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: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that the low number of interleukin-4 receptors (IL-4Rc) on HL-60 leukemia cells render this population susceptible to differentiation by IL-4. As it occurs with normal human monocytes, IL-4 induces the expression of HLA-DR surface antigens on HL-60 cells as well. The second messenger pathway(s) involved after the IL-4 stimulation leading to class II up-regulation has not been fully examined. Here we show that IL-4-induced class II antigen expression on the HL-60 cell line or normal human monocytes is calcium/calmodulin-independent since theophylline (TPH, a calmodulin inhibitor) does not block the IL-4 effect. In addition, the pyruvate kinase C (PKC) pathway does not seem to participate in the process either because in our system activation of PKC by 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) is insufficient by itself to induce HLA-DR. We found, however, that a second messenger pathway can be mediated by a G protein system since IL-4 concomitantly induces class II and p21ras expression which can be successfully blocked by a highly specific anti-p21ras monoclonal antibody. In addition, using another p21ras inducer, the 5-azacytidine C (5-AzaC), we showed that this agent can also induce the expression of p21ras and class II, both of which can be inhibited by the same antibody. Thus, it appears that IL-4 selects the G protein system as a signaling pathway in order to exert its action for the induction of HLA-DR on human normal monocytes or M2 leukemia target cells. Since monocytes and macrophages participate in virtually all immune reactions, the regulation of class II induction is of obvious importance.
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PMID:The p21ras protein as an intermediate signaling molecule in the IL-4-induced HLA-DR expression on normal and leukemic human myeloid cells. 137 87

In vitro the immunosuppressive drug cyclosporin A (CS-A) strongly inhibited histamine release from human basophils (HB) and the rat basophilic leukemia cell line (RBL) 2H3. It also inhibited leukotriene release from HB. In HB the IC50 values for inhibition of histamine release induced by Con A, anti-IgE, calcium ionophore A23187 and antigen (mite) were 0.03, 0.12, 0.36 and 2.0 microM, respectively. In fact, these figures underestimate the potency of CS-A, since studies with 3H-CS-A showed substantial adsorption to plastic experimental wares which was inversely proportional to drug concentration. With anti-IgE and A23187, the drug acted promptly when added at the same time as the inducers but, with antigen, inhibition increased with time of pre-incubation. Washing of HB after pre-incubation with CS-A did not remove the drug effect. Inhibition of histamine release was abolished by Ca2+ excess (5 mM). For TPA-induced release, the drug inhibited the Ca2(+)-dependent but not the Ca2(+)-independent component. In Ca2(+)-free conditions, ionophore A23187, which caused little or no histamine release on its own, was able to synergize with TPA in causing release, apparently by mobilizing intracellular Ca2+. CS-A blocked the synergism but not the original TPA effect. CS-A was compared with the calmodulin inhibitors, W7, TFP and ABCNS; all inhibited histamine release. CS-A also potently inhibited IgE-mediated histamine release from RBL-2H3 cells, without affecting their growth or viability.
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PMID:Anti-allergic properties of cyclosporin A: inhibition of mediator release from human basophils and rat basophilic leukemia cells (RBL-2H3). 169 10

In RBL-2H3 rat basophilic leukemia cells, cholera toxin does not per se stimulate secretion but it enhances secretion stimulated by antigens that crosslink IgE receptors, by the Ca2+ ionophore, ionomycin, and by thapsigargin, a tumor promoter that releases cytoplasmic Ca2+ stores. Calmodulin inhibitors reduce both the basal and cholera toxin-enhanced secretory responses to antigen and Ca2(+)-mobilizing agents. These synergistic effects suggest that the activation of a Gs-like GTP-binding protein, together with a (probably calmodulin-dependent) event activated by an increase in cytoplasmic Ca2+ levels, may jointly provide a sufficient signal for secretion. Antigen-stimulated secretion is inhibited by depleting cells of GTP with mycophenolic acid but is maximal in cells treated with mycophenolic acid plus cholera toxin. The simplest explanation is that cholera toxin selectively reactivates the Gs-coupled pathway leading to secretion in GTP-depleted cells without restoring the activity of a separate GTP-binding protein(s) that constrains antigen-stimulated secretion.
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PMID:Regulation of IgE receptor-mediated secretion from RBL-2H3 mast cells by GTP binding-proteins and calcium. 182 63

Murine leukemia L1210 cells selected for progressive resistance to doxorubicin (DOX) display both the multidrug resistant (MDR) phenotype and reductions in drug induced topoisomerase II-mediated DNA cleavage in nuclear extracts (Ganapathi, R.; Grabowski, D.; Ford, J.; Heiss, C.; Kerrigan, D.; Pommier, Y., Cancer Commun. 1:217-224; 1989). The present study was performed to characterize the results of exposure of the sensitive (S) and progressively DOX-resistant (10-fold, R1, and 40-fold, R2) L1210 cells to the topoisomerase II inhibitor, etoposide, and to investigate the modulating effects of the calmodulin inhibitor, trifluoperazine (TFP). Immunoblotting experiments indicated no apparent decrease in the p170 or p180 isoforms of topoisomerase II in the resistant sublines versus parental sensitive cells. Cross-resistance to etoposide (VP-16) was similar to that of DOX (10- and 40-fold). A non-cytotoxic concentration of 5 microM TFP enhanced cell kill 1.5- fold in the sensitive and 3- to 5-fold in the progressively DOX-resistant cells. Accumulation of VP-16 was 30% to 50% lower in the resistant sublines versus similarly treated sensitive cells, and a marked enhancement of drug uptake in the presence of TFP was observed in the sensitive but not in the resistant cells exposed to equivalent extracellular levels of VP-16. Although equimolar concentrations of VP-16 produced fewer DNA single strand breaks (SSB) and DNA protein crosslinks (DPC) in the resistant versus sensitive cells, similar DNA damage was apparent when S and R1, but not R2, cells were treated at VP-16 concentrations that produced equivalent cell death.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Trifluoperazine modulation of resistance to the topoisomerase II inhibitor etoposide in doxorubicin resistant L1210 murine leukemia cells. 199 27

The ability of a variety of analogues of tamoxifen to inhibit calmodulin dependent cyclic AMP phosphodiesterase has been determined. Effective inhibition requires that the aminoethoxy side chain bears a positive charge at physiological pH and is not too bulky. Amongst 4-substituents, inhibitory potency increases with lipophilicity. The stereochemistry about the olefinic linkage is not important. The most potent agent found (IC50 1.4 microM, compare tamoxifen = 6.75 microM) has a 4-iodine substituent and pyrrolidino in place of dimethylamino. This analogue is also more cytotoxic than tamoxifen against MCF-7 human breast cancer cells as determined in a 24-hr assay, but there was no correlation found between calmodulin inhibition and cytotoxicity against the L1210 murine leukaemia or Walker rat carcinosarcoma cells in culture. The results are consistent with the possibility that calmodulin is important to the functioning of oestrogen receptor mediated growth in MCF-7 cells.
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PMID:Variation of the inhibition of calmodulin dependent cyclic AMP phosphodiesterase amongst analogues of tamoxifen; correlations with cytotoxicity. 216 3

This article reviews the authors' investigation of the enzyme RNase H (EC 3.1.4.34.) in human leukemic cells and presents the accumulated available data, based on which this enzyme is proposed to serve as a new biological parameter in the study of progression of human leukemias. The introduction gives a brief account of the occurrence, characterization and possible biological role of RNase H in cells and in retroviruses. The results reviewed briefly concern: (1) the development of a new convenient, economic and reliable assay for normal and leukemic blood mononuclear cell RNase H, which is capable of resolving subtle activity differences between samples; (2) the differentiation of RNase H levels between normal and leukemic cells; (3) the correlation of RNase H levels from different leukemia types with the severity of the disease; (4) the correlation of RNase H levels in leukemic cells with clonogenic stages in the clonal differentiation pathway; (5) the predictive potential of a RNase H activity-based parameter (phi) in assessing progression in acute myelocytic leukemia and (6) the possibility of differentiation of the RNase H levels between normal and leukemic cells via regulation of the enzyme activity at the level of antagonistic phosphorylations mediated by cAMP and calmodulin.
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PMID:RNase H of human leukemic cells: a new biological parameter in the study of human leukemias (review). 217 71

The stimulation of the rat basophilic leukemia cells (RBL-2H3) mediated either through the IgE receptor or by the Ca2+ ionophore A23187 results in 45Ca2+ influx, phospholipase activation, and histamine release. This study compared in parallel the effects of pharmacological agents on 45Ca2+ influx, phospholipase activation as measured by the release of [14C]-arachidonic acid, and histamine release. Microtubule-depolymerizing agents (demecolcine, colchicine, and vinblastine sulfate) did not affect 45Ca2+ influx, but blocked the IgE- or A23187-mediated [14C]-arachidonic acid and histamine release (e.g., IC50 for vinblastine sulfate = 10 nM). In contrast, a microtubule-stabilizing agent (taxol) blocked the IgE- and A23187-mediated 45Ca2+ influx and [14C]-arachidonic acid and histamine release (IC50 = 20 microM). Microfilament-disrupting agents (cytochalasin B, C, D, and E) enhanced 45Ca2+ influx and [14C]-arachidonic acid and histamine release in the same dose-dependent fashion (e.g., EC50 for cytochalasin B = 0.4 microM). Other pharmacological agents such as a metabolic inhibitor (antimycin A), calmodulin inhibitors (W-7, trifluoperazine, and chlorpromazine), and protease inhibitors (TPCK and TLCK) blocked the IgE- and A23187-mediated 45Ca2+ influx and [14C]-arachidonic acid and histamine release. Therefore, the coupling of Ca2+ influx and the phospholipase activation step requires a functioning microtubule system. Other inhibitors act at sites prior to the Ca2+ influx step in the release process.
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PMID:Pharmacologic modulation of the IgE or Ca2+ ionophore A23187 mediated Ca2+ influx, phospholipase activation, and histamine release in rat basophilic leukemia cells. 241 72

Deuterium oxide (D2O), which is known to stimulate microtubule aggregation, enhanced the IgE-mediated 45Ca2+ influx, (14C)-arachidonic acid and histamine release in rat basophilic leukemia cells (RBL-2H3) in the same dose-dependent manner (up to 90% (v/v]. We compared the interaction between D2O and a variety of groups of pharmacological agents. A microtubule depolymerizing agent, demecolcine, which inhibited the IgE-mediated (14C)-arachidonic acid and histamine release without affecting 45Ca2+ influx, was counteracted by 45% D2O. Taxol, a microtubule stabilizing agent, which had an inhibitory effect on the above three steps, was also reversed by 45% D2O. These results would support the previous data on the interaction between D2O and microtubules and would further suggest that the status of microtubule aggregation may be related to the secretory process. Calmodulin inhibitors (W-7, trifluoperazine) blocked the IgE-mediated 45Ca2+ influx, (14C)-arachidonic acid and histamine release in the same dose-dependent manner, but were counteracted by 45% D2O. In contrast, the effects of proteinase inhibitors (TPCK, TLCK), an adenylate cyclase inhibitor (ddAdo), a phosphodiesterase inhibitor (aminophylline), a phospholipid methylation inhibitor (DZA + Hcy) and microfilament blockers (cytochalasin B and D) were not counteracted by 45% D2O. These results would suggest that D2O may be associated with calmodulin directly or indirectly possibly through some relationship between calmodulin and microtubules.
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PMID:Effect of deuterium oxide (D2O) on the IgE-mediated Ca2+ influx, arachidonic acid and histamine release in rat basophilic leukemia cells. 247 27

Both S-100 antigen and calmodulin were shown in normal lymphocytes with S-100 being decreased in lymphocytic leukemia cells. Although small amounts of S-100 antigen and calmodulin were shown in acute myeloblastic leukemia cells, they could not be detected in normal granulocytes. In lymphoblastic leukemia, S-100 antigen levels in T-cell leukemia cells were higher than in B-cell leukemia cells, while calmodulin was decreased in chronic leukemia cells. In mitogen-stimulated lymphocytes, the levels of S-100 antigen were decreased, while those of calmodulin were either increased or unchanged. Calcium-dependent cyclic nucleotide phosphodiesterase was highest in acute lymphoblastic leukemia. These data suggest, therefore, that calcium ions may play a role in the proliferation, differentiation or leukemic change in lymphocytes and, hence, that measurement of calcium binding proteins may be useful in the investigation of leukemia cells or lymphocytes.
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PMID:S-100 antigen and calmodulin in human leukemic cells. 253 71

Previous studies demonstrated that activation of T lymphocytes by phorbol ester or mitogenic lectin leads to phosphorylation of Ser 126 of the CD3 antigen gamma chain, whereas treatment with ionomycin results in phosphorylation of both Ser 123 and 126 [Davies, A. A. et al. (1987) J. Biol. Chem. 262, 10918-10921]. In the present study, the dephosphorylation of Ser 123 and Ser 126 of the gamma chain was investigated. Phorbol-ester-induced phosphorylation of the gamma-chain Ser 126 in vivo was reversed following removal of phorbol ester. Dephosphorylation of both Ser 123 and 126 was also observed in vitro using the microsome fraction of T lymphocytes. In order to identify the phosphatases acting at these two sites, the immunoprecipitated gamma chain was used as substrate either following treatment with protein kinase C in vitro, in which case phosphorylation occurs mainly at Ser 123, or following in vivo phosphorylation of Ser 126. Purified oligomeric forms of the polycation-stimulated phosphatases were more effective in dephosphorylating both phosphorylated forms of the gamma chain compared with equivalent amounts of ATP,Mg2+-dependent phosphatases or calcineurin. By using phosphopeptide analogues of the CD3 gamma chain containing Ser 123 or Ser 126 as substrates (A3 and A6), it was shown that polycation-stimulated phosphatases selectively dephosphorylated Ser 123 compared to Ser 126. In order to determine which phosphatases dephosphorylate the gamma chain in microsomes, A3 and A6 were used as substrates for characterising phosphatases in microsomes from human T leukaemia Jurkat 6 cells. Three phosphopeptide phosphatases (250-400 kDa) co-eluted through five purification steps with three forms of polycation-stimulated phosphorylase phosphatase. The partially purified A3/A6 phosphopeptide phosphatases were insensitive to Ca2+, calmodulin and inhibitor-1, and dephosphorylated A3 preferentially compared with A6. A latent form of microsomal ATP,Mg2+-dependent phosphorylase phosphatase was stimulated 10-fold by trypsinisation, but did not dephosphorylate phosphopeptides A3 and A6. The results show that high-Mr forms of polycation-stimulated phosphatases are the only enzymes in human T leukaemia cell microsomes which dephosphorylate gamma chain phosphopeptides. The data point to an important role for polycation-stimulated phosphatases in regulating the phosphorylation state, and so function(s), of the CD3 antigen.
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PMID:Dephosphorylation of the human T lymphocyte CD3 antigen. 254 Sep 70


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