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)

The pathophysiological responses to immune stress (IS) include activation of several processes which are dependent on cytosolic Ca2+ elevation. Magnesium frequently acts as a natural Ca2+ antagonist. In this study we have observed that Mg2+ can protect guinea-pigs against IS. Antigen-sensitized guinea-pigs, which had been fed a magnesium-deficient diet, were given a single dose (15 mg) of MgCl2 intraperitoneally 1 h before antigen challenge. The development of anaphylactic shock (AS) was observed during the next 2 h, and the hearts were subsequently examined histologically for signs of cardiac myolysis (CM). Magnesium (i) reduced the incidence of CM from 40% to 10% (p < 0.05); (ii) reduced the incidence of AS from 61% to 35% (p < 0.05); (iii) attenuated the severity of the AS; and (iv) lowered mortality from 39% in the control to 19% in the Mg(2+)-treated group (p = 0.1). Serum and tissue total [Mg2+] were not affected by the administration of MgCl2. Also, the serum and heart Mg2+ levels were the same whether or not the guinea-pigs developed AS or CM. In cell culture we demonstrated that by elevating the [Mg2+] in the medium bathing sensitized rat basophilic leukemia (RBL) cells, the increase in cytosolic [Ca2+] subsequent to antigen challenge was reduced from 174 +/- 23.28% (1 mM) to 82.74 +/- 13.22% (3 mM). We conclude that a single treatment with Mg2+ can considerably diminish damage induced by immune stress, probably by its altering the Ca2+: Mg2+ ratio. Since the physiological reaction to different types of stress is similar, Mg2+ could prove beneficial in preventing stress-induced shock in general. Studies examining the mechanisms by which Mg2+ exerts its effects thus provide a scientific basis for the current clinical use of Mg2+ in acute myocardial infarction (AMI) and asthma.
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PMID:Magnesium protects against anaphylactic shock and cardiac myolysis in guinea-pigs. 873 70

Whole-cell patch clamp experiments were performed to examine the effects of the nonhydrolyzable GTP analogue, guanosine 5'-3-O-(thio)triphosphate, on membrane currents in rat basophilic leukemia cells. Guanosine 5'-3-O-(thio)triphosphate activated an inward sodium current. This current had a new permeability sequence to monovalent cations and a different pharmacological profile to that of other characterized Na+ channels. Long hyperpolarizing steps revealed that the current declined during the pulse, and the decline was voltage-dependent. Activation of the current required Mg2+ and ATP. The nonhydrolyzable ATP analogues, adenosine 5'-O-(thio)triphosphate and adenosine 5'-(beta,gamma-imino)triphosphate, could not substitute for ATP. Soluble second messengers like cAMP, cGMP, inositol polyphosphates, and Ca2+ did not activate the Na+ current. These results suggest that nonhydrolyzable GTP analogues activate a Na+ current in rat basophilic leukemia cells that is new in terms of its selectivity, pharmacology, and activation mechanism. It may be the prototype for a new family of Na+ channels expressed in certain nonexcitable cells.
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PMID:Nonhydrolyzable analogues of GTP activate a new Na+ current in a rat mast cell line. 879 10

An ultra-sensitive assay for reverse transcriptase (RT) activity called Amp-RT has been developed. An in vitro transcribed heteropolymeric RNA sequence was used as a template, and polymerase chain reaction (PCR) amplification with Southern-blot hybridization served as a detection system for the cDNA product of the reaction. Titration of Mg2+ and Mn2+ concentrations using the human immunodeficiency virus type 1 (HIV-1) and the human T lymphotropic virus type 1 (HTLV-I), respectively, showed optimal assay reactivity for both viruses at 2-20 mM of Mg2+. Analysis of density banded HIV-1 showed that the peak RT activity of the assay was associated with the fractions consistent with retrovirus particles. The sensitivity of Amp-RT was also compared with that of three conventional RT assays by using seven different retroviruses including HIV-1, simian immunodeficiency virus (SIV), caprine arthritis-encephalitis virus (CAEV), HTLV-I and HTLV-II, simian retrovirus type 2 (SRV-2), and gibbon ape leukemia virus (GALV). HTLV-I, HTLV-II, and GALV could not be detected by the three conventional RT assays. Amp-RT was able to detect all these viruses in 10(1)-10(3)-fold dilutions. Similarly, Amp-RT was found to be 10(3)-10(6)-fold more sensitive than the other RT assays in detecting HIV-1, SIV< or CAEV. Culture supernatants from uninfected cell lines were all Amp-RT negative. A quantitative Amp-RT assay was also developed by using recombinant HIV-1 RT and signal quantitation. The assay was found to have a 5 log linear range, and therefore, provides a useful tool for quantitating RT and retroviruses. Amp-RT offers a sensitive generic tool for the qualitative and quantitative detection of known and unknown retroviruses.
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PMID:Highly sensitive qualitative and quantitative detection of reverse transcriptase activity: optimization, validation, and comparative analysis with other detection systems. 888 46

Aggregation of the high-affinity receptor for IgE (Fc eta RI) on the surface of intact or permeabilized rodent mast cells results in tyrosine phosphorylation of phospholipase C-gamma 1 (PLC gamma 1) and PLC gamma 2, and translocation of both isozymes to the particulate fraction. We report here that activation of resident tyrosine kinases by the addition of adenosine triphosphate (ATP), orthovanadate, and Mg2+ to rat basophilic leukemia cell (RBL) lysates induces an association of PLC gamma 2 with the Triton-insoluble particulate fraction, with a parallel increase in tyrosine phosphorylation of cellular proteins. Both PLC gamma 2 translocation and tyrosine phosphorylation are supported by millimolar Mg2+ or Mn2+ but not by Ca2+. Both tyrosine phosphorylation and PLC gamma 2 translocation are inhibited by genistein. These data suggest that in vitro activation of tyrosine kinase activity in broken cell preparations induces the formation of association between PLC gamma 2 and ligands with the Triton-insoluble fraction.
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PMID:Translocation of phospholipase C-gamma 2 induced by in vitro activation of protein tyrosine kinase activity in mast cell lysates. 895 50

The reverse transcriptase-associated RNase H activity of Moloney murine leukemia virus specifically cleaves within the polypurine tract region of the viral genome to generate the primer for plus-strand DNA synthesis and removes the tRNA primer after minus-strand initiation by preferentially cleaving the RNA one nucleotide before the RNA-DNA junction. Moreover, the enzyme is unable to cleave the extended tRNA substrate at the RNA-DNA junction even at high enzyme concentrations. The RNase H domain of the reverse transcriptase was expressed as a glutathione S-transferase fusion protein and purified from Escherichia coli extracts. Following removal of the glutathione S-transferase portion of the protein, the specificity of the isolated RNase H domain was determined in the plus-strand primer reaction and in the tRNA primer removal reaction. Although the isolated domain lacked specificity in both cases, it was still unable to cleave the tRNA substrate precisely at the RNA-DNA junction. Specificity in both cases could be restored by adding back a truncated form of Moloney murine leukemia virus reverse transcriptase lacking the RNase H domain. These results implicate the polymerase domain as a specificity determinant for the RNase H activity of reverse transcriptase. The isolated RNase H domain had higher activity in the presence of Mn2+ than in the presence of Mg2+, but neither the RNase H domain alone nor the RNase H domain coupled to the polymerase domain in wild-type protein exhibited the normal cleavage specificities in the presence of the nonphysiological divalent cation.
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PMID:RNase H domain of Moloney murine leukemia virus reverse transcriptase retains activity but requires the polymerase domain for specificity. 897 Sep 88

Using an autodigestion method, we investigated endogenous endonuclease(s) in leukemia cells freshly obtained from pediatric patients with various types of leukemia. Endonucleolytic activity was found to cause both high molecular weight and internucleosomal DNA fragmentation at a neutral pH in whole cell lysates of all common acute lymphoblastic leukemia (cALL) blasts, which was Mg2+-dependent and Ca2+-independent. Whole lysates from most acute myeloblastic leukemia (AML) cells possessed similar endonuclease activity, but both Mg2+ and Ca2+ were required for the activity. Our results suggest that leukemia cells of different lineages have distinct constitutive endonucleases, which may play a role in the occurrence of apoptosis in these cells.
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PMID:Constitutive endonuclease to induce high molecular weight or internucleosomal DNA fragmentation in freshly isolated leukemia cells. 923 28

Cleavage of cellular DNA into high molecular weight (predominantly 50 kb) fragments is an early event during apoptosis. We previously reported that this fragmentation was a Ca2+-independent process during apoptosis, which was induced by anticancer agents in human leukemia cells. The present study demonstrated that a high molecular weight DNA fragmentation activity (HDFA) was induced in the drug-treated cells and, upon fusion of the drug-treated cells with untreated target cells prelabeled with [14C]thymidine, caused fragmentation of the labeled DNA in the target cells. Furthermore, extracts of the drug-treated cells caused high molecular weight DNA fragmentation in nuclei isolated from untreated cells. Biochemical characterization of HDFA revealed the following properties: HDFA was proteinaceous in nature, as evidenced by its inactivation by heating or by digestion with proteinase K; HDFA required Mg2+ for optimal activity but was inhibited by Zn2+ and K+; HDFA was active in vitro at pH 6.0-8.0 and was inactive under more acidic conditions (pH < 6.0); addition of ATP (0.5-2 mM) substantially potentiated HDFA activity in isolated nuclei; and HDFA was not inhibited by actin (an inhibitor of DNase I) but was inhibited by the extracts from K562 cells, which were resistant to drug-induced apoptosis. The specific inhibitor of cysteine proteases (interleukin 1beta-converting enzyme protease family) blocked the generation of drug-induced high molecular weight DNA fragmentation in whole cells, whereas in isolated nuclei, the cysteine protease inhibitors did not prevent the cleavage of chromatin by exogenous HDFA. These results suggest that, once HDFA is activated during apoptosis, it does not require the presence of cysteine proteases for its endonucleolytic activity and that the cysteine proteases may be involved in the apoptotic process upstream of the activation of HDFA in whole cells.
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PMID:Biochemical characterization of the protein activity responsible for high molecular weight DNA fragmentation during drug-induced apoptosis. 927 6

Unfolding of an mRNA pseudoknot that induces ribosome suppression of the gag gene stop codon in Moloney murine leukemia virus has been studied by UV hyperchromicity and calorimetry. The pseudoknot melts in two steps, corresponding to its two helical stems. The total enthalpy of denaturation is approximately 170 kcal/mol, approximately the value expected for the secondary structure. At low salt concentrations (<50 mM KCl) the unfolding transitions are not two-state, but they approach two-state behavior at higher salt concentrations. The structure is preferentially stabilized by smaller alkali metal ions (Li+ > Na+ > K+ > Rb+ > Cs+) and by NH4+; the same preferences are exhibited by one of the stems in the context of a hairpin. Divalent metal ions are not required to fold the pseudoknot but do stabilize it further. To examine divalent ion effects over a wide concentration range, urea was used to lower the RNA unfolding temperature and was shown not to affect characteristics of the pseudoknot unfolding in other respects. The pseudoknot binds divalent ions somewhat more tightly than a hairpin but shows only weak selectivity for different size ions. It is suggested that a region of "intermediate" divalent ion binding affinity, in between highly ligated specific sites and purely delocalized ion binding in character, is created by the pseudoknot fold but that nonspecific, delocalized ion binding contributes at least half the free energy of pseudoknot stabilization by Mg2+.
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PMID:Folding of an mRNA pseudoknot required for stop codon readthrough: effects of mono- and divalent ions on stability. 940 51

Thymidylate synthase (TS) inhibition causes cell death, and this enzyme is the target for the important chemotherapy regime 5-fluorouracil/leucovorin. GW1843 (1843U89) is a potent and specific folate analog TS inhibitor in clinical development. Because of the importance of TS as a chemotherapy target, we are studying the mechanism of TS inhibition-induced cell death by GW1843. Ceramide is a regulatory lipid generated by the action of sphingomyelinase and is believed to signal apoptosis. The role of the ceramide in apoptotic signaling was studied in Molt-4 human T-cell leukemia cells undergoing cell death after treatment with GW1843. In response to GW1843, Molt-4 cells undergo apoptosis with both acidic pH, Mg2+-independent sphingomyelinase (ASMase) and neutral pH, Mg2+-dependent sphingomyelinase (NSMase) activities elevated as early steps in the initiation of apoptosis before Molt-4 commitment to death. These activities lead to ceramide production with kinetics consistent with a role as an effector molecule signaling the initiation of apoptosis in Molt-4 cells. These changes were found to be independent of caspase 3-like (CPP32/apopain) activity and DNA degradation, but were not separable from membrane blebbing or cell lysis in this cell line. In this report, kinetic evidence is provided for a role of ceramide in initiating GW1843-induced cell death of Molt-4 T-cell leukemia cells.
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PMID:Increases in neutral, Mg2+-dependent and acidic, Mg2+-independent sphingomyelinase activities precede commitment to apoptosis and are not a consequence of caspase 3-like activity in Molt-4 cells in response to thymidylate synthase inhibition by GW1843. 959 84

We investigated the effect of diphenylthiocarbazone (dithizone) and its structurally related compounds on the differentiation and apoptosis of two human myeloid leukemia cell lines. Dithizone caused a time- and concentration-dependent induction of differentiation in both the promyelocytic leukemia cell line HL-60 cells and the myeloblastic leukemia cell line ML-1 cells, as measured by nitroblue tetrazolium (NBT) reducing activity. Morphological changes and esterase activities confirmed that this differentiation took place. The induction of differentiation required the addition of dithizone to the culture medium for at least 12 h. The differentiation inducing activity was inhibited by the preincubation of dithizone with various metal ions such as Pb2+, Zn2+, Cu2+ and Mn2+ ions, but not with Fe3+ and Mg2+ ions. In addition, the DNA extracted from dithizone-treated HL-60 cells showed a typical ladder pattern characteristic of apoptosis in agarose gel electrophoresis. A quantitative analysis of DNA fragmentation revealed that this apoptosis was concentration- and time-dependent in both the HL-60 and ML-1 cells. Dithizone-induced apoptosis was also inhibited by preincubation with Mn2+ ions, but not with Mg2+ ions. These results indicate that dithizone induces both differentiation and apoptosis in HL-60 and ML-1 cells through a unique mechanism including metal chelation.
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PMID:Induction of differentiation and apoptosis by dithizone in human myeloid leukemia cell lines. 965 26


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