain genes were used to clone portions of two members of the ABC gene superfamily from Saccharomyces cerevisiae DNA. These genes were designated MDL1 and MDL2 (for multidrug resistance-like). Each MDL gene is predicted to encode a single set of transmembrane domains and a single ATP-binding domain, thus the MDL gene products are 'half-molecule' ABC proteins. The two genes were mapped to precise regions on chromosomes XII and XVI and show a considerable similarity to the mammalian P-glycoprotein/multidrug resistance (MDR) and peptide transporter (TAP) genes. Preliminary analysis of null mutants constructed by gene replacement has indicated that the MDL genes are not essential for viability of yeast. The sequences have been deposited in the GenBank data library under Accession Numbers L16958 (Locus YSCBCSA) and L16959 (Locus YSCBCSB).
 ...
PMID:Mapping and sequencing of two yeast genes belonging to the ATP-binding cassette superfamily. 791 68

The induced expression of multiple drug resistance (MDR)-associated genes as a direct response of tumor cells to antineoplastic drugs could be an important factor influencing the success of cancer chemotherapy. We investigated the effects of such compounds on mdr1/P-glycoprotein (P-gp) gene expression and drug sensitivities in the T-lymphoblastoid human cell line CCRF-CEM and MDR sublines. Thereby, we observed that actinomycin D or adriamycin administered at sublethal concentrations induced increases of mdr1 mRNA levels and resistance within 72 h. Furthermore, on leukemia cell samples collected before and after chemotherapy we checked by a complementary DNA polymerase chain reaction (cDNA-PCR) approach for similar alterations in the relative expression levels of the MDR-associated genes (a) mdr1/P-gp (b) mrp (MDR related protein), and (c) the topoisomerase II isoforms alpha and beta. We found a concomitant increase in mdr1 and mrp gene expression combined with a decreased expression of topoisomerase II alpha in the course of the second relapse of an acute lymphoblastic leukemia (ALL). This points to the emergence of at least three different MDR mechanisms in this type of leukemia unresponsive to chemotherapy. A chronic myeloid leukemia (CML) in blast crisis, however, showed combined increases in mdr1 (about 20-fold) and mrp (about four fold) gene expression after intense but unsuccessful chemotherapy over a 6-month period. Our results indicate the occurrence of induced resistance in vitro and in vivo and suggest a contribution of the newly identified ATP-binding cassette (ABC) transporter MRP in MDR.
 ...
PMID:Drug-induced changes in the expression of MDR-associated genes: investigations on cultured cell lines and chemotherapeutically treated leukemias. 791 48

We have previously identified and characterized a novel member of the ATP-binding cassette superfamily of transport proteins, multidrug resistance protein (MRP), and subsequently demonstrated that its overexpression is sufficient to confer multidrug resistance on previously sensitive cells (Cole et al., Science (Washington DC), 258: 1650-1654, 1992; Grant et al., Cancer Res. 54: 357-361, 1994). In the present study, we have transfected two different eukaryotic expression vectors containing MRP complementary DNA into HeLa cells to study the pharmacological phenotype produced exclusively by overexpression of human MRP. The drug resistance patterns of the two MRP-transfected cell populations were similar. They were characterized by a moderate (5- to 15-fold) level of resistance to doxorubicin, daunorubicin, epirubicin, vincristine, and etoposide, and a low (< or = 3-fold) level of resistance to taxol, vinblastine, and colchicine. The transfectants were not resistant to 9-alkyl anthracyclines, mitoxantrone, or cisplatin. The MRP-transfected cells were also resistant to some heavy metal anions including arsenite, arsenate, and trivalent and pentavalent antimonials but were not resistant to cadmium chloride. Accumulation of radiolabeled vincristine was reduced by 45% in the MRP-transfected cells and could be restored to the levels found in sensitive cells by depletion of ATP. Rates of vincristine efflux did not differ greatly in the sensitive and resistant cells. The cytotoxic effects of vincristine and doxorubicin could be enhanced in a dose-dependent fashion by coadministration of verapamil. Cyclosporin A also increased vincristine toxicity but had less effect on doxorubicin toxicity. The degree of chemosensitization by verapamil and cyclosporin A was similar in MRP-transfected cells and in cells transfected with the vector alone, suggesting that sensitization involved mechanisms independent of MRP expression. Verapamil and cyclosporin A caused a modest increase in vincristine accumulation in the resistant cells but did not restore levels to those of the sensitive cells. Taken together, these data indicate that drug-resistant cell lines generated by transfection with MRP complementary DNA display some but not all of the characteristics of MRP-overexpressing cell lines produced by drug selection in vitro. They further demonstrate that the multidrug resistance phenotype conferred by MRP is similar but not identical to that conferred by P-glycoprotein and includes resistance to arsenical and antimonial oxyanions.
 ...
PMID:Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. 795 21

Genes have been identified in Plasmodium falciparum which belong to the ATP-binding cassette superfamily of transport systems based upon sequence and structural homology. One of these genes, the pfmdr 1 gene, is homologous to the mammalian mdr 1 gene, which encodes the P-glycoprotein product. Strong phenotypic data suggests the involvement of a P-glycoprotein-like molecule in the mediation of drug resistance in P. falciparum. The goal of this work was to characterize the expression of the pfmdr 1 messenger RNA: both the stage specific expression and the level of expression in mefloquine sensitive or resistant parasites. We identified two messenger RNA homologous to this gene, one of 8.5 kb expressed in ring and trophozoite stages, and a second messenger RNA of 7.5 kb expressed only in trophozoites. Previously we had reported an increased expression of messenger RNA for pfmdr 1 in a mefloquine-resistant clone. Here we extend this and demonstrate that overexpression of the pfmdr 1 gene is consistent with the mefloquine resistance phenotype in a panel of recent isolates from Thailand.
 ...
PMID:Stage-specific transcripts of the Plasmodium falciparum pfmdr 1 gene. 809 38

The Plasmodium falciparum P-glycoprotein homologue 1 (PGH1) is structurally similar to several members of the ATP-binding cassette (ABC) superfamily of membrane transporters. We have examined whether the nucleotide binding domains predicted from the deduced amino sequence are functional by photoaffinity labeling of purified parasite digestive vacuoles with the analogue 8-azido-alpha-[32P]ATP (8-N3-ATP). This reagent labels a 160-kDa protein in vacuoles from both a chloroquine sensitive and a chloroquine-resistant parasite isolate. The 160-kDa protein could be immunoprecipitated with affinity-purified antibodies against the P. falciparum P-glycoprotein homologue (PGH1). Inhibition of photoaffinity labeling of PGH1 could be achieved with ATP, ADP, GTP and GDP but not with AMP or GMP. In order to map the 8-N3-ATP binding sites on PGH1, photoaffinity-labeled PGH1 was digested with trypsin and immunoprecipitated with site-specific antibodies. Taken together, these results indicate that 8-N3-ATP specifically labels PGH1 and that one binding site resides within the amino terminal half of the molecule. This supports the contention that PGH1 is involved in a nucleotide-regulated transport function across the membrane of the digestive vacuole.
 ...
PMID:Nucleotide binding properties of a P-glycoprotein homologue from Plasmodium falciparum. 809 60

The haemolysin exporter HlyB and its homologues are central to the unconventional signal-peptide-independent secretion of toxins, proteases and nodulation proteins by bacteria. HlyB is a member of the ATP-binding cassette (ABC) or traffic ATPase superfamily, and resembles closely in structure and function mammalian exporters such as the multidrug-resistance P-glycoprotein, combining both integral membrane and cytosolic domains. Overproduction of the HlyB cytoplasmic domain as a C-terminal peptide fused to glutathione S-transferase allowed the direct affinity purification and concentration of 30-50 mg ml-1 of soluble protein (GST-Bctp) in an apparently dimeric form possessing both transferase and ATPase activity. GST-Bctp bound to ADP-agarose and was eluted specifically by ATP and ADP, affinity behaviour which was confirmed in both the full-length HlyB and the unfused HlyB cytoplasmic domain synthesized in vitro. The stoichiometry of binding to MgATP and MgADP was close to equimolar and both ligands induced substantial conformational change in the protein. Mg(2+)-dependent ATPase activity of GST-Bctp (Vmax 1 mumol min-1 mg-1, Km 0.2 mM) was comparable with the activity of the bacterial importer MalK and human P-glycoprotein reconstituted into proteoliposomes, and over an order of magnitude higher than in vitro measurements of disaggregated MalK purified from inclusion bodies. Activity was unaffected by inhibitors of F- and V-type ATPases, non-hydrolysable ATP analogues, or translocation substrate, but was severely inhibited by inhibitors of E1E2 (P-type) ATPases, and the acidic phospholipid phosphatidyl glycerol.
 ...
PMID:ATPase activity and ATP/ADP-induced conformational change in the soluble domain of the bacterial protein translocator HlyB. 836 61

Two doxorubicin-selected human tumor cell lines, H69AR and HT1080/DR4, display a multidrug resistance phenotype but do not overexpress P-glycoprotein. Recently, a 6.5-kilobase mRNA encoding a novel member of the ATP-binding cassette superfamily of transport proteins, designated multidrug resistance-associated protein (MRP), has been identified in the H69AR cell line. In the present study, the levels of MRP mRNA were found to be 14-fold higher in HT1080/DR4 cells relative to sensitive HT1080 cells. Southern blotting indicates that gene amplification contributes to the overexpression of MRP in HT1080/DR4 cells. Using a 4-kilobase MRP complementary DNA probe, MRP genes were localized to 2-5 chromosomes bearing homogeneously staining regions and to multiple double minute chromosomes in H69AR cells. Resistant H69AR cells also contained a new der(16) with a structural aberration affecting 16p13.1, the normal cellular locus of the MRP gene. The MRP probe hybridized to two small homogeneously staining regions (hsr) in HT1080/DR4 cells including hsr(7)(p12p15). MRP localization was restricted to the normal cellular locus, 16p13.1, in the parental H69 and HT1080 cells and the drug-sensitive H69PR revertant cells. Our data provide combined evidence that amplification of the MRP gene is associated with the expression of drug resistance in selected solid tumor cell lines.
 ...
PMID:Localization of a novel multidrug resistance-associated gene in the HT1080/DR4 and H69AR human tumor cell lines. 839 19

We have isolated the cDNA of the 70-kDa peroxisomal membrane protein (PMP70) from rat and human liver cDNA libraries. The nucleotide sequence of the cDNA of PMP70 contains an open reading frame of 1977 bp which encodes an amino acid sequence of 659 residues. Possible two domains were identified by hydropathy analysis. One is a hydrophobic region, which presumably contains six transmembrane segments. The other is a hydrophilic domain, which shows striking similarity to the sequences of the ATP-binding cassette (ABC) transporter proteins, including bacterial periplasmic transport proteins, the human multidrug resistance P-glycoprotein (MDR1), cystic fibrosis transmembrane conductance regulator (CFTR), and the putative adrenoleukodystrophy gene product (ALDP). Based on its transmembrane structure and the homology to ABC proteins, PMP70 may be involved in ATP-dependent transport through peroxisomal membrane.
 ...
PMID:[PMP70, the 70-kDa peroxisomal membrane protein: a member of the ATP-binding cassette transporters]. 841 12


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