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)

To study Moloney murine leukemia virus (M-MulV) proteins associated with the integration of proviral DNA into the host chromosome, we isolated endonuclease activities from purified virion preparations of the wild type and two of its replication mutants. A major endonuclease activity was identified in virions of M-MuLV; the enzyme catalyzed nicks in double-stranded DNA in the presence of either Mn2+ or Mg2+ and was stimulated by ATP. The endonuclease nicked DNA adjacent to all four nucleotides with some preference for G and C. The same enzyme, and in comparable amounts, was isolated from two virus replication mutants: dl2905, deficient in the processing of Pr65gag and Pr200gag-pol, and dl50401, deficient for the virus integration function. In the process of these experiments, the residual reverse transcriptase in mutant dl2905 was shown to be the mature size, implying that the uncleaved precursor lacks enzymatic activity. It appears that the major endonuclease activity found in virions of M-MuLV is not encoded by either the gag or pol genes.
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PMID:Characterization of endonuclease activities in Moloney murine leukemia virus and its replication-defective mutants. 303 6

Tyrosine-specific protein kinases that transfer the terminal phosphate from ATP to protein acceptors are associated with certain transforming viruses and cell surface growth factor receptors. Here we describe the synthesis and testing of potential multisubstrate inhibitors of this class of enzymes. The inhibitors were prepared by covalent attachment of the terminal phosphate of ATP or its tetraphosphate analogue to tyrosine mimics. Testing against p60v-abl, the tyrosine kinase from the Abelson murine leukemia virus, showed that the series of inhibitors was moderately potent (IC50 values as low as 13 microM). However, structural modification of the tyrosine mimic, including replacement with a serine-like moiety, had little effect on potency. It is therefore concluded that the ATP moiety is largely responsible for binding and that the enzyme requires additional structural features for recognition of the tyrosine-containing substrate.
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PMID:Synthesis and evaluation of multisubstrate inhibitors of an oncogene-encoded tyrosine-specific protein kinase. 2. 304 21

In this communication we show that activation of poly(ADP-ribose) polymerase by DNA damage can produce drastic alterations in carbohydrate metabolism. We examined alterations in NAD+, NADP+, ATP and glucose-6-phosphate in L1210 murine leukemia cells, following exposure to different concentrations of N-methyl-N'-nitro-N-nitrosoguanidine. Treatment of cells with 20 micrograms/ml MNNG produced rapid depletion of NAD+ and ATP. The G-6-P pool showed a biphasic change: first the pool size decreased, then increased to a level greater than that present in control cells. Nicotinamide treatment prevented the total depletion of NAD+ and this in turn helped preserve the ATP pools and prevented the biphasic alteration in G-6-P pool sizes.
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PMID:Metabolic consequences of DNA damage: DNA damage induces alterations in glucose metabolism by activation of poly (ADP-ribose) polymerase. 308 Sep 86

In vivo effects of DL-alpha-difluoromethylornithine (DFMO) on the metabolism of polyamines and nucleotide phosphates were monitored in P388/S leukemia cells grown intraperitoneally in BDF1 inbred male mice. Inhibiting the ornithine decarboxylase (ODC) activity DFMO depleted putrescine and spermidine to 30-50 and 50-60%, respectively, and increased spermine to 25-60% compared with the controls, when given as 2% solution in drinking water of the tumor-bearing animals. DFMO treatment caused a parallel 56% elevation of total nucleotide content in tumor cells with distinct and significant increase of some nucleotide phosphates. The most pronounced alterations were shown in the intracellular UTP (202%), CTP (103%), ADP (92%) and ATP (71%) concentrations. Changes in polyamine and nucleotide phosphate metabolisms were dependent on tumor progression. A possible explanation of the metabolic events induced by DFMO is discussed.
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PMID:In vivo effects of DL-alpha-difluoromethylornithine on the polyamine and nucleotide phosphate metabolism in P388/S leukemia cells. 308 89

Phosphorylation of a 36,000-dalton (36k-Da) protein of rat basophilic leukemia (RBL-2H3) cell membranes was investigated. This phosphoprotein has been suggested to be the beta-subunit protein of the immunogloblin E (IgE) receptor of RBL-2H3 cells [Teshima et al., Biochem. biophys. Res. Commun. 125, 867-874 (1984)]. Phospholipids such as phosphatidyl serine, phosphatidyl inositol and phosphatidyl ethanolamine, which are known to be activators of protein kinase C, enhanced the phosphorylation of the 36K-Da protein. In contrast, 1-(5-isoquinoline sulfonyl)-2-methylpiperazine (H-7) which has been identified as a potent inhibitor of protein kinase C in vitro decreased incorporation of radioactive phosphate from [gamma-32P]ATP into this protein. These results indicate that the phosphorylation of the 36K-Da protein of RBL-2H3 cell membranes is catalyzed by protein kinase C. H-7 also inhibited the release of serotonin from RBL-2H3 cells stimulated with an antigen or calcium ionophore A23187 and 12-O-tetradecanoyl phorbol 13-acetate (TPA). Treatment of the antigen-stimulated cells with TPA caused a synergistic effect on the serotonin release. A similar effect was obtained by treatment of A23187-stimulated cells with TPA or 1-oleoyl-2-acetyl glycerol.
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PMID:Possible involvement of phosphorylation of a 36,000-dalton protein of rat basophilic leukemia (RBL-2H3) cell membranes in serotonin release. 308 12

Kinetic analysis of vincristine transport in parental and multidrug-resistant P388 leukemia cells was attempted by indirect assessment of its efflux. Practically, the initial velocity and steady-state level of vincristine uptake by ATP-depleted cells, and its steady-state level in untreated cells, were measured. As a result, a saturable process of not only influx but also efflux of vincristine was observed for the first time with both cell lines, suggesting the existence of a carrier-mediated system for influx and efflux. With increasing extracellular drug concentrations, the contribution of the mediated transport to the total flux was decreased and that of the unsaturable process, that is, simple diffusion, was increased. It should be particularly noted that the Km and Vmax values of efflux in the resistant cells were significantly less and greater, respectively, than those of the sensitive cells, providing a biochemical basis for enhanced efflux as a mechanism of multidrug-resistance. No significant difference in kinetic parameters of vincristine influx and intracellular binding contributing to resistance was found between the two cell lines.
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PMID:Kinetic analysis of active efflux of vincristine from multidrug-resistant P388 leukemia cells. 310 19

Protein phosphorylation mediated by murine IL3 and other factors has been studied in two different IL3-dependent lines, AC2 and 123. In both lines, responses to rat recombinant IL3 are enhanced or induced by growth in rat spleen lymphocyte conditioned medium. Growth stimulation by murine and rat IL3, by rat lymphokine(s), and by ATP in ATP-responsive cells is closely associated with the rapid (2-4 min) phosphorylation of a 33-kDa protein (p33) in all the cells examined. p33 phosphorylation is not stimulated by another lymphokine, IL4, nor by TPA or calcium ionophore alone, which are unable to stimulate growth by themselves, and is independent of serum. p33 phosphorylation is inhibited by trifluoperazine, an inhibitor of calcium-calmodulin, but is less sensitive to inhibition by H7, an inhibitor of protein kinase c, in AC2 cells. A spontaneous IL3-independent clone of AC2 (AC-) has been isolated. AC- cells are aggressively leukemic, do not produce detectable IL3, but phosphorylate p33 constitutively where it is associated with a particulate cell fraction. It is suggested that p33 is a common intermediate molecule involved in signal transduction by the various ligands which result in growth stimulation and that its constitutive phosphorylation may play a key role in the maintenance of the leukemic state.
Leukemia 1988 Feb
PMID:Rapid phosphorylation of a specific 33-kDa protein (p33) associated with growth stimulated by murine and rat IL3 in different IL3-dependent cell lines, and its constitutive expression in a malignant independent clone. 312 92

The adenine nucleotide profiles (AMP, ATP, NAD and NADH2) of peripheral blood lymphocytes isolated from patients with common variable hypogammaglobulinaemia (CVH) were similar to those in control cells. AMP and ATP levels were also similar in the lymphocytes of patients with chronic lymphatic leukaemia (CLL). Since CVH and CLL patients have reduced activity of plasma membrane ecto-5'-nucleotidase, our data suggests that this enzyme does not regulate the levels of intracellular adenine nucleotides, at least in "resting" cells.
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PMID:Adenine nucleotide concentrations in peripheral blood lymphocytes from patients with common variable hypogammaglobulinaemia and B-cell chronic lymphatic leukaemia. 318 62

Incubation of L1210 murine leukemia cells in vitro with 10 microM of the bifunctional alkylating agent bis(2-chloroethyl)methylamine (nitrogen mustard, HN2) for 10 min brought about a fall of more than 99.9% in their ability to form colonies when the cells were suspended in 0.5% nutrient agar. Incubation with HN2 also inhibited the influx of the potassium congener 86Rb+ to exponentially proliferating L1210 cells in a concentration-dependent manner. This inhibition was specific and was accounted for by a reduction of a diuretic-sensitive component of 86Rb+ influx, identified in the preceding paper (Wilcock, C. and Hickman, J.A. (1988) Biochim. Biophys. Acta 946, 359-367) as being mediated by a Na+/K+/Cl- cotransporter. Inhibition by 10 microM HN2 was complete after a 3-h incubation. There was no inhibition at this time of the ouabain-sensitive component of 86Rb+ influx, mediated by Na+/K+-ATPase. After 3 h of incubation with 10 microM HN2 there was also no change in the membrane potential of the treated cells as measured by the distribution of the [3H]TPMP+, no decrease in cellular ATP concentration and no change in intracellular pH, and the ability of the cells to exclude the vital dye Trypan blue was not significantly different from control values. These effects of HN2, therefore, appeared to follow lethal damage, but precede cell death. In the stationary phase of L1210 cell growth, the component of HN2 and diuretic-sensitive K+ influx to L1210 cells was reduced, whilst the component constituting the HN2-insensitive ouabain-sensitive sodium pump was increased. The monofunctional alkylating agent MeHN1 (2-chloroethyldimethylamine) which cannot cross-link cellular targets and has no antitumor activity, did not inhibit 86Rb+ influx to L1210 cells when incubated at equimolar or equitoxic concentrations to HN2. Intracellular potassium concentration was maintained close to control values of 138 +/- 10 mM in HN2-treated cells because of an approx. 35% fall in cell volume. The results suggest that the Na+/K+/Cl- cotransporter is a selectively inhibitable target for HN2, and the lesion is discussed with reference to the cytotoxic effects of this agent.
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PMID:Selective inhibition by bis(2-chloroethyl)methylamine (nitrogen mustard) of the Na+/K+/Cl- cotransporter of murine L1210 leukemia cells. 320 52

Previous studies with antigen-stimulated rat basophilic leukemia (RBL-2H3) cells indicated the formation of multiple isomers of each of the various categories of inositol phosphates. The identities of the different isomers have been elucidated by selective labeling of [3H]inositol 1,3,4,5-tetrakisphosphate with [32P]phosphate in the 3'-or 4',5'-positions and by following the metabolism of different radiolabeled inositol phosphates in extracts of RBL-2H3 cells. We report here that inositol 1,3,4,5-tetrakisphosphate, when incubated with the membrane fraction of extracts of RBL-2H3 cells, was converted to inositol 1,4,5-trisphosphate and inositol 1,3,4-trisphosphate. Further dephosphorylation of the inositol polyphosphates proceeded rapidly in whole extracts of cells, although the process was significantly retarded when ATP (2 mM) levels were maintained by an ATP-regenerating system. The degradation of inositol 1,4,5-trisphosphate proceeded with the sequential formation of inositol 1,4-bisphosphate, the inositol 4-monophosphate (with smaller amounts of the 1-monophosphate), and finally inositol. Inositol 1,3,4-trisphosphate, on the other hand, was converted to inositol 1,3-bisphosphate and inositol 3,4-bisphosphate and subsequently to inositol 4-monophosphate and inositol 1-monophosphate (stereoisomeric forms were undetermined). The possible implications of the apparent interconversion between inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate in regulating histamine secretion in the RBL-2H3 cells are discussed.
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PMID:Formation of inositol 1,4,5-trisphosphate and inositol 1,3,4-trisphosphate from inositol 1,3,4,5-tetrakisphosphate and their pathways of degradation in RBL-2H3 cells. 326 12


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