Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resistance to chemotherapy in cancer cells is mainly mediated by overexpression of P-glycoprotein (Pgp), a plasma membrane ATP-binding cassette (ABC) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. Pgp consists of two homologous halves each containing a transmembrane domain and a cytosolic nucleotide-binding domain (NBD) which contains two consensus Walker motifs, A and B, involved in ATP binding and hydrolysis. The protein also contains an S signature characteristic of ABC transporters. The molecular mechanism of Pgp-mediated drug transport is not known. Since the transporter has an extraordinarily broad substrate specificity, its cellular function has been described as a "hydrophobic vacuum cleaner". The limited knowledge about the mechanism of Pgp, partly due to the lack of a high-resolution structure, is well reflected in the failure to efficiently inhibit its activity in cancer cells and thus to reverse multidrug resistance (MDR). In contrast to the difficulties encountered when studying the full-length Pgp, the recombinant NBDs can be obtained in large amounts as soluble proteins. The biochemical and biophysical characterization of recombinant NBDs is shown here to provide a suitable alternative route to establish structure-function relationships. NBDs were shown to bind ATP and analogues as well as potent modulators of MDR, such as hydrophobic steroids, at a region close to the ATP site. Interestingly, flavonoids also bind to NBDs with high affinity. Their binding site partly overlaps both the ATP-binding site and the steroid-interacting region. Therefore flavonoids constitute a new promising class of bifunctional modulators of Pgp.
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PMID:P-glycoprotein-mediated resistance to chemotherapy in cancer cells: using recombinant cytosolic domains to establish structure-function relationships. 1045 53

Both the overexpression of P-glycoprotein and the broad range of substrates of this ATP-binding cassette (ABC) transporter induce the phenomenon of multidrug resistance, one major cause of the failure of cancer chemotherapy in humans. This study reports that [125I]iodipine, a structural analogue of the 1,4-dihydropyridine azidopine, shares a common binding site with iodomycin, a Bolton-Hunter derivative of the anthracycline daunomycin. This binding site is different from that described for iodoarylazidoprazosin, which is presumed to share a common binding site with azidopine. Edman sequencing revealed that [125I]iodipine had photolabelled the same peptide as iodomycin and spans the primary sequence of hamster isoform pgp1 from amino acid 230 to amino acid 312.
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PMID:Iodomycin and iodipine, a structural analogue of azidopine, bind to a common domain in hamster P-glycoprotein. 1049 Nov 26

The potential for the development of ivermectin (IVM) resistance in microfilariae of Onchocerca volvulus and the existence of IVM tolerance in adult worms of this human pathogen are major concerns for the effective control of onchocerciasis. P-glycoprotein (P-gp), an ATP-binding transporter protein associated with multidrug resistance in mammals, protozoa and the nematode, Haemonchus contortus, might play important roles in the development of IVM resistance and/or in the tolerance of adult O. volvulus. In order to find the homologues of P-gp in O. volvulus, reverse transcription polymerase chain reaction (RT-PCR) has been performed in a specially synthesized cDNA pool and two full-length cDNAs have been cloned and sequenced. The first, ovpgp-1, encodes a 1278-amino-acid putative protein (OVPGP-1) with tandemly duplicated halves, each containing six putative transmembrane motifs and an ATP-binding cassette. OVPGP-1 is most similar in sequence to other eukaryotic P-gps. The second cDNA, ovplp-1, encodes a 587-amino-acid P-gp-like protein, which is only half the size of typical P-gps although it still shares high homology with them. Expression patterns of the two genes in different developmental stages have been investigated by semiquantitative RT PCR, suggesting that the expression levels of the two genes (especially ovpgp-1) may be linked with IVM sensitivity; low levels were found in IVM sensitive larval stages while high levels were found in IVM tolerant adult worms.
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PMID:Identification and stage-specific expression of two putative P-glycoprotein coding genes in Onchocerca volvulus. 1049 83

Four ATP-binding cassette (ABC) half-transporters have been identified in mammalian peroxisomes: adrenoleukodystrophy protein (ALDP), adrenoleukodystrophy-related protein (ALDRP), 70-kDa peroxisomal membrane protein (PMP70) and PMP70-related protein (P70R). Inherited defects in ALDP cause the neurodegenerative disorder X-linked adrenoleukodystrophy (X-ALD). By comparative Northern blot analyses we found each of the four murine peroxisomal ABC transporter mRNA species at maximum abundance only in a few tissues, which differed for each family member. The four genes were also regulated differentially during mouse brain development: ALDP mRNA was most abundant in embryonic brain and gradually decreased during maturation; ALDRP and P70R mRNA accumulated in the early postnatal period; and the amount of PMP70 transcript increased slightly during the second and third postnatal week. The different expression patterns could explain why beta-oxidation is defective in X-ALD, although ALDRP and PMP70 can replace ALDP functionally in fibroblasts. Dietary fenofibrate had no effect on the ALD and P70R genes, but strongly increased expression of the ALDR and PMP70 genes in mouse liver. However, in P-glycoprotein Mdr1a-deficient mice fenofibrate treatment increased ALDR gene expression also in the brain, suggesting that the multidrug-transporter P-glycoprotein restricts entry of fenofibrate to the brain at the blood-brain barrier. Analysis of the promoter sequences revealed a cryptic nuclear hormone receptor response element of the DR+4 type in the ALDR promoter and a novel 18-bp sequence motif present only in the 5' flanking DNA of the ALDR and PMP70 genes. The mouse ALDR gene uses a single transcription start site but alternative polyadenylation sites. These data are of importance for the use of ALDP-deficient mice as a model in pharmacological gene therapy studies.
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PMID:The four murine peroxisomal ABC-transporter genes differ in constitutive, inducible and developmental expression. 1050 4

Multidrug resistance of cancer cells is, at least in part, conferred by overexpression of P-glycoprotein (P-gp), a member of the ATP-binding cassette (ABC) superfamily of active transporters. P-gp actively extrudes chemotherapeutic drugs from cells, thus reducing their efficacy. As a typical ABC transporter, P-gp has four domains: two transmembrane domains, which form a pathway through the membrane through which substrates are transported, and two hydrophilic nucleotide-binding domains (NBDs), located on the cytoplasmic side of the membrane, which couple the energy of ATP hydrolysis to substrate translocation. It has been proposed that the NBDs of ABC transporters, including the histidine permease of Salmonella typhimurium and the cystic fibrosis transmembrane conductance regulator, are accessible from the extracellular surface of the cell, spanning the membrane directly or potentially contributing to the transmembrane pore. Such organization would have significant implications for the transport mechanism. We determined to establish whether the NBDs of P-gp are exposed extracellularly and which amino acids are accessible, using cysteine-scanning mutagenesis and limited proteolysis. In contrast to other transporters, the data provided no evidence that the P-gp NBDs are exposed to the cell surface. The implications for the structure and mechanism of P-gp and other ABC transporters are discussed.
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PMID:Cysteine-scanning mutagenesis provides no evidence for the extracellular accessibility of the nucleotide-binding domains of the multidrug resistance transporter P-glycoprotein. 1058 Dec 53

The active extrusion of cytotoxic compounds from the cell by multidrug transporters is one of the major causes of failure of chemotherapeutic treatment of tumor cells and of infections by pathogenic microorganisms. A multidrug transporter in Lactococcus lactis, LmrA, is a member of the ATP-binding cassette (ABC) superfamily and a bacterial homolog of the human multidrug resistance P-glycoprotein. Another multidrug transporter in L. lactis, LmrP, belongs to the major facilitator superfamily, and is one example of a rapidly expanding group of secondary multidrug transporters in microorganisms. Thus, LmrA and LmrP are transport proteins with very different protein structures, which use different mechanisms of energy coupling to transport drugs out of the cell. Surprisingly, both proteins have overlapping specificities for drugs, are inhibited by the same set of modulators, and transport drugs via a similar transport mechanism. The structure-function relationships that dictate drug recognition and transport by LmrP and LmrA represent an intriguing area of research.
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PMID:Structure-function analysis of multidrug transporters in Lactococcus lactis. 1058 56

The expression of two members of the ATP-binding cassette family of transport proteins, P-glycoprotein (P-gp) and the canalicular multispecific organic anion transporter (cMOAT or Mrp2), was evaluated in renal brush-border membranes (BBM) and various rat tissues after cisplatin treatment. One administration of cisplatin (5 mg/kg) increased P-gp expression by >200-300% in renal BBM and in crude membranes from liver and intestine. The increase in P-gp expression in the kidney was also detected in photolabeling experiments, suggesting the induction of functional P-gp. cMOAT expression was increased by >10-fold in renal BBM after cisplatin administration, although it had no effect on liver cMOAT expression. The increase in the levels of both proteins was maximal at 2 days after cisplatin treatment and lasted for at least 8 days. These results indicate that a single administration of cisplatin induces overexpression of P-gp and cMOAT in specific tissues. This may be of significant relevance to the design of clinical trials using cisplatin as a single chemotherapeutic agent or in combination with other drugs.
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PMID:Cisplatin induces renal expression of P-glycoprotein and canalicular multispecific organic anion transporter. 1060 Sep 29

Sister of P-glycoprotein (SPGP), a novel murine cDNA and member of the ATP-binding cassette superfamily highly homologous to P-glycoprotein (Pgp), was cloned. Moreover, its genomic clone was isolated and localized to chromosome 2 by fluorescence in situ hybridization. SPGP was functionally evaluated relative to MDR1 after subcloning SPGP cDNA into a retroviral bicistronic vector capable of expressing both SPGP and the green fluorescent protein. LLC-PK1 and MDCKII cells were transduced with this retrovirus and SPGP-positive clones were isolated. Drug uptake and efflux was compared in cells ectopically expressing either SPGP or human MDR1. SPGP cells had decreased uptake of taurocholate and vinblastine compared with LLC-PK1 cells. Additional studies revealed that vinblastine efflux was accelerated by SPGP compared with LLC-PK1. Further comparison revealed that although MDR1 easily impaired uptake of vincristine, daunomycin, paclitaxel, and digoxin, SPGP had no effect on uptake of these drugs. However, further studies demonstrated that, like MDR1, SPGP effluxed calcein-acetoxymethyl ester (AM). Unlike MDR1, SPGP was incapable of effluxing rhodamine 123. Although cyclosporine A and reserpine blocked calcein-AM transport by MDR1, these drugs had either minimal or no effect, respectively, on blocking SPGP efflux of calcein-AM. In contrast, ditekiren, a linear hexapeptide, readily and preferentially inhibited SPGP efflux of calcein-AM. Further studies with three structural analogs of ditekiren revealed that one analog inhibited SPGP efflux of calcein-AM, although not as potently as ditekiren. These are the first studies to reveal that SPGP has distinct transport properties compared with MDR1.
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PMID:Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein. 1061 75

MDR results from overexpression of P-glycoprotein (Pgp) and multidrug resistance protein (MRP or MRP1) that function as ATP-dependent efflux pumps. Lung resistance related protein (LRP) is also supposed to be involved in MDR. The human canalicular multispecific organic anion transporter (cMOAT) gene that is responsible for the defects in Dubin-Johnson syndrome was isolated. cMOAT is homologous to MRP1 and supposed to be involved in drug resistance. Human cMOAT cDNA transfected LLC-PK1 cells, LLC/cMOAT-1, have increased resistance to vincristine (VCR), 7-ethyl-10-hydroxycamptothecin (SN-38), and cisplatin. The multidrug resistance (MDR)-reversing agents, cyclosporin A (CsA) and PAK-104P, almost completely reversed the resistance to VCR, SN-38 and cisplatin of LLC/cMOAT-1 cells by interacting with the substrate binding site of cMOAT. Treatment of human colorectal carcinoma SW-620 cells with sodium butyrate(NaB) induced LRP in the cells and conferred resistance to Adrianycin(ADM), VCR, VP-16, gramicidin D and taxol. Two LRP-specific ribozymes inhibited the NaB-induced expression of LRP in SW-620 cells and almost completely abolished their acquisition of the MDR phenotype. The accumulation of ADM, VCR and taxol was not decreased in NaB-treated cells, suggesting that ATP-binding cassette transporters are not involved in the MDR of NaB-treated cells. ADM was mainly located in the nuclei of untreated and the cytoplasm of NaB-treated cells. The accumulation level of ADM in the nuclei isolated from untreated cells or those from treated cells in the presence of anti-LRP polyclonal antibody was higher than that from treated cells in the absence of the antibody. Efflux of ADM from nuclei isolated from NaB-treated cells was enhanced compared with those from untreated cells and NaB-treated cells transfected with a LRP-specific ribozyme. The polyclonal antibody against LRP inhibited the enhanced efflux of ADM from nuclei isolated from NaB-treated cells. These findings indicate that LRP is involved in resistance to ADM, VCR, VP-16, taxol and gramicidin D, and has an important role in the transport of ADM from the nucleus to the cytoplasm.
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PMID:[Mechanisms for resistance to anticancer agents and the reversal of the resistance]. 1069 15

A key issue in the treatment of acute leukemia is the development of resistance to chemotherapeutic drugs. Several mechanisms may account for this phenomenon, including failure of the cell to undergo apoptosis in response to chemotherapy, or failure of the drug to reach and/or affect its intracellular target. This review focuses on the latter mechanism, and on intracellular drug transport resistance mechanisms in particular. Expression of the ATP-binding cassette (ABC) transporter P-glycoprotein (Pgp) has generally been reported to correlate with prognosis in acute myeloid leukemia (AML). Additionally, but more controversial, expression of the ABC transporter multidrug resistance protein (MRP) and the vault-transporter lung resistance protein (LRP) have been correlated with outcome in AML. Despite these findings, functional efflux assays indicate the presence of non-Pgp, non-MRP transporters in AML. Recently, a novel ABC transporter, breast cancer resistance protein (BCRP) was cloned and sequenced in our laboratory. Transfection and overexpression of BCRP in drug-sensitive cells confers drug-resistance to the cells. BCRP is a half-transporter, and may homodimerize or form heterodimers (with a yet unknown half-transporter) to produce an active transport complex. Relatively high expression of BCRP mRNA is observed in approximately 30% of AML cases, suggesting a potential role for this new transporter in drug resistance in leukemia.
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PMID:Novel mechanisms of drug resistance in leukemia. 1072 Jan 43


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