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)

P-glycoprotein (P-gp) is a 170-kDa glycoprotein encoded by the MDR-1 gene. In tumor cells overexpression of P-gp is associated with resistance to chemotherapy-induced apoptosis. P-gp is also expressed on cells of the immune system; however, its role in lymphocyte physiology remains unclear. Therefore, in this investigation, we examined a possible role of P-gp in the survival of in vitro activated peripheral blood mononuclear cells (MNCs). MNCs were activated with anti-CD3 monoclonal antibody (mAb) for 96 hr in the presence or absence of anti-P-gp mAb or isotype control and examined for apoptosis by TUNEL assay. Activation of caspase was determined by colorimetric assay. Activated lymphocytes (96 hr) are resistant to apoptosis. However, anti-P-gp mAb-induced apoptosis in anti-CD3 activated MNC. Induction of apoptosis was associated with increased expression of CD95L; activation of caspase 3, however, did not affect the expression of Bcl-2 and Bcl-xL. Furthermore, both recombinant Fas-Fc fusion protein, a blocker of CD95-CD95L interactions, and Z-DEVD-FMK, a cell-permeable caspase 3 inhibitor, reversed anti-P-gp-induced apoptosis. These data demonstrate that anti-P-gp mAb promotes apoptosis in activated T lymphocytes by up-regulating CD95L expression and via CD95-CD95L interactions and suggest a possible role of P-gp in lymphocyte survival.
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PMID:Anti-P-glycoprotein antibody-induced apoptosis of activated peripheral blood lymphocytes: a possible role of P-glycoprotein in lymphocyte survival. 1181 87

Lysosome-associated protein transmembrane 4 alpha (LAPTM4 alpha) and homologues comprise a family of conserved proteins, which are found in mammals, insects and nematodes. LAPTM4 alpha functions to regulate the intracellular compartmentalization of amphipathic solutes and possibly the sensitivity of cells toward anthracyclines, antibiotics, ionophores, nucleobases and organic cations. This is similar to the multidrug-resistance phenotype exhibited by cells synthesizing high levels of P-glycoprotein. Accordingly, it is possible that LAPTM4 alpha may be a suitable target for development of novel chemotherapeutic agents. LAPTM4 alpha contains four putative membrane-spanning domains and a 55 amino acid C-terminal region that faces the cytoplasm. Localization of LAPTM4 alpha to endosomes and lysosomes appears to be tightly controlled as transient high-level expression of LAPTM4 alpha in cultured cells resulted in no detectable protein on the cell surface. Mutagenic analysis of the C-terminus of LAPTM4 alpha indicated that two tandomly arranged tyrosine-containing motifs in the cytoplasmic domain are required for efficient localization of LAPTM4 alpha to vesicles containing the lysosomal marker lysosomal glycoprotein 120. Although a number of membrane proteins that localize to endosomes/lysosomes contain more than one independently functioning sorting signal, to our knowledge, LAPTM4 alpha is the first example of a membrane protein that requires two tandemly arranged tyrosine-based sorting signals for efficient localization in these compartments.
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PMID:Lysosome-associated protein transmembrane 4 alpha (LAPTM4 alpha) requires two tandemly arranged tyrosine-based signals for sorting to lysosomes. 1198 May 62

Multidrug resistant (MDR) cancer cells overexpressing P-glycoprotein (P-gp) display variations in invasive and metastatic behavior. We previously reported that these properties of MDR cancer cell lines overexpressing P-gp could be altered by chemotherapeutic drugs or MDR modulators (R. S. Kerbel et al., Cancer Surv., 7: 597-629, 1988). To attempt to clarify the mechanism(s) underlying these observations, we studied the expression of extracellular matrix metalloproteinase inducer (EMMPRIN), a glycoprotein enriched on the surface of tumor cells that can stimulate the production of matrix metalloproteinases (MMPs), in sensitive and MDR cancer cells. Using immunofluorescence staining and fluorescence-activated cell sorting analysis, we found that EMMPRIN expression was increased in MDR carcinoma cell lines, MCF-7/AdrR, KBV-1, and A2780Dx5, as compared to their parental counterparts. The MDR cell lines produced more matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9), as determined by zymography, Western blot, and reverse transcription-PCR. Treatment of MDR cells with an anti-EMMPRIN antibody inhibited the activity of MMP-1, MMP-2, and MMP-9. In MDR cell line MCF-7/AdrR, an increased in vitro invasive ability was observed as compared with the sensitive line MCF-7, and EMMPRIN antibody could inhibit the in vitro invasion in drug-resistant cells. In addition, the expression and activity of MMP-1, MMP-2, and MMP-9 in MDR cells were decreased by treatment with U-0126, an inhibitor of mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/Erk). Our results suggest that during the development of MDR, the expression of EMMPRIN is responsible for the increased activity of MMP in MDR cell lines.
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PMID:Overexpression of extracellular matrix metalloproteinase inducer in multidrug resistant cancer cells. 1269 61

Due to the size, glycosylation, and location in the plasma membrane of the sialomucin complex Muc4, which has been implicated in ErbB2 signaling, in the repression of apoptosis and cell adhesion, and in tumor metastasis, studies were initiated to determine whether its presence could influence cell sensitivity to anticancer drugs. Growth inhibition assays using melanoma cell lines that either express the glycoprotein (Muc4(+)) or do not (Muc4(-)) showed that Muc4 renders cells resistant to taxol, doxorubicin, vinblastine, rhodamine 123, and 2-deoxyglucose. When treated with various concentrations of doxorubicin, Muc4(+) cells were blocked less frequently in G(2) and underwent less DNA fragmentation (apoptosis and/or necrosis) than Muc4(-) cells. All of the drugs tested (except for 2-deoxyglucose) are well recognized by P-glycoprotein-mediated multidrug resistance 1 (MDR1) and to a lesser degree by multidrug resistance related protein 1 (MRP1) transporters. Therefore, transporter gene expression in these cells was assayed. Surprisingly, Muc4(+) cells expressed lower levels of both transporter genes than Muc4(-) cells. Moreover, rhodamine 123 was retained more highly in the Muc4(+) than in the Muc4(-) cells, demonstrating that these transporters are functional. Overall, these results indicate that although Muc4(+) cells express less MDR1 and MRP1, they are more resistant to drugs recognized by these transporters.
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PMID:Multidrug resistance correlates with overexpression of Muc4 but inversely with P-glycoprotein and multidrug resistance related protein in transfected human melanoma cells. 1273 53

An abnormal HLA expression has been detected in some tumors including rhabdomyosarcoma (RMS). Classical cytotoxic treatment of these tumors, the most common childhood soft tissue malignancy, may induce multidrug resistance (MDR) associated with the expression of a 170-kDa membrane-associated glycoprotein (P-glycoprotein). In order to analyse the connection between modulation of HLA expression and the development of the MDR phenotype mediated by P-glycoprotein in RMS, we used three resistant RMS cell lines; two of these resistant cell lines (TE.32.7.DAC and RD-DAC) were established by in vitro exposure to actinomycin D, a drug of choice in the treatment of RMS; the resistant RMS- GR cell line was established from an embryonal RMS tumor after polychemotherapy. Our results showed that all the resistant cell lines showed a significant increase in the expression of HLA class I surface antigens in comparison to drug-sensitive cells. Blockade of P-glycoprotein with verapamil led to a decrease in HLA class I expression in RMS resistant cell lines. However, no modulation of HLA class II expression was observed in any of the three analyzed cell lines. These findings support the hypothesis that the development of resistance mediated by mdr 1/P-glycoprotein, directly influences the expression of HLA class I in RMS cells, inducing to upregulation. This effect may be relevant to the application in RMS of immunotherapy against tumor-associated antigens presented by HLA class I molecules.
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PMID:Modulation of HLA class I expression in multidrug-resistant human rhabdomyosarcoma cells. 1274 Jun 41

The objective of the current investigation was to examine the transport characteristics of choline, an endogenous quaternary ammonium compound, into human intestinal Caco-2 cells; the transport of choline has not been characterized in human intestine. The cellular accumulation of choline was independent of an inwardly directed Na(+) gradient and demonstrated temperature dependence and saturability. Using the initial uptake rates, choline accumulation was best characterized by a Michaelis-Menten equation and a diffusion component with a K(m) and V(max) of 110 +/- 3 micro mol/L and 2800 +/- 250 pmol/(mg protein. 10 min), respectively. Choline uptake was significantly inhibited by an excess of choline itself and by hemicholinium-3, a structural analog of choline. However other hydrophilic organic cations, such as tetraethylammonium (TEA) and N-methylnicotinamide (NMN), did not affect choline uptake in Caco-2 cells. Additionally, two typical p-glycoprotein substrates, daunomycin and verapamil, both inhibited choline accumulation. However the opposite was not true: choline did not inhibit DNM accumulation in Caco-2 cells. These results indicate the presence of a carrier-mediated transport system for choline in Caco-2 cells. The substrate specificity of this carrier is unlike that seen in the rat intestinal epithelium, and the human transport protein is distinct from those for TEA and NMN. P-glycoprotein substrates may inhibit choline uptake through specific or nonspecific interactions with the choline transporter.
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PMID:Choline uptake in human intestinal Caco-2 cells is carrier-mediated. 1288 45

The aim of this study was to test the prognostic value of p-glycoprotein expression and the proliferative index of tumor cells on the clinical response to chemotherapy, on the brief disease-free interval (< 12 months) and on cause-specific survival in advanced ovarian carcinoma. We evaluated 83 ovarian carcinoma patients homogeneous for stage, type and grade histological. Brief disease-free interval and cause-specific survival rates (Kaplan-Meier method) were compared using the log rank test. Multivariate analysis (Cox proportional hazards models) was used to determine the independent effect of each variable on prognosis. In the univariate analysis, P-glycoprotein expression (P < 0.0005) and proliferative index (P = 0.0003 and P = 0.0006) were independent predictors of survival and brief disease-free interval; residual disease was associated with survival (P = 0.021). In multivariate analysis (Cox proportional hazards models), P-glycoprotein expression (P = 0.001 and P = < 0.0005) and proliferative index (P = 0.081 and P = 0.041) were independent predictors of brief disease-free interval and survival. P-glycoprotein expression (P < 0.0005) and proliferative index (P = 0.008) were associated with clinical response to chemotherapy.
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PMID:Prognostic value of P-glycoprotein and proliferative index in advanced low grade serous ovarian carcinomas. 1296 67

CD4(+) T cells from old mice show defects in the activation process including deficiency in the formation of immunosynapses with antigen-presenting cells. We show that CD4(+) T cells from old mice express unusually high levels of glycosylated forms of the bulky T cell glycoprotein CD43, particularly on a subset of functionally anergic cells expressing P-glycoprotein. T cells from old donors also show a decline in the association of CD43 with cytoskeletal matrix and in the proportion of T cells that can exclude CD43 from the synapse. O-sialoglycoprotein endopeptidase, which removes the external domain of CD43 and other O-sialoglycoproteins from the aged naive CD4(+) T cells of TCR-transgenic mice, restores early agonist-independent stages and later agonist-dependent stages of synapse formation as well as expression of the activation markers CD69 and CD25 to the levels found in the young mice. These data support a model in which O-glycosylated forms of T cell surface molecules, including CD43, are largely responsible for age-related defects in TCR signaling and function.
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PMID:Age-related defects in CD4+ T cell activation reversed by glycoprotein endopeptidase. 1463 57

We have recently shown that drug conjugation catalysed by UDP-glucuronosyltransferases (UGTs) functions as an intrinsic mechanism of resistance to the topoisomerase I inhibitors 7-ethyl-10-hydroxycamptothecin and NU/ICRF 505 in human colon cancer cells and now report on the role of drug transport in this mechanism. The ability of transport proteins to recognise NU/ICRF 505 as a substrate was evaluated in model systems either transfected with breast cancer-resistance protein 1 (Bcrp1), multidrug-resistance protein 2 (Mrp2) or Mrp3, or overexpressing MRP1 or P-170 glycoprotein. Results from chemosensitivity assays suggested that NU/ICRF 505 was not a substrate for any of the above proteins. In drug accumulation studies in human colon cancer cell lines NU/ICRF 505 was taken up avidly and retained in cells lacking UGTs (HCT116), whereas, following equally rapid uptake, it was cleared rapidly from cells displaying UGT activity (HT29) as glucuronide metabolites. HT29 cells were shown to express MRP1 and 3, but not P-170 glycoprotein, MRP2 or breast cancer-resistance protein. The major glucuronide of NU/ICRF 505 inhibited ATP-dependent transport of estradiol 17-beta-glucuronide in Sf9 insect cell membrane vesicles containing MRP1 or MRP3, while co-incubation of HT29 cells with the MRP antagonist, MK571, significantly restored intracellular concentrations of NU/ICRF 505. These data lead us to conclude that the presence of a glucuronide transporter is essential for glucuronidation to represent a major de novo resistance mechanism and that UGTs will contribute more as a primary resistance mechanism when the parent drug (e.g. NU/ICRF 505) is not itself recognised by transport proteins.
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PMID:Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins. 1466 26

The macrocyclic lactone ivermectin (Mectizan(R)) is widely used for the control of human filarial infections, particularly as a donated product for onchocerciasis and lymphatic filariasis. In the case of control of lymphatic filariasis in Africa, it is used in combination with donated albendazole. In areas co-endemic for Onchocerciasis and Loa loa, serious adverse reactions have been observed in patients with apparently high microfilaria counts of Loa loa. Recent findings suggest that the severe central nervous system side effects seen in various vertebrates following ivermectin treatment may be due to an absence of, or functional deficiency in P-glycoprotein. P-glycoprotein is expressed in the apical membrane of brain capillary epithelial cells and is responsible for limiting the brain penetration of a range of compounds. Toxicity of ivermectin in some collie dogs may be explained by a 4-bp deletion mutation of the mdr1 gene resulting in a frame shift, generating stop codons that prematurely terminate synthesis of P-glycoprotein. Additionally, sub-populations of CF-1 identified as expressing reduced levels of P-glycoprotein exhibit increased toxicity to substrates of this transporter. Furthermore, while the traditional view of drug-drug interactions is alteration in drug clearance mediated through a change in hepatic drug metabolism, some of these changes may arise through competition for binding sites on P-glycoprotein in the blood-brain barrier, resulting in reduced extracellular efflux and enhanced CNS toxicity. In conclusion, P-glycoprotein is an integral component of the human blood brain barrier and plays a central role in limiting drug uptake into the brain. Altered expression or function of p-glycoprotein could conceivably allow elevation of brain concentrations of ivermectin and produce severe neurotoxicity. This might arise through a genetic polymorphism in p-glycoprotein or co-administration of ivermectin with a drug or foodstuff that might inhibit this efflux transporter.
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PMID:Ivermectin: does P-glycoprotein play a role in neurotoxicity? 1497 65


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