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 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

The expression of myeloid antigens has been extensively examined using two-color analysis in 43 children with B-lineage acute lymphoblastic leukemia (ALL). On pre-culture cells, CD33 expression was frequently observed in CD19+, CD10- B-precursor ALL, and CD14 was expressed only on the cells from B-precursor ALL expressing CD19, CD10 and CD20, and B-ALL. After 2 or 3 days of culture without TPA, CD13 emerged on the cells from 21 of 29 patients irrespective of the presence or the absence of fetal calf serum in the culture. Of four patients with CD10+ B-precursor ALL, which showed no expression of CD13 after culture, two had T-cell associated antigens. Whereas the addition of TPA to the culture enhanced the expression of CD13 on the cells from acute non-lymphocytic leukemia (ANLL), TPA reduced the expression of this antigen on B-precursor cells. These findings suggest that the regulatory mechanism of CD13 expression may be different between B-precursor ALL and ANLL. Co-culture with cycloheximide mostly abrogated the induction of CD13, suggesting that CD13 expression was mainly dependent on de novo protein synthesis.
Leukemia 1991 Jan
PMID:In vivo and in vitro expression of myeloid antigens on B-lineage acute lymphoblastic leukemia cells. 170 35

The commitment process of a human megakaryoblastic cell line (MEG-O1) induced with phorbol ester, TPA, was investigated with special reference to glycoprotein (GP) IIb/IIIa expression, multinuclear formation, and DNA replication. TPA (10(-7) mol/L) completely inhibited cellular division in MEG-O1, but did not suppress de novo DNA synthesis. Two days' culture with 10(-7) mol/L TPA was sufficient for MEG-O1 cells to initiate an irreversible commitment process. These cells could not resume cell growth and expressed GP IIb/IIIa antigen; some of them showed multinuclear form and DNA polyploidy even after removal of TPA from the culture medium. DNA histogram analysis showed that, upon treatment with TPA, the percentage of cells whose DNA ploidy was more than 8N was 5 to 10 times higher than that of control cells. Precise analysis using cell size fractionation by centrifugal elutriation method showed that there was strong correlation between the percentage of multinuclear cells and DNA polyploidy in TPA-treated cells. The percentage and staining intensity of GP IIb/IIIa and other megakaryocytic phenotypes such as von Willebrand factor and PAS staining were highest in large multinuclear cell populations, suggesting that these cells are the most differentiated population in this system. In TPA-treated cells, the activity of DNA polymerase alpha, a marker for cell growth, remained at the same level as in control cells. Aphidicolin, a specific inhibitor of DNA polymerase alpha, completely inhibited the differentiation induction of MEG-O1 cells with TPA measured by either GP IIb/IIIa expression or multinuclear cell formation. Therefore, DNA replication appears to be involved in the process of phenotypic expression as well as endomitosis in megakaryocyte differentiation of MEG-O1 cells. Aphidicolin was also effective in inhibiting megakaryocytic differentiation of other leukemia cell lines such as human erythroleukemia (HEL) and K562 cell lines induced with TPA, suggesting the close interplay of DNA replication and phenotypic expression in megakaryopoiesis.
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PMID:Aphidicolin, an inhibitor of DNA replication, blocks the TPA-induced differentiation of a human megakaryoblastic cell line, MEG-O1. 174 84

Cremophor EL, a polyloxyethylene castor oil derivative used clinically as a parenteral vehicle, inhibits protein kinase c activity in vitro. The tumor promoting agent TPA (12-0-tetradecanoylphorbol-13-acetate) activated protein kinase C and induced phosphorylation of cellular proteins of human myeloblastic leukemia ML-1 cells. Polypeptides of 56 KDa, 44 KDa, 37 KDa, 35 KDa and 31 KDa were particularly phosphorylated in response to TPA activation. However, the phosphorylations of these polypeptides, especially that of 37 KDa, were greatly reduced by treatment of the TPA-activated ML-1 cells with Cremophor EL. Cremophor EL also inhibited the growth of ML-1 cells. On the other hand, the TPA-induced cell differentiation in ML-1, which is considered a separate event from protein kinase C activation, was not affected by Cremophor EL. These studies suggest biological implications for the observed in vitro activity of Cremophor EL. The studies may also provide a mechanism for the Cremophor EL-associated cytotoxicities observed when it is used clinically as a parenteral vehicle.
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PMID:Cremophor EL inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced protein phosphorylation in human myeloblastic leukemia ML-1 cells. 174 8

The signaling pathways used by interleukin-3 (IL-3) and by active phorbol ester (12-0-tetradecanoyl phorbol-13-acetate, TPA) to stimulate mitogenesis in the growth factor dependent myeloid cell line FDC-P1 were studied by 'reporter' analysis of nuclear proto-oncogene expression. These studies revealed that IL-3 strongly stimulated c-myc expression by a transcriptional mechanism but IL-3 poorly stimulated c-jun expression, a measure of protein kinase C dependent signals. On the other hand, the protein kinase C agonist, TPA, strongly activated c-jun expression but poorly promoted expression (transcription) of c-myc in FDC-P1. These findings appeared to correlate with the poor mitogenic capacity of TPA for FDC-P1. However, stable transfection of FDC-P1 with a c-myc expression vector driven by a human methallothionein IIA promoter containing the TPA responsive element (TRE), led to a cell clone, FDMT myc.A1, in which TPA mediated selective transcription of the transfected TRE driven c-myc vector and down-regulated expression of the endogenous c-myc gene. IL-3 selectively failed to stimulate expression of the TRE driven c-myc vector in FDMT myc.A1. Augmented TPA dependent vector derived c-myc expression was accompanied by enhanced mitogenesis of the cell line FDMT myc.A1 compared with FDC-P1. In addition, TPA mediated expression of the transfected c-myc gene in FDMT myc.A1 was accompanied by augmented transcription of c-jun and c-fos in response to TPA. These studies show the importance of a non-protein kinase C dependent pathway for IL-3 mediated c-myc transcription. However, these studies reveal that protein kinase C mediated pathways can be promitogenic, especially when complemented by unregulated c-myc expression (in this case driven by an alternative, TRE containing promoter).
Leukemia 1991 Dec
PMID:Interleukin-3 dependent mitogenesis in murine cells involves a predominant non-protein kinase C (pKC) dependent pathway for c-myc transcription. Role of a myc expression vector in rescuing pKC dependent mitogenesis. 177 59

A protein variously termed leukemia inhibitory factor (LIF), differentiation-inducing factor, differentiation inhibitory activity or human interleukin for DA cells can control the differentiation and proliferation of hematopoietic cells as well as of several other cellular lineages. In order to further elucidate the spectrum of LIF-producing cells, we examined different cell types for the expression of LIF mRNA using Northern blot analysis. LIF mRNA was detected in activated normal human T-cells and in two T-cell lines but was undetectable in a B-lymphoid cell line, in both resting and activated normal human granulocytes and monocytes and in human myeloid cell lines K562 and HL-60. In human lung fibroblasts and in human umbilical vein endothelial cells, LIF was constitutively expressed and its accumulation was increased in a time-dependent manner following treatment with the phorbol ester TPA and in the presence of the two immediate response cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1-beta. We conclude that mRNA for LIF is not only expressed by T-cells but also in human mesenchymal cells. Expression of LIF transcripts in these cells is constitutive and can be significantly enhanced by phorbol ester, TNF-alpha and IL-1-beta.
Leukemia 1991 May
PMID:Expression of leukemia inhibitory factor is regulated in human mesenchymal cells. 190 79

We have earlier reported changes in the GTP binding of several membrane proteins including Gs alpha and Gi alpha during thymic differentiation of T cells. Using an [alpha-32P]GTP-photoaffinity labeling technique we have studied the pattern of GTP binding proteins in activated and resting T lymphocytes and in T cells induced to differentiate by TPA. The GTP binding proteins in mitogen-activated T cells resembled those seen in leukemia T cell lines. Treatment of Jurkat, but not of CCRF-CEM, T cells with TPA caused increased GTP-labeling of a 34 kDa protein and Gi alpha. The GTP labeling pattern in TPA-treated Jurkat cells resembled that in resting T lymphocytes. TPA induced de novo expression of functional TCR/CD3 on CCRF-CEM and downregulation of TCR/CD3 on Jurkat cells but these changes did not correlate with the altered GTP-labeling patterns.
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PMID:GTP-binding membrane proteins in activated and differentiating T cells. 190 70

We have conducted functional studies of the enhancer elements of human T-cell leukemia virus type I (HTLV-I) using the human T-cell lines Jurkat and MOLT 4, which are negative for HTLV-I, and MT-2 and TL-Mor, which carry the proviral genome of HTLV-I. Two distinct elements have been implicated in function of the HTLV-I enhancer. One is the 21-base-pair (bp) core element that is responsible for trans-activation by the HTLV-I trans-activator p40tax and that has the ability to bind to cyclic-AMP responsive element binding factor (CREB)-like factor(s). The other is a region interposed between the 21-bp elements. In this study we demonstrate that a subfragment (C26) in the region between the 21-bp elements is involved in trans-activation by p40tax, possibly through binding to an NF-kappa B-like nuclear factor or factors. Formation of the protein-DNA complex with the C26 subfragment was positively affected by p40tax. The C26 element conferred partial responsiveness to p40tax when linked to one copy of the 21-bp element that, by itself, showed little activation in response to p40tax. However, the C26 element alone, even when repeated, could not be activated by p40tax, unlike other NF-kappa B-binding elements. In contrast, the C26 element itself was profoundly activated upon stimulation with 12-O-tetradecanoylphorbol-13-acetate. These findings therefore suggest that the HTLV-I enhancer contains multiple functional elements, including binding sites for at least CREB- and NF-kappa B-like factors, which synergistically cooperate in activation of the HTLV-I enhancer in response to p40tax. Our results also demonstrate that TPA-dependent activation of the HTLV-I enhancer may be mediated through the C26 element.
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PMID:Synergism between two distinct elements of the HTLV-I enhancer during activation by the trans-activator of HTLV-I. 193 34

The Ku protein is a DNA-binding nuclear protein complex composed of 86 kDa and 70 kDa subunits. Recently, in vitro studies suggested a role of the Ku protein in the activation of gene transcription. We studied the expression of these proteins during cell proliferation by Northern blot hybridizations using specific cDNA probes and by immunofluorescence and immunoblot analysis using specific monoclonal antibodies. The genes coding for both subunits were activated during late G1-phase in the transition of human PHA-stimulated lymphocytes from quiescent (G0 phase) to proliferative (S phase) state. These genes were inactivated when human leukemia cells HL60 were differentiated into monocytes upon treatment with the phorbol ester TPA. Changes at the protein level were significantly smaller than changes at the mRNA levels in both cell systems, suggesting a high stability of the Ku protein. Immunofluorescence studies demonstrated nucleolar as well as nuclear localization of the Ku protein in quiescent lymphocytes and during the early G1-phase; during the late G1, S and G2 phases, the Ku protein was only localized in discrete structures in the nucleoplasm. These results demonstrate that the gene expression for the Ku protein is associated with the proliferative state of the cells and that the nucleolar localization of the Ku protein is cell-cycle-dependent.
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PMID:Expression of the Ku protein during cell proliferation. 193 9

Rat basophilic leukemia (RBL-2H3) cells serve as a model to examine the role of external and internal free Ca2+ concentration [Ca2+]i, following ionomycin induced stimulation of leukotriene C4 (LTC4) formation. Brief exposure of RBL cells to Ca(2+)-free medium abolished the effect of ionomycin on elevation of [Ca2+]i (monitored by Quin-2/AM) and on stimulation of LTC4 production. In Ca(2+)-rich medium (1.8 mM) however there was a large increase in both parameters. We showed recently (Her et al., 1990) that hydrocortisone (HC) and dexamethasone markedly suppressed the elevated [Ca2+]i induced by antigen. Following HC pretreatment, there was a modest (35%) suppression of [Ca2+]i elevation induced by submaximal (0.1 microM) as well as maximal (1 microM) doses of ionomycin (nevertheless, 8 fold increase above basal level was still observed), LTC4 formation, however, was only inhibited (47%) by HC when induced by submaximal dose of ionomycin, but not that induced by higher doses of ionomycin. Phorbol ester (TPA) abolished elevation of [Ca2+]i induced by antigen. Short treatment with TPA had a modest inhibitory (28%) effect on elevation of [Ca2+]i and on LTC4 formation (23%) induced by ionomycin. It is proposed that high [Ca2+]i, possibly originated mainly from extracellular source, is essential for induction of LTC4 formation.
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PMID:The role of external and internal free Ca2+ concentration on ionomycin induced leukotriene C4 formation in rat basophilic leukemia cells. 195 35


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