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)

Reverse transcriptase (RT) is a modular enzyme carrying polymerase and ribonuclease H (RNase H) activities in separable domains. Retroviral replication requires both of these activities. The RNase H domain is responsible for hydrolysis of the RNA portion of RNA x DNA hybrids, and this activity requires the presence of divalent cations (Mg2+ or Mn2+) that bind its active site. This domain is a part of a large family of homologous RNase H enzymes of which the RNase HI protein from Escherichia coli is the best characterized. Although the isolated RNase H domain from human immunodeficiency virus RT is inactive, the Moloney murine leukemia virus (MMLV) domain is active in the absence of the polymerase domain, making functional studies more accessible. Using circular dichroism spectroscopy, we characterized the stability and folding of two different fragments of MMLV RT that retain RNase H activity. The smaller fragment corresponding to the 157 C-terminal residues of RT is predominantly unfolded in the absence of divalent cations, but folding can be induced by the addition of metal. The larger fragment corresponding to the 175 C-terminal residues, however, is stably folded in the absence of metal. Thus, an 18 residue N-terminal extension outside the region homologous to E. coli RNase HI is important for the structural stability of the RNase H domain of MMLV RT. Therefore, this region should be considered part of the RNase H domain.
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PMID:Folding the ribonuclease H domain of Moloney murine leukemia virus reverse transcriptase requires metal binding or a short N-terminal extension. 974 51

Epigenetic factors are known to influence the differentiation of neocortical neurons. The present study analyses the role of spontaneous bioelectrical activity (SBA) and neurotrophic factors on the expression of neuropeptide Y (NPY) in rat visual cortical neurons using organotypic monocultures prepared from newborn animals and in situ hybridization to detect the NPY messenger ribonucleic acid (mRNA). Spontaneously active cortex cultures display NPY mRNA expression in about 7% of all cortical neurons from 10 days in vitro (DIV) on. Blocking the SBA by chronic application of 10 mM Mg2+ for 3-30 DIV reduces the percentage of NPY neurons to about 2%. Allowing an initial phase of SBA (1-20 DIV) followed by an SBA blockade (for 21-50 DIV) results in 2% labelled neurons, indicating a dramatic reduction of NPY mRNA expression in the absence of SBA. Surprisingly, the reverse experiment (a period of SBA blockade for 1-20 DIV followed by a period of SBA recovery for 21-40 DIV) does not cause an upregulation of NPY mRNA expression. However, allowing cultures to differentiate as spontaneously active cultures, then applying a transient period of SBA blockade which is followed by a second period of SBA, does rescue the NPY mRNA expression in 7% of the cortical neurons. We conclude that SBA is a main trigger for NPY mRNA expression and it is particularly important during an early postnatal period of differentiation. We then analysed whether neurotrophic factors known to modulate cortical neuropeptide expression are able to do so in the absence of SBA. Supplementing chronically blocked cultures with the neurotrophins, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5) and the cytokine, leukaemia inhibitory factor (LIF), reveals that BDNF and NT-3 are unable to increase the percentage of NPY neurons. In contrast, LIF and NT-4/5 increase the percentage of NPY neurons to 4 and 6-7%, respectively. Moreover, neurons treated with NT-4/5 display a very high level of NPY mRNA expression in somata and in the dendritic trees. The data suggest a complex interplay and a hierarchy of epigenetic factors in regulating the neurochemical architecture of the developing neocortex.
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PMID:NT-4/5 and LIF, but not NT-3 and BDNF, promote NPY mRNA expression in cortical neurons in the absence of spontaneous bioelectrical activity. 974

Despite progress in leukemia therapy, only 20-30% of patients with acute myelogenous leukemia (AML) are cured. 1-beta-D-arabinofuranosylcytosine- and topoisomerase II-reactive drugs are the primary therapeutic agents used. The aim of this study was to evaluate the potential activity of tallimustine in leukemia. In this study, we first investigated the efficacy and toxic effects of tallimustine, a distamycin-A derivative, in a human leukemia model in severe combined immunodeficient (SCID) mice. On the basis of its dramatic activity in this preclinical study, a Phase I study of tallimustine at a starting dose of 300 microgram/m2/day for 3 days every 3-4 weeks was conducted in patients with refractory or relapsed leukemia. In SCID mice grafted with a human myelomonocytic leukemia cell line, tallimustine resulted in complete remission of disease in most mice at tolerable dosages ranging from 0.86 to 3.0 mg/kg/day for 3 days and was combined effectively and safely with a 2-day schedule of high-dose ara-C. In the Phase I study, 26 patients with refractory or relapsed leukemia were treated. The maximum tolerated dose was 900 microgram/m2/day for 3 days every 3-4 weeks. This dose was 3 times higher than the maximum tolerated dose in solid tumors and was limited by severe mucositis. Magnesium and potassium wasting were also observed, but other side effects (fatigue and gastrointestinal) were minor. Two (8%) patients with AML achieved complete remission and two achieved hematological improvement with persistent thrombocytopenia. The results of this study indicate that tallimustine has promising activity in AML. Future studies may combine tallimustine with other agents known to be active against AML, and investigate its activity in other hematological malignancies. The recommended Phase II single-agent dose of tallimustine is 750-900 microgram/m2/day for 3 days, and combination studies may start at 50-66% of this dose schedule. The SCID mouse model of human leukemia may be promising in the preclinical evaluation and selection of potential antileukemic agents.
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PMID:Tallimustine, an effective antileukemic agent in a severe combined immunodeficient mouse model of adult myelogenous leukemia, induces remissions in a phase I study. 981 37

The accumulation of molecular genetic defects selected during the adaptation process in the development of cisplatin-resistance was studied using progressive cisplatin-resistant variants (L1210/DDP2, L1210/DDP5, L1210/DDP10) derived from a murine leukemia cell line (L1210/0). Of these cell lines, only the most resistant L1210/DDP10 was cross-resistant to etoposide and deficient in apoptosis induced by these two drugs, indicating that resistance to DNA-damaging agents correlates with a defect in apoptosis. This defect was tightly associated with the loss of a Ca2+/Mg2+-dependent nuclear endonuclease activity present in the less cisplatin-resistant cells. Evidence is presented that p53-dependent function (a) is lost not only in the apoptosis defective L1210/DDP10 cells, but also in the apoptosis susceptible L1210/DDP5 cells; (b) is unrelated to drug-induced cell cycle perturbations. These results suggest that deficiency in the p53 pathway and resistance to DNA-damaging agents due to a defect in apoptosis are independent events.
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PMID:Alteration in p53 pathway and defect in apoptosis contribute independently to cisplatin-resistance. 1020 Apr 88

1. Genes related to trp (transient receptor potential) are proposed to encode store-operated channels. We examined the ionic permeation of recombinant channels formed by stable and transient expression of the TRP homologue bCCE1 in Chinese hamster ovary (CHO) cells (CHO(CCE1)) and rat basophilic leukaemia (RBL) cells, respectively. 2. Store-operated currents were activated in CHO(CCE1) cells by internal dialysis of IP3 under strong buffering of intracellular Ca2+. The action of IP3 was mimicked by thapsigargin but not by IP4. 3. With extracellular Ca2+, Na+ and Mg2+, the store-operated currents of CHO(CCE1) rectified inwardly in the presence of internal Cs+. Outward currents were not detected below +80 mV. Identical currents were recorded with external Ba2+ and also with no external Na+ and Mg2+. In the absence of external Mg2+, the inward currents showed an anomalous mole fraction behaviour between Ca2+ and Na+. Half-maximal inhibition of Na+ currents was observed with approximately 100 nM and full block with 2-5 microM external Ca2+. 4. In the parental CHO(-) cells, IP3 dialysis evoked inward currents that also displayed anomalous mole fraction behaviour between Ca2+ and Na+. However, half-maximal block of Na+ currents required 5 times higher Ca2+ concentrations in CHO(-) cells. Additionally, the density of Ca2+ and Na+ currents at -80 mV was 5 and 2 times larger in CHO(CCE1) cells, respectively. 5. In RBL cells, dialysis of IP3 evoked store-operated currents that showed 1.4-fold larger densities at -80 mV in cells expressing bCCE1. 6. The enhanced density of store-operated currents in CHO(CCE1) cells and in bCCE1-transfected RBL cells probably reflects the phenotype of CCE1. These results suggest a highly selective permeation of Ca2+ through recombinant channels formed by CCE1 either alone or in combination with endogenous channel proteins.
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PMID:Phenotype of a recombinant store-operated channel: highly selective permeation of Ca2+. 1042 2

Tight-seal whole-cell patch-clamp experiments were carried out in order to investigate the effects of different holding potentials on the rate of development and amplitude of the Ca2+ release-activated Ca2+ current ICRAC in rat basophilic leukaemia (RBL-1) cells. ICRAC was monitored at -80 mV from fast voltage ramps, spanning 200 mV in 50 ms. At hyperpolarised potentials, the macroscopic CRAC conductance was lower than that seen at depolarised potentials. The conductance increased almost 5-fold over the voltage range -60 to +40 mV and was seen when the stores were depleted either by the combination of IP3 and thapsigargin in high Ca2+ buffer, or passively with 10 mM EGTA or BAPTA. The voltage-dependent conductance of the CRAC channels could not be fully accounted for by Ca2+-dependent fast inactivation, nor by other slower inhibitory mechanisms. It also did not seem to involve intracellular Mg2+ or the polycations spermine and spermidine. Voltage step relaxation experiments revealed that the voltage-dependent conductance changes developed and reversed slowly, with a time constant of several seconds at -60 mV. In the presence of physiological levels of intracellular Ca2+ buffers, ICRAC was barely detectable when cells were clamped at -60 mV and dialysed with IP3 and thapsigargin, but at 0 mV the current in low Ca2+ buffer was as large as that seen in high Ca2+ buffer. Our results suggest that CRAC channels exhibit slow voltage-dependent conductance changes which can triple the current amplitude over the physiological range of voltages normally encountered by these cells. The role of this conductance change and possible underlying mechanisms are discussed.
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PMID:Voltage-dependent conductance changes in the store-operated Ca2+ current ICRAC in rat basophilic leukaemia cells. 1110 41

The role of protein kinases on store-operated Ca2+ entry in rat basophilic leukaemia cells (RBL) has been studied using the whole-cell configuration of the patch-clamp technique and Ca2+ imaging with fura-2. Specific inhibitors of tyrosine kinase (lavendustin A), mitogen-activated protein (MAP) kinase (SB 203580, PD 98059), Ca2+/calmodulin-dependent kinase (CaMK, KN-62, KN-93) and protein kinase C (PKC, bisindolylmaleimide I) had no significant effect on peak current amplitude and time constant of activation. Likewise, the broad spectrum kinase blockers H-7 and staurosporine did not alter Ca2+ entry compared to control recordings. Store-mediated Ca2+ entry was unaffected if intracellular ATP was substituted by either adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS) or adenylyl-imidodiphosphate (AMP-PNP). Similarly, buffering intracellular Mg2+, an essential cofactor for protein kinases, had no effect on Ca2+ influx. These results indicate that protein phosphorylation by various kinases is not required for the activation of the store-operated Ca2+ current in RBL cells.
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PMID:Activation of store-operated Ca2+ entry in RBL cells without the contribution of protein kinases. 1141 58

Targeting of PML/RARalpha using a loss of function strategy in acute promyelocytic leukemia (APL) is a direct therapeutic approach for patients and may be the basis of future gene therapy for this leukemia. To achieve this, we designed specific maxizymes, novel allosterically controllable ribozymes, against both short and long PML/RARalpha isoforms. The maxizyme has sensor arms that can only recognize target sequences, and it can form a cavity that captures catalytically indispensable Mg2+. We deleted 1 base nucleotide in the Mg2+-binding pocket designed MzPRT50 and MzPRK55. The distance from the PML/RARalpha junction site to the center of effectors is only 2 bases, and there are 8 and 9 complementary bases in their inactive forms, respectively. Both maxizymes specifically cleaved PML/RARalpha mRNA but not wild-type RARalpha mRNA in a cell-free system. Modification of the sequence of the Mg2+-binding pocket will be important in designing the sequence-specific maxizymes against oncogenic genes.
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PMID:A novel therapeutic technology of specific RNA inhibition for acute promyelocytic leukemia: improved design of maxizymes against PML/RARalpha mRNA. 1174 52

Flavonoids are a group of naturally occurring compounds with interesting medical properties, such as antiinflammatory, antiallergic, antiviral, antibacterial and antitumor activities. In our experiments we were trying to examine the tumoricidal activity of newly synthesized derivatives of two flavonoids: 3,5,7,2',4'-pentahydroxyflavone (morin) and 3,5,7,3',4'-pentahydroxyflavone (quercetin). These derivatives were: natrium salt of morin-5'-sulfonic acid (NaMSA), natrium salt of quercetin-5'-sulfonic acid (NaQSA), complex of Mg2+ with quercetin-5'-sulfonic acid (QSA), complex of iron(II) with QSA. The antitumor activity of these agents was tested in vitro on two cell lines: L1210--murine lymphocytic leukaemia and P-815--murine mastocytoma. Our experiments showed that sulfonic derivatives of these two flavonoids were less potent than the original agents in their cytostatic and cytotoxic activities. However, their solubility in water was greater than that of the original agents and higher culture medium concentration of these derivatives was obtained. The results indicate that the ability of flavonoids to act tumoricidally is reciprocally correlated with their lipophilicity.
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PMID:Synthesis and tumoricidal activity evaluation of new morin and quercetin sulfonic derivatives. 1202 18

Explicit solvent molecular dynamics (MD) simulations were carried out for three RNA kissing-loop complexes. The theoretical structure of two base pairs (2 bp) complex of H3 stem-loop of Moloney murine leukemia virus agrees with the NMR structure with modest violations of few NMR restraints comparable to violations present in the NMR structure. In contrast to the NMR structure, however, MD shows relaxed intermolecular G-C base pairs. The core region of the kissing complex forms a cation-binding pocket with highly negative electrostatic potential. The pocket shows nanosecond-scale breathing motions coupled with oscillations of the whole molecule. Additional simulations were carried out for 6 bp kissing complexes of the DIS HIV-1 subtypes A and B. The simulated structures agree well with the X-ray data. The subtype B forms a novel four-base stack of bulged-out adenines. Both 6 bp kissing complexes have extended cation-binding pockets in their central parts. While the pocket of subtype A interacts with two hexacoordinated Mg2+ ions and one sodium ion, pocket of subtype B is filled with a string of three delocalized Na+ ions with residency times of individual cations 1-2 ns. The 6 bp complexes show breathing motions of the cation-binding pockets and loop major grooves.
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PMID:Molecular dynamics simulations of RNA kissing-loop motifs reveal structural dynamics and formation of cation-binding pockets. 1462 27


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