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:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cell cycle phase-dependent induction of DNA damage and apoptosis by etoposide (VP-16) and its modulation by 1-[N,O-bis(1, 5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-piperazine (KN-62), an inhibitor of calcium-calmodulin-dependent enzymes, were examined in sensitive (HL-60/S) and VP-16-resistant (HL-60/DOX0.05) HL-60 cells. Cells from exponential-phase cultures were enriched by centrifugal elutriation into G(1), S, and G(2)+M fractions. Modulation of VP-16-induced apoptosis by KN-62 in HL-60/S cells was apparent only in the S phase at the IC(50) concentration. However, in the HL-60/DOX0.05 cells, significant (P < 0.001) potentiation of VP-16-induced apoptosis by a non-cytotoxic concentration of 2 microM KN-62 was apparent in cells in the G(1), S, and G(2)+M phases, as well as over the entire concentration range tested. VP-16-induced apoptosis and its potentiation by a non-cytotoxic concentration of 2 microM KN-62 were correlative with drug-stabilized DNA cleavable complex formation based on a band depletion assay. In agreement with the results on apoptosis in the resistant HL-60/DOX0.05 cells, the enhanced depletion of the alpha and beta isoforms of topoisomerase II by VP-16 + KN-62 was observed in G(1), S, and G(2)+M cells. Results suggest that the effects of KN-62 in reversing resistance are based on its role as a potent sensitizer of VP-16-induced DNA damage and apoptosis in a cell cycle phase-independent manner.
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PMID:Cell cycle phase specificity in the potentiation of etoposide-induced DNA damage and apoptosis by KN-62, an inhibitor of calcium-calmodulin-dependent enzymes. 1113 8

DNA damage in neurons is implicated in the pathogenesis of several neurodegenerative disorders and may also contribute to the often severe neurological complications in cancer patients treated with chemotherapeutic agents. DNA damage can trigger apoptosis, a form of controlled cell death that involves activation of cysteine proteases called caspases. The excitatory neurotransmitter glutamate plays central roles in the activation of neurons and in processes such as learning and memory, but overactivation of ionotropic glutamate receptors can induce either apoptosis or necrosis. Glutamate receptors of the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate) type mediate such physiological and pathological processes in most neurons. We now report that DNA damage can alter glutamate receptor channel activity by a mechanism involving activation of caspases. Whole-cell patch clamp analyses revealed a marked decrease in AMPA-induced currents after exposure of neurons to camptothecin, a topoisomerase inhibitor that induces DNA damage; N-methyl-d-aspartate (NMDA)-induced currents were unaffected by camptothecin. The decrease in AMPA-induced current was accompanied by a decreased calcium response to AMPA. Pharmacological inhibition of caspases abolished the effects of camptothecin on AMPA-induced current and calcium responses, and promoted excitotoxic necrosis. Combined treatment with glutamate receptor antagonists and a caspase inhibitor prevented camptothecin-induced neuronal death. Caspase-mediated suppression of AMPA currents may allow neurons with damaged DNA to withdraw their participation in excitatory circuits and undergo apoptosis, thereby avoiding widespread necrosis. These findings have important implications for treatment of patients with cancer and neurodegenerative disorders.
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PMID:Caspase-mediated suppression of glutamate (AMPA) receptor channel activity in hippocampal neurons in response to DNA damage promotes apoptosis and prevents necrosis: implications for neurological side effects of cancer therapy and neurodegenerative disorders. 1130 Jul 17

Mammalian interphase and mitotic cells were analyzed for their cation composition using a three-dimensional high resolution scanning ion microprobe. This instrument maps the distribution of bound and unbound cations by secondary ion mass spectrometry (SIMS). SIMS analysis of cryofractured interphase and mitotic cells revealed a cell cycle dynamics of Ca2+, Mg2+, Na+, and K+. Direct analytical images showed that all four, but no other cations, were detected on mitotic chromosomes. SIMS measurements of the total cation content for diploid chromosomes imply that one Ca2+ binds to every 12.5-20 nucleotides and one Mg2+ to every 20-30 nucleotides. Only Ca2+ was enriched at the chromosomal DNA axis and colocalized with topoisomerase IIalpha (Topo II) and scaffold protein II (ScII). Cells depleted of Ca2+ and Mg2+ showed partially decondensed chromosomes and a loss of Topo II and ScII, but not hCAP-C and histones. The Ca2+-induced inhibition of Topo II catalytic activity and direct binding of Ca2+ to Topo II by a fluorescent filter-binding assay supports a regulatory role of Ca2+ during mitosis in promoting solely the structural function of Topo II. Our study directly implicates Ca2+, Mg2+, Na+, and K+ in higher order chromosome structure through electrostatic neutralization and a functional interaction with nonhistone proteins.
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PMID:Cation-chromatin binding as shown by ion microscopy is essential for the structural integrity of chromosomes. 1173 3

Anthracyclines are a class of antitumor drugs widely used for the treatment of a variety of malignancy, including leukemias, lymphomas, sarcomas, and carcinomas. Different mechanisms have been proposed for anthracycline antitumor effects including free-radical generation, DNA intercalation/binding, activation of signaling pathways, inhibition of topoisomerase II and apoptosis. A life-threatening form of cardiomyopathy hampers the clinical use of anthracyclines. According to the prevailing hypothesis, anthracyclines injure the heart by generating damaging free radicals through iron-catalyzed redox cycling. Although the "iron and free-radical hypothesis" can explain some aspects of anthracycline acute toxicity, it is nonetheless disappointing when referred to chronic cardiomyopathy. An alternative hypothesis implicates C-13 alcohol metabolites of anthracyclines as mediators of myocardial contractile dysfunction ("metabolite hypothesis"). Hydroxy metabolites are formed upon two-electron reduction of the C-13 carbonyl group in the side chain of anthracyclines by cytosolic NADPH-dependent reductases. Anthracycline alcohol metabolites can affect myocardial energy metabolism, ionic gradients, and Ca2+ movements, ultimately impairing cardiac contraction and relaxation. In addition, alcohol metabolites can impair cardiac intracellular iron handling and homeostasis, by delocalizing iron from the [4Fe-4S] cluster of cytoplasmic aconitase. Chronic cardiotoxicity induced by C-13 alcohol metabolite might be primed by oxidative stress generated by anthracycline redox cycling ("unifying hypothesis"). Putative cardioprotective strategies should be aimed at decreasing C-13 alcohol metabolite production by means of efficient inhibitors of anthracycline reductases, as short-chain coenzyme Q analogs and chalcones that compete with anthracyclines for the enzyme active site, or by developing novel anthracyclines less susceptible to reductive metabolism.
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PMID:Human heart cytosolic reductases and anthracycline cardiotoxicity. 1179

DNA damage is believed to be the main cause of the antiproliferative effect of cisplatin, a cornerstone agent in anticancer therapy. However, cisplatin can be expected to react also with nucleophiles other than DNA. Using enucleated cells (cytoplasts) we demonstrate here that cisplatin-induced apoptotic signaling may occur independently of DNA damage. Cisplatin-induced caspase-3 activation in cytoplasts required calcium and the activity of the calcium-dependent protease calpain. It is known that calpain activation may be associated with endoplasmic reticulum (ER) stress, suggesting that the ER is a cytosolic target of cisplatin. Consistent with this hypothesis, cisplatin induced calpain-dependent activation of the ER-specific caspase-12 in cytoplasts as well as in intact cells. Cisplatin also induced increased expression of Grp78/BiP, another marker of ER stress. By contrast, the DNA-damaging topoisomerase II inhibitor etoposide did not induce apoptotic signaling in cytoplasts nor ER stress in intact cells. We have thus identified a novel mechanism of action of cisplatin. The results have implications for the understanding of resistance mechanisms as well as the unique efficiency of this drug.
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PMID:Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. 1250 15

Anthracyclines play a major role in the treatment of solid malignancies, but their clinical use is limited by acute or chronic cardiac toxicity. This is not due to the same molecular action involved in the antineoplastic effect, i.e. topoisomerase II inhibition, but can be attributed to different mechanisms: free radical generation, stimulation of sarcoplasmic reticulum calcium release, binding to anionic phospholipids, alteration of sphingolipid metabolism, modulation of gene expression. Anthracycline metabolites, particularly 13-hydroxy derivatives, might contribute to impair iron and calcium homeostasis. Unresolved issues are the relative importance of such injurious mechanisms and the relationship between acute and chronic toxicity. Attempts to reduce anthracycline toxicity have been focused on the development of new derivatives, on the adoption of peculiar delivery systems, and on the association with substances able to interfere with the mechanism responsible for cardiotoxicity. Many anthracyclines have been synthesized and screened, but no major improvement in therapeutic index has been obtained. A possible exception might be represented by the new disaccharidic derivatives, which have provided promising results in preclinical studies. Liposome encapsulation and association with the iron chelator dexrazoxane have also proved to be useful. Novel approaches are targeted at the effects of anthracyclines on nitric monoxide metabolism and on sphingolipid metabolism.
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PMID:Cardiac toxicity of antineoplastic anthracyclines. 1267 9

FK506, a calcineurin inhibitor, shows potent neuroprotective effects in animal models such as those of stroke and neurodegenerative diseases. However, the mechanism underlying these neuroprotective effects is unclear. In this study, an in vitro model, in which FK506 protected the cells against cell death, was established and analyzed in detail by pharmacological experiments. Thapsigargin (TG), an inhibitor of endoplasmic reticulum calcium-ATPase, induced SH-SY5Y cell death. FK506 concentration-dependently protected the cells from this type of death. In contrast, FK506 did not suppress SH-SY5Y cell death caused by the following molecules: tunicamycin (TM), an inhibitor of N-linked glycosylation; etoposide (Eto), a topoisomerase II inhibitor; and staurosporine (STS), a phospholipid/calcium-dependent protein kinase inhibitor. Additionally, FK506 did not inhibit TG-induced cell death in either SK-N-MC or HeLa cell lines. FK506 completely inhibited caspase-3 activation and apoptosis caused by TG in a concentration-dependent manner, but not that caused by TM, Eto, and STS. TG did not activate caspase-3 in SK-N-MC cells, although it slightly activated caspase-3 in HeLa cells. FK506 did not change caspase-3 activity in either SK-N-MC or HeLa cell lines. Cyclosporin A, another calcineurin inhibitor, showed the same results as FK506 in this study, whereas rapamycin, an immunosuppressant not associated with calcineurin activity, did not have any effect in this context. Thus, the suppressive effects of FK506 on cell death are specific to SH-SY5Y cells treated with TG and are caused by the inhibition of calcineurin and subsequent suppression of caspase-3 activation. Therefore, an in vitro system using SH-SY5Y cells treated with TG could provide a model reflective of certain aspects of the neuroprotective activity of FK506.
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PMID:Detailed in vitro pharmacological analysis of FK506-induced neuroprotection. 1287 56

We report the production, purification, and characterization of a type IA DNA topoisomerase, previously designated topoisomerase I, from the hyperthermophilic archaeon Sulfolobus solfataricus. The protein was capable of relaxing negatively supercoiled DNA at 75 degrees C in the presence of Mg2+. Mutation of the putative active site Tyr318 to Phe318 led to the inactivation of the protein. The S. solfataricus enzyme cleaved oligonucleotides in a sequence-specific fashion. The cleavage occurred only in the presence of a divalent cation, preferably Mg2+. The cofactor requirement of the enzyme was partially satisfied by Cu2+, Co2+, Mn2+, Ca2+, or Ni2+. It appears that the enzyme is active with a broader spectrum of metal cofactors in DNA cleavage than in DNA relaxation (Mg2+ and Ca2+). The enzyme-catalyzed oligonucleotide cleavage required at least 7 bases upstream and 2 bases downstream of the cleavage site. Analysis of cleavage by the S. solfataricus enzyme on a set of oligonucleotides revealed a consensus cleavage sequence of the enzyme: 5'-G(A/T)CA(T)AG(T)G(A)X / XX-3'. This sequence bears more resemblance to the preferred cleavage sites of topoisomerases III than to those of topoisomerases I. Based on these data and sequence analysis, we designate the enzyme S. solfataricus topoisomerase III.
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PMID:DNA topoisomerase III from the hyperthermophilic archaeon Sulfolobus solfataricus with specific DNA cleavage activity. 1294 2

Deoxycytidine kinase (dCK) plays a central role in the deoxynucleoside salvage processes, phosphorylating dC, dA, and dG to their monophosphates. In mammalian cells, the major source of dTTP comes also from dC via dCMP deaminase. Moreover, based on its broad substrate specificity, this enzyme is responsible for the activation of several nucleoside analogues of therapeutical importance, influencing the sensitivity of malignant tissues towards chemotherapy. The expression of dCK is highest in different lymphoid cells/tissues, in embryonic cells and in most malignant cells (2, 7, 13-15, 18). The activity of dCK is not cell cycle-regulated. In contrast to this, dCK activity was found to be elevated several fold upon short-term treatments of normal human lymphocytes with therapeutic nucleoside analogs, and other genotoxic agents as well as by DNA damaging agents including the DNA polymerase inhibitor aphidicolin, the topoisomerase II inhibitor etoposide and gamma-irradiation, which might be a potentially important phenomenon with respect to the clinical practice, too. These findings indicated that the main trigger of activation could be the damaged DNA itself, and the biological relevance might be to supply the dNTPs for the enhanced DNA repair. Activation of dCK was paralleled by elevated levels of intracellular dATP, raising the possibility that dCK activation is linked to the induction of apoptosis. With regard to the mechanism of enzyme activation, no changes were found in the protein and mRNA levels of dCK upon stimulation, while the activation process was calcium dependent and comprised a protein phosphorylation step. A positive correlation was found between the enzymatic activity and the native immunoreactivity of dCK, strongly arguing that dCK undergoes a conformational change during activation, which results in the formation of a catalytically more active steric structure (8-11, 22, 26, 32-34, 35, 36).
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PMID:[Special function of deoxycytidine kinase (dCK) in the activation of chemotherapeutic nucleoside analogs and in the inhibition of cell proliferation]. 1552 Aug 73

Antigen-induced cell death is essential for function, growth and differentiation of T-lymphocytes through legation of the T cell receptor. Since TCR-induced cell death occurs at late G1 checkpoint of the cell cycle and considering that ICBP90 is critical for G1/S transition, we studied the ICBP90 regulation through the TCR pathway in Jurkat cells. ICBP90 expression was strongly decreased after TCR triggering concomitantly to cyclin D3 and topoisomerase IIalpha expression decreases. Cell stimulation with PMA and/or calcium ionophore A23187 down-regulated ICBP90 expression. The decrease of ICBP90 protein and mRNA expressions was accompanied with cell growth arrest. A luciferase reporter assay demonstrated that activation of TCR pathways inhibit ICBP90 gene promoter activity. Three consensus E2F binding sites (called from E2F-a to E2F-c) were identified in the ICBP90 gene promoter and were subjected to mutations. The E2F-a, located in a highly active promoter fragment, shows a strong positive functional activity in proliferating cells. E2F-a and E2F-c binding sites are involved in the TCR-induced down-regulation of ICBP90 gene transcription. Altogether, our data demonstrate that TCR signaling pathways regulate ICBP90 gene expression through pRb/E2F complex. We propose that ICBP90 down-regulation is a key event in G1 arrest preceding T cell death.
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PMID:TCR pathway involves ICBP90 gene down-regulation via E2F binding sites. 1596 57


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