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)

The family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters is the largest gene family known. While some ABC transporters translocate single substances across membranes with high specificity, others transport a wide variety of different lipophilic compounds. They are responsible for many physiological processes and are also implicated in a number of diseases. The present review focuses on ABC transporter genes which are involved in ageing and age-related diseases. Expression of ABCB1 (MDR1, P-glycoprotein) increases with age in CD4(+) and CD8(+) T-lymphocytes indicating that P-glycoprotein may be involved in the secretion of cytokines, growth factors, and cytotoxic molecules. As T cells in aged individuals are hyporesponsive leading to a reduced immunodefence capability, a role of ABCB1 in age-related immunological processes is presumed. The ABCA1 (ABC1) gene product translocates intracellular cholesterol and phospholipids out of macrophages. Genetic aberrations in ABCA1 cause perturbations in lipoprotein metabolism and contribute to atherosclerosis. ABCA4 (ABCR) represents a retina-specific ABC transporter expressed in rod photoreceptor cells. The ABCA4 gene product translocates retinyl-derivatives. Mutations in the ABCA4 gene contribute to age-related macular degeneration. Polymorphisms in the sulfonylurea receptor gene (ABCC8, SUR1) are associated with non-insulin-dependent diabetes mellitus (NIDDM). Sulfonylureas inhibit potassium conductance and are used to treat NIDDM by stimulation of insulin secretion across ATP-sensitive potassium channels in pancreatic beta-cell membranes. Possible diagnostic and therapeutic implications of ABC transporters for age-related diseases are discussed.
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PMID:Adenosine triphosphate-binding cassette transporter genes in ageing and age-related diseases. 1243 93

P-glycoprotein (P-gp, ABCB1) actively transports a broad range of cytotoxic compounds out of the cell. The COOH terminus of P-gp contains a dileucine motif (Leu(1260)-Leu(1261)) and a conserved phenylalanine (Phe(1268)). Similar residues in SUR1 (ABCC8) were reported to be important plasma membrane-targeting signals (Sharma, N., Crane, A., Clement, J. P. t., Gonzalez, G., Babenko, A. P., Bryan, J., and Aguilar-Bryan, L. (1999) J. Biol. Chem. 274, 20628-20632). Here, we used alanine-scanning mutagenesis to test whether these residues were essential for trafficking of P-gp to the cell surface. Mutant L1260A expressed a 150-kDa immature protein that did not reach the cell surface and was sensitive to digestion by Endo H(f). By contrast, mutants L1261A, F1268A, and wild-type P-gps expressed the 170-kDa mature proteins at the cell surface. Mutation of Leu(1260) to Gly, Ile, Trp, Lys, or Glu also resulted in the expression of the 150-kDa immature protein. All of the mutants, however, expressed the 170-kDa protein in the presence of the drug substrate/specific chemical chaperone cyclosporin A. Mutant L1260A P-gp exhibited drug-stimulated ATPase activities similar to that of wild-type enzyme after rescue with cyclosporin A. Deletion of the last 22 amino acids (Q(1259)-Q(1280)) also caused misprocessing. The mutant, however, was rescued by expression in the presence of cyclosporin A and conferred resistance to colchicine in transfected cells. These results show that the dileucine motif is not a plasma membrane targeting signal. The COOH terminus is required for proper folding of P-gp but not for activity.
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PMID:The dileucine motif at the COOH terminus of human multidrug resistance P-glycoprotein is important for folding but not activity. 1554 93

A multixenobiotic resistance (MXR) mechanism mediated by ABC binding cassette (ABC) transport proteins is an efficient chemical defence mechanism in sea urchin embryos. The aim of our work was to evidence whether exposure to sub-lethal doses of specific contaminants (oxybenzone (OXI), mercuric chloride (HgCl2) and trybutiltin (TBT)) would induce MXR transporter activity during embryonic development (from zygote to blastula stage) in purple sea urchin (Paracentrotus lividus) embryos. Further, we present data on molecular identification, transport function, expression levels and gene localisation of two ABC efflux transporters-P-glycoprotein (ABCB1/P-gp) and sulfonylurea-receptor-like protein (ABCC9/SUR-like). Partial cDNA sequences of abcb1 and abcc9 were identified and quantitative PCR (qPCR) evidenced an increase in mRNA transcript levels of both ABC transporters during the two-cell, as well as an overall decrease during the blastulae stage. Calcein-AM efflux activity assay indicated the activation of multidrug resistance-associated protein/ABCC-like transport in the presence of HgCl2 and TBT in exposed blastulae. The in situ hybridisation of the two-cell and blastula stages showed ubiquitous localisation of both transcripts within cells, supporting qPCR data. In conclusion, ABCB1 and ABCC9 are constitutive, as are HgCl2, TBT and OXI-inducible ABC membrane transporters, coexpressed in the zygote, two-cell and blastula stages of the P. lividus. Their ubiquitous cell localisation further fortifies their protective role in early embryonic development.
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PMID:Quantification and in situ localisation of abcb1 and abcc9genes in toxicant-exposed sea urchin embryos. 2369 80