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 examined the effect of the two protein tyrosine kinase inhibitors, alpha-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamide (ST638) and herbimycin A, on the activation processes of rat basophilic leukemia (RBL-2H3) cells by cross-linking of IgE receptors. RBL-2H3 cells sensitized with DNP-specific monoclonal IgE antibody were stimulated with multivalent antigen (DNP conjugate of bovine serum albumin). Analysis of phosphotyrosine-containing proteins in their lysates by SDS-PAGE and immunoblotting revealed that these two inhibitors efficiently inhibited the tyrosine phosphorylation of several proteins (32, 42, 56, 66, 72, 92, 150 kDa) including phospholipase C-gamma 1. The inhibitors also caused parallel inhibitions of the histamine release, the formation of inositol 1,4,5-trisphosphate, and the increase in cytosolic calcium ion concentration at the late sustained phase. A digital imaging fluorescence microscopic analysis of antigen-dependent calcium signals in individual cells showed that these two tyrosine kinase inhibitors inhibited the calcium influx from the external medium more powerfully than the mobilization of calcium ion from internal stores. In contrast, the inhibitors did not affect the increase in the cytosolic calcium ion concentration or the histamine release induced by the calcium ionophore A23187. Taken together, our results suggest that tyrosine phosphorylation following antigen stimulation regulates phosphatidylinositol hydrolysis and the influx of extracellular calcium.
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PMID:Effects of herbimycin A and ST638 on Fc epsilon receptor-mediated histamine release and Ca2+ signals in rat basophilic leukemia (RBL-2H3) cells. 751 May 21

Rat basophilic leukemia cells (RBL-2H3) undergo morphological and cytoskeletal changes during antigen (DNP-BSA) or calcium ionophore-induced secretion of allergic mediators from intact or permeabilized cells. We describe the novel finding that the phosphatase-resistant ATP analogue, ATP gamma S, mimics antigen-induced serotonin secretion and cytoskeletal rearrangements in permeabilized cells. Confocal microscopy of unstimulated cells shows that myosin and F-actin are concentrated at the plasma membrane. Upon addition of ATP gamma S, F-actin becomes rearranged into membrane ruffles and also associates with myosin in a cytoplasmic meshwork, concentrated perinuclearly. F-actin and myosin ultimately become colocalized into parallel microfilament bundles located on the basolateral membrane. During this period the cell height decreases whilst the cell area increases more than twofold. Gel electrophoresis shows that the cytoskeletal proportion of actin remains unchanged, indicating that the rearrangements occur within the total F-actin pool. The distribution of microtubules and intermediate filaments is unchanged in the presence of ATP gamma S. These results suggest that overcoming a phosphatase may be sufficient to induce secretion in RBL-2H3 cells, and that this secretion may be regulated by F-actin and myosin rearrangements.
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PMID:ATP gamma S induces actin and myosin rearrangement during histamine secretion in a rat basophilic leukemia cell line (RBL-2H3). 752 81

We have used two bivalent ligands that bind IgE to study the relationship between the aggregation of receptors with high affinity for IgE (Fc epsilon RI) and the responses (receptor immobilization, Ca2+ influx, and degranulation) of rat basophilic leukemia (RBL-2H3) cells. One of these is a symmetric bivalent ligand, N,N'-bis[[epsilon-[(2,4-dinitrophenyl)amino]caproyl]-L-tyrosyl]-L- cystine ((DCT)2-cys), which binds specifically to the combining sites of a mAb anti-DNP IgE and efficiently cross-links cell surface IgE, but does not trigger significant degranulation or increases in intracellular Ca2+. Several lines of evidence, including lateral mobility measurements, indicate that this ligand preferentially forms stable cyclic complexes containing two (DCT)2-cys and two IgE. The second ligand is a mAb anti-IgE, B1E3, which causes lateral mobility changes consistent with dimerized IgE-Fc epsilon RI and also does not trigger increases in intracellular Ca2+ or degranulation. The two ligands together trigger robust responses. In the presence of B1E3, (DCT)2-cys causes immobilization of IgE-Fc epsilon RI in a broad concentration range; in a more narrow concentration range, it is a potent stimulant of changes in both degranulation and Ca2+. We have compared the dose-response curves for cellular activation to simulated IgE aggregation curves, i.e., curves that predict the equilibrium IgE aggregate size distribution as a function of the (DCT)2-cys concentration. Our results indicate that maximal cellular activation occurs at a much higher (DCT)2-cys concentration than maximal IgE aggregation. When IgE aggregation is maximal, almost all aggregated IgE is in cyclic dimers. Thus, cyclic dimers appear to be functionally ineffective, even after they have been cross-linked by B1E3. Aggregated IgE-Fc epsilon RI that is effective in stimulating a cellular response may have particular structural or dynamic properties that allow critical interactions for initiating the signaling cascade.
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PMID:Simultaneous cross-linking by two nontriggering bivalent ligands causes synergistic signaling of IgE Fc epsilon RI complexes. 756 Oct 59

Rat basophil leukemia (RBL) cells were sensitised with varying proportions of monoclonal IgE anti-ovalbumin (OVA) and anti-DNP antibodies, and serotonin release was measured after challenge with aggregated OVA or dinitrophenylated human serum albumin (DNP-HSA). Highly aggregated OVA was shown to provoke the degranulation of RBL cells that had been sensitised with an IgE preparation containing 2% IgE anti-OVA antibodies. Highly substituted DNP32-HSA induced degranulation of RBL cells sensitised with just 0.5% antigen-specific IgE. When cells were sensitised with high percentages of specific IgE, maximum degranulation was seen at concentrations of 2 micrograms/ml (aggregated OVA) and 50 ng/ml (DNP-HSA), while moderate degranulation was still seen at antigen concentrations as low as 50 and 2 ng/ml, respectively. Low-molecular weight aggregates of OVA and low-valency DNP4-HSA only stimulated degranulation when high percentages of RBL Fc epsilon receptor were occupied by antigen-specific IgE. The sensitising abilities of two anti-DNP monoclonal antibodies of differing affinities were compared. When challenged with low-valency antigen, only cells sensitised with the higher-affinity monoclonal antibody exhibited moderate levels of degranulation. Degranulation required exposure to high antigen challenge doses (5 micrograms/ml). Cells sensitised with either monoclonal antibody responded strongly when challenged with a wide range of concentrations (1-250 ng/ml) of high-valency DNP32-HSA, although greater sensitivity was always seen with the higher-affinity antibody. These results suggest that antigen valency is a critical parameter for mast cell function, and that low-affinity antibody may be capable of sensitising mast cells to high-valency antigen.
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PMID:Antigen valency as a determinant of the responsiveness of IgE-sensitised rat basophil leukemia cells. 762 Mar 69

Adhesion molecules of the integrin family are implicated not only in leukocyte migration but also in leukocyte activation. Here we characterize the expression and function of fibronectin receptor integrins on rat mast cells. A rat basophilic leukemia cell line (RBL-2H3) and phorbol ester-stimulated rat peritoneal mast cells adhered to fibronectin (FN), vitronectin and fibrinogen. These mast cells expressed fibronectin receptor integrins, including very late antigen (VLA)-4, VLA-5 and vitronectin receptor (VNR), as estimated by immunofluorescent staining and inhibition of FN adherence by newly established mAbs reactive with the rat alpha 4 (MR alpha 4-1), alpha 5 (HM alpha 5-1) or beta 3 (HM beta 3-1) chains of the integrin molecules. The beta-hexosaminidase release, a marker for mast cell degranulation, triggered by high affinity IgE receptor (Fc epsilon RI)-mediated stimulation, was enhanced by adhesion of RBL-2H3 cells to either immobilized FN, MR alpha 4-1, HM alpha 5-1 or HM beta 3-1. This FN enhancement of beta-hexosaminidase release was inhibited by soluble MR alpha 4-1, HM alpha 5-1 and HM beta 3-1 as well as by GRGDSP and DELPQLVTLPHPNHLGPEILDVPST peptides which abrogate VLA-5/VNR and VLA-4 binding to FN respectively. In vivo, passive cutaneous anaphylaxis induced by IgE anti-DNP and DNP-BSA was inhibited by concurrent s.c. injection of MR alpha 4-1, HM alpha 5-1 and HM beta 3-1. These results demonstrate that FN receptor integrins expressed on rat mast cells play an important role in regulating mast cell activation both in vitro and in vivo.
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PMID:Expression and function of fibronectin binding integrins on rat mast cells. 773 20

Cross-linking of the immunoglobulin E receptor on rat basophilic leukemia (RBL)1 cells by multivalent antigen activates phosphatidylinositol (PI) kinase and phosphatidylinositol 4-phosphate (PIP) kinase leading to the increased production of PIP and phosphatidylinositol 4,5-bisphosphate (PIP2). Activators of protein kinase C (PKC), such as phorbol myristate acetate (PMA) and the synthetic diacylglycerol, 1,2-dioctanoyl-sn-glycerol (diC8), were found to have the same effect even though PMA and diC8 do not cause the activation of phospholipase C. Although the kinetics are different depending on the stimulant, activation of PKC using multivalent antigen, PMA or diC8 also causes the polymerization of actin and an increase in the F-actin content of the cells. In all cases, a good correlation was observed between F-actin levels, activation of PI and PIP kinases, and the increased production of PIP and PIP2. However, in the case of antigen, there is no correlation between actin polymerization and the total amount of PIP and PIP2. Staurosporine, an inhibitor of protein kinases, blocks the F-actin response and the increased synthesis of PIP and PIP2 with similar dose dependencies. Furthermore, depletion of PKC activity through long-term exposure to PMA, inhibited both the F-actin response and the increased synthesis of PIP and PIP2 induced by either DNP-BSA or diC8. These results suggest that activation of PKC precedes the activation of PI and PIP kinases and that under certain circumstances activation of the kinases and the increased synthesis of PIP and PIP2 may be involved in the polymerization of actin in RBL cells, possibly through the interaction of the polyphosphoinositides with actin-binding proteins such as gelsolin and profilin.
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PMID:Activation of protein kinase C in rat basophilic leukemia cells stimulates increased production of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate: correlation with actin polymerization. 774 99

Crosslinking of the IgE receptor on rat basophilic leukemia (RBL) cells using the multivalent antigen DNP-BSA leads to a rapid and sustained increase in the filamentous actin content of the cells. Stimulation of RBL cells through the adenosine receptor also induces a very rapid polymerization of actin, which peaks in 45-60 s and is equivalent in magnitude to the F-actin response elicited through stimulation of the IgE receptor. However, in contrast to the IgE mediated response, which remains elevated for over 30 min, the F-actin increase induced by the adenosine analogue 5'-(N-ethylcarboxamido)-adenosine (NECA) is relatively transient and returns to baseline values within 5-10 min. While previous work has shown that the polymerization of actin in RBL cells stimulated through the IgE receptor is mediated by protein kinase C (PKC), protein kinase inhibitors have no effect on the F-actin response activated through the adenosine receptor. In contrast, pretreatment of the cells with pertussis toxin completely inhibits the F-actin response to NECA but has relatively little effect on the response induced through the IgE receptor. Stimulation of RBL cells through either receptor causes increased production of phosphatidylinositol mono-phosphate (PIP) and phosphatidylinositol bis-phosphate (PIP2), which correlates with the F-actin response. Production of PIP and PIP2 may be important downstream signals since these polyphosphoinositides are able to regulate the interaction of gelsolin and profilin with actin. Thus the polymerization of actin can be triggered through either the adenosine receptor or the IgE receptor, but different upstream signaling pathways are being used. The IgE mediated response requires the activation of PKC while stimulation through the adenosine receptor is PKC independent but involves a G protein.
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PMID:Polymerization of actin in RBL-2H3 cells can be triggered through either the IgE receptor or the adenosine receptor but different signaling pathways are used. 804 23

Transmembrane signaling initiated by the receptor with high affinity for Fc stem of IgE(Fc epsilon RI) requires the diffusion-dependent cross-linkage and persistent aggregation of the Fc epsilon RI. Disruption or prevention of receptor cross-links at any time during the secretory response quickly terminates secretion. We found that in the rat basophilic leukemia mast cell line, addition of wheat germ agglutinin, a lectin that binds to the Fc epsilon RI alpha subunit, caused a precipitous decline in the lateral diffusional and electrokinetic mobilities of the Fc epsilon RI. Both the unoccupied Fc epsilon RI and IgE-Fc epsilon RI complexes became immobilized, as determined from in situ electromigration and postelectric field relaxation. Immobilization of the Fc epsilon RI by wheat germ agglutinin was accompanied by a ligand-reversible association of 125I-IgE-Fc epsilon RI complexes with the Triton X-100-insoluble cytoskeletal fraction. Wheat germ agglutinin rapidly inhibited Fc epsilon RI-mediated signal transduction and secretion, whether cross-linkage was initiated by multivalent antigen, covalent IgE oligomers, anti-IgE, or anti-Fc epsilon RI antibody. Inhibition of signaling and secretion occurred on simultaneous addition of wheat germ agglutinin and antigen, and also when wheat germ agglutinin was added at increasing times after induction of Fc epsilon RI cross-linkage. Wheat germ agglutinin neither reduced the affinity of anti-DNP IgE for haptenic DNP-lysine nor reversed the binding of IgE to the Fc epsilon RI. Although wheat germ agglutinin caused internalization of the Fc epsilon RI, the onset of inhibition preceded and its extent exceeded that of internalization. Wheat germ agglutinin did not interfere with the secretory apparatus, as indicated by its lack of inhibition of secretion elicited by calcium ionophores. These findings suggest that inhibition of signal transduction is secondary to an initial event linked to immobilization of the Fc epsilon RI. Implications of these results are discussed with respect to the dynamics of Fc epsilon RI aggregation on rat basophilic leukemia cells.
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PMID:Immobilization of Fc epsilon receptors by wheat germ agglutinin. Receptor dynamics in IgE-mediated signal transduction. 839 54

A modified in vitro method to measure murine ovalbumin-specific IgE antibody as an alternative to the in vivo rat passive cutaneous anaphylaxis assay is presented in this report. This assay uses rat basophil leukemia (RBL) 2H3 cells that have been loaded with [3H]serotonin. Exposure of RBL-2H3 cells to mouse antisera and subsequent antigen challenge results in the release of [3H]serotonin. Using a monoclonal mouse anti-DNP IgE antibody and DNP-human serum albumin as the antigen, various steps of this assay were optimized to decrease the amount of time and reagents needed for the assay. The percent [3H]serotonin released was used to calculate antibody titer of sera from ovalbumin-immunized mice. Mouse anti-ovalbumin IgE titers determined by the RBL release method and passive cutaneous anaphylaxis assay were found to correlate very well over a wide range of antibody titers (correlation coefficient, r2 = 0.94).
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PMID:Measurement of murine ovalbumin-specific IgE by a rat basophil leukemia cell serotonin release assay. Comparison to the rat passive cutaneous anaphylaxis assay. 850 56

The carcinogenicities of 1-nitropyrene (1-NP), 4-nitropyrene (4-NP), 1,3-dinitropyrene (1,3-DNP), 1,6-dinitropyrene (1,6-DNP), 1,8-dinitropyrene (1,8-DNP), 3-hydroxy-1-nitropyrene (3-OH-1-NP) and a mixture of 6- and 8-hydroxy-1-nitropyrene (6/8-OH-1-NP) were investigated in newborn female rats. Newborn female CD rats were treated s.c. eight times at weekly intervals with a total dose of 6.3 mumol 1-NP,1,3-DNP,1,6-DNP or 1,8-DNP; control animals received only dimethylsulfoxide (DMSO). The experiment was terminated at 67 weeks. With the exception of 1,6-DNP- and 1,8-DNP-treated animals, which had average survival periods of 149 and 164 days respectively, the animals administered the other compounds did not show decreased survival. Malignant fibrous histiocytomas were observed in 12%, 100% and 100% of the rats treated with 1,3-, 1,6- and 1,8-DNP respectively. Leukemia was found in 20% and 22% of the animals treated with 1,6- and 1,8-DNP respectively. No control rats developed these tumors. Additionally, mammary tumors were induced in rats treated with 1-NP. Newborn female CD rats were similarly treated with 1-NP, 4-NP, 3-OH-1-NP, 6/8-OH-1-NP or DMSO and newborn female F344 rats were treated with 1-NP or DMSO. The experiment was terminated at 86 weeks, 1-NP and 4-NP produced mammary adenocarcinoma in CD rats. Although 1-NP did not produce mammary adenocarcinoma in F344 rats, it induced leukemia. 4-NP also induced malignant fibrous histiocytomas in CD rats. This study demonstrates that 4-NP is more carcinogenic than 1-NP and that CD rats are more susceptible than F344 rats to mammary carcinogenesis by 1-NP. Additionally, 1,6- and 1,8-DNP are more potent than 1-NP in inducing malignant fibrous histiocytomas and leukemia.
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PMID:Carcinogenicity of nitropyrenes in the newborn female rat. 860 80


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