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)

Rat basophilic leukaemia cells (RBL-2H3) were transfected with either the wild type human C5a receptor or a truncated form lacking the last 23 C-terminal residues. Transfected cells bound human C5a specifically, with affinities in the range 3-20nM, and 12-166,000 receptors per cell, similar values to those obtained on human neutrophils and monocytic cells. The stimulation of secretion by human C5a was completely inhibited by pertussis toxin and partially sensitive to cholera toxin, indicating that both wild-type and mutated receptors are coupled to G proteins. Cells transfected with the mutated receptor were equally sensitive to hC5a, suggesting that this portion of the C terminus is not an absolute requirement for signal transduction.
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PMID:C5a stimulus-secretion coupling in rat basophilic leukaemia (RBL-2H3) cells transfected with the human C5a receptor is mediated by pertussis and cholera toxin-sensitive G proteins. 801 77

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

We have shown that pertussis toxin (PTx) modulates the effect of tumor necrosis factor-alpha (TNF-alpha) in inducing monocytic differentiation of WEHI-3B (JCS) myeloid leukemic cells in vitro. PTx (0.1-2 ng/ml) alone was not cytotoxic and did not induce morphological changes in JCS cells. In the presence of a suboptimal concentration of TNF-alpha (25 U/ml), however, PTx (1 ng/ml) acted synergistically in inhibiting proliferation and in inducing monocytic differentiation of the JCS cells. Expression of the macrophage differentiation marker (Mac-1) on JCS cells was increased by the combination of PTx and TNF-alpha, and phagocytic activity of the cells was also enhanced. Moreover, JCS cells treated with PTx and TNF-alpha had reduced tumorigenic capacity in vivo. The data suggest that a PTx-sensitive G protein may be involved in regulating the TNF-alpha-induced monocytic differentiation of the myeloid leukemic JCS cells and that combination of PTx and TNF-alpha may be useful in the treatment of some forms of myelomonocytic leukemia.
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PMID:Augmentation of tumor necrosis factor-alpha-induced monocytic differentiation of a myelomonocytic leukemia (WEHI-3B JCS) by pertussis toxin. 808 77

The rat basophilic leukemia (RBL) mast cell line possesses cell surface receptors for adenosine whose ligation markedly potentiates antigen-driven Ca2+ influx and secretion. Here we show that engagement of these receptors and of separate P2 purinergic receptors rapidly activates an outwardly rectifying K+ conductance [GK(OR)] in RBL cells. Activation of GK(OR) by the ligands 5'-(N-ethylcarboxamido)adenosine (NECA), ADP, and ATP was prevented by cytoplasmic guanosine 5'-[beta-thio]diphosphate as well as by pretreatment of the cells with pertussis toxin, implicating mediation by a G protein. Multiple cycles of induction and decay of GK(OR) were produced upon application and removal of ligand. Induction of GK(OR) by either ligand was much faster than the induction caused by guanosine 5'-[gamma-thio]triphosphate (t1/2 < 10 sec vs. 210 sec.). In control cells the maximal whole-cell conductance elicited by ADP (2.25 +/- 0.30 nS) or ATP (2.50 +/- 0.33 nS) was about twice as large as that induced by NECA (1.03 +/- 0.11 nS), and similar to that previously reported for the guanosine 5'-[gamma-thio]triphosphate-elicited GK(OR) in RBL cells (2.58 +/- 1.59 nS). Treatment of RBL cells with dexamethasone upregulated Ca2+ responses to NECA, and it also nearly doubled the maximal conductance elicited by NECA without appreciable effect on responses to ADP or ATP. The failure of water-soluble second messengers to activate GK(OR) and the inability of 11 mM EGTA (< 10 nM Ca2+) to prevent activation by ADP suggest that the relevant pathway is membrane-delimited. Two ion-channel blockers inhibited antigen-stimulated secretion with IC50 values similar to those at which they blocked GK(OR), suggesting that activity of the outwardly rectifying K+ channel may be important for stimulus-response coupling in these cells. Potentiation of the secretory response by NECA may reflect, in part, the activation of GK(OR), which serves to repolarize the membrane more effectively than does the constitutive mechanism, thereby enhancing antigen-driven Ca2+ influx. This channel and its functionally associated receptors may allow neighboring cells of the host to modulate the response of mast cells to exogenous antigen.
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PMID:Activation of mast cell K+ channels through multiple G protein-linked receptors. 835 92

Formyl peptides stimulate binding of the stable GTP analogue, guanosine 5'-O-[gamma-thio]triphosphate (GTP[S]), to G-proteins in membranes of myeloid differentiated human leukaemia (HL-60) cells. On the other hand, agonist-activated formyl peptide receptors can also cause rapid and substantial release of GTP[S] bound to HL-60 membrane G-proteins. For fMet-Leu-Phe-stimulated dissociation of labelled GTP[S], an additional guanine nucleotide, in the potency order, unlabelled GTP[S] >> GTP >> guanosine 5'-[beta,gamma-imino]triphosphate > or = guanosine 5'-O-[beta-thio]diphosphate > or = GDP > GMP = ATP (no effects at 1 mM), was absolutely necessary. While with unlabelled GTP[S] and GTP similar concentrations were required for control and fMet-Leu-Phe-stimulated release, about 50-100-fold higher concentrations of the other nucleotides were necessary for agonist-stimulated than for basal release of bound GTP[S]. The receptor action appeared to be catalytic, required Mg2+ and was pertussis toxin sensitive. The data indicate that binding of GTP[S] to HL-60 membrane G-proteins is reversible and that agonist-activated formyl peptide receptors can interact, either directly or indirectly, with GTP[S]-liganded Gi-proteins, resulting in release of bound GTP[S].
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PMID:Receptor-stimulated dissociation of GTP[S] from Gi-proteins in membranes of HL-60 cells. 837 24

Sphingosine-1-phosphate (SPP) has attracted much attention as a possible second messenger controlling cell proliferation and motility and as an intracellular Ca(2+)-releasing agent. Here, we present evidence that SPP activates a G protein-coupled receptor in the plasma membrane of various cells, leading to increase in cytoplasmic Ca2+ concentration ([Ca2+]i), inhibition of adenylyl cyclase, and opening of G protein-regulated potassium channels. In human enbryonic kidney (HEK) cells, SPP potently (EC50, 2 nM) and rapidly increased [Ca2+]i in a pertussis toxin-sensitive manner. Pertussis toxin-sensitive increase in [Ca2+]i was also observed with sphingosylphosphorylcholine (EC50, 460 nM), whereas other sphingolipids, including ceramide-1-phosphate, N-palmitoyl-sphingosine, psychosine, and D-erythro-sphingosine at micromolar concentrations did not or only marginally increased [Ca2+]i. Furthermore, SPP inhibited forskolin-stimulated cAMP accumulation in HEK cells and increased binding of guanosine 5'3-O-(thio) triphosphate to HEK cell membranes. Rapid [Ca2+]i responses were also observed in human transitional bladder carcinoma (J82) cells, monkey COS-1 cells, mouse NIH 3T3 cells, Chinese hamster ovary (CHO-K1) cells, and rat C6 glioma cells, whereas human HL-60 leukemia cells and human erythroleukemia cells failed to respond to SPP. In guinea pig atrial myocytes, SPP activated Gi protein-regulated inwardly rectifying potassium channels. Activation of these channels occurred strictly when SPP was applied at the extracellular face of atrial myocyte plasma membrane as measured in cell-attached and inside-out patch clamp current recordings. We conclude that SPP, in addition to its proposed direct action on intracellular Ca2+ stores, interacts with a high affinity Gi protein-coupled receptor in the plasma membrane of apparently many different cell types.
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PMID:Activation of a high affinity Gi protein-coupled plasma membrane receptor by sphingosine-1-phosphate. 856 63

The wasp venom, mastoparan (MP), is a direct activator of reconstituted pertussis toxin-sensitive G-proteins and of purified nucleoside diphosphate kinase (NDPK) [E.C. 2.6.4.6.]. In HL-60 membranes, MP activates high-affinity GTPase [E.C. 3.6.1.-] and NDPK-catalyzed GTP formation, but not photolabeling of G-protein alpha-subunits with GTP azidoanilide; this suggests that the venom activates G-proteins in this system indirectly via stimulation of NDPK. Moreover, the MP analogue, mastoparan 7 (MP 7), is a much more effective activator of reconstituted G-proteins than MP, whereas with regard to NDPK and GTPase in HL-60 membranes, the two peptides are similarly effective. In our present study, we investigated NDPK- and G-protein activation by MP in membranes of the human neuroblastoma cell line, SH-SY5Y, the human erythroleukemia cell line, HEL, the rat basophilic leukemia cell line, RBL 2H3, and the hamster ductus deferens smooth muscle cell line, DDT1MF-2. All these membranes exhibited high NDPK activities that were increased by MP. Compared to basal GTP formation rates, basal rates of high-affinity GTP hydrolysis in cell membranes were low. MP activated high-affinity GTP hydrolysis in cell membranes but did not enhance incorporation of GTP azidoanilide into G-protein alpha-subunits. As with HL-60 membranes, MP and MP 7 were similarly effective activators of NDPK and GTPase in SH-SY5Y membranes. Pertussis toxin inhibited MP-stimulated GTP hydrolyses in SH-SY5Y- and HEL membranes, whereas NDPK activations by MP were pertussis toxin-insensitive. Our data suggest that indirect G-protein activation via NDPK is not restricted to HL-60 membranes but is a more general mechanism of MP action in cell membranes. Pertussis toxin-catalyzed ADP-ribosylation of alpha-subunits may inhibit the transfer of GTP from NDPK to G-proteins. NDPK may play a much more important role in transmembrane signal transduction than was previously appreciated and, moreover, the GTPase of G-protein alpha-subunits may serve as GDP-synthase for NDPK.
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PMID:Activation of GTP formation and high-affinity GTP hydrolysis by mastoparan in various cell membranes. G-protein activation via nucleoside diphosphate kinase, a possible general mechanism of mastoparan action. 857 86

Exogenous sphingosine 1-phosphate (S1P) induced Ca2+ mobilization, in association with an increase in inositol polyphosphate production reflecting activation of phospholipase C in HL60 leukemia cells. The increase in intracellular Ca2+ concentration ([Ca2+]i) induced by S1P was inhibited by an appropriate treatment of the cells with pertussis toxin (PTX), U73122 (a phospholipase C inhibitor) or phorbol 12-myristate 13-acetate (PMA). In parallel with the Ca2+ response, these agents also inhibited inositol polyphosphate production. The S1P-induced Ca2+ response was also attenuated in the dibutyryl cAMP-induced differentiated cells, where GTP-binding protein-induced Ca2+ response suggested to be enhanced. Lysophosphatidic acid (LPA) also increased [Ca2+]i in the cels, but the maximal response was about half of that of S1P, and furthermore PTX and dibutyryl cAMP treatment hardly affected the LPA-induced Ca2+ mobilization. We conclude that exogenous S1P mobilizes Ca2+ through phospholipase C activation. The S1P-induced enzyme activation is at least partly mediated by PTX-sensitive GTP-binding protein-coupled receptors which may be different from LPA receptors.
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PMID:Involvement of pertussis toxin-sensitive GTP-binding proteins in sphingosine 1-phosphate-induced activation of phospholipase C-Ca2+ system in HL60 leukemia cells. 860 2

The first-generation histamine H1-receptor antagonists, chlorpheniramine (CPHE) and diphenhydramine (DPH), may activate histamine release from basophils and mast cells. Because CPHE and DPH are cationic-amphiphilic and because several substances with such physicochemical properties activate heterotrimeric regulatory guanine nucleotide-binding proteins (G-proteins) in a receptor-independent manner, we asked the question of whether or not H1-receptor antagonists could be G-protein activators as well. In dibutyryl cAMP-differentiated HL-60 cells, CPHE and DPH increased cytosolic Ca2+ concentration and azurophilic granule release in pertussis toxin (PTX)-sensitive manners. In HL-60 membranes, PTX-sensitive stimulations of GTPase [E.C. 3.6.1.] and binding of guanosine 5'-[gamma-thio]triphosphate by H1 receptor antagonists were observed. CPHE and DPH also increased GTP hydrolysis by the purified PTX-sensitive G-protein, transducin. In all-trans-retinoic acid-differentiated HL-60 cells and rat basophilic leukemia cells (RBL 2H3 cells), H1-receptor antagonists induced, unlike in dibutyryl cAMP-differentiated HL-60 cells, Ca2+ influx without Ca2+ mobilization from intracellular stores. CPHE and DPH also induced serotonin release from RBL 2H3 cells. Our data indicate that first-generation H1-receptor antagonists are receptor-independent G-protein activators and that such a mechanism of action accounts for their stimulatory effects in HL-60 cells, basophils, and mast cells.
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PMID:Receptor-independent G protein activation may account for the stimulatory effects of first-generation H1-receptor antagonists in HL-60 cells, basophils, and mast cells. 861 80

The sphingolipids, sphingosylphosphorylcholine (SPPC) and sphingosine-1-phosphate (SPP), induce a rapid and transient rise in intracellular free calcium concentration ([Ca2+]i) in a variety of cell lines via activation of pertussis toxin-sensitive G protein-coupled receptors. We investigated whether these sphingolipids act on different receptors by testing the effect of varying concentrations of SPPC on [Ca2+]i in human leukemia HL-60 cells, which have been found to be nonresponsive to SPP. SPPC potently (EC50 = 1.5 microM) and rapidly increased [Ca2+]i in HL-60 cells in a pertussis toxin-sensitive manner. Differentiation of HL-60 cells through treatment with dibutyryl cAMP into granulocyte-like cells did not change the magnitude or the pertussis toxin sensitivity of the SPPC-induced [Ca2+]i rise, indicating that the receptor for SPPC is constitutively expressed in HL-60 cells. SPPC did not activate phospholipase C or D in HL-60 cells. However, SPPC, but not SPP, stimulated the generation of superoxide anions in dibutyryl cAMP-differentiated HL-60 cells as well as in human neutrophils, suggesting that the SPPC receptor may play a role in the inflammatory defense against invading microorganisms. On the basis of these results, we conclude that there apparently is a heterogeneity of G protein-coupled receptors for sphingolipids in mammalian cells.
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PMID:A distinct G(i) protein-coupled receptor for sphingosylphosphorylcholine in human leukemia HL-60 cells and human neutrophils. 864 55


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