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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lck gene encodes a membrane-associated protein tyrosine kinase that is expressed specifically in lymphoid cells, especially thymocytes. Structural analysis of the murine and human lck genes previously identified conserved 5' flanking sequences that were proposed to represent transcriptional regulatory elements. Here we demonstrate that a murine lck promoter construct containing these sequences directs the expression of the SV40 T-antigen gene in lymphoid cells. Remarkably, expression of SV40 T-antigen in transgenic animals dramatically disturbs thymic development, resulting in preferential loss of CD4+CD8+ thymocytes. In contrast, immature cells lacking both CD4 and CD8 markers are present in near-normal numbers. Thus SV40 T-antigen expression appears partially to arrest thymopoiesis. Mice bearing the lck-SV40 transgene develop readily explantable thymic tumors at 12-18 weeks of age. Fluorocytometric analyses of lck-SV40 tumor cells reveal that immature thymocytes are frequently immortalized. The lck-SV40 mouse may therefore provide materials for the in vitro investigation of thymocyte differentiation.
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PMID:Disruption of thymocyte development and lymphomagenesis induced by SV40 T-antigen. 196 44

It was recently discovered that murine epidermal Langerhans cells (LC) changed significantly in function and phenotype when maintained in culture. Notably, accessory cell function for primary immune responses increased while cytologic markers like ATPase, nonspecific esterase, and Birbeck granules were lost. To further analyze LC differentiation, we used flow cytometry and a panel of 22 monoclonal antibodies to quantitate changes in surface antigens at the single-cell level. A striking change was a fivefold increase in the amount of Ia antigens (which are expressed on class II MHC products) during the first day of culture. The increase was evident within 3 h and reached a plateau at 15-24 h. Both I-A and I-E products behaved similarly. The increase in Ia was blocked by 1 microgram/ml cycloheximide. Expression of other surface antigens was then monitored on Ia+ LC by two-color flow cytometry. Low levels of class I (H-2D and H-2K) MHC products were detected on freshly isolated LC, and these antigens also increased severalfold during the first day of culture. Fc receptors (identified with the 2.4G2 mAb) and the F4/80 macrophage antigen decreased, as reported previously. Three antigens that were detected in fresh suspensions were expressed at constant levels in culture. These were the C3bi receptor and the pan leukocyte and interdigitating cell antigens. Several leukocyte antigens that were not found initially on LCs did not appear, including B220 anti-B cell, 33D1 anti-dendritic cell, and CD4, CD5, CD8 T-cell specificities. We conclude that the surface of cultured LCs undergoes selective changes in culture. As a result, the cells are rich in Ia and H-2 and have detectable C3bi receptors, but have little or no LFA-1, Ti, CD4, 5, and 8, 33D1, 2.4G2, F4/80, and B220 antigens.
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PMID:Quantitation of surface antigens on cultured murine epidermal Langerhans cells: rapid and selective increase in the level of surface MHC products. 327 34

To date no hematopoietic progenitors of dendritic Langerhans' cells (DLC), which represent an highly efficient class of antigen presenting cells, have been identified or the cytokines they elaborate have been defined. Here we describe an acute leukemia patient whose blasts (90-96% in peripheral blood and bone marrow) had a phenotype consistent with putative progenitors of DLC. The patient was treated with ara-C and VP-16 but did not achieve remission. The blasts had lobulated nuclei, no cytoplasmic vacuolation or Auer rods and were weakly positive for acid phosphatase and non-specific esterase and negative for PAS, granzyme A, dipeptidyl aminopeptidase IV, ATPase/ADPase and lysozyme production. The blasts were positive for CD1a, CD4, CD16, CD35, HLADR, HLADQ, CD11b, CD11c, CD14, CD33, CD34, CD11a, CD71, CD19, CD25, IL-2R beta and negative for CD2, CD7, CD8, CD10, CD22, CD56, CD57, surface or cytoplasmic CD3, TCR delta and TCR beta, HTLV-1p19 and P-glycoprotein. On liquid culture with or without 5 x 10(-9) M 12-O-tetradecanoylphorbol-13-acetate (TPA) for 3 days, the blasts formed aggregates of proliferating and elongating cells on the wall of the flasks with a decline in CD34, numerous dendritic processes appeared on the cells and there was strong positivity for ATPase/ADPase, but no other changes in phenotype. No macrophages were observed, indicating derivation from separate DLCs. Cytogenetic analysis showed chromosomal abnormalities and electron microscopy showed Birbeck granules. Southern blotting of DNA showed rearrangement of one allele for both JH and TCR beta but no HTLV-1 related sequences. Culture supernatants from blasts cultured with or without TPA showed the production of large amounts of IL-8, IL-6, TNF-alpha, MIP-1 alpha, IL-10 and interferon gamma and modest amounts of IL-1 alpha, GM-CSF and stem cell factor. The presence not only of CD1a, HLADR, HLADQ and many other characteristics including Birbeck granules, but also differentiation along the lines of DLC with appearance of dendritic processes on the cells and expression of ATPase/ADPase activity, indicate that the leukemic blasts in our patient represented a leukemic counterpart of normal progenitors of DLC and the leukemia a new entity which could possibly be classified as AML-M8. Lastly, many pro-inflammatory cytokines produced by DLC could contribute to inflammation and IL-10 to immunosuppression.
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PMID:Phenotype, genotype and cytokine production in acute leukemia involving progenitors of dendritic Langerhans' cells. 791 55

Activation of immature thymocytes or transformed T lymphocytes via T-cell receptor (TCR)/CD3 signalling can induce programmed cell death (apoptosis). Recent data indicate that anti-CD3/TCR monoclonal antibodies (mAb) also trigger apoptosis in activated (but not resting) mature peripheral blood T lymphocytes. Here we report that triggering of resting CD4-CD8-TCR alpha beta+ and/or TCR gamma delta+ via the alternative CD2-dependent activation pathway is able to induce programmed cell death. A pair of mitogenic anti-CD2 mAb provoked a dramatic rise in [Ca2+]i that was almost entirely sustained by extracellular fluxes, and the inhibition of membrane [Ca2+/Mg2+] ATPase. The resulting endonuclease activation was able to induce DNA fragmentation, as revealed by propidium iodide staining and gel electrophoresis. Induction of apoptosis was prevented by the presence of interleukin-4 (IL-4) as well as by endonuclease inactivation with 100 microM ZnCl2, but enhanced by the contemporary block of protein kinase C. Thus it seems that in resting T lymphocytes the strong calcium signal delivered by the alternative CD2 activation pathway may act as a negative apoptotic signal in both alpha beta and gamma delta T cells with low (non-major histocompatibility complex restricted) antigenic affinity, so limiting the extension of polyclonal T-cell growth.
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PMID:IL-4 is able to reverse the CD2-mediated negative apoptotic signal to CD4-CD8- alpha beta and/or gamma delta T lymphocytes. 855 74

The structure/function relationship of oligomycin sensitivity-conferring protein (OSCP), subunit 5 of the mitochondrial ATP synthase, from yeast Saccharomyces cerevisiae has been studied by a combination of genetic and biochemical methods. OSCP was studied by deletion mutagenesis of the N- and C-terminal regions by modifying the gene coding for OSCP. Two deletion mutations were made immediately downstream of the leader peptide of OSCP and five were made at the C-terminus. OSCP was functional with deletions of amino acids 3 to 17 (ND15) and of the last 8 amino acids (CD8), while deletion of amino acids 3 to 31 (ND29) and the last 9 amino acids (CD9) inactivated the ATP synthase, as determined by in vivo analysis. The deletion mutants were expressed in Escherichia coli, purified, and studied by in vitro reconstitution studies. Circular dichroism studies suggested that the mutant proteins, with the possible exception of ND29, were folded in a similar fashion as wild-type OSCP. Mutants ND15 and CD8 were able to reconstitute an oligomycin-sensitive ATPase complex, although not as well as wild-type OSCP, while ND29 and CD9 were completely ineffective. Binding studies of ND29 and CD9 indicate that these mutants in OSCP were unable to bind to the membrane portion of the ATP synthase, F0, and these results were supported by competition binding studies. These results support the hypothesis that the N- and C-terminal regions of subunit 5 interact with F0 and suggest that the central region interacts with F1.
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PMID:Structural interactions of the oligomycin sensitivity-conferring protein in the yeast ATP synthase. 899 Feb 62

Murine autoimmune gastritis, induced by neonatal thymectomy, is characterized by a mononuclear infiltrate within the gastric mucosa, loss of parietal and zymogenic cells and circulating autoantibodies to the gastric H/K ATPase. The infiltrate contains both CD4+ and CD8+ T cells. Here we have investigated the roles of CD4+ and CD8+ T cells in the development of gastritis by in vivo treatment with depleting rat anti-CD4 and anti-CD8 monoclonal antibodies. Depletion of CD4+ T cells decreased the incidence of gastric mononuclear infiltrates from 63% (5/8), observed in normal rat immunoglobulin G (IgG)-injected mice, to 8% (1/12) and also abolished the production of antigastric autoantibodies. In contrast, depletion of CD8+ T cells did not reduce the incidence of gastritis. The absence of CD8+ T cells in the infiltrate of the stomach of anti-CD8(+)-treated mice was confirmed by immunocytochemistry. These results argue that neonatal thymectomy-induced autoimmune gastritis is mediated by CD4+ T cells and that CD8+ T cells do not play a significant role in the development of the gastric lesion.
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PMID:CD4+ T cells, but not CD8+ T cells, are required for the development of experimental autoimmune gastritis. 964 Feb 52

Contact tolerance describes an immunological state which is caused by ordinary contact allergens painted in doses too low to sensitize, either once or repeatedly, onto healthy intact skin. The tolerance state accomplished by this means in BALB/c and C57BI/6 mice was found to be mediated by hapten-specific T cells that adoptively transferred tolerance to naive recipients. Furthermore, these cells were shown to be sensitive to cyclophosphamide, to express the Lyt2+ (CD8) phenotype, and to produce, upon restimulation in vitro, predominantly anti-inflammatory cytokines such as IL-4, IL-5 and IL-10. These data indicate that contact tolerance of the low zone type is actively mediated by Th2-like CD8 T cells rather than arising as a consequence of clonal anergy. The induction of contact tolerance appeared to be strictly dose-dependent. As opposed to sensitizing doses of allergen, subsensitizing doses did not involve epidermal Langerhans cells discernibly. This was suggested by their normal ultrastructure, their unaffected adenosine triphosphatase system, the inefficacy of functional blocking and excision experiments. Both radiolabeled and fluorescent contact sensitizers were observed to readily enter the bloodstream, thereby being dispersed throughout the body. Presumably, contact tolerance is induced systemically rather than locally. The presence of hapten-specific tolerance can only be uncovered through a subsequent attempt to sensitize. If the attained sensitization turns out to be significantly lower than that of immunologically naive controls, and if sensitization to chemically unrelated sensitizers is not impaired, hapten-specific tolerance does exist. Thus, contact tolerance is a result obtained from experimental sensitization in animals. Nonetheless, it is assumed to occur also in humans, although it is not demonstrable unless different proofs of existence become available.
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PMID:Contact tolerance. 1072 10

Phosphatidylserine (PS) was exposed at the surface of human umbilical vein endothelial cells (HUVECs) and cultured cell lines by agonists that increase cytosolic Ca(2+), and factors governing the adhesion of T cells to the treated cells were investigated. Thrombin, ionophore A23187 and the Ca(2+)-ATPase inhibitor 2, 5-di-tert-butyl-1,4-benzohydroquinone each induced a PS-dependent adhesion of Jurkat T cells. A23187, which was the most effective agonist in releasing PS-bearing microvesicles, was the least effective in inducing the PS-dependent adhesion of Jurkat cells. Treatment of ECV304 and EA.hy926 cells with EGTA, followed by a return to normal medium, resulted in an influx of Ca(2+) and an increase in adhering Jurkat cells. Oxidised low-density lipoprotein induced a procoagulant response in cultured ECV304 cells and increased the number of adhering Jurkat cells, but adhesion was not inhibited by pretreating ECV304 cells with annexin V. PS was not significantly exposed on untreated Jurkat cells, as determined by flow cytometry with annexin V-FITC. However, after adhesion to thrombin-treated ECV304 cells for 10 min followed by detachment in 1 mM EDTA, there was a marked exposure of PS on the Jurkat cells. Binding of annexin V-FITC to the detached cells was inhibited by pretreating them with unlabelled annexin V. Contact with thrombin-treated ECV304 cells thus induced the exposure of PS on Jurkat cells and, as Jurkat cells were unable to adhere to thrombin-treated ECV304 cells in the presence of EGTA, the adhesion of the two cell types may involve a Ca(2+) bridge between PS on both cell surfaces. The number of T cells from normal, human peripheral blood that adhered to ECV304 cells was not increased by treating the latter with thrombin. However, findings made with several T cell lines were generally, but not completely, consistent with the possibility that adhesion to surface PS on endothelial cells may be a feature of T cells that express both CD4(+) and CD8(+) antigens. Possible implications for PS-dependent adhesion of T cells to endothelial cells in metastasis, and early in atherogenesis, are discussed.
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PMID:Phosphatidylserine-dependent adhesion of T cells to endothelial cells. 1083 84

To isolate the apoptosis-linked genes involved in the cell death of thymocytes induced by glucocorticoids, we developed a functional cloning assay. Murine CD4(+)CD8(+) thymic cell line 2-257-20 cells were transfected with cDNA expression libraries obtained from a dexamethasone-resistant cell line. The transfected cells were selected in the presence of dexamethasone, and the plasmids which episomally expanded were then extracted from the surviving cells. One of the rescued cDNAs was found to be an antisense cDNA fragment identical to the mouse mitochondrial ATPase 6 gene. In the stable transfectants with the ATPase 6 antisense gene, the induction of apoptosis by dexamethasone was significantly delayed. Furthermore, the ATP synthesis in these transfectants was also reduced to some extent. ATPase 6 is a subunit of F(o)F(1) ATPase and our results support that ATP synthesis from the mitochondria is necessary for the induction of apoptosis induced by glucocorticoids.
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PMID:Inhibition of glucocorticoid-induced apoptosis by the expression of antisense gene of mitochondrial ATPase subunit 6(1). 1092 65

Mechanisms leading to breakdown of immunological tolerance and initiation of autoimmunity are poorly understood. Experimental autoimmune gastritis is a paradigm of organ-specific autoimmunity arising from a pathogenic autoimmune response to gastric H/K ATPase. The gastritis is accompanied by autoantibodies to the gastric H/K ATPase. The best characterized model of experimental autoimmune gastritis requires neonatal thymectomy. This procedure disrupts the immune repertoire, limiting its usefulness in understanding how autoimmunity arises in animals with intact immune systems. Here we tested whether local production of GM-CSF, a pro-inflammatory cytokine, is sufficient to break tolerance and initiate autoimmunity. We generated transgenic mice expressing GM-CSF in the stomach. These transgenic mice spontaneously developed gastritis with an incidence of about 80% after six backcrosses to gastritis-susceptible BALBc/CrSlc mice. The gastritis is accompanied by mucosal hypertrophy, enlargement of draining lymph nodes and autoantibodies to gastric H/K ATPase. An infiltrate of dendritic cells and macrophages preceded CD4 T cells into the gastric mucosa. T cells from draining lymph nodes specifically proliferated to the gastric H/K ATPase. CD4 but not CD8 T cells transferred gastritis to nude mouse recipients. CD4(+) CD25(+) T cells from the spleen retained anergic suppressive properties that were reversed by IL-2. We conclude that local expression of GM-CSF is sufficient to break tolerance and initiate autoimmunity mediated by CD4 T cells. This new mouse model should be useful for studies of organ-specific autoimmunity.
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PMID:Local transgenic expression of granulocyte macrophage-colony stimulating factor initiates autoimmunity. 1116 Feb 60


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