UMLS:C0023418 - FACTA Search

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

Using modified nuclear lysis and binding conditions, we have examined the binding of an embryonal carcinoma (EC) cell factor, binding factor A, to a stem cell-specific silencer which acts at the DNA level and overlaps the Moloney murine leukemia virus (M-MuLV) proline primer binding site (PBS). Following our protocol, we found that in vitro binding of factor A correlated with the in vivo activity of the M-MuLV silencer. Factor A bound specifically to the wild-type silencer element at room temperature and 30 degrees C, but not at 4 degrees C, and bound 10-fold better to the full-length silencer than to a minimal silencer core element. The factor was enriched in nuclear compared with cytosolic extracts and in undifferentiated EC cells compared with differentiated cells in which the silencer is nonfunctional. Salt and ion requirements for factor A binding were investigated, and partial purification steps indicated the factor to be a heparin-Sepharose-binding moiety of greater than 100 kDa. To examine possible relationships between silencer and PBS activities, sequences representing phenylalanine, isoleucine, lysine-1,2, lysine-3, methionine, and tryptophan PBS DNA fragments were tested in vivo for stem cell-specific repression of M-MuLV expression and in vitro in DNA binding assays. Of these PBS elements, only the lysine-1,2 PBS DNA fragment showed consistently high levels of repression. Interestingly, the lysine-1,2 PBS DNA fragment also formed a complex with an EC cell factor with characteristics similar to those of factor A. However, the two factors did not cross-compete in binding studies, suggesting that they may be different but related factors. Our results suggest that expression of Mason-Pfizer monkey virus, visna virus, and spumavirus, which use the lysine-1,2 PBS, may be inhibited in undifferentiated stem cells.
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PMID:Stem cell factor binding to retrovirus primer binding site silencers. 752 29

The effects of Na+ and Ca2+ ions on histamine release from human basophils stimulated by anti-IgE, N-formyl-methionyl-leucyl-phenylalanine (FMLP), 4 beta-phorbol 12-myristate 13-acetate (PMA) and Ca2+ ionophore A23187 were evaluated. Isosmotic replacement of Na+ in the extracellular medium with the nonpermeant Na+ analogue choline+ or with glucose led to a significant increase in anti-IgE- (1/5000: 43.7 +/- 7.3% in high Na+ vs 68.9 +/- 7.3% in low Na+, mean +/- SEM, n = 8, P < 0.001), FMLP- (1 microM: 37.9 +/- 2.3% vs 49.5 +/- 4.3%, n = 8, P < 0.01) and PMA-(160 nM: 12.7 +/- 0.9% vs 27.3 +/- 4.3%, n = 8, P < 0.05) induced histamine release, whereas A23187-induced histamine release was reduced (1 microM: 90.4 +/- 2.4% vs 45.4 +/- 3.4%, n = 8, P < 0.0001). The progressive increase in extracellular Na+ concentration was accompanied by a decrease of basophil response to anti-IgE, FMLP and PMA; in contrast, A23187-induced histamine release was up-regulated by Na+. The Na+/H+ exchanger monensin, in the concentration range of 10(-8)-10(-4) M, exerted a dose-dependent inhibitory effect on anti-IgE-, FMLP- and PMA-induced histamine release, but not on A23187-induced histamine release. Extracellular Ca2+ up-regulated the histamine release induced by all the above stimuli. Removal of extracellular Na+ lowered the requirement of extracellular Ca2+ for anti-IgE, FMLP- and PMA-induced histamine release. In contrast with previous observations showing that Na+ supports histamine release from rat peritoneal mast cells and rat basophilic leukaemia cells, these results indicate that Na+ strongly inhibits histamine release from human basophils stimulated by anti-IgE, FMLP and PMA, whereas it enhances Ca2+ ionophore A23187-induced histamine release. The effects of Na+, which are probably related to modulation of membrane potential and/or intracellular pH, vary depending on the cell type and the stimulus employed for cell activation.
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PMID:Ionic regulation of human basophil releasability. III. Effects of Na+ and Ca2+ on histamine release induced by different stimuli. 753 2

Methotrexate (MTX), one of the earliest cancer chemotherapy agents, continues to be used extensively in the treatment of leukemia and a variety of other tumors. The efficacy of this drug results from its facile uptake by cells, rapid polyglutamylation and virtually stoichiometric inhibition of dihydrofolate reductase (DHFR), a key enzyme in cell replication. From the work of a multitude of biochemists, molecular biologists, organic chemists and pharmacologists, much is known about the mode of action of MTX and the mechanisms by which tumors exhibit inherent or acquired resistance to this drug. MTX enters cells primarily by a carrier-mediated active transport system whose principal substrate is 5-methyltetrahydrofolate, and additional glutamates are added to the gamma-position of the parent glutamate moiety. The tight binding of MTX to DHFR is defined from NMR and X-ray crystallographic studies of the enzyme and its drug or substrate complexes, supplemented by site-directed mutagenesis to confirm specific interactions. Resistance to the drug, encountered in cell culture model systems or in cancer patients, can result from an increased level of DHFR (due to gene amplification), mutant DHFR with reduced affinity for MTX, or decreased uptake or polyglutamylation of the drug. Although DHFR is an extremely well-studied enzyme, there is still some uncertainty about its kinetics, mechanism for reduction of folate, multiple forms, and activation by a diverse group of agents. Prodrug forms of MTX, e.g., MTX alpha-phenylalanine, which can be activated by carboxypeptidase A-monoclonal antibody conjugates, offer promise for improved efficacy of the drug by selective targeting to tumors. The large body of information summarized above has aided in the development of other folate antagonists, provides a paradigm for assessing the status of other cancer chemotherapeutic agents in current use, and offers a platform from which to speculate about the future of the field.
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PMID:The methotrexate story: a paradigm for development of cancer chemotherapeutic agents. 794 84

Dibutyryl cAMP-differentiated HL-60 human leukemia cells possess receptors for the chemoattractants N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), C5a and leukotriene B4 (LTB4). We compared the effects of these chemoattractants in HL-60 membranes and in intact HL-60 cells. fMLP, C5a and LTB4 stimulated GTP hydrolysis and guanosine 5'-O-[3-thio]triphosphate (GTP[gamma S]) binding in HL-60 membranes with similar effectiveness and in a pertussis toxin (PTX)-sensitive manner. They also stimulated photolabeling of the alpha-subunits of the guanine nucleotide-binding proteins (G-proteins), Gi2 and Gi3 with similar effectiveness. Chloride salts of monovalent cations differentially enhanced and inhibited chemoattractant-induced GTP hydrolyses. C5a was less effective than fMLP in enhancing cholera toxin-catalysed ADP-ribosylation of Gi alpha 2 and Gi alpha 3, and LTB4 was ineffective. fMLP was more effective than C5a and LTB4 in stimulating Ca2+ influx in HL-60 cells. C5a- and LTB4-induced rises in cytosolic Ca2+ concentration ([Ca2+]i) were PTX-sensitive, whereas the effect of fMLP was partially PTX-insensitive. LTB4-induced rises in [Ca2+]i were more sensitive towards homologous desensitization than those induced by C5a, and the effect of fMLP was resistant in this regard. C5a was considerably less effective than fMLP in activating superoxide anion formation and azurophilic granule release, and LTB4 was ineffective. Our data suggest that fMLP, C5a and LTB4 effectively activate the G-proteins, Gi2 and Gi3, in HL-60 cells and that fMLP may additionally activate PTX-insensitive G-proteins. fMLP, C5a and LTB4 are full, partial and incomplete secretagogues, respectively, and these differences may be due to differences in homologous receptor desensitization and qualitative Gi-protein activation.
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PMID:Differential activation of dibutyryl cAMP-differentiated HL-60 human leukemia cells by chemoattractants. 798 96

We have previously reported that polymorphonuclear granulocyte (PMN) chemiluminescence (CL) and superoxide anion production are abnormally low in patients with polycythaemia vera (PV) after simulation with n-formyl-methionyl-leucyl-phenylalanine (fMLP), but normal when elicited by phorbol myristate acetate (PMA). This study documents that both fMLP and PMA induced CL was normal in PMN from patients with chronic myelogenous leukaemia (CML) and essential thrombocythaemia (ET). Furthermore, we monitored intracellular hydrogen peroxide (H2O2) production in PMN and monocytes from patients with PV, CML and ET by flow cytometry. H2O2 production in resting and PMA-stimulated cells was normal in all diseases. So also was fMLP induced H2O2 generation in ET PMN and monocytes. In contrast, fMLP-induced H2O2 production was significantly lower both in PV PMN (1.8 +/- 0.7 mean fluorescence intensity units in PV compared to 8.4 +/- 3.4 in healthy controls; P < 0.02), and in PV monocytes (0.3 +/- 0.5 compared to 2.5 +/- 0.7 in controls; P < 0.02). A less pronounced reduction of fMLP stimulated H2O2 production was noted in CML PMN (3.8 +/- 3.1 compared to 8.4 +/- 3.4 in controls; P < 0.05), and monocytes (1.3 +/- 0.6 compared to 2.5 +/- 0.7 in controls; P < 0.05). The reduction of H2O2 generation in PV and CML PMN was not attributed to subpopulations of less responsive cells. However, one ET and one CML patient showed a subpopulation of less responsive PMN. Thus intracellular H2O2 (as well as extracellular release of superoxide ions) is reduced in fMLP-stimulated PV PMN and monocytes but normal after PMA stimulation, a phenomenon that is not consistently found in other myeloproliferative disorders.
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PMID:Studies of neutrophil and monocyte oxidative responses in polycythaemia vera and related myeloproliferative disorders. 799 85

The role played by the Src-related tyrosine kinase, Hck, in embryonic stem (ES) cell differentiation was investigated by replacing a conserved C-terminally located tyrosine with phenylalanine by gene targeting. Targeted ES cells display a 7- to 9-fold elevation in constitutive Hck kinase activity and require approximately 15 times less leukaemia inhibitory factor (LIF) than parental ES cells to maintain their stem cell character in vitro. We also demonstrate a rapid and transient increase in Hck tyrosine kinase activity in parental ES cells stimulated by LIF and, finally, show that Hck is physically associated with gp130, an affinity converter and signal transducing component of the LIF receptor. Thus, these results provide biological and biochemical evidence that Hck participates in signal transduction from the LIF receptor.
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PMID:Functional and biochemical association of Hck with the LIF/IL-6 receptor signal transducing subunit gp130 in embryonic stem cells. 815 96

The Jun protein binds DNA and regulates transcription as a component of the AP-1 transcription factor complex. In its oncogenic form, Jun can transform cells in culture and cause tumors in animals. Both trans-activation and transformation require several functional domains of Jun, including an amino-terminal trans-activation domain. In this study, properties of Jun required for trans-activation and transformation were explored by replacing the trans-activation domains of c-Jun and its oncogenic counterpart, v-Jun, with the constitutively active trans-activation domain from the herpes simplex virus VP16 protein. The VP16-v-Jun chimera retained similar oncogenic properties to its parent, v-Jun. The VP16-c-Jun chimera, however, was considerably more oncogenic than c-Jun. Substitutions of a phenylalanine in the VP16 domain of the VP16-c-Jun chimera diminished or abolished transformation. Each of the chimeras bound to the AP-1 consensus recognition sequence from the collagenase promoter or from the human T-cell leukemia virus type I long terminal repeat in vitro. None of the VP16-Jun chimeras efficiently stimulated transcription from the collagenase promoter or an artificial promoter containing the human T-cell leukemia virus type I element in vivo. These results demonstrate that the Jun trans-activation domain can be replaced by a heterologous trans-activation domain with retention of oncogenic activity. However, this oncogenic activity is not reflected in the trans-activating properties of the chimeras.
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PMID:Chimeras of herpes simplex viral VP16 and jun are oncogenic. 824 Oct 24

We looked for chemotaxin/interleukin 8 (CT/IL-8) activity in the culture fluids of 97 human leukemia cell lines and found it in two of the T cell lines, six of the myeloid cell lines, and one of the normal B-cell lines. It was particularly strong in the culture fluids of two cell lines. These cell lines secreted a chemotactic protein into the culture fluids under certain conditions of stimulation with phorbol-12-myristate 13-acetate (PMA), lipopolysaccharide, or hemagglutinin-P. A myeloid leukemia cell line, ML-1, secreted an inducible chemotaxin when stimulated with PMA (1 ng/ml) for 24 h. We purified the chemotaxin from ML-1 cell culture fluid using an improved procedure: concentration with DEAE-Sepharose CL-6B and CM-Sepharose CL-6B, CM-Sepharose column chromatography, and reverse-phase 5TMS-300 column on HPLC with the retention time coinciding with that of LUCT/IL-8 [Suzuki et al., 1989, J. Exp. Med. 169, 1895]. The yield was 200 micrograms protein from 6 liters of the culture fluid. The N terminus of CT/IL-8 was AVLPR-SAKELRXQXIKTYSK- - -, the same as that of LUCT/IL-8, which is constitutively secreted from lung giant cell carcinoma LU65C cells. The optimal concentration in the chemotactic activity of CT/IL-8, equivalent to that of bacterial chemotactic peptide fMet-Leu-Phe (10 nM), was found to be 5 nM. The results show that this chemotaxin is identical to LUCT/IL-8.
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PMID:Isolation and amino acid sequence of a chemotactic protein, LECT/interleukin 8, from a human myeloid leukemia cell line, ML-1. 834 17

Apoptosis is a morphologically and biochemically distinct form of cell death that occurs under a variety of physiological and pathological conditions. In the present study, the proteolytic cleavage of poly(ADP-ribose) polymerase (pADPRp) during the course of chemotherapy-induced apoptosis was examined. Treatment of HL-60 human leukemia cells with the topoisomerase II-directed anticancer agent etoposide resulted in morphological changes characteristic of apoptosis. Endonucleolytic degradation of DNA to generate nucleosomal fragments occurred simultaneously. Western blotting with epitope-specific monoclonal and polyclonal antibodies revealed that these characteristic apoptotic changes were accompanied by early, quantitative cleavage of the M(r) 116,000 pADPRp polypeptide to an M(r) approximately 25,000 fragment containing the amino-terminal DNA-binding domain of pADPRp and an M(r) approximately 85,000 fragment containing the automodification and catalytic domains. Activity blotting revealed that the M(r) approximately 85,000 fragment retained basal pADPRp activity but was not activated by exogenous nicked DNA. Similar cleavage of pADPRp was observed after exposure of HL-60 cells to a variety of chemotherapeutic agents including cis-diaminedichloroplatinum(II), colcemid, 1-beta-D-arabinofuranosylcytosine, and methotrexate; to gamma-irradiation; or to the protein synthesis inhibitors puromycin or cycloheximide. Similar changes were observed in MDA-MB-468 human breast cancer cells treated with trifluorothymidine or 5-fluoro-2'-deoxyuridine and in gamma-irradiated or glucocorticoid-treated rat thymocytes undergoing apoptosis. Treatment with several compounds (tosyl-L-lysine chloromethyl ketone, tosyl-L-phenylalanine chloromethyl ketone, N-ethylmaleimide, iodoacetamide) prevented both the proteolytic cleavage of pADPRp and the internucleosomal fragmentation of DNA. The results suggest that proteolytic cleavage of pADPRp, in addition to being an early marker of chemotherapy-induced apoptosis, might reflect more widespread proteolysis that is a critical biochemical event early during the process of physiological cell death.
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PMID:Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. 835 26

Chronic lymphocytic leukemia and lymphoma cells were treated with antitumor drugs in vitro and analyzed by flow cytometry to measure the number of apoptotic (AP) cells and DNA damage in the cells that escaped apoptotic death. AP cells were identified by a high sensitivity of DNA to thermal denaturation, which induced binding of antibody to single-stranded DNA, and by decreased stainability of cells with the intercalating DNA dye propidium iodide. The appearance of AP cells was prevented by Zn++ and inhibited by phorbol ester. AP cells were induced by alkylating agents, antimetabolites, and anthracyclines. A linear relationship between L-phenylalanine mustard dose and the number of AP cells was observed. A synergistic interaction between drugs was detected by an increased number of AP cells and by the intensity of DNA damage in non-apoptotic cells. A most interesting example of synergism was the combination of alkylating agents with fludarabine. Linearity of dose-response curves, and the capability to detect drug synergism and to evaluate variable response of cells from different patients to single agents and combinations suggest that flow cytometry of apoptosis will provide a basis for chemosensitivity tests in leukemia and lymphoma.
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PMID:Apoptosis (programmed cell death) and the evaluation of chemosensitivity in chronic lymphocytic leukemia and lymphoma. 836 74

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