Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biochemical bases of the multidrug-resistant (MDR) phenotype were investigated in drug-resistant sublines derived from LoVo human colon carcinoma cell lines by doxorubicin (DOX) and teniposide (VM26) selection. In addition to P-glycoprotein-mediated drug extrusion through the plasma-membrane, LoVo MDR cells display a further drug-resistance mechanism. That is, to achieve equitoxic effects, LoVo MDR sublines require much higher intracellular drug concentrations than those required by LoVo drug-sensitive parent cell line. Involvement of mdr1, topoisomerase II and glutathione-S-transferase-pi (GST-pi) drug-resistance systems in intracellular drug resistance was investigated. Pharmacologic and biochemical data indicated that intracellular drug resistance in LoVo MDR sublines is uniquely consequent to the drug-transporting property of intracytoplasmic membrane-bound P-glycoprotein molecules which compartment drugs in vacuole-like structures.
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PMID:P-glycoprotein but not topoisomerase II and glutathione-S-transferase-pi accounts for enhanced intracellular drug-resistance in LoVo MDR human cell lines. 135 86

Human colorectal and pulmonary carcinomas have been shown to contain high levels of opioid peptides and their corresponding membrane-bound receptors. Therefore possible targeted drugs, consisting of modified enkephalins linked to cytotoxic drugs, were designed. Such conjugates were expected to be specifically internalized within opioid receptor-bearing cells. As a model to this approach, we have synthesized enkephalin-ellipticinium conjugates in which the D-Ala2-D-Leu5-enkephalin (DADLE) was coupled to the 2-nitrogen of either ellipticine or 9-hydroxyellipticine, two drugs acting through different mechanisms of cytotoxicity. These conjugates, DADLE-ellipticinium (NME) and DA-DLE-9-hydroxyellipticinium (NMHE), respectively, were previously shown to retain in vitro both opioid receptors and DNA affinities close to those of the parent compounds. In this paper, we first show that each individual moiety in the complexes remains capable of recognizing its cellular targets. Thus, pretreatment of NG108-15 cells containing delta-opioid receptors by the DADLE-ellipticinium conjugates induced a loss of opioid receptor (down-regulation), while the smaller peptide conjugates, tyrosinyl-D-alanylglycine-ellipticinium, prepared as control, do not. On the other hand, peptide-NMHE conjugates were able to induce DNA topoisomerase II-associated DNA strand breaks suggesting that they have a mode of action similar to that of their parent molecule, NMHE. We then examined whether or not these molecules could exert a specific toxicity on opioid receptor-bearing cells. However, when tested on NG108-15 tumor cells and L-fibroblasts as control, the enkephalin-ellipticinium conjugates (DADLE-NME and DADLE-NMHE) proved to be similarly more cytotoxic on both cell lines than their ellipticinium (NME and NMHE) precursors. In order to understand this apparent lack of specificity we examined the cellular accumulation and distribution of DADLE-NME by fluorescence techniques. These experiments revealed that an important intracellular overconcentration caused by a nonspecific process is probably masking the specific targeted effect of the conjugates. Hence, the project of linking DADLE to highly cytotoxic molecules which cannot cross the plasma membrane without site-directed targeting is discussed.
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PMID:Attempts to target antitumor drugs toward opioid receptor-rich mouse tumor cells with enkephalin-ellipticinium conjugates. 253 35

We have recently shown that the aggregation factor (AF) from the sponge Geodia cydonium stimulates DNA synthesis in quiescent, dissociated cells from the same organism; this event was correlated with the release of the two second messengers: inositol trisphosphate and diacylglycerol. Here we describe that after binding of the AF to the plasma membrane-bound aggregation receptor, a rapid and drastic increase in the incorporation of 32Pi into a series of proteins in the pore complex-lamina fraction occurs. Addition of the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate, to quiescent cells resulted in a similar stimulation of phosphorylation of nuclear proteins. Among them we have selected one protein with a polypeptide Mr of 170,000 (pp170) for detailed studies. By immunoblotting pp170 was identified as DNA topoisomerase II. In vitro studies with nuclei and purified, homogeneous protein kinase C together with the required activators of this enzyme also showed a phosphorylation of pp170. After phosphorylation, DNA topoisomerase II activity was found to be 2.5-fold that of the non-phosphorylated enzyme. From these data we conclude that protein kinase C is involved in AF induced transmembrane signalling, ultimately leading to an initiation of DNA synthesis.
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PMID:Specific phosphorylation of proteins in pore complex-laminae from the sponge Geodia cydonium by the homologous aggregation factor and phorbol ester. Role of protein kinase C in the phosphorylation of DNA topoisomerase II. 283 45

An increase in the amount of membrane-bound DNA was found in B. subtilis cells with UV-induced DNA repair synthesis as compared to untreated cells. It was shown that DNA repair synthesis occurred in DNA membrane complexes (DMC) formed during UV-irradiation. UV-induced formation of DMC was observed in cells of wild type strains which were capable of repairing damaged DNA but not in a mutant defective in DNA-polymerase I. It was demonstrated that DNA-polymerase I is located on the membrane of B. subtilis cells. This suggested a participation of DNA-polymerase I in binding of the chromosome to the membrane in UV-irradiated cells. UV-induced DMC did not dissociate when the cells were treated with inhibitors of DNA-gyrase. It, therefore, was qualitatively different from the DMC found during replication. The mechanisms of binding of the damaged DNA to the membrane in UV-irradiated cells of B. subtilis are discussed.
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PMID:Formation of additional contacts of chromosome with membrane in the process of DNA repair synthesis in bacterial cells. 642 52

A preparation of bacteriophage T4-induced deoxyribonucleotide synthetase complex is described. This very large complex of enzymes can be separated by centrifugation at 100,000 X g, by sucrose step gradient centrifugation, or with molecular exclusion columns. By direct assay and by unidimensional and two-dimensional acrylamide electrophoretic separations the following T4-coded enzymes were shown to be associated with the complex: ribonucleoside diphosphate reductase, dCMP deaminase, dCTP/dUTPase, dCMP hydroxymethylase, dTMP synthetase, and DNA polymerase. Other phage-coded prereplicative proteins related to DNA replication and other phage functions such as the proteins coded by genes 32, 46, rIIA, and rIIB as well as many unidentified proteins were also consistently associated with the isolated fractions. T4 DNA topoisomerase, a membrane-bound enzyme, was found in quantity in all purified fractions of the complex, even in preparations apparently free of membrane and of T4 DNA. The functional integrity of a segment of the complex was followed by measuring the conversion of [5-3H]CDP to the level of 5-hydroxymethyl dCMP. This series of reactions requires the actions of T4-coded ribonucleoside diphosphate reductase and its associated reducing system, dCTP/dUTPase and dCMP hydroxymethylase, 3H being lost to water at the last step. In this reaction sequence an intermediate, [5-3H]dCMP, is maintained at low steady state concentrations, and argument is presented that the synthesis of deoxyribonucleotides is channeled and normally tightly coupled to DNA replication. One of the primary characteristics of this complex is its ready dissociation of dilution into smaller complexes of proteins and to the free forms of the proteins. That the complex is held together by weak electrostatic forces was supported by its sensitivity to dissociation at moderate salt concentrations. Not only the enzymes required in deoxyribonucleotide synthesis but T4 DNA polymerase, T4 DNA topoisomerase, and a number of other proteins dissociate to varying degrees from the larger complexes under these conditions.
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PMID:Characteristics of a bacteriophage T4-induced complex synthesizing deoxyribonucleotides. 675 52

The administration of 150 nM etoposide, an inhibitor of DNA topoisomerase II activity, decreased the proliferation and induced the differentiation of U937 human promonocytic cells, as determined by nitroblue tetrazolium reduction, surface accumulation of CD11b/CD18 and CD11c/CD18 integrins, and c-fms protooncogene expression. The expression of these differentiation markers started to be detected at 24 h of treatment. Etoposide caused little cell damage, as determined by trypan blue exclusion and by apoptotic-like DNA degradation, which was slightly initiated at 48 h. The treatment induced a transient increase in c-fos, c-jun, and jun B mRNA levels, with maximum values at 12 h, a transient increase in collagenase mRNA level, with maximum value at 48 h, and a progressive increase in vimentin and lamin A and C mRNAs. These changes were qualitatively similar to those produced by 12-O-tetradecanoylphorbol-13-acetate. Etoposide also caused a transient increase of total AP-1 binding activity, with maximum value at 12 h of treatment, as determined by gel retardation assays. The drug produced an early transient activation (3-6 h) of membrane-bound protein kinase C, followed by the later activation (48 h) of both the membrane and cytosolic enzyme. The protein kinase C inhibitors, sphinganine and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), attenuated the induction of differentiation markers by etoposide. These results suggest that protein kinase C and AP-1-dependent gene expression could be involved in myeloid cell differentiation by DNA topoisomerase II inhibitors.
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PMID:Etoposide-induced differentiation of U937 promonocytic cells: AP-1-dependent gene expression and protein kinase C activation. 781 32

We have compared the action on U-937 human promonocytic leukemia cells of two DNA topoisomerase II inhibitors, namely the epipodophyllotoxin etoposide and the bisdioxopiperazine ICRF-193. One hour pulse-treatment with 3 microM etoposide caused topoisomerase associated, primary DNA breakage, which was rapidly followed by apoptosis. By contrast, these effects were not observed upon pulse-treatment with 6 microM ICRF-193. However, continuous treatments with subcytotoxic concentrations of etoposide (0.15 microM) and ICRF-193 (0.3 microM) produced several similar effects, namely decreased cell proliferation, accumulation of cells at G2, increase in cell mass, and induction of differentiation. Under these conditions, etoposide produced a biphasic activation of protein kinase C, which consisted in an early transient activation (from hours 1 to 6) of the membrane-bound enzyme followed by a later activation (hour 48) of the total, membrane-bound and cytosolic enzyme. By contrast, ICRF-193 only provoked a late activation (from hours 72 to 96) of the total enzyme. When used at differentiation-inducing concentrations, both topoisomerase inhibitors caused a great stimulation of AP-1 binding activity, with maximum value at hour 12 in etoposide-treated cells and at hour 48 in ICRF-193-treated cells. By contrast, the binding activity of the NF-kappa(B) and EGR-1 transcription factors was little affected. It is concluded that topoisomerase II inhibitors may induce the differentiation of promonocytic cells, independently of their capacity to cause DNA strand breaks. However, there are other effects, such as the early activation of protein kinase C, which are probably derived from the production of primary DNA breakage by some anti-topoisomerase drugs.
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PMID:Differentiation of U-937 promonocytic cells by etoposide and ICRF-193, two antitumour DNA topoisomerase II inhibitors with different mechanisms of action. 905 86

Streptococcus pneumoniae is uniquely sensitive to amino alcohol antimalarials in the erythro configuration, such as optochin, quinine, and quinidine. The protein responsible for the optochin (quinine)-sensitive (Opts, Qins) phenotype of pneumococcus is the proteolipid c subunit of the FzeroF1 H(+)-ATPase. OptR/QinR isolates arose by point mutations in the atpC gene and produce different amino acid changes in one of the two transmembrane alpha-helices of the c subunit. In addition, comparison of the sequence of the atpCAB genes of S. pneumoniae R6 (Opts) and M222 (an OptR strain produced by interspecies recombination between pneumococcus and S. oralis), and S. oralis (OptR) revealed that, in M222, an interchange of atpC and atpA had occurred. We also demonstrate that optochin, quinine, and related compounds specifically inhibited the membrane-bound ATPase activity. Equivalent differences between Opts/Qins and OptR/QinR strains, both in growth inhibition and in membrane ATPase resistance, were found. Pneumococci also show a characteristic sensitivity to coumarin drugs, and a relatively high level of resistance to most quinolones. We have cloned and sequenced the gyrB gene, and characterized novobiocin resistant mutants. The same amino acid substitution (Ser-127 to Leu) confers novobiocin resistance on four isolates. This residue position is equivalent to Val-120 of Escherichia coli ryGB, a residue that lies inside the ATP-binding domain but is not involved in novobiocin binding in E. coli, as revealed by crystallographic data. In addition, the genes encoding the ParC and ParE subunits of topoisomerase IV, together with the region encoding amino acids 46 to 172 (residue numbers as in E. coli) of the pneumococcal ryGA subunit, were characterized in respect to fluoroquinolone resistance. The gyrA gene maps to a physical location distant from the gyrB and parEC loci on the chromosome. Ciprofloxacin-resistant (CpR) clinical isolates had mutations affecting amino acid residues of the quinolone resistance-determining region of ParC (low-level CpR), or in both resistance-determining regions of ParC and GyrA (high-level CpR). Mutations were found in residue positions equivalent to Ser-83 and Asp-87 of the E. coli GyrA subunit. Transformation experiments demonstrated that topoisomerase IV is the primary target of ciprofloxacin, DNA gyrase being a secondary one.
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PMID:Molecular bases of three characteristic phenotypes of pneumococcus: optochin-sensitivity, coumarin-sensitivity, and quinolone-resistance. 918 46

Chemotherapy is the principal strategy to systemically challenge metastasized cancers of genitourinary origin. Unfortunately, the efficacy of chemotherapy is often hampered by multidrug resistance, the resistance to a variety of structurally and functionally distinct cytotoxic agents. Multidrug resistance can be either intrinsic or acquired, and can be caused by several mechanisms. The so-called classical multidrug resistance, mediated by the MDR1 gene product P-glycoprotein, has been held mainly responsible for inferring the multidrug resistance phenotype on urologic malignancies. However, several other multidrug resistance pathways have been identified. Multidrug resistance can be caused by the membrane-bound multidrug-resistance-associated protein, the detoxifying glutathione metabolism, the antiapoptotic protein BCL2, and changes in levels or activity of the topoisomerase enzymes. Strategies to overcome multidrug resistance of genitourinary tumors have arisen from the better understanding of the biologic and molecular mechanisms of multidrug resistance, and have been studied in experimental and clinical settings. However, attempts to modulate multidrug resistance in clinical renal cell, bladder, prostate, and testicular cancer have not been very rewarding so far, despite the optimism that had arisen from experimental data. Nevertheless, application of novel therapies to reverse multidrug resistance and to increase efficacy of chemotherapy for urologic cancers should be further pursued, within the setting of controlled clinical trials, to improve on current strategies.
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PMID:Circumvention of multidrug resistance in genitourinary tumors. 953 94

Lamina-associated polypeptide 2 alpha (LAP2 alpha) is a non-membrane-bound isoform of the LAP2 family involved in nuclear structure organization. Using various cell systems, including Jurkat, HL-60, and HeLa cells, and different death-inducing agents, such as anti-Fas antibody, topoisomerase inhibitors, and staurosporine, we found that LAP2 alpha was cleaved during apoptosis as rapidly as lamin B in a caspase-dependent manner yielding stable N- and C-terminal fragments of approximately 50 and 28 kDa, respectively. Based on fragment size and localization of immunoreactive epitopes, four potential cleavage sites were mapped between amino acids 403-485. These sites were located within a domain that has previously been described to be essential and sufficient for association of LAP2 alpha with chromosomes, suggesting that LAP2 alpha cleavage impairs its chromatin-binding properties. Immunofluorescence microscopy demonstrated that, unlike full length protein, apoptotic fragments did not colocalize with condensed chromatin, but remained in the nuclear compartment as long as a single nucleus was visible. Subfractionation analyses showed that the N-terminal LAP2 alpha fragment was extracted from intranuclear structures in detergent/salt buffers, whereas the C-terminal fragment remained associated with a residual framework devoid of chromatin. Our data suggest that early cleavage of LAP2 alpha) is important for chromatin reorganization during apoptosis.
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PMID:Caspase-mediated cleavage of the chromosome-binding domain of lamina-associated polypeptide 2 alpha. 1103 5


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