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)

Two closely related but functionally distinct P-glycoprotein isoforms are encoded by the murine multidrug-resistance genes mdr1a and mdr1b. In a series of independently selected multidrug-resistant (MDR) J774.2 cell lines, mdr gene amplification and/or overexpression and overproduction of either the mdr1a or mdr1b products, or both gene products, correlates with the MDR phenotype. To investigate the possibility that mutations in the promoter regions of the mdr1a or mdr1b genes could influence their differential expression, mdr promoter-specific probes were used to detect and map potential structural alterations. An unusual structural rearrangement was found in the 5'-region of the amplified mdr1a allele in J7.T1, a cell line selected with taxol. To characterize this rearrangement, the regulatory regions of the mdr1a and mdr1b genes were analyzed. Whereas no gross structural alterations were detected by Southern blot hybridization using the mdr1b promoter probe, a novel amplified EcoRI fragment was detected by the mdr1a promoter probe. To determine the precise nature of this mutation, an mdr1a 5'-genomic clone was isolated from J7.T1 cells. Sequence analysis revealed an unusual DNA rearrangement consisting of the mdr1b gene, from its fourth intron toward its 3'-end, upstream of an intact mdr1a promoter on the amplified allele. We propose that this event occurred by an unequal sister chromatid exchange that was mediated by LINE-1 repetitive elements.
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PMID:The involvement of a LINE-1 element in a DNA rearrangement upstream of the mdr1a gene in a taxol multidrug-resistant murine cell line. 135 77

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

Cellular resistance to cytotoxic drugs is a major obstacle to the treatment of disseminated cancers. Multidrug resistance protein (MRP) subfamily is a member of the ATP-binding cassette transporters which has been shown to cause multidrug resistance, except for P-glycoprotein. A new MRP subfamily gene, mrp7A (Abcc10), and its splicing variant, mrp7B, were isolated from mouse. The lengths of the open reading frames of mouse mrp7A and mrp7B are 4383 and 4506 bp, respectively. Estimated polypeptide sequences of mrp7A and mrp7B are 1460 and 1501 amino acids. The mouse mrp7 gene consists of at least 21 exons and 20 introns spanning around 20 kb that is almost the same as the one in human MRP7 gene, but different with the other MRP subfamily genes. The promoter region was isolated from the genomic clone and shown to support the luciferase activity seven fold over the promoterless negative control and two fold activity higher than the positive control of SV40 promoter. The analysis of tissue expression of mrp7A and mrp7B showed that these two transcripts express differentially in specific tissues.
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PMID:cDNA cloning and genomic organization of the murine MRP7, a new ATP-binding cassette transporter. 1194 85