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)

We have successfully established one murine hybridoma that secretes a monoclonal antibody specific for the 77,000 subunit of human DNA polymerase alpha. The results of immunochemical studies, using HDR-854-E4 monoclonal antibody (MAb) and immunoperoxidase detection methods, demonstrate intranuclear and intracytoplasmic localisation of the subunit in all the human culture cell lines tested. The immunoperoxidase reaction product exhibits a diffuse pattern of distribution within the cytoplasm and nucleoplasm, but nucleoli are clearly negative. In cultured cell lines, HeLa and KATO III, more than 95% of the cells are positive, suggesting that the subunit antigens persist throughout the mitotic cycle. No subunit antigen was recognised in resting mononuclear cells (MNC). Immuno-electron microscopic examination of HeLa cells confirms and extends these observations. We have further examined the expression level of the subunit antigen in various normal and cancerous tissues. Strong reaction was observed in proliferating normal and cancer cells such as cancer cells from the gastrointestinal (GI) tract, thyroid, malignant lymphoma, breast, cells in the germinal centres of lymph nodes, epithelial cells in the GI tract and nephrogenic zones in fetal kidney. Finally, we utilised this antibody as a diagnostic tool in biopsies of the thyroid and GI tract. Thyroid cancer was stained positively with this antibody, while follicular adenoma was not. Gastric cancer was stained strongly and adenomatous polyp and hyperplastic polyp were stained moderately. This antibody is not only specific and powerful for application of a novel approach to the complex biochemical mechanisms of mammalian DNA replication, but also useful for distinction between proliferative and non-proliferative lesions.
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PMID:Intracellular localisation of a subunit of human DNA polymerase alpha affecting primase activity recognised by monoclonal antibody (HDR-854-E4) and its application to distinction between proliferative and non-proliferative lesions. 276 63

In tissues obtained from patients undergoing gastrectomy, the activities of 12 enzymes involved in pyrimidine nucleotide synthesis: cytidine triphosphate (CTP) synthetase, deoxycytidine monophosphate (dCMP) deaminase, thymidine monophosphate (dTMP) kinase, uridine (Urd), deoxycytidine (dCyd) and thymidine (dThd) kinases, Urd, deoxyuridine (dUrd) and dThd phosphorylases, cytidine (Cyd) and dCyd deaminases, and DNA polymerase were examined in the eight-well-differentiated and 12 poorly differentiated gastric cancer tissues and the ten normal tissues. These cases were clinically advanced and serosal invasions were evident. Activities of these enzymes were higher in the poorly differentiated tissues than the well differentiated type and in the normal tissues. Significant differences were noted between the poorly differentiated and well-differentiated types, in dTMP kinase (P less than 0.02), dThd kinase (P less than 0.05), dThd phosphorylase (P less than 0.01), and DNA polymerase (P less than 0.05). The authors' findings show that the level of pyrimidine nucleotide synthesis, in both de novo and salvage pathways, is higher in the poorly differentiated gastric cancer tissues than in the well-differentiated type and suggest that antitumor drugs have an increased susceptibility in cases of poorly differentiated gastric carcinoma.
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PMID:Pyrimidine nucleotide synthesis is more extensive in poorly differentiated than in well-differentiated human gastric carcinoma. 291 Apr 29

DNA polymerase beta (polbeta) is one of mammalian DNA polymerases and is known to be involved in a G:T/G:U mismatch repair. In order to investigate an involvement of this enzyme in a base excision repair, we searched a mutation of human polbeta in human gastric cancer and studied a function of the mutation. We observed cancer-specific missense mutations in 6 of 20 samples. All of these mutations were, however, heterozygous. We further analyzed the base excision repair activity of these mutants to know whether these mutants cause an error of mismatch repair. One of these mutants, which resulted in an amino acid substitution of Glu for Lys at codon 295, showed an inhibitory effect by in vitro base excision repair assay, suggesting that this mutation might play some role in carcinogenesis of the gastric mucosa.
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PMID:Functional mutation of DNA polymerase beta found in human gastric cancer--inability of the base excision repair in vitro. 1055 92

Dehydroaltenusin was found to be an inhibitor of mammalian DNA polymerase alpha (pol. alpha) in vitro, but did not influence the activities of the other replicative DNA polymerases including even other vertebrate pol. alpha. In this study, we purified or synthesized various slightly modified derivatives of dehydroaltenusin, and using them, investigated the relationship between the chemical structure and the inhibitory effects, and the in vitro and in vivo effects of dehydroaltenusin to determine to what extent the pol. alpha activity inhibition influences cell proliferation. Most of the derivatives lost the enzyme species-specific inhibitory effect, suggesting that dehydroaltenusin is three-dimensionally inserted into a pocket present only in mammalian pol. alpha. Dehydroaltenusin inhibited the cell proliferation of the human gastric cancer cell line NUGC-3 by arresting the cells at G1/S-phase, and prevented the incorporation of thymidine into the cells, indicating that it blocks the primary step of in vivo DNA replication by inhibiting pol. alpha. This compound also induced apoptosis of the cells. Dehydroaltenusin is a mammalian pol. alpha-specific inhibitor useful in both of in vivo and in vitro experiments.
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PMID:Actions of derivatives of dehydroaltenusin, a new mammalian DNA polymerase alpha-specific inhibitor. 1185 93

Retinoic acids, vitamin A-related compounds, are known to be inhibitors of telomerase. We found that fucoxanthin from the sea alga Petalonia bingamiae is a potent inhibitor of mammalian replicative DNA polymerases (i.e., pol alpha, delta and epsilon). Since fucoxanthin is a carotenoid (provitamin A-related) compound, we characterized the biochemical modes of vitamin A-related compounds including vitamin A and provitamin A in this report. Subsequently, we found that fucoxanthin, all-trans retinal (RAL, vitamin A aldehyde) and all-trans retinoic acid (RA, vitamin A acid) inhibited the activities of replicative DNA polymerases with IC(50) values of 18-190, 14-17 and 8-30 microM, respectively. On the other hand, all-trans retinol (vitamin A) did not influence any of the DNA polymerase activities. RA inhibited not only the activities of pol alpha, delta and epsilon with IC(50) values of 30, 28 and 8 microM, respectively, but of pol beta with an IC(50) value of 27 microM. The tested vitamin A-related compounds did not influence the activities of DNA polymerases from a higher plant, cauliflower, prokaryotic DNA polymerases, or DNA metabolic enzymes such as human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. RAL and RA should be called selective inhibitors of mammalian DNA polymerases including telomerase, and RAL was a specific inhibitor of mammalian replicative DNA polymerases. As expected from these results in vitro, some of them could prevent the growth of NUGC-3 human gastric cancer cells, and especially RAL was a potent antineoplastic agent with an LD(50) value of 19 microM. The cells were halted at G1 phase in the cell cycle by RAL.
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PMID:Vitamin A-related compounds, all-trans retinal and retinoic acids, selectively inhibit activities of mammalian replicative DNA polymerases. 1195 16

We reported previously that sulfo-glycolipids such as sulfoquinovosyl-diacylglycerol (SQDG) and sulfoquinovosyl-monoacylglycerol (SQMG) are potent inhibitors of DNA polymerase alpha and beta and antineoplastic agents. Then, we succeeded in synthesizing SQDG and SQMG chemically, including their stereoisomers, glucopyranosyl-diacylglycerol (GDG) and glucopyranosyl-monoacylglycerol (GMG). In this study, we demonstrated the structure-function relationship of the synthetic sulfo-glycolipids to DNA polymerase alpha and beta and their relationship to the cytotoxic activity. Both SQDG and SQMG inhibited the activity of mammalian DNA polymerase alpha with IC(50) values of 3-5 microM, but GMG only moderately inhibited it. GDG, diacylglycerol (DG), and monoacylglycerol (MG) did not influence any of the DNA polymerase activities. The sulfate moiety in the quinovose was important in inhibiting the enzyme activity. The one-fatty-acid-sulfo-glycolipids, SQMG, GMG, and MG, prevented the growth of NUGC-3 human gastric cancer cells and induced apoptotic cell death, but the two-fatty-acid-sulfo-glycolipids, SQDG, GDG, and DG, did not. SQMG and GMG could halt the cell cycle at the G1 phase, but the cell cycle was not changed by MG. The relationship between the DNA polymerase inhibition and the cell growth effect by these compounds are discussed.
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PMID:Structure-function relationship of synthetic sulfoquinovosyl-acylglycerols as mammalian DNA polymerase inhibitors. 1213 72

We purified the major glycolipids in the class of monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG) and sulfoquinovosyl diacylglycerol (SQDG) from a green vegetable, spinach (Spinacia oleracea L.). MGDG was an inhibitor of the growth of NUGC-3 human gastric cancer cells, but DGDG and SQDG had no such cytotoxic effect. Therefore, we studied MGDG and its monoacyglycerol-form, monogalactosyl monoacylglycerol (MGMG), in detail. MGMG with one fatty acid molecule was obtained from MGDG with two fatty acid molecules by hydrolyzing with a pancreatic lipase. MGMG was also found to prevent the cancer cell growth. MGDG was a potent inhibitor of replicative DNA polymerases such as alpha, delta and epsilon. MGMG inhibited the activities of all mammalian DNA polymerases including repair-related DNA polymerase beta with IC(50) values of 8.5-36 microg/mL, and the inhibition by MGMG was stronger than that by MGDG. Both MGDG and MGMG could halt the cell cycle at the G1 phase, and subsequently induced severe apoptosis. The relationship between the DNA polymerase inhibition and the cell growth effect by these glycolipids is discussed.
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PMID:Effects of glycolipids from spinach on mammalian DNA polymerases. 1250 1

As described previously (H. Togashi et al. Biochem Pharmacol. 1998;56:583-590), the irradiated products of provitamin D(2) (ergosterol) inhibit the activities of eukaryotic DNA polymerases. In this report, therefore, we investigated whether vitamin D and its related compounds inhibited the activities of DNA polymerases. As expected, vitamin D(2) and vitamin D(3) were found to be selective inhibitors of mammalian DNA polymerase alpha (pol alpha) with IC(50) values of 123 and 96 micro M, respectively. On the other hand, provitamin D(2), provitamin D(3), and the active form of vitamin D(3) such as 1alpha,25-dihydroxyvitamin D(3) could not influence any of the DNA polymerase activities. Interestingly, vitamin D(3)-3beta-sulfate was a much stronger pol alpha inhibitor with an IC(50) value of 7.1 micro M. Vitamin D(2), vitamin D(3), and vitamin D(3)-3beta-sulfate could prevent the growth of NUGC-3 human gastric cancer cells with LD(50) values of 133, 77, and 44 micro M, respectively, but provitamin D(2) and provitamin D(3) could not. The cells were halted at the G1 phase in the cell cycle by these compounds.
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PMID:Selective inhibition of mammalian DNA polymerase alpha by vitamin D2 and D3. 1289 Aug 94

Traditional Chinese medicinal plants are a treasure house for screening novel inhibitors of DNA polymerases and DNA topoisomerases from mammals; in the present study, nine lanostane-type triterpene acids were found in sclerotium of Poria cocos. Among the nine compounds, only dehydroebriconic acid could potently inhibit DNA topoisomerase II (topo II) activity (IC(50) = 4.6 microM), while the compound moderately inhibited the activities of DNA polymerases alpha, beta, gamma, delta, epsilon, eta, iota, kappa and lambda only from mammals, to similar extents. Another compound, dehydrotrametenonic acid, also showed moderate inhibitory effects against topo II (IC(50) = 37.5 microM) and weak effects against all the polymerases tested. Both compounds showed no inhibitory effect against topo I, higher plant (cauliflower) DNA polymerase I (alpha-like polymerase) or II (beta-like polymerase), calf thymus terminal deoxynucleotidyl transferase, human immunodeficiency virus type-1 reverse transcriptase, prokaryotic DNA polymerases such as the Klenow fragment of E. coli DNA polymerase I, Taq DNA polymerase and T4 DNA polymerase, or DNA metabolic enzymes such as T 7 RNA polymerase, T4 polynucleotide kinase and bovine deoxyribonuclease I. These findings suggest that dehydroebriconic acid and dehydrotrametenonic acid should be designated as topo II-preferential inhibitors, although they also moderately inhibited all the mammalian DNA polymerases tested. Both dehydrotrametenonic acid and dehydroebriconic acid could prevent the growth of human gastric cancer cells, and their LD(50) values were 63.6 and 38.4 microM, respectively. The cells were halted at the G1 phase in the cell cycle. The relation between the structure of triterpene acids and their inhibitory activities is discussed.
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PMID:A novel DNA topoisomerase inhibitor: dehydroebriconic acid, one of the lanostane-type triterpene acids from Poria cocos. 1507 95

To explore whether DNA polymerase beta (pol beta) contributes to the malignant transformation of gastric mucosa, we examined pol beta in gastric tumor cell lines, primary tumors and precancerous lesions. Point mutations of pol beta were detected in 6 of 13 cell lines and 23 of 104 tissues including 35.0% (14/40) of gastric cancer (GC), 30.0% (3/10) of dysplasia (Dys), 28.6% (4/14) of intestinal metaplasia (IM) and 10.5% (2/19) of chronic atrophic gastritis (CAG), respectively. A frequent mutation was a T to C transition at nucleotide 889, which was observed in 4 GC cell lines, 7 GC, 2 Dys, and 2 IM. The level of pol beta expression in tumors was higher than that of their matched normal tissues and gradual changes from GC, Dys, CAG to IM. These results indicate that the mutation and overexpression of pol beta may influence the progression during gastric carcinogenesis.
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PMID:Frequent mutation related with overexpression of DNA polymerase beta in primary tumors and precancerous lesions of human stomach. 1573 93


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