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)

To detect occult lymphoma, the polymerase chain reaction (PCR) technique was used to amplify joined bcl-2/JH DNA sequences at the juncture of the t(14:18) translocation in follicular lymphoma. Using the heat-stable DNA polymerase Taq and automated cycling of the reaction, we were able to detect as few as one to two copies of bcl-2/JH. Under these conditions, PCR proved to be at least 10,000-fold more sensitive than either conventional flow cytometry or Southern blot restriction analysis. In addition, genomic DNA sequences of four lymphomas confirmed that the size of the amplified segment serves as a tumor marker. Direct application of PCR to patient staging revealed occult malignant lymphoma in tissue otherwise considered uninvolved by standard criteria. We conclude that the striking enhancement in diagnostic sensitivity attained by DNA amplification can serve as a valuable adjunct to the staging and clinical monitoring of follicular lymphoma.
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PMID:Detection of occult follicular lymphoma by specific DNA amplification. 314 Sep 14

High levels of bcl-2 protein have been found in a wide variety of human cancers. Since p53 gene inactivation occurs in over half of human cancers, it is possible that loss of p53-mediated repression of bcl-2 gene expression accounts, at least in part, for the frequent abnormalities in bcl-2 protein production seen in tumours. By using immunohistochemical methods, we have analysed thirty-three nasopharyngeal carcinomas for p53 and bcl-2 expression. We found an inverse correlation between the expression of these two proteins (P < 0.001). Moreover, we utilized universal oligonucleotide primers of a region 5' to the bcl-2 MBR and at the 3' end of JH segments to initiate a DNA polymerase chain reaction that amplified these bcl-2-JH junctures. Of the twelve nasopharyngeal carcinomas expressing bcl-2, none showed a t(14;18) chromosome translocation. These findings may indicate potential mechanisms by which bcl-2 regulates apoptosis.
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PMID:Down regulation of bcl-2 by p53 in nasopharyngeal carcinoma and lack of detection of its specific t(14;18) chromosomal translocation in fixed tissues. 873 40

B-cell leukemia/lymphoma (bcl-2) expression can override the apoptosis development in lymphoid and hormonally regulated tissue-like breast. The presence of estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) have revealed in breast carcinomas, but they have not been correlated to the bcl-2 protein expression and DNA fragmentation markers. We evaluated the immunohistochemical expression of bcl-2 protein and hormonal receptors (ER, PR, AR) and differentiation grade in 37 infiltrating ductal carcinomas of the breast for which frozen tissues were available for DNA extraction. The immunohistochemical reaction for bcl-2 was considered positive if more than 50% of neoplastic cells had intense cytoplasmic staining, whereas for steroid receptor evaluation Battifora's criteria were used. The DNA was extracted according to the phenol-chloroform procedure and used for bcl-2 gene rearrangement study of the major breakpoint region (Southern blot) and for membrane-based end-labeling using digoxigenin-labeled nucleotides and E. coli DNA polymerase I (Klenow fragment). The results were quantified by three different observers. Low-grade carcinomas were positive for bcl-2 protein (27/28, 96.4%) and ER (15/28, 53.6%), whereas the remaining neoplasms were negative for bcl-2 (9/9, 100.0%) and ER (8/9, 53.6%) (p < 0.001). No statistically significant differences were revealed at the bcl-2, PR and AR comparisons. The Southern blot analysis for bcl-2 major breakpoint region showed neither rearrangement nor genetic amplification (densitometric study). Only the membrane-based end-labeling of DNA fragments showed correlation with bcl-2 protein and ER expressions: all except one bcl-2-negative tumor and two bcl-2-positive tumors had positive labeling using 7 pg of DNA at dot blot analysis (p < 0.002). The bcl-2 protein expression would allow both proliferation and cell progression by blocking apoptosis in well-differentiated, ER-positive breast carcinomas. In these neoplasms, DNA fragmentation as a molecular marker of apoptosis was prevented by bcl-2 expression.
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PMID:Bcl-2 expression and DNA fragmentation in breast carcinoma, pathologic and steroid hormone receptors correlates. 936 Aug 41

Alveolar epithelial cell (AEC) injury and repair are important in the pathogenesis of oxidant-induced lung damage. Keratinocyte growth factor (KGF) prevents lung damage and mortality in animals exposed to various forms of oxidant stress, but the protective mechanisms are not yet established. Because DNA strand break (DNA-SB) formation is one of the earliest cellular changes that occurs after cells are exposed to an oxidant stress, we determined whether KGF reduces H2O2-induced pulmonary toxicity by attenuating AEC DNA damage. KGF (10-100 ng/ml) decreased H2O2 (0.05-0.5 mM)-induced DNA-SB formation in cultured A549 and rat alveolar type II cells measured by an alkaline unwinding, ethidium bromide fluorometric technique. The protective effects of KGF were independent of alterations in catalase, glutathione (GSH), or the expression of bcl-2 and bax, two protooncogenes known to regulate oxidant-induced apoptosis. Actinomycin D and cycloheximide abrogated protective effects of KGF. Furthermore, protection by KGF was completely blocked by 1) genistein, a tyrosine kinase inhibitor; 2) staurosporine and calphostin C, protein kinase C (PKC) inhibitors; and 3) aphidicolin, butylphenyl dGTP, and 2',3'-dideoxythymidine 5'-triphosphate, inhibitors of DNA polymerase. We conclude that KGF attenuates H2O2-induced DNA-SB formation in cultured AECs by mechanisms that involve tyrosine kinase, PKC, and DNA polymerases. These data suggest that the ability of KGF to protect against oxidant-induced lung injury is partly due to enhanced AEC DNA repair.
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PMID:Keratinocyte growth factor promotes alveolar epithelial cell DNA repair after H2O2 exposure. 975 11

Cisplatin is among the most widely used broadly active cytotoxic anticancer drugs; however, its clinical efficacy is often limited by primary or the development of secondary resistance. Several mechanisms have been implicated in cisplatin resistance, including reduced drug uptake, increased cellular thiol/folate levels and increased DNA repair. More recently, additional pathways have been characterized indicating that altered expression of oncogenes that subsequently limit the formation of cisplatin-DNA adducts and activate anti-apoptotic pathways may also contribute to the resistance phenotype. Several lines of evidence suggest that expression of ras oncogenes can confer resistance to cisplatin by reducing drug uptake and increasing DNA repair; however, this is not a uniform finding. Tumor cells, in contrast to normal cells, respond to cisplatin exposure with transient gene expression to protect or repair their chromosomes. The c-fos/AP-1 complex, a master switch for turning on other genes in response to DNA-damaging agents, has been shown to play a major role in cisplatin resistance. In addition, AP-2 transcription factors, modulated by protein kinase A, are also implicated in cisplatin resistance by regulating genes encoding for DNA polymerase beta and metallothionines. Furthermore, considerable evidence indicates that mutated p53 plays a significant role in the development of cisplatin resistance since several genes implicated in drug resistance and apoptosis (e.g. mismatch repair, bcl-2, high mobility group proteins, DNA polymerases alpha and beta, PCNA, and insulin-like growth factor) are known to be regulated by the p53 oncoprotein. Improved understanding of molecular factors for the development of cisplatin resistance may allow the prediction of clinical response to cisplatin-based treatment. Furthermore, the identification of oncogenes involved in cisplatin resistance has already led to in vitro approaches which successfully inactivated these genes using ribozymes or antisense oligodeoxynucleotides, thus restoring cisplatin sensitivity. It is conceivable that these strategies, once transferred to a clinical setting, may have the potential to enhance the efficacy of cisplatin against a great variety of malignancies and thus more fully exploit the antineoplastic and curative potential of this drug.
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PMID:Cisplatin resistance and oncogenes--a review. 1089 36

Arsenic trioxide has recently been shown to inhibit growth and induce apoptosis in acute promyelocytic leukemia (APL), but little is known about the molecular mechanisms mediating these effects. Here we demonstrate that treatment of promonocytic U937 cells with arsenic trioxide leads to G2/M arrest which was associated with a dramatic increase in the levels of cyclin B and cyclin B-dependent kinase and apoptosis. We further show that apoptosis occurs after bcl-2 phosphorylation and caspase-3 activation followed by cleavage of PARP and PLC-gamma1 degradation and DNA fragmentation. The arsenic trioxide-induced apoptosis could be blocked by the protein synthesis inhibitor cycloheximide. In addition, pretreatment of U937 cells with the DNA polymerase inhibitor aphidicolin also blocked apoptosis, but did not cause the arrest of cells in the G2/M phase. The findings suggest that arsenic trioxide exerts its growth-inhibitory effects by modulating expression and/or activity of several key G2/M regulatory proteins. Furthermore, arsenic trioxide-mediated G2/M arrest correlates with the onset of apoptosis.
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PMID:Arsenic trioxide induces G2/M growth arrest and apoptosis after caspase-3 activation and bcl-2 phosphorylation in promonocytic U937 cells. 1152 58

Cells deficient in DNA polymerase beta (beta-pol) are impaired in base excision repair (BER) and hypersensitive to various DNA damaging agents, including methylating mutagens. Hypersensitivity of beta-pol-deficient cells to methylating agents is because of induction of apoptosis (Ochs et al., Cancer Res., 59: 1544-1551, 1999), indicating incompletely repaired DNA damage to trigger the response. Here we show that defective BER in beta-pol-null cells results in an early and transient increase in the frequency of DNA single-strand breaks on treatment with methyl methanesulfonate. These breaks arising as repair intermediates are not likely to trigger apoptosis directly because they were repaired efficiently and generated both in resting and proliferating cells, whereas only proliferating cells underwent with high frequency apoptosis after methylation. Therefore, we propose that single-strand breaks are converted into another kind of critical apoptosis-triggering lesion during replication. These critical secondary DNA lesions are likely to be non-repaired DNA double-strand breaks (DSBs), which are formed at higher frequency in beta-pol-null than in wild-type cells. Apoptosis was a late response not detectable before 24 h after methylation and was preceded by DSBs formation, extensive chromosomal breakage, and decline in Bcl-2 level and caspase-9 and caspase-3 activation. Caspase-8 was not significantly activated. Transfection of beta-pol-null cells with bcl-2 protected against methylation-induced apoptosis, indicating Bcl-2 to be causally involved. Overall, the data demonstrate that in cells lacking beta-pol, defective BER results in incompletely repaired DNA damage, which triggers apoptosis in a replication-dependent way by activating the mitochondrial death pathway. It is suggested that DSBs act as a critical ultimate apoptosis-inducing lesion.
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PMID:Deficiency in DNA polymerase beta provokes replication-dependent apoptosis via DNA breakage, Bcl-2 decline and caspase-3/9 activation. 1188 30

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