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)

In RBL-2H3 rat basophilic leukemia cells, Ag that crosslink IgE-receptor complexes stimulate the turnover of inositol phospholipids, the mobilization of Ca2+ from intra- and extracellular sources, the release of serotonin and other substances from granules and the transformation of the cell surface from a microvillous to a lamellar architecture. This study explores the role of GTP-binding proteins (G proteins) in the control of these biochemical and functional responses. We report that incubating RBL-2H3 cells for 4 h with 10 microM mycophenolic acid (MPA), an inhibitor of de novo GTP synthesis, reduces GTP levels by over 60% and causes an average reduction of 50% in Ag-stimulated serotonin release. This inhibition of secretion is associated with a 50% decrease in the rate of 45Ca2+ influx in MPA-treated cells. In contrast, Ag-stimulated inositol trisphosphate production is only slightly reduced, indicating that the phosphatidylinositol-specific phospholipase C can be activated by Ag in GTP-depleted cells. The membrane responses to IgE receptor cross-linking are unaffected by incubating cells with MPA. Exogenous guanine or guanosine protects the GTP pools in MPA-treated cells and permits normal ion transport and secretory responses to Ag; adenine does not. These results implicate a guanine nucleotide-binding protein in the control of IgE receptor-dependent signal transduction in RBL-2H3 cells. This protein may particularly control the Ca2+ influx pathway that is essential for secretion.
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PMID:Depletion of guanine nucleotides with mycophenolic acid suppresses IgE receptor-mediated degranulation in rat basophilic leukemia cells. 252 48

The two major forms of the c-abl gene differ from their activated counterpart, the v-abl oncogene of the Abelson murine leukemia virus by the replacement of their N-terminal sequences with viral gag sequences. Overexpression of p150c-abl type IV in a retroviral vector similar to Abelson virus does not transform NIH 3T3 fibroblasts, even though it is expressed and myristoylated at levels comparable to pp160v-abl. Members of a nested set of deletion mutations of the N-terminus of c-abl type IV in this expression system will activate abl to transform murine fibroblasts. The smallest of these deletions, delta XB, efficiently transforms lymphoid cells in vitro and causes leukemia in vivo demonstrating that gag sequences are not necessary for abl-induced leukemogenesis. The delta XB mutation defines an N-terminal regulatory domain, which shares a surprising homology with chicken oncogene v-crk and phospholipase C-II. Although overexpression of the myristoylated form of c-abl does not transform cells, it nonetheless has a profound effect on cell growth.
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PMID:N-terminal mutations activate the leukemogenic potential of the myristoylated form of c-abl. 254 16

The synthetic nucleoside tiazofurin(2-beta-ribofuranosylthiazole-4-carboxyamide) and its selenium analog selenazofurin inhibited the growth of L1210 leukemia cell culture in a dose dependent manner with IC50 value of 2.0 and 0.2 Um respectively. The GTP/ATP ratio was diminished 4-6 fold as measured by HPLC, while IMP/ATP increased 6-8 fold. The decreased guanylate pools may explain the 30% reduction in cyclic GMP levels and GTPase activity measured after the treatment with the nucleosides. Inhibition of phospholipase C activity is suggested since diacylglycerol content, protein kinase C activity and phorbol ester binding of the membrane fraction were also reduced 20-40%. These results reveal a novel aspect in the action of these compounds which may play a role in their therapeutic action and selectivity.
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PMID:Tiazofurin and selenazofurin induce depression of cGMP and phosphatidylinositol pathway in L1210 leukemia cells. 255 3

Neomycin, an inositol-phospholipid-binding aminoglycoside antibiotic, is known to interfere with signal transduction mechanisms involving phospholipase C as effector enzyme. In this study, we report that neomycin can also markedly influence agonist binding of G-protein-coupled receptors. In membranes of differentiated human leukemia cells (HL 60 cells), neomycin (0.1-10 mM) was found to induce high-affinity binding of the chemotactic tripeptide, N-formyl-methionylleucylphenylalanine (fMet-Leu-Phe), to its receptor sites in a manner similar to magnesium. Gentamycin and streptomycin, two other aminoglycoside antibiotics, were as potent and as effective as neomycin or magnesium in inducing high-affinity agonist receptor binding. Pretreatment of the cells with pertussis toxin reduced the effects of magnesium and neomycin on agonist receptor binding likewise. In contrast, magnesium but not neomycin largely enhanced the potency of guanine nucleotides, particularly of GTP and its analog, guanosine-5'-O-(3-thiotriphosphate), to reduce fMet-Leu-Phe receptor binding, while maximal inhibition of agonist receptor binding by guanine nucleotides was identical with magnesium and neomycin. Furthermore, neomycin could not replace magnesium in providing stimulation of HL 60 membrane high-affinity GTPase by fMet-Leu-Phe. In close agreement to these findings on the pertussis-toxin-sensitive Gi-protein-coupled formyl peptide receptors, neomycin in a manner similar to magnesium induced high-affinity agonist binding of Gs-protein-coupled beta-adrenoceptors. Similar to formyl peptide receptor binding, high-affinity binding of isoproterenol to beta-adrenoceptors in guinea pig lung membranes induced by magnesium and neomycin was inhibited by the GTP analog, guanosine-5'-O-(3-thiotriphosphate), to a similar maximal extent but with an about 100-fold higher potency in the presence of magnesium than in the presence of neomycin. The data presented thus indicate that neomycin and other aminoglycoside antibiotics can mimic the action of magnesium (or other divalent cations) in inducing high-affinity agonist binding of Gi- and Gs-protein-coupled receptors, but not in inducing subsequent G-protein activation by guanosine triphosphates. The data, furthermore, suggest that neomycin by this selective action will be a powerful tool to dissect the multiple sites of magnesium's action in the agonist receptor-G-protein interaction.
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PMID:Neomycin induces high-affinity agonist binding of G-protein-coupled receptors. 255 74

We have recently shown that activation of protein kinase C by tumour promoting phorbolesters, such as 4 beta-phorbol-12,13-dibutyrate, stimulates adenosine-induced accumulation of cAMP in Jurkat cells, a human T-leukaemia line. Activating the CD3 complex associated with the T-cell receptor by means of the monoclonal antibody OKT3 caused a concentration-dependent accumulation of inositol phosphates and an increase in the phosphorylation of an endogenous protein kinase C substrate. OKT3 also mimicked the previously reported effects of protein kinase C since it potentiated the cAMP stimulation by either an adenosine analogue, NECA, or cholera toxin. Thus, our results indicate that stimulation of a receptor activating phospholipase C and protein kinase C can secondarily enhance the action of agonists that act on adenylate cyclase-coupled receptors.
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PMID:Activation of protein kinase C via the T-cell receptor complex potentiates cyclic AMP responses in T-cells. 256 6

T cell activation via the CD2 molecule involves phospholipase C and phosphoinositide hydrolysis. Here we demonstrate that the triggering of subclones of the human T leukemia Jurkat cell line by anti-CD2 as well as anti-CD3 monoclonal antibodies is able to induce activation (i.e. translocation from cytosol to cell membrane) of protein kinase C (PKC), which is dependent on the formation of 1,2-diacylglycerol from inositol 4-5-bisphosphate. The kinetics of PKC translocation parallels the rise in intracellular calcium following both CD2 and CD3 stimulations. These results further demonstrate that CD2 and CD3 activation pathways use similar signal transduction mechanisms.
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PMID:T cell activation via the CD2 molecule is associated with protein kinase C translocation from the cytosol to the plasma membrane. 256 74

Antigen-mediated exocytosis in intact rat basophilic leukemia (RBL-2H3) cells is associated with substantial hydrolysis of membrane inositol phospholipids and an elevation in concentration of cytosol Ca2+ ([ Ca2+i]). Paradoxically, these two responses are largely dependent on external Ca2+. We report here that cells labeled with myo-[3H]inositol and permeabilized with streptolysin O do release [3H]inositol 1,4,5-trisphosphate upon stimulation with antigen or guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) at low (less than 100 nM) concentrations of free Ca2+. The response, however, is amplified by increasing free Ca2+ to 1 microM. The subsequent conversion of the trisphosphate to inositol 1,3,4,5-tetrakisphosphate is enhanced also by the increase in free Ca2+. Although [3H]inositol 1,4,5-trisphosphate accumulates in greater amounts than is the case in intact cells, [3H]inositol 1,4-bisphosphate is still the major product in permeabilized cells even when the further metabolism of [3H]inositol 1,4,5-trisphosphate is suppressed (by 77%) by the addition of excess (1000 microM) unlabeled inositol 1,4,5-trisphosphate and the phosphatase inhibitor 2,3-bisphosphoglycerate. It would appear that either the activity of the membrane 5-phosphomonoesterase allows virtually instantaneous dephosphorylation of the inositol 1,4,5-trisphosphate under all conditions tested or both phosphatidylinositol 4-monophosphate and the 4,5-bisphosphate are substrates for the activated phospholipase C. The latter alternative is supported by the finding that permeabilized cells, which respond much more vigorously to high (supraoptimal) concentrations of antigen than do intact RBL-2H3 cells, produce substantial amounts of [3H]inositol 1,4-bisphosphate before any detectable increase in levels of [3H]inositol 1,4,5-trisphosphate.
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PMID:Receptor-mediated release of inositol 1,4,5-trisphosphate and inositol 1,4-bisphosphate in rat basophilic leukemia RBL-2H3 cells permeabilized with streptolysin O. 264 90

Two peaks of phosphoinositide-specific phospholipase C (PI-PLC) activity were resolved when guinea pig uterus cytosolic proteins were chromatographed on a DEAE-Sepharose column. The first peak of enzyme activity eluting from the DEAE-Sepharose column (PI-PLC I) was further purified to homogeneity, whereas the second peak of enzyme activity was enriched 300-fold. PI-PLC I migrated as a 62-kDa protein on sodium dodecyl sulfate-polyacrylamide gels. Antibodies prepared against PI-PLC I failed to react with PI-PLC II. PI-PLC I hydrolyzed all three phosphoinositides, exhibiting a greater Vmax for phosphatidylinositol 4,5-bisphosphate greater than phosphatidylinositol 4-phosphate greater than phosphatidylinositol. Hydrolysis of phosphatidylinositol was calcium-dependent, whereas significant hydrolysis of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate occurred in the presence of 2.5 mM EGTA. At physiological concentrations of calcium, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate were the preferred substrates. Antibodies specific for PI-PLC I reacted with a 62-kDa protein in both the cytosol and membrane fractions from guinea pig uterus. Quantitation of the immunoblots revealed that 25% of the 62-kDa protein was membrane-associated, whereas only 5% of the total enzyme activity was membrane-associated. Approximately 20% of the membrane-bound phospholipase C activity and immunoreactive material were loosely bound, whereas the remainder required detergent extraction for complete solubilization. The 62-kDa protein associated with the membrane fractions did not bind lectin affinity columns, suggesting that it was not glycosylated. PI-PLC I was identified as a phosphoprotein in [32P]orthophosphate-labeled rat basophilic leukemia (RBL-1) cells by two-dimensional gel electrophoresis followed by immunoblotting. In untreated cells, 32P-labeled PI-PLC I was found in the cytosolic fraction. Treatment of RBL-1 cells with those phorbol esters which are known to activate the Ca2+/phospholipid-dependent enzyme protein kinase C, resulted in a time-dependent increase in the phosphorylation of both membrane-bound and cytosolic PI-PLC I. Thus, in RBL-1 cells, protein kinase C may play an important role in the regulation of phospholipase C through protein phosphorylation.
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PMID:Purification and characterization of a phosphoinositide-specific phospholipase C from guinea pig uterus. Phosphorylation by protein kinase C in vivo. 282 Sep 80

The interaction of feline leukaemia viruses (FeLV) with erythrocytes was investigated. Haemadsorption (HAd) was observed on the surface of feline embryonic fibroblast cells infected with FeLV. HAd was detected in various degrees when cat, hamster or horse erythrocytes were incubated with cells infected with viruses of subgroup C (FeLV-C) and on cells infected with some FeLV subgroup A viruses (FeLV-A), but not on cells infected with FeLV subgroup B viruses (FeLV-B). HAd of sheep erythrocytes was detected on cells infected with some FeLV-C viruses. The HAd of hamster erythrocytes on cells infected with FeLV-C/Sarma virus was inhibited by antisera against gp70 or p15(E) but not by sera to the other FeLV structural polypeptides. HAd inhibition was also exhibited by cat sera which had FeLV-neutralizing activity but not by sera of specific pathogen-free cats. Haemagglutination by FeLV-C viruses was demonstrated after the virus was treated with neuraminidase and phospholipase C, or Tween-80 and ether. Contrary to expectations from the pattern observed by HAd, all FeLV-A viruses had similar haemagglutinin (HA) activity to FeLV-C viruses. FeLV-B viruses did not possess an HA.
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PMID:Haemadsorption and haemagglutination by feline leukaemia viruses. 298 74

Addition of phytohaemagglutinin (PHA) to the [32P]Pi-prelabelled JURKAT cells, a human T-cell leukaemia line, resulted in a decrease of [32P]phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] to about 35% of the control value. The decrease was almost complete within 30s after the PHA addition. This decrease was followed by an increase in the 32P-labelling of phosphatidic acid (maximally 2.8-fold at 2 min). The stimulation of myo-[2-3H]inositol-prelabelled JURKAT cells by PHA induced an accumulation of [2-3H]inositol trisphosphate in the presence of 5 mM-LiCl. The result indicates hydrolysis of PtdIns (4,5)P2 by a phospholipase C. The PHA stimulation of JURKAT cells induced about 6-fold increase in the cytosolic free Ca2+ concentration, [Ca2+]i, which was reported by Quin-2, a fluorescent Ca2+ indicator. Studies with partially Ca2+-depleted JURKAT cells, with the Ca2+ ionophore A23187, and with 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate indicate that the breakdown of PtdIns(4,5)P2 is not mediated through changes of [Ca2+]i. These results therefore indicate that the PHA-induced breakdown of PtdIns(4,5)P2 in JURKAT cells is not dependent on the Ca2+ mobilization.
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PMID:Breakdown of phosphatidylinositol 4,5-bisphosphate in a T-cell leukaemia line stimulated by phytohaemagglutinin is not dependent on Ca2+ mobilization. 298 10


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