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:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent small-scale studies have shown that 30% of human tumors examined to date express DNA polymerase beta variant proteins. One of the DNA polymerase beta colon cancer-associated mutants, K289M, has been shown to synthesize DNA with a lower fidelity than wild-type Pol beta. Thus, the K289M protein could confer a mutator phenotype to the cell, resulting in genomic instability. Another DNA polymerase beta variant identified in colon carcinoma interferes with base excision repair in cells. This may result in unfilled gaps which can serve as substrates for recombination and result in genomic instability. DNA polymerase beta has also been shown to be overexpressed in a variety of tumors. In some cases, overexpression of polymerase beta in cells confers a transformed phenotype to the cells. In other cases, overexpression results in telomere fusions. Thus, mutant forms or aberrant quantities of polymerase beta confer a mutator phenotype to cells. Combined with the small-scale tumor studies, these mechanistic studies implicate variant forms of DNA polymerase beta in the etiology of human cancer.
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PMID:Is there a link between DNA polymerase beta and cancer? 1528 Jun 58

We studied the cytotoxic effects of various DNA replication inhibitors on MMR-deficient and -proficient colon carcinoma cell lines. DNA polymerase (pol) inhibitors including aphidicolin and gemcitabine, and hydroxyurea were more toxic (1.7 to 2.8-fold) to hMLH1-deficient HCT116 than to hMLH1-proficient HCT116+ch3. Similarly, pol inhibitors were more toxic to hMSH2-deficient LoVo than to hMSH2-proficient LoVo+ch2. In contrast, DNA topoisomerase I inhibitors, such as CPT-11, SN-38, and topotecan, were more toxic to MMR-proficient cells. Our results suggest that MMR-deficient colon carcinoma cells are hypersensitive to inhibitors of the pol reaction.
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PMID:Hypersensitivity in DNA mismatch repair-deficient colon carcinoma cells to DNA polymerase reaction inhibitors. 1573 91

Novel N-1-sulfonylpyrimidine derivatives have a strong antiproliferative activity and an ability to induce apoptosis in treated tumor cells. The purpose of this study was to elucidate the effects of two N-1-sulfonylpyrimidine nucleobases on catalytic activity of tumor cells' enzymes involved in DNA and RNA synthesis, and in de novo and salvage pyrimidine and purine syntheses. Investigations were performed in vitro on colon carcinoma cells (Caco2). The biosynthetic activity of the tumor cells' enzymes was determined using sensitive radio-assays. Enzyme activity in treated cells was calculated relative to untreated control cells. Both of the investigated compounds, 1-(p-toluenesulfonyl) cytosine (TsC) and 5-bromo-1-(methanesulfonyl) uracil (BMsU) inhibited activities of specific enzymes involved in nucleic acid synthesis. BMsU strongly inhibited activities of DNA polymerase alpha (53%), thymidine kinase (68%), thymidilate synthase (43%), and ribonucleotide reductase (46%). De novo biosynthesis of pyrimidine and purine was reduced by 20%. TsC was able to inhibit RNA polymerase (37%), orotate phosphoribosyltransferase (39%), uridine kinase (44%), ribonucleotid reductase (47%), and de novo purine synthesis (61%). Antitumor activity of 1-(p-toluenesulfonyl) cytosine (TsC) and 5-bromo-1-(methanesulfonyl) uracil (BMsU) is closely associated with their inhibitory activity on enzymes that play an important role in the metabolism of tumor cells.
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PMID:Metabolic effects of novel N-1-sulfonylpyrimidine derivatives on human colon carcinoma cells. 1591 14

Thirty percent of the 189 tumors studied to date express DNA polymerase beta variants. One of these variants was identified in a prostate carcinoma and is altered from isoleucine to methionine at position 260, within the hydrophobic hinge region of the protein. Another variant was identified in a colon carcinoma and is altered at position 289 from lysine to methionine, within helix N of the protein. We have shown that the types of mutations induced by these cancer-associated variants are different from those induced by the wild-type enzyme. In this study, we show that expression of the I260M and K289M cancer-associated variants in mouse C127 cells results in a transformed phenotype in the great majority of cell clones tested, as assessed by focus formation and anchorage-independent growth. Strikingly, cellular transformation occurs after a variable number of passages in culture but, once established, does not require continuous expression of the polymerase beta variant proteins, implying that it has a mutational basis. Because DNA polymerase beta functions in base excision repair, our results suggest that mutations that arise during this process can lead to the onset or progression of cancer.
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PMID:Expression of DNA polymerase {beta} cancer-associated variants in mouse cells results in cellular transformation. 1617 90

Synthetic DNA templates were compared with authentic cDNA templates as standards for the real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). The single-stranded DNA template used here targeted the multidrug resistant transporter P-glycoprotein/MDR1. The double-stranded DNA template, targeting glyceraldehyde-3-phosphate dehydrogenase (GAPDH), was synthesized using an exonuclease-free large fragment E. coli DNA polymerase I. The human colon carcinoma cell line Caco-2 and human duodenum biopsies were used to prepare the authentic cDNA templates. The standard lines were comparable for the synthetic DNA templates and authentic cDNA templates. Long-term cryopreservation at -80 degrees C resulted in the destabilization of the synthetic single-stranded DNA template compared with the authentic cDNA templates in the case of MDR1, whereas for GAPDH, the stability of the synthetic double-stranded DNA template was comparable with that of the authentic cDNA templates. Even for the synthetic DNA templates, repetitive freeze-thawing resulted in destabilization, especially at lower concentrations, and degradation products might have interfered with the RT-PCR's efficiency. The synthetic DNA templates are better than the authentic cDNA templates, but more than 5 cycles of repetitive freeze-thawing should be avoided.
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PMID:Comparison of synthetic DNA templates with authentic cDNA templates in terms of quantification by real-time quantitative reverse transcription polymerase chain reaction. 1650 61

Increasing efforts are directed toward finding applications for natural products and their derivatives in the treatment of human diseases. Among such products, propolis, a resinous substance produced by honey bees from various plant sources, has been found to be a promising source of potential therapeutics. In the present work, we aimed at studying the perspective of Cuban propolis as a source of possible anti-cancer agents. We found an anti-metastatic effect in mice and considerable cytotoxicity without cross-resistance in both wild-type and chemoresistant human tumor cell lines. Plukenetione A--identified for the first time in Cuban propolis--induced G0/G1 arrest and DNA fragmentation in colon carcinoma cells. Furthermore, the activities of both topoisomerase I and DNA polymerase were inhibited, while the expression of topoisomerase II-beta, EGF receptor, and multidrug resistance-related protein genes was found repressed. We assume that plukenetione A contributes to the anti-tumoral effect of Cuban propolis mainly by targeting topoisomerase I as well as DNA polymerase.
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PMID:The contribution of plukenetione A to the anti-tumoral activity of Cuban propolis. 1895 5

This paper describes the inhibitory activities of diacylglyceride phospholipids, such as phosphatidylcholine (lecithin), phosphatidylethanolamine (cephalin), phosphatidylserine, phosphatidylglycerol, bisphosphatidylglycerol (cardiolipin), phosphatidylinositol, and phosphatidic acid (phosphatidate) (compounds 1 - 7, respectively) against DNA polymerase (pol), DNA topoisomerase (topo), and human cancer cell growth. Among the compounds tested, compounds 3 - 7 were revealed to be potent inhibitors of animal pols: compound 4 was the strongest inhibitor, with IC(50) values for different pols of 1.7 - 15 mM. Compounds 4 - 7 also inhibited the activity of human topo II: compound 7 was the strongest inhibitor, with an IC50 value of 20 mM. The glycerophospholipids had no effect on the activities of plant (cauliflower) pol a, prokaryotic pols, or other DNA metabolic enzymes, such as calf primase of pol a, T7 RNA polymerase, T4 polynucleotide kinase, and bovine deoxyribonuclease I. These results suggest that compounds 3 - 7 are selective inhibitors of animal pols and human topos. Compounds 4 and 7 also suppressed the growth of a human colon carcinoma cell line that lacked p53 (HCT116 p53(-/-)); their LD(50) values were 63.6 and 51.1 mM, respectively, suggesting that cell growth inhibition by these compounds leads to the inhibition of pols and/or topos. From these findings, diacylglyceride phospholipids, which are present in various foods, might be effective nutrients for promoting human anti-cancer health promotion.
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PMID:Inhibitory effects of diacylglyceride phospholipids on DNA polymerase and topoisomerase activities, and human cancer cell growth. 2050 70

We previously found six compounds of alkyl p-coumarates from a composite plant Artemisia annua L., and chemically synthesized these compounds (cis-isomer of C20, C22 and C24, and trans-isomer of C20, C22 and C24 of p-coumarates are compounds 1-6, respectively). This report describes the inhibitory activities of these alkyl p-coumarates against DNA polymerase (pol), DNA topoisomerase (topo), and human cancer cell growth. Among the compounds tested, compounds 1 and 4 weakly inhibited repair-related pol beta activity, but no compound influenced the activity of replicative pol alpha. Compounds 4-6 and compounds 2 and 5 were potent inhibitors of human topos I and II, respectively. Compounds 2, 4, 5 and 6 also suppressed the growth of human colon carcinoma cell line, HCT116, with or without p53, suggesting that cell growth inhibition had the same tendency as the inhibition of topos rather than pols. Compound 5 (docosyl p-coumarate), which was the strongest inhibitor of topo II and cancer cell growth in the compounds tested, halted HCT116 p53(+/+) cells in G2/M phases, and induced apoptosis, although this compound did not affect the cell cycle of HCT116 p53(-/-) cells. These results suggest that the effect of p53-dependent cell cycle arrest may be effective for topo inhibition by com-pound 5. From these findings, the action mode of alkyl p-coumarates as an anti-cancer agent is discussed.
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PMID:Inhibitory effects of docosyl p-coumarate on DNA topoisomerase activity and human cancer cell growth. 2081 21

The polymerase chain reaction (PCR) theoretically offers a very powerful means of quantifying gene expression in cells and tissues of different histological classes. From a technical viewpoint however, the use of RT-PCR to quantify gene expression can be demanding with poor reproducibility arising from several diverse sources. In this study, we describe and fully characterise an RT-PCR assay which generates highly reproducible estimates of DNA polymerase beta gene expression relative to the expression of beta-actin in a semi-quantitative manner. Particular emphasis has been placed on the efficiency of first strand cDNA synthesis and to aspects of primer design. In addition, various aspects associated with the quantification of gene expression required to generate reproducible results are discussed. Using the techniques described herein, the quantification of DNA polymerase beta expression in three independent experiments using human colon carcinoma cells was highly reproducible with ratios of target to internal standard gene expression of 3.68x10(-4) +/- 0.23x10(-4). Provided that careful consideration is given to key areas of the RT-PCR assay during experimental work up procedures, this assay can be used to provide an accurate measure of gene expression in cell lines.
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PMID:Semiquantitative measurement of gene-expression by rt-PCR - a cautionary tale. 2157 79

Catechins in green tea display anti-cancer and anti-angiogenesis activities. We previously found that some catechins, such as epigallocatechin-3-O-gallate (EGCG), inhibit the activities of eukaryotic DNA polymerases (pols) (Y. Mizushina et al.: Structural analysis of catechin derivatives as mammalian DNA polymerase inhibitors. Biochem Biophys Res Commun 333, 101-109 (2005)). In this study, we discuss the effects of chemical modifications of catechin and epicatechin that enhance their anti-cancer and anti-angiogenic activities based on pol inhibition. Catechins conjugated with fatty acid (3-O-acylcatechins) are stronger inhibitors of mammalian pol than epicatechins conjugated with fatty acid (3-O-acylepicatechins). Moreover, 3-O-acylcatechins are more potent inhibitors of cultured cell growth both of the human colon carcinoma cell line (HCT116 cells) and human umbilical vein endothelial cell (HUVEC) line, as well as angiogenesis by comparison with 3-O-acylepicatechins. Catechin conjugated with stearic acid ((2R,3S)-3',4',5,7-tetrahydroxyflavan-3-yl octadecanoate; C-C18) was the strongest inhibitor in replicative pol alpha and repair-related pol beta, as well as the cultured cell growth and angiogenesis assays in the compounds tested. C-C18 also suppressed HUVEC tube formation on reconstituted basement membrane suggesting that it affected not only pols but also signal transduction pathways in HUVECs. These data indicate that the acylated catechins target both pols and angiogenesis as anti-cancer agents. Moreover, the results suggest that acylation of catechin is an effective chemical modification to improve the anti-cancer activity of catechin.
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PMID:Acylated catechin derivatives: inhibitors of DNA polymerase and angiogenesis. 2162 40


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