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)

Electron microscopy studies demonstrate unequivocally that the observed oligonucleosome-sized secondary DNA fragmentation in human promyelocytic HL-60 cells treated with the topoisomerase inhibitors camptothecin and teniposide is correlated with the morphological changes in cell structure typical of programmed cell death (apoptosis). Since apoptosis has been associated with potential involvement of intracellular signaling linked to the Ca2+/calmodulin and protein kinase C transduction pathways, we also investigated the effects of signaling modulators on camptothecin- and teniposide-induced secondary DNA fragmentation in HL-60 cells. Neither calcium chelators, calcium/calmodulin inhibitors (calmidazolium or cyclosporine A), protein kinase C stimulation by TPA, protein phosphatase inhibition by okadaic acid, protein kinase inhibition by staurosporine, calphostin C, genistein or H7, nor cell cycle alterations by caffeine had any detectable effect. Interestingly, most of these intracellular signaling modulators were able to induce DNA fragmentation in HL-60 cells by themselves. These results may suggest that even though modulation of these signaling pathways was unable to prevent topoisomerase inhibitor-induced apoptosis, their sole deregulations could induce apoptosis in HL-60 cells. In contrast, aphidicolin blocked camptothecin-induced secondary DNA fragmentation, indicating that replication-induced DNA damage is required for camptothecin- but not teniposide-induced secondary DNA fragmentation. Zinc, 3-aminobenzamide, and spermine also modulated both camptothecin- and teniposide-induced secondary DNA fragmentation without significant alteration of topoisomerase-mediated primary DNA strand breaks. Hence, poly(ADP-ribosyl)ation and chromatin structure may be important in modulating oligonucleosome-sized DNA fragmentation associated with apoptosis in HL-60 cells treated with topoisomerase inhibitors.
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PMID:Apoptosis and its modulation in human promyelocytic HL-60 cells treated with DNA topoisomerase I and II inhibitors. 768 16

We have recently demonstrated that cell lines deficient in poly(ADP-ribose) synthesis due to deficiency in the enzyme poly(ADP-ribose) polymerase (PADPRP) or depletion of its substrate NAD+ overexpress GRP78. Furthermore, this overexpression of GRP78 is associated with the acquisition of resistance to topoisomerase II-directed drugs such as etoposide (VP-16); (S. Chatterjee et al., Cancer Res., 54: 4405-4411, 1994). Thus, our studies suggest that interference with NAD+-PADPRP metabolism could provide an important approach to (a) define pathways of GRP78 induction, (b) study the effect of GRP78 on other cellular processes, (c) elucidate the mechanism of GRP78-dependent resistance to topoisomerase II targeted drugs, and (d) modulate responses to chemotherapy in normal and tumor tissues. However, in the in vivo situation, it is impractical to interfere with NAD+-PADPRP metabolism by mutational inactivation of PADPRP or by depletion of its substrate NAD+. Therefore, we have examined several inhibitors of NAD+-PADPRP metabolism including 3-aminobenzamide, PD128763, and 6-aminonicotinamide for their ability to reproduce the results obtained with cell lines deficient in NAD+-PADPRP metabolism relative to the induction of GRP78 and subsequent development of resistance to VP-16. Our studies show that 6-aminoicotinamide treatment is highly effective in the induction of GRP78 and subsequent development of resistance to VP-16, whereas treatment with 3-aminobenzamide or PD128763 does not induce GRP78 and thus does not result in VP-16 resistance.
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PMID:Effect of inhibitors of poly(ADP-ribose) polymerase on the induction of GRP78 and subsequent development of resistance to etoposide. 785 Aug 1

The association of the proliferating cell nuclear antigen (PCNA) to DNA synthesis sites was investigated in human quiescent fibroblasts after UV irradiation. Associated PCNA was detected with the monoclonal antibody (MoAb) PC10 and by immunofluorescence assessment with flow cytometry, after a hypotonic lysis step in order to release unbound molecules. Immunofluorescence levels, relatively low in untreated control cells, increased by about threefold after uv irradiation. The time course of PCNA complex formation showed a maximum after about 30 min from irradiation and was found to be dose-dependent up to about 10 J/m2, after that it reached a plateau. Formation of the PCNA-chromatin complex was neither significantly affected by the topoisomerase II inhibitor VP-16, nor by the poly(ADP-ribose)polymerase inhibitor 3-aminobenzamide. In contrast, a significant reduction was obtained either after ATP depletion or after incubation with the protein-kinase inhibitor staurosporine. Immunoprecipitation studies on nuclear extracts from 32P-labeled cells showed that PCNA bound to DNA synthesis sites was phosphorylated. The results indicate that PCNA associated to DNA repair synthesis sites may be detected with PC10 MoAb after a hypotonic lysis step, and provide evidence that the transition from soluble to chromatin-associated form of the protein is dependent on a phosphorylation mechanism.
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PMID:Proliferating cell nuclear antigen complex formation induced by ultraviolet irradiation in human quiescent fibroblasts as detected by immunostaining and flow cytometry. 809 24

We have studied the nonhistone proteins which are modified by ADP-ribosylation in HeLa cells. When isolated nuclei were incubated with 32P-NAD, the main labeled proteins presented sizes of 170, 116, 70, and 45 kDa. To provide evidence for the identification of the 170-kDa band as DNA topoisomerase II, the enzyme was immunoprecipitated from isolated nuclei incubated with 32P-NAD and a labeled peptide of 170 kDa was observed. The label was sensitive to the action of venom phosphodiesterase which specifically degrades ADP-ribose. ADP-ribosylated proteins were also isolated from HeLa cells by affinity chromatography on boronate-agarose gel. Using a monoclonal antibody against the 170-kDa isoform of topoisomerase II, a single 170-kDa immunoreactive peptide was recognized by Western blot among the retained protein acceptors. When ADP-ribosylation was blocked by treating HeLa cells with 3-aminobenzamide, topoisomerase II was no longer retained on the boronate column. These results provide experimental evidence indicating that DNA topoisomerase II is ADP-ribosylated in HeLa cells. To possibly correlate ADP-ribosylation of nuclear proteins with the extent of DNA damage, permeabilized HeLa cells were incubated with 32P-NAD after treatment with the alkylating agent dimethylsulfate. ADP-ribosylated proteins were isolated by boronate chromatography. A strong increase in the ADP-ribosylation of the poly(ADP-ribose)polymerase was observed, whereas no further modification of topoisomerase II was noted.
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PMID:ADP-ribosylation of nonhistone proteins in HeLa cells: modification of DNA topoisomerase II. 838 22

There is compelling evidence for the central role of oxidative damage in the aging process and for the participation of reactive oxygen species in tumor initiation and promotion. Caloric restriction (CR) or energy restriction retards age-associated increases in mitochondrial free-radical production and reduces the accumulation of oxidatively damaged cell components. CR has also been shown to slow down age-related declines in various repair capabilities, including some types of DNA repair. It is proposed that inhibitors of mitochondrial electron transport and/or uncouplers of oxidative phosphorylation (rotenone, amytal, amiodarone, valinomycin, etc.), when used at extremely low doses, could mimic the effects of CR in model systems. The objective is to lower mitochondrial free-radical production by decreasing the fraction of electron carriers in the reduced state. In addition to a variety of other effects, CR has been shown to increase the rate of apoptosis, particularly in preneoplastic cells, and in general, to promote elevated levels of free glucocorticoids (GCs). GCs are known to induce tissue-specific apoptosis and to upregulate gap-junction-mediated intercellular communication (GJIC). Tumor promoters like phorbol esters have the opposite effect, in that they inhibit both the process of apoptosis and GJIC. The enzyme poly (ADP-ribose) polymerase (PARP) is thought to play a central role in apoptosis, in a manner that has been highly conserved in evolution. There is good evidence that the apoptosis-associated Ca/Mg-dependent DNA endonuclease is maintained in a latent form by being poly (ADP-ribosylated). Apoptosis would require the removal of this polymer from the endonuclease, and, most likely, its removal from topoisomerase II and histone H1 as well. The role of poly (ADP-ribose) in apoptosis, carcinogenesis, and aging could be studied by the use of modulators of PARP activity (3-aminobenzamide, 3-nitrosobenzamide, 1% ethanol, etc.), inhibitors of poly ADP-ribose) glycohydrolase activity (ethacridine, 43 degrees C, etc.), and inhibitors of the PARP-specific protease (interleukin-1 beta converting enzyme (ICE)-like protease). Also, it would be of interest to determine if CR can decrease the half-life of poly (ADP-ribose), upregulate GJIC, and modulate the activities of PARP, the glycohydrolase, and the PARP-specific protease, factors potentially important in these processes.
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PMID:The beneficial effects of dietary restriction: reduced oxidative damage and enhanced apoptosis. 865 88

The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is present in tobacco smoke and is hepatocarcinogenic in rats. Its bioactivation in rat hepatocytes leads to methylation and pyridyloxobutylation of DNA. Rat hepatocytes were cultured in serum-free William medium E on collagen-coated dishes. We demonstrated that some enzymes of the base and/or excision-repair pathways were involved in repair of NNK-induced DNA damage, measured by [methyl-3H] thymidine incorporation. Unscheduled DNA synthesis (UDS) induced by N-methyl-N-nitrosourea (MNU), NNK, N'-nitrosonornicotine (NNN) and 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc) increased 2.9-, 2.8-, 1.5- and 3.5-fold, respectively, suggesting that methylated and/or pyridyloxobutylated-DNA by these four nitroso compounds is repaired by the excision pathway. Moreover, levels of NNK-induced UDS were dose (1-3 mM) and time (1-18 h) dependent. Enzymes involved in the excision repair pathways were selectively inhibited. Inhibitors of DNA topoisomerase I (camptothecin) and topoisomerase II (etoposide, nalidixic acid) did not decrease the induction of UDS, suggesting that topoisomerases are not involved in the repair of NNK-induced damage. While aphidicolin and arabinocytidine (DNA polymerase alpha, delta, epsilon inhibitors) totally inhibited NNK- and NNKOAc-induced UDS, dideoxythymidine (DNA polymerase beta inhibitor) inhibited NNK- and NNKOAc-induced UDS by 40 and 33%, respectively. We conclude that DNA polymerase alpha, delta or epsilon and to a lesser degree polymerase beta are involved in the repair of pyridyloxobutylated DNA. Previous studies showed that inhibition of poly(ADP-ribosyl) polymerase (PARP) by 3-aminobenzamide (3-ab) facilitated DNA ligation. Our results demonstrate that 3-ab increased NNK-induced UDS, but does not affect NNKOAc-induced UDS. These observations suggest that the ligation step is rate limiting in the repair of methylated DNA but not of pyridyloxobutylated DNA.
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PMID:Modulation of DNA repair by various inhibitors of DNA synthesis following 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced DNA damage. 956 22

We have studied the relationship between tumor necrosis factor (TNF)-sensitivity and doxorubicin-resistance in our doxorubicin-resistant cell line panel consisting of the parental cell line GLC4 plus GLC4-Adr2x and GLC4-Adr350x with respective resistance factors of 2 and 350 compared with GLC4. At the highest dose of 1000 ng/ml TNF, GLC4 was almost completely resistant to TNF, whereas 37% and 68% growth inhibition was observed in GLC4-Adr2x and GLC4-Adr350x, respectively. Sensitivity to TNF appeared to correlate inversely with the expression and gene copies of topoisomerase IIalpha in these cell lines. The gene encoding for c-erbB2 is in the proximity of the topoisomerase IIalpha gene and its product is a known cause for TNF-resistance. We found that our doxorubicin-resistant cell lines with decreased topoisomerase IIalpha gene copies have a simultaneous decrease in c-erbB2 gene copies, probably due to linkage between these 2 genes. This reduced number of c-erbB2 gene copies resulted in decreased c-erbB2 expression and subsequently in increased sensitivity to TNF. Additionally, we tried to establish some of the mechanisms associated with TNF-resistance in GLC4 related to c-erbB2 overexpression. There was no difference in TNF-receptor-1 expression between the cell lines. Compared with the TNF-sensitive GLC4-Adr350x, GLC4 appeared to have a decreased activation of NF-kappaB after exposure to TNF that might indicate a reduced TNF-receptor function. In GLC4, increased Bcl-2 expression was found, a protein described to confer TNF-resistance. Moreover, it was demonstrated that combining TNF with the poly-ADP-ribose polymerase (PARP) inhibitors 6-aminonicotinamide and 3-aminobenzamide did not affect TNF-sensitivity in GLC4 and GLC4-Adr350x, excluding a pivotal role of PARP in TNF-resistance in these cell lines. In conclusion, our data show that doxorubicin-resistant tumor cell lines with decreased topoisomerase IIalpha gene copies can become sensitive to TNF due to loss of c-erbB2 gene copies. We also found that several mechanisms associated with c-erbB2 overexpressing contribute to TNF-resistance in GLC4.
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PMID:Enhanced sensitivity to tumor necrosis factor-alpha in doxorubicin-resistant tumor cell lines due to down-regulated c-erbB2. 963

A study was made of the influence of inhibitors of poly(ADP-ribose)polymerase, topoisomerase I and topoisomerase II on the frequency of gene targeting of hprt gene as well as on the frequency of random integration of targeting vector pRV9.1 into genome of mouse F9 teratocarcinoma cells. We found that the treatment of cells with the inhibitor of poly(ADP-ribose)polymerase 3-aminobenzamide after electroporation resulted in 3-4-times increase of homologous integration of exogenic vector into chromosomal DNA, and did not affect the frequency of random insertion of transfected DNA. The treatment of cells after electroporation with inhibitors of topoisomerases VP-16, ICRF-193 enhanced random integration of transfected DNA but exerted no effect on the frequency of gene targeting in this experimental system.
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PMID:[Effect of inhibitors of topoisomerases and poly(ADP-ribosylation) on homologous and non-homologous integration of exogenous DNA in genes of mammalian somatic cells]. 1064 51


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