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)

In a longitudinal design in which each animal was examined repeatedly throughout its life, we used flow cytometry to determine the numbers or proportions of a variety of T lymphocyte subsets in the peripheral blood of mice aged 8-20 months. Half of the 128 mice were given a low calorie diet which is known to extend lifespan and to reduce the rate of age-associated change in T cell immune function. In these genetically heterogeneous mice, bred as the progeny of CB6F1 females and C3D2F1 males, aging led to statistically significant increases in the number of CD3 cells and the proportions of CD4 memory and CD8 memory cells, and declines in the proportions of CD4 cells and CD4 virgin cells. Older mice also had increased proportions of CD4 and CD8 cells that were able to extrude the fluorochrome R123 through the action of P-glycoprotein. Caloric restriction delayed or prevented most of these age-dependent changes, but had little effect on expression of P-glycoprotein. Correlation analysis showed that those individual mice with high levels of CD4 memory or CD8 memory T cells tended also to have relatively low levels of CD4 virgin cells and low proportions of CD4 T cells, particularly at older ages. In addition, those mice which had the greatest rate of increase in CD4 memory and CD8 memory T cells also tended to show the greatest decline in CD4 virgin and in the proportion of CD4 cells. High numbers of CD4R (and high rates of change in the CD4R subset) were associated with high numbers (and change scores) for the CD8R subset, but there were no strong correlations between the R123-extruding subsets and other age-sensitive markers. Thus some, but not all, age-sensitive T cell subsets show correlated levels and correlated rates of change throughout the middle of the lifespan.
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PMID:Age-related changes in T cell surface markers: a longitudinal analysis in genetically heterogeneous mice. 922 20

A multidrug-resistant murine lymphoid leukemia P388/ADR overexpresses P-glycoprotein (P-gp), an active transporter that pumps cytotoxic drugs out of cells and a product of mdr1 gene. Cytotoxic T lymphocytes (CTL) that showed cytotoxicity against P388/ADR were generated from mixed lymphocyte tumor cell culture. CTL do not kill drugsensitive parental P388 (P388/parent) that does not express P-gp. Monoclonal antibody against P-gp inhibited cytotoxic activity. Similar results were obtained in another multidrug-resistant cell line P388/VP-16. Cytotoxic activity was mediated by Thy1+ CD4- CD8+ T-cells. When P388/ADR was treated with murine IL-4, expression of P-gp was downregulated. Monoclonal antibody against interleukin-4 (IL-4) abrogated the IL-4-induced suppression of P-gp. Cytolytic activity of CTL against IL-4-treated P388/ADR was dose dependently inhibited. These results suggest that P-gp is immunogenic and can be a target of CTL in this murine leukemia model.
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PMID:Cytotoxic T-lymphocytes recognizing P-glycoprotein in murine multidrug-resistant leukemias. 926 May 76

Aging leads to changes in the relative proportions of several functionally distinct T cell subsets, including increases in the proportions of memory cells in the CD4 and CD8 subsets and in the proportion of T cells expressing the multiple-drug resistance pump P-glycoprotein. To see whether individual differences in T cell subset levels predict life span, we measured the levels of five age-sensitive T cell subsets, at 8 and again at 18 months of age, in the peripheral blood of genetically heterogeneous mice bred as the progeny of CB6F1 females and C3D2F1 males. The strongest immunological predictor of life span in univariate regression analyses was the proportion of CD4 memory cells measured at 18 months of age (P=0.003). CD4 memory cell levels remained strongly correlated with life span (P<0.0003) in a multiple regression analysis after adjustment for sex. The proportion of CD4 cells expressing P-glycoprotein was also correlated with life span (P<0.01), but only in male mice. Weaker relationships were observed between life span and 8-month tests of CD8 memory and CD8 P-glycoprotein levels, for CD4 naive cells at 18 months, and for the change in CD4 naive cells between 8 and 18 months of age; these were, however, near the margin of statistical significance and could reflect chance relationships. The relationship between CD4 memory cell levels and life span was similarly strong regardless of the cause of death in mice whose death was attributable to lymphoma, fibrosarcoma, mammary carcinoma, and other forms of terminal pathology. Additional work is needed to discriminate between two hypotheses: 1) that high levels of CD4 memory cell themselves predispose to disease and early death, particularly from neoplasia; or 2) that accumulation of CD4 memory cells is a biomarker of some underlying process-perhaps accelerated aging-that itself leads to early mortality.
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PMID:CD4 memory T cell levels predict life span in genetically heterogeneous mice. 927 62

We have used a T-cell receptor transgenic mouse model to study the role of antigen in the changes that occur as T cells age. We find that the characteristic shift in the CD4 population to a predominance of memory phenotype T cells which accompanies aging in non-transgenic mice does not occur, suggesting that this shift is a result of antigenic stimulation. Thus at least one component of aging must be antigen dependent. When responses of naive CD4 T cells from aged and young mice are directly compared in vitro, the former are relatively deficient in their ability to produce IL-2 and IL-3, they express altered levels of P-glycoprotein and they proliferate less well in the absence of exogenous cytokines. When the ability of both naive populations to generate effectors is compared, the number of effectors generated from aged naive cells is much reduced and the effectors generated express lower levels of IL-2R alpha and produce reduced levels of cytokines. Importantly, addition of IL-2 restores proliferation of aged naive T cells, restores efficient effector generation and results in effectors seemingly indistinguishable from those derived from young CD4 cells. Similar phenotypic and functional changes seen with aging are also found in T-cell populations from IL-2 and IL-2R alpha knockout mice. Thus the loss of optimal IL-2 production may participate in the aging process and may represent the main antigen-independent defect in the CD4 T-cell population.
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PMID:From naive to effector--alterations with aging. 947 61

Previous work has established that aging in mice leads to an accumulation of T cells that express high levels of P-glycoprotein, a plasma membrane pump that mediates multiple drug resistance in tumor cells but whose function in normal T cells is still obscure. Pgp+ cells seem to be functionally defective: isolated from the CD4 memory population of young mice, they are unresponsive to T cell receptor-dependent stimuli in tests for proliferation and cytokine production. The proliferative defect can, however, be overcome by exposure to PMA plus the calcium ionophore ionomycin, suggesting that the Pgp+ cells may have a specific defect in calcium signal generation. We show here that Pgp+ T cells, from young or old mice, do indeed show smaller changes in intracellular calcium ion concentration than Pgp- cells, when activated either by Con A, anti-CD3 antibodies, or ionomycin. The difference between Pgp+ and Pgp- cells is apparent even in experiments on isolated CD4 memory T cells from young mice and thus is not simply a consequence of the age-dependent increase in memory cell numbers. Although the molecular basis for the abnormality in calcium signal generation by Pgp+ cells is still uncertain, our data suggest that the effect could be due to inter-subset differences in levels of sorcin, a 22 kDa cytoplasmic protein that is co-expressed with P-glycoprotein in many tumor cells and which binds free calcium ion with high affinity. Sorcin levels are higher in Pgp+ CD4 cells than in Pgp- CD4 cells of young mice and increase with age in CD4 cells, consistent with the hypothesis that sorcin interferes with calcium signals in the age-sensitive Pgp+ T cell subset.
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PMID:Calcium signal abnormalities in murine T lymphocytes that express the multidrug transporter P-glycoprotein. 1022 45

N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing doxorubicin (DOX) and different targeting moieties were developed with the aim of specific chemotherapy. Two of them, HPMA-conjugated DOX and galactosamine-targeted DOX, are in phase II clinical trials in the U.K. We studied the effect of conjugates with different targeting moieties (anti-CD71, antithymocyte globulin, anti-CD4, transferrin) on human or mouse multidrug resistance (MDR) cell lines (CEM/VLB, P388-MDR). It was shown that targeting decreases the level of MDR for DOX and the level of MDR depends on the targeting moiety used. The combination of these conjugates with chemosensitisers (cyclosporin A, D, G) restored almost completely the sensitivity of MDR cell lines to that of parental sublines. These results suggest that different intracellular trafficking of these conjugates (in membrane-limited organelles) in contrast to free diffusion for low molecular weight compounds might partially overcome P-glycoprotein (Pgp)-mediated MDR. We also report here the development of biodegradable HPMA hydrogels suitable for prolonged release of the cytostatic drug and chemosensitiser as a potential approach to overcome MDR mediated by Pgp.
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PMID:A possibility to overcome P-glycoprotein (PGP)-mediated multidrug resistance by antibody-targeted drugs conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carrier. 1044

The plasma membrane transport protein P-glycoprotein (P-gp) is expressed by subsets of both CD4+ and CD8+ T cells in mice. The proportion of T cells that express P-gp goes up with age, and the P-gp-expressing subset of the CD4 memory population is hyporesponsive in many in vitro assays. The significance of P-gp expression for T cell function has not been well established, although several reports have suggested that it may promote cytokine export and/or cytotoxic T cell function. To elucidate which T cell functions may require P-gp, we have compared a variety of responses using T cells from wt and P-gp knockout mice. Protein expression and rhodamine-123 efflux studies revealed that peripheral T cells exclusively utilize the mdr1a-encoded isoform rather than the homologous mdr1b or mdr2 isoforms. Comparisons of T cells from mdr1a+/+ and mdr1a-/- mice showed no differences in proliferation or in secretion of IL-2, IL-4, IL-5, IL-10, or IFN-gamma in response to polyclonal stimulation. Moreover, mdr1a-/- T cells produced strong allospecific cytotoxic responses comparable to those of wt T cells. Our results show that P-gp is not a necessary component of peripheral T cell functional responses. Further investigation will be needed to determine the significance of P-gp expression in T lymphocytes.
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PMID:mdr1a-encoded P-glycoprotein is not required for peripheral T cell proliferation, cytokine release, or cytotoxic effector function in mice. 1045 1

The MDR1 multidrug transporter P-gp (P-glycoprotein) is an efflux pump that extrudes diverse hydrophobic drugs and peptides from cells. Since the entry of HIV-1 into cells involves an initial interaction of the viral gp41 hydrophobic peptide with the plasma membrane, a potential effect of P-gp on HIV-1 infectivity was explored. Virus production was greatly decreased when P-gp was overexpressed at the surface of a continuous CD4(+) human T-leukemic cell line (12D7) infected with HIV-1(NL4-3), a T-tropic molecular clone of HIV-1. P-gp overexpression did not significantly alter the surface expression or distribution of either the HIV-1 receptor CD4 or the coreceptor CXCR4. Reduction of HIV-1 infectivity in P-gp-expressing cells occurred both during the fusion of viral and plasma membranes and at subsequent step(s) in the HIV-1 life cycle.
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PMID:Effect of ABC transporters on HIV-1 infection: inhibition of virus production by the MDR1 transporter. 1069 67

The existence of sanctuary sites for human immunodeficiency virus type 1 (HIV-1) may potentially endanger the efficacy of antiretroviral therapy in the long term and may even make eradication of HIV-1 from the infected body impossible. Potential 'classic' sanctuary sites for HIV-1 are the central nervous system and the testes, but long-lived cell populations (such as macrophages) or latently infected (resting) CD4 cells may also be considered a sanctuary for HIV-1. These potential sanctuary sites, and putative underlying biochemical mechanisms such as the divergent phosphorylation properties of nucleoside reverse transcriptase inhibitors in different cell populations and the affinity of drugs for the multidrug transporter P-glycoprotein, are discussed.
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PMID:Sanctuary sites in HIV-1 infection. 1072 4

In young mice, memory CD4 T lymphocytes with high P-glycoprotein activity (P-gp(high)) are unresponsive to TCR stimulation in vitro but can be activated by PMA plus ionomycin. The proportion of these hyporesponsive cells increases considerably with age. The earliest events in T cell activation were studied in P-gp(high) and P-gp(low) CD4 memory cells at the single-cell level using confocal immunofluorescence methods. Recruitment of both linker for activation of T cells (LAT) and protein kinase C-theta to the immunological synapse, i.e., the site of T cell interaction with stimulator cells, was greatly impaired in P-gp(high) cells from both young and old mice. Translocation of NF-AT to the nucleus, CD69 expression, and proliferative capacity were also diminished to a similar extent in P-gp(high) cells under the same activation conditions. In contrast, movement of c-Cbl to the synapse region occurred in a high proportion of CD4 memory T cells regardless of P-gp subset or age. Moreover, although P-gp(low) cells frequently recruited both c-Cbl and LAT to the APC synapse, cells in the less responsive P-gp(high) subset frequently relocated c-Cbl, but not LAT, to the interface region. In some systems, c-Cbl can act as a negative regulator of receptor-dependent tyrosine kinases, and alterations of c-Cbl to LAT ratios in the P-gp(high) subset may thus contribute to the hyporesponsiveness of this age-dependent, anergic memory cell population.
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PMID:Altered composition of the immunological synapse in an anergic, age-dependent memory T cell subset. 1084 59


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