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)

Associations between hematopoietic cells and their microenvironment are central to the development and maintenance of a functional hematopoietic system. It is important, therefore, to identify the surface receptors that mediate adhesive interactions among hematopoietic cells, stromal cells, and extracellular matrix components. In this study, we examined the expression of mRNA transcripts encoding a number of cell adhesion molecules and surface antigens in primitive hematopoietic cells isolated from murine bone marrow and fetal liver. Using a panel of probes, we hybridized a library of globally amplified cDNA prepared by reverse transcriptase-polymerase chain reaction of poly(A)+ mRNA from individual precursors and mature cell populations, representing precisely defined positions within the hematopoietic developmental hierarchy. The panel included probes specific for the CD45, CD34, P-glycoprotein (mdr1), Ly-6A/E (Sca-1), heat stable antigen (CD24), Fc receptor for IgG FcgammaRII (CD32), CD44, CD22, and ICAM-1 (CD54) genes, as well as alphaL (CD11a), alphaM (CD11b), beta2 (CD18), alpha4 (CD49d), alpha5 (CD49e), beta1 (CD29), and beta7 integrin subunit sequences. The data, which revealed stage- and lineage-specific expression patterns, should prove useful in designing future mechanistic studies aimed at elucidating the role played by adhesion receptors in normal and abnormal hematopoiesis.
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PMID:Expression mapping of adhesion receptor genes during differentiation of individual hematopoietic precursors. 932 54

P-glycoprotein (MDR-1) is a well-known transporter that mediates efflux of chemotherapeutic agents from the intracellular milieu and thereby contributes to drug resistance. MDR-1 also is expressed by nonmalignant cells, including leukocytes, but physiologic functions for MDR-1 are poorly defined. Using an initial screening assay that included >100 mAbs, we observed that neutralizing mAbs MRK16, UIC2, and 4E3 against MDR-1 specifically and potently blocked basal-to-apical transendothelial migration of mononuclear phagocytes, a process that may mimic their migration into lymphatic vessels. Antagonists of MDR-1 then were used in a model of authentic lymphatic clearance. In this model, antigen-presenting dendritic cells (DC) migrate out of explants of cultured human skin and into the culture medium via dermal lymphatic vessels. DC and T cells derived from skin expressed MDR-1 on their surfaces. Addition of anti-MDR-1 mAbs MRK16, UIC2, or the MDR-1 antagonist verapamil to skin explants at the onset of culture inhibited the appearance of DC, and accompanying T cells, in the culture medium by approximately 70%. Isotype-matched control mAbs against other DC molecules including CD18, CD31, and major histocompatibility complex I did not block. In the presence of MDR-1 antagonists, epidermal DC were retained in the epidermis, in contrast to control conditions. In summary, this work identifies a physiologic function for MDR-1 during the mobilization of DC and begins to elucidate how these critical antigen-presenting cells migrate from the periphery to lymph nodes to initiate T lymphocyte-mediated immunity.
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PMID:A physiologic function for p-glycoprotein (MDR-1) during the migration of dendritic cells from skin via afferent lymphatic vessels. 961 15

In this study with cycloheximide (CHX, an inhibitor of protein synthesis) and the human leukaemic cell line U937, a novel form of chemoresistance, which we termed sudden drug resistance (SDR), was identified using Hoechst33258 staining, Western blot and DNA Ladder. CHXhigh (10-100 microg/ml)-induced apoptosis can spontaneously subside after 4-6 h or can be inhibited by short-term preincubation with CHXlow (2.5 microg/ml). Unlike typical multidrug resistance, SDR is not caused by reduced drug accumulation or altered protein expression, and may be associated with a non-P-glycoprotein mechanism. To uncover this underlying mechanism, we focused on U937 cell aggregation promoted by CHX, because cell adhesion has been suggested to influence cell survival and prevent apoptosis. EDTA, or anti-CD18 monoclonal antibody, but not EGTA, acetylsalicylic acid or RGDS tetrapeptide, abrogated this homotypic aggregation and greatly increased CHX-induced apoptosis in a time-dependent manner, while fibrinogen and soluble intercellular adhesion molecule-1 exerted opposite effects. These results establish that beta2-integrin engagement is a key mediator of SDR, although it may be non-exclusive. This finding supplements the classical basis of chemoresistance and may provide another opportunity for improved leukemia therapy.
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PMID:beta2-integrins mediate a novel form of chemoresistance in cycloheximide-induced U937 apoptosis. 1531 56

Reports showing susceptibility of multidrug resistant (MDR) cancer cells to immune effectors, together with P-glycoprotein (P-gp) expression in immune effector subsets, including immature natural killer (NK) cells, and some activated T cells, suggest P-gp or some changes associated with it, have implications in immune-mediated mechanisms. A series of experiments were done to determine the nature of alterations associated with susceptibility to immune effector cells of MDR tumor cells. A cell line isolated from the malignant pleural effusion of a breast cancer patient was transfected with human and murine MDR1 genes, and four variants with different levels of MDR were obtained. Lymphokine-activated killer (LAK) activity was measured by a 51Chromium release, and conjugate formation assays. MDR1 transfectant P-gp+ breast carcinoma lines had increased LAK susceptibility compared to their parent line. Some part of the increased LAK susceptibility of drug-resistant cell lines was at the binding/recognition level as shown by conjugate formation assays. This suggests that differences may exist between paired cell lines with respect to the expression of cell adhesion molecules (CAMs). Monoclonal antibodies (mAbs) to CAMs and flow cytometry were used to quantitate these antigens. The CAMs studied were those previously found to be upregulated by stimulating NK cells with (interleukin-2) IL-2; ICAM-1 (CD54), LFA-3 (CD58), N-CAM (CD56), and the beta chain of LFA-1 (CD18). Although no differences in these CAMs were found between the breast carcinoma line and its MDR1-transfected variants, the target susceptibility results given above suggest that IL-2 treatment could be effective in combination with current protocols using chemotherapeutics, monoclonal antibodies (mAbs) and stem cell transplantation.
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PMID:Lymphokine-activated killer cell susceptibility and adhesion molecule expression of multidrug resistant breast carcinoma. 1708 16