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 antitumor effect of a new derivative of taxol, docetaxel (RP56976), was examined in K562 human tumor system in vitro. K562 cells presenting a multidrug resistant phenotype showed cross resistance to docetaxel. However, the resistance levels of docetaxel in these cell lines were much lower than for adriamycin and vincristine. Flow cytometric analysis showed the accumulation of cells into G2/M phase after 18hrs. Wright-Giemsa staining showed a marked increase of metaphase population. Docetaxel was shown to promote the assembly of microtubule protein without GTP in vitro, but no inhibitory effect on DNA, RNA and protein synthesis. Moreover, topoisomerase activities were not affected by docetaxel. These results indicate that docetaxel acts as a strong mitotic inhibitor in cancer chemotherapy.
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PMID:[Effect of a new anticancer drug, docetaxel (RP56976), on human leukemia cell lines]. 790 6

The rate of relaxation of supercoiled DNA by purified vaccinia topoisomerase I is stimulated 20-fold by 5 mM ATP. A similar effect is elicited by GTP, CTP, UTP, dATP, and adenosine 5'-(beta, gamma-imido)triphosphate. ATP-mediated rate enhancement requires salt as a coactivator. ADP and inorganic pyrophosphate also stimulate relaxation 10-20-fold, whereas AMP and inorganic phosphate have little effect. A model for allosteric activation of topoisomerase by nucleotides is suggested.
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PMID:Stimulation of vaccinia topoisomerase I by nucleoside triphosphates. 796 68

Topoisomerase I (Topo I) is involved in many cellular functions that involve unwinding of supercoiled DNA, such as transcription and replication. Topo I is also the target of autoimmune antibodies in progressive systemic sclerosis (scleroderma), and abnormal regulation of Topo I may influence the excessive production of collagen found in scleroderma. Topo I is phosphorylated in vivo at serine residues and, in vitro, the activity of Topo I is increased by phosphorylation by casein kinase type II (CKII) and protein kinase C (PKC). In this study, a protein kinase activity from rat liver nuclei is shown to copurify with Topo I during Bio-Rex 70 cation exchange chromatography. The kinase can phosphorylate Topo I at serine residues, resulting in a threefold increase in topoisomerase activity. A relatively tight association between this kinase and Topo I is demonstrated by the ability to coprecipitate the kinase with scleroderma autoimmune anti-Topo I antibodies. The kinase activity is similar to CKII since it is Ca2+ and cyclic nucleotide independent, it can utilize either ATP or GTP as phosphate donor, and it can phosphorylate casein and phosvitin, but not histones. However, unlike typical CKII, the Topo I-associated kinase could utilize Mn2+ almost as well as Mg2+, it is not stimulated by polyamines, and it does not appear to undergo autophosphorylation. In conclusion, we demonstrate that rat liver Topo I is relatively tightly associated with a CKII-like protein kinase that can phosphorylate and activate Topo I. These findings provide corroborative evidence that CKII, or a CKII-like protein kinase, is a physiologic regulator of Topo I.
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PMID:A casein kinase type II (CKII)-like nuclear protein kinase associates with, phosphorylates, and activates topoisomerase I. 826 Jan 98

A Z-DNA binding protein has been isolated and characterized by biochemical means from Drosophila melanogaster tissue culture cells and embryos. This protein shares the following properties with the known, cloned Drosophila topoisomerase II: (1) expression of an ATP-dependent relaxation activity on supercoiled DNA; (2) a monomer mass of 165 kDa in SDS denaturing gels; (3) a sedimentation coefficient, S20,w, of approximately 10 S for the active enzyme; (4) cross-reactivity for the respective monoclonal and polyclonal antibodies; (5) generation of covalent enzyme-DNA intermediates at preferred cutting sites in the Drosophila HSP70 intergenic spacer region; (6) inhibition of DNA relaxation activity by antitumor drugs, e.g., the etoposide VM26, and by monospecific antibodies raised against the protein; and (7) in vitro phosphorylation by a casein kinase activity. However, we have identified new properties for our topoisomerase II preparation not previously reported for the conventionally isolated enzyme: (1) The enzyme binds to Z-DNA with an affinity 2 orders of magnitude greater than that for B-DNA. (2) The binding to Z-DNA is increased 5-10-fold by GTP or GTP-gamma-S. (3) GTP and GTP-gamma-S inhibit the catalytic activity of topoisomerase II through a proposed allosteric mechanism. (4) Z-DNA inhibits the relaxation of closed circular supercoiled DNA. (5) The preparation consists of a single polypeptide chain of 165 kDa on denaturing SDS gels with no evidence of proteolytic degradation. We postulate that the Z-DNA binding activity of undegraded topoisomerase II may be important in targeting the enzyme both to structural motifs required for chromatin organization and to sites of local supercoiling. Some of these features arise during processes such as replication and gene expression and may be more frequent during embryogenesis and early development.
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PMID:Z-DNA binding and inhibition by GTP of Drosophila topoisomerase II. 838 19

Welwitindolinones are a family of novel alkaloids recently isolated from the blue-green alga Hapalosiphon welwitschii. We demonstrate that incubation of SK-OV-3 human ovarian carcinoma cells and A-10 vascular smooth muscle cells with welwitindolinone C isothiocyanate, now termed welwistatin, results in dose-dependent inhibition of cell proliferation, which is correlated with increases in the percentage of cells in mitosis. Treatment of A-10 cells with welwistatin resulted in reversible depletion of cellular microtubules but did not affect microfilaments. Pretreatment of A-10 cells with paclitaxel prevented microtubule depolymerization in response to welwistatin. Welwistatin inhibited the polymerization of purified tubulin in vitro but did not alter the ability of tubulin to bind [3H]colchicine or to hydrolyze GTP. Also, welwistatin did not induce the formation of topoisomerase/DNA complexes. Results of the present study indicate that welwistatin is a new antimicrotubule compound that circumvents multiple drug resistance and so may be useful in the treatment of drug-resistant tumors.
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PMID:Microtubule effects of welwistatin, a cyanobacterial indolinone that circumvents multiple drug resistance. 863 61

We examined the effects of the introduction of H-ras oncogene into murine cell line NIH3T3 on growth inhibition by topoisomerase-I (topo-I) inhibitors. The H-ras-transformed cells (pT22-3) showed approximately 12-fold increased sensitivity to a novel topo-I inhibitor, NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H-indolo(2,3-a)pyrrolo(3,4-c) carbazole-5,7(6H)-dione], compared with the parental NIH3T3 cells. pT22-3 also showed increased sensitivity to other topo-I inhibitors such as camptothecin (approx. 3.0-fold) and CPT-11 (irinotecan, approx. 3.0-fold). Transformation of NIH3T3 by another oncogene (erbB2) did not affect their sensitivity to these topo-I inhibitors. pT22-3 had approximately 32-fold higher topo-I activity than NIH3T3, but the same topo-I content. In a cell-free system, topo-I activity was increased 2-fold by addition of the H-ras protein precipitated from pT22-3 cells. Topo I in the nuclear extract of pT22-3 was eluted easily by low concentrations of NaCl compared with that of NIH3T3, suggesting a qualitative change in pT22-3 topo 1. Increased phosphorylation of topo I was observed in pT22-3. Furthermore, NB-506 decreased the amount of the GTP-bound form of the H-ras product in pT22-3 cells. These results suggest that the high growth-inhibitory effect of a topo-I inhibitor, NB-506, on H-ras-transformed NIH3T3 cells is due to the H-ras-mediated signal-transduction pathway.
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PMID:Hypersensitivity of NIH3T3 cells transformed by H-ras gene to DNA-topoisomerase-I inhibitors. 878 62

Tiazofurin, an oncolytic drug, reduces PI kinase activity and arrests chiefly in S phase. Genistein, an inhibitor of PIP kinase, tyrosine kinase, and topoisomerase-II, induces arrest in G2 and/or early M phase in most carcinoma cells. Both tiazofurin and genistein reduce second messenger IP3 concentration in ovarian carcinoma cells. Because genistein and tiazofurin attack different enzymic targets and arrest the cell cycle at different phases, we tested the hypothesis that tiazofurin might be synergistic with genistein. Human ovarian carcinoma OVCAR-5 cells were grown in flasks in monolayers. In growth inhibition assay for tiazofurin and genistein the IC50s were 26 and 18 microM, respectively, and in clonogenic assays the LC50s were 17 and 4 microM, respectively. Various combinations of the two drugs were tested. The best protocol took into consideration that tiazofurin decreased GTP concentration in cells by 50% at 12 h after administration. Tiazofurin (20 microM) and genistein (20 microM) as single agents reduced cell counts to 60% and 50%, respectively. The predicted value, as a sum of the effect of two drugs, would have been 30% of controls. However, genistein added 12 h after tiazofurin decreased cell counts to 8%, showing synergistic action of the two drugs for growth inhibition. Similar results were observed in the clonogenic assays, which also revealed synergistic cytotoxicity. The protocol yielding synergism might be of value in the clinical treatment of human ovarian carcinoma.
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PMID:Synergistic action of tiazofurin and genistein in human ovarian carcinoma cells. 970 Jul 22

The 3F3/2 antibody recognizes a phosphoepitope that is implicated in the mitotic checkpoint regulating the metaphase-to-anaphase transition. Immunoprecipitation and Western blotting revealed that the 3F3/2 antibody binds to human DNA topoisomerase II alpha (HsTIIalpha) from mitotic but not interphase HeLa cells. Extracts from mitotic cells efficiently catalyzed the formation of the 3F3/2 phosphoepitope on fragments of HsTIIalpha expressed in bacteria. Expression and site-directed mutagenesis of various HsTIIalpha protein fragments mapped the 3F3/2 phosphoepitope to the region of HsTIIalpha containing phosphorylated threonine 1342. This threonine lies within a consensus sequence for phosphorylation by casein kinase II (CKII). CKII is present in cellular extracts and is associated with isolated mitotic chromosomes. The 3F3/2 phosphoepitope kinase present in mitotic cell extracts was able to create the epitope using GTP and was inhibited by heparin. A kinase associated with the isolated chromosomes also generated the 3F3/2 phosphoepitope on HsTIIalpha. Recombinant CKII catalyzed the formation of the 3F3/2 phosphoepitope on fragments of HsTIIalpha containing threonine 1342. These results indicate that the mitotic 3F3/2 phosphoepitope kinase activity is attributable to CKII. We suggest that the 3F3/2 phosphoepitope reflects a CKII-catalyzed phosphorylation of threonine 1342 that may regulate mitotic functions of HsTIIalpha.
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PMID:Casein kinase II catalyzes a mitotic phosphorylation on threonine 1342 of human DNA topoisomerase IIalpha, which is recognized by the 3F3/2 phosphoepitope antibody. 980 34

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), an oncolytic drug, inhibits IMP DH (inosine 5'-monophosphate dehydrogenase, EC 1.1.1.205), reduces signal transduction activity and IP3 (inositol 1,4,5-trisphosphate) concentration and arrests the cell cycle chiefly in S phase. Genistein (4',5,7-trihydroxyisoflavone), an inhibitor of PIP kinase (1-phosphatidylinositol 4-phosphate 5-kinase, EC 2.7.1.68), tyrosine kinase and topoisomerase-II, induces arrest in G2 and/or early M phase in most carcinoma cells. Both drugs, as single agents, induce differentiation. Since tiazofurin and genistein attack different enzymic targets and arrest the cell cycle at different phases and they each induce differentiation, we tested the hypothesis that tiazofurin might be synergistic with genistein in inducing differentiation. Human leukemic K-562 cells were grown in suspension culture and were seeded in 24-well culture plates. In growth inhibition assays for tiazofurin and genistein IC50s (drug concentration that inhibits 50% of cell proliferation) were 7 and 37 microM, respectively. For tiazofurin and genistein the concentrations of drug that induce differentiation in 50% of the cells were 35 and 45 microM, respectively. Various combinations of these two drugs were tested. Since tiazofurin decreased GTP concentration in cells by 50% at 12 hr after administration, genistein (10 to 30 microM) was added 12 hr after tiazofurin (5 to 15 microM). Synergistic action on differentiation was obtained from all tiazofurin and genistein combinations and in most combinations on growth inhibition. The percent of differentiating cells induced by genistein (10 microM) and tiazofurin (10 microM) as single agents increased 1.1- and 2.8-fold, respectively, of the control values. The two drugs together caused 5.9-fold elevation in inducing differentiation. Similar action was observed on inhibition of proliferation.
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PMID:Synergistic action of tiazofurin and genistein on growth inhibition and differentiation of K-562 human leukemic cells. 983 41

MLL (ALL1, Htrx, HRX), which is located on chromosome band 11q23, frequently is rearranged in patients with therapy-related acute myeloid leukemia who previously were treated with DNA topoisomerase II inhibitors. In this study, we have identified a fusion partner of MLL in a 10-year-old female who developed therapy-related acute myeloid leukemia 17 months after treatment for Hodgkin's disease. Leukemia cells of this patient had a t(11;17)(q23;q25), which involved MLL as demonstrated by Southern blot analysis. The partner gene was cloned from cDNA of the leukemia cells by use of a combination of adapter reverse transcriptase-PCR, rapid amplification of 5' cDNA ends, and BLAST database analysis to identify expressed sequence tags. The full-length cDNA of 2.8 kb was found to be an additional member of the septin family, therefore it was named MSF (MLL septin-like fusion). Members of the septin family conserve the GTP binding domain, localize in the cytoplasm, and interact with cytoskeletal filaments. A major 4-kb transcript of MSF was expressed ubiquitously; a 1.7-kb transcript was found in most tissues. An additional 3-kb transcript was found only in hematopoietic tissues. By amplification with MLL exon 5 forward primer and reverse primers in MSF, the appropriately sized products were obtained. MSF is highly homologous to hCDCrel-1, which is a partner gene of MLL in leukemias with a t(11;22)(q23;q11.2). Further analysis of MSF may help to delineate the function of MLL partner genes in leukemia, particularly in therapy-related leukemia.
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PMID:MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related acute myeloid leukemia with a t(11;17)(q23;q25). 1033 4


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