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)

Multidrug-resistant cells can manifest an increase in epidermal growth factor (EGF) receptor number along with increased P-glycoprotein (Pgp) synthesis. An interrelationship of the two membrane proteins in actinomycin D-resistant Chinese hamster lung cells (DC-3F/AD X) in terms of the effect of EGF on Pgp phosphorylation was investigated. EGF was not a mitogen for the resistant cells, nor was it mitogenic for DC-3F, the parental drug-sensitive line. Brief treatment of DC-3F/AD X cells with EGF resulted in a 30-50% decrease in the level of Pgp phosphorylation, and treatment of the cells with okadaic acid, a specific inhibitor of protein phosphatases-1 and -2A (PP1 and 2A), increased Pgp phosphorylation. Okadaic acid also increased phosphorylation of Pgp in plasma membranes isolated from DC-3F/AD X cells by 30-40%. Protein phosphatase activity in extracts of cells grown in EGF-containing medium was greater by 30% than that of cells grown in standard medium, and okadaic acid inhibited the increases. The results suggested that EGF activated PP1 and PP2A in DC-3F/AD X cells and that Pgp was a substrate for the phosphatases. The properties of Pgp may be modulated by the signalling system transduced by ligand-activated EGF receptor.
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PMID:Crosstalk between epidermal growth factor receptor and P-glycoprotein in actinomycin D-resistant Chinese hamster lung cells. 790 16

Okadaic acid (OA)-resistant variants of Chinese hamster ovary cells, clones CHO/OAR6-6 and CHO/OAR2-3, were isolated from a CHO-K1 culture. These variant cells were 17- to 26-fold more resistant to OA than the parental cells. The phosphorylase phosphatase activity of the variant cell extracts was 2- to 4-fold more resistant to OA than that of the parental cells in the presence of inhibitor 2, a specific inhibitor of type 1 protein serine/threonine phosphatase (PP1). Nucleotide sequencing of PP2A alpha (an isotype of PP2A catalytic subunit) cDNA demonstrated that both variants have a T-->G transversion at the first base of codon 269 (805 nt), which results in substitution of glycine for cysteine. We expressed in COS-1 cells a mutant PP2A alpha tagged with the influenza hemagglutinin epitope. The recombinant mutant PP2A alpha protein immunoprecipitated with an anti-influenza hemagglutinin antibody was more resistant than the wild type to OA, their IC50 values being 0.65 nM and 0.15 nM, and their IC80 values being 4.0 nM and 0.45 nM, respectively. The cysteine at residue 269 present only in highly OA-sensitive protein serine/threonine phosphatase catalytic subunit isozymes, PP2A alpha, PP2A beta, and PPX, is suggested to be involved in the binding of OA. CHO/OAR6-6 and CHO/OAR2-3 cells also overexpressed the P-glycoprotein, and the efflux of OA was more rapid. It is suggested that the PP2A alpha mutation in cooperation with a high level of P-glycoprotein makes the CHO-K1 variants highly resistant to OA.
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PMID:Characterization of the PP2A alpha gene mutation in okadaic acid-resistant variants of CHO-K1 cells. 793 53

Okadaic acid as well as other, structurally different, inhibitors of serine/threonine phosphatases 1 and 2A induce apoptosis in pituitary GH3 cells. Incubation with stepwise raised concentrations of okadaic acid resulted in the isolation of cells that were increasingly less sensitive to the cytotoxic effect of this agent. After about 18 months cells were selected that survived at 300 nM okadaic acid, which is about 30 times the initially lethal concentration. This study revealed that a major pharmacokinetic mechanism underlying cell survival was the development of a P-glycoprotein-mediated multidrug resistance (MDR) phenotype. The increase in mRNA levels of the mdr1b P-glycoprotein isoform correlated with the extent of drug resistance. Functional assays revealed that increasing drug resistance was paralleled by a decreased accumulation of rhodamine 123, a fluorescent dye which is a substrate of mdr1-mediated efflux activity. Resistance could be abolished by structurally different chemosensitizers of P-glycoprotein function like verapamil and reserpine but not by the leukotriene receptor antagonist MK571 which is a modulator of the multidrug resistance-associated protein (MRP). Okadaic acid resistance included cross-resistance to other cytotoxic agents that are substrates of mdr1-type P-glycoproteins, like doxorubicin and actinomycin D, but not to non-substrates of mdr1, e.g. cytosine arabinoside. Thus, functional as well as biochemical features support the conclusion that okadaic acid is a substrate of the mdr1-mediated efflux activity in rat pituitary GH3 cells. Maintenance of resistance after withdrawal of okadaic acid as well as metaphase spreads of 100 nM okadaic acid-resistant cells suggested a stable MDR genotype without indications for the occurrence of extrachromosomal amplifications, e.g. double minute chromosomes.
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PMID:Contribution of mdr1b-type P-glycoprotein to okadaic acid resistance in rat pituitary GH3 cells. 1049 79

Properties of inwardly rectifying K+ channels in small-cell lung cancer (SCLC) cells have not been clarified in detail. Here, we found inwardly rectifying K+ channels in a human SCLC cell line (RERF-LC-MA), which expresses no multidrug resistance-associated protein 1 (MRP1) and multidrug resistance P-glycoprotein (MDR1). Extracellular Ba2+ and Cs+ inhibited inwardly rectifying K+ currents of RERF-LC-MA cells in a concentration-dependent manner, but tetraethylammonium ion and glibenclamide were ineffective. Okadaic acid, an inhibitor of phosphatases 1 and 2A, and phorbol-12,13-dibutyrate, an activator of protein kinase C, significantly decreased the inwardly rectifying K+ current. Lowering the intracellular pH but not the extracellular pH decreased the K+ current. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting analysis showed that RERF-LC-MA cells express Kir2.1 mRNA and protein. The inwardly rectifying K+ current is suggested to be generated by Kir2.1 protein in the human small-cell lung cancer cell, and that the K+ channel is negatively regulated by protein kinase C and the intracellular acidic pH.
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PMID:Molecular and pharmacological properties of inwardly rectifying K+ channels of human lung cancer cells. 1182 Oct 18

Okadaic acid (OA) is a dinoflagellate toxin, accumulating in shellfish and causing diarrhetic shellfish poisoning (DSP) in humans. OA is a highly cytotoxic agent in most cell lines because of its inhibiting properties of protein phosphatases. So far, the cytotoxicity of OA in mussels, the main vectors of DSP, has not been investigated. In this paper, the viability of mussel (Mytilus edulis) blood cells incubated in 10 nM-1 microM OA was studied. After 72 h of exposure, viability was reduced to 54% in 1 microM OA compared with 88% in control cells. This yielded a LC50 of >1 microM for OA, which is 30-1000-times higher compared with other cell types. It was hypothesised that P-glycoprotein (p-gp) activity (multixenobiotic resistance, MXR) contributed to the resistance to OA. Vincristine and rhodamine B was used as p-gp substrates and verapamil or staurosporine (ST) as inhibitors of p-gp transport. However, no indications of cell membrane p-gp activity were detected. Instead, experimental observations led to the conclusion that a MXR transport system was present within lysosomal membranes. Various concentrations of OA did not affect the dynamics of vincristine in blood cells. As a positive control for the assay, p-gp activity was measured in mussel gill tissue. The efflux of rhodamine B was reduced by verapamil, which is, considered evidence for cell membrane p-gp activity, thus the accuracy of the method was confirmed. Rhodamine B efflux was also reduced by OA in gill tissue, which suggested that OA is either a competitive substrate or inhibitor of p-gp activity. When the volume of the lysosomal compartment was measured in blood cells pre-exposed to OA, a significant increase was detected compared with control cells. It was proposed that uptake and storage of OA within the lysosomal system might protect mussel blood cells from the cytotoxic effects of this compound.
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PMID:Mussel blood cells, resistant to the cytotoxic effects of okadaic acid, do not express cell membrane p-glycoprotein activity (multixenobiotic resistance). 1293 99