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:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is increasing evidence that the calcium ion plays a critical role in both toxic cell killing and programmed cell death. Thus, in a variety of experimental systems a perturbation of intracellular Ca2+ homeostasis due to increased Ca2+ influx and/or inhibition of Ca2+ extrusion has been found to be an early event in the development of cell injury. It is clear that sustained increases in intracellular Ca2+ can activate cytotoxic mechanisms which result in perturbations of cellular structure and function. For example, the stimulation of Ca(2+)-dependent proteases can result in a disruption of cytoskeletal organization and the formation of surface protrusions (blebs) and Ca(2+)-mediated phospholipase activation can result in an impairment of mitochondrial function with collapse of membrane potential and cessation of ATP synthesis. The activation of a Ca2+, Mg(2+)-dependent nuclear endonuclease is associated with chromatin cleavage and appears to play a crucial role in programmed cell death (apoptosis) in the immune system and other tissues. There is also recent evidence that this process may be responsible for the immunotoxicity of dioxins and organotin compounds and involved in the killing of adenocarcinoma cells by tumor necrosis factor alpha. Although calcium ions appear to be required for endonuclease activity during apoptosis, this process is also influenced by other factors, e.g. protein kinase C activity, intracellular polyamine and Zn2+ levels, chromatin structure, etc. Thus, the regulation of endonuclease activity under both physiological and toxicological conditions appears to be complex and to involve multiple factors.
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PMID:Ca(2+)-dependent mechanisms of cytotoxicity and programmed cell death. 133 78

Resistance to 0.8 microM 4'-(9-acridinylamino)methanesulphon-m-anisidide (m-AMSA) was induced by stepwise increases of drug concentration in the human tumor cell line CALc18 originating from a breast adenocarcinoma. The resistant cell line CALc18/AMSA exhibited a resistance index of 10 and a cross-resistance to other topoisomerase II inhibitors. A 3-fold decrease in the levels of topoisomerase II decatenating activity was found in CALc18/AMSA cells. By contrast, topoisomerase I activity was increased by about 3-fold in resistant cells. Interestingly this line was hypersensitive to camptothecin, a specific inhibitor of topoisomerase I. Restriction endonuclease patterns of the topoisomerase I and topoisomerase II loci were found to be identical in CALc18/AMSA and CALc18 with no evidence of gene amplification and rearrangements. Alkaline elution of m-AMSA-treated cells showed that DNA single strand breaks and DNA-protein crosslinks were decreased in CALc18/AMSA. The DNA lesions also obtained in m-AMSA-treated nuclei indicated that no drug uptake modification occurred in both cells. Moreover, the in vitro m-AMSA-induced DNA cleavage per unit of decatenating activity and the inhibitory effects of antitumoral drugs on decatenation were not found to be different with topoisomerase II from sensitive or resistant cells. However the specific cleavage induced by m-AMSA/per mg of crude protein from resistant cells was 2 to 3 times decreased. Multidrug resistance gene transcripts were not detected while levels of acidic glutathione S transferase mRNA were found to be 8 to 10-fold greater in resistant than in sensitive cell line with no amplification of the gene. In conclusion, the diminution of topoisomerase II activity and the increase of both topoisomerase I and acidic glutathione S transferase transcripts could contribute to the resistant phenotype of these breast cancer cells.
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PMID:Study of molecular markers of resistance to m-AMSA in a human breast cancer cell line. Decrease of topoisomerase II and increase of both topoisomerase I and acidic glutathione S transferase. 164 55

The incubation of human mammary adenocarcinoma cells (BT-20) with tumor necrosis factor alpha in the absence or presence of cycloheximide resulted in progressive DNA fragmentation. This was preceded by a sustained increase in intracellular free Ca2+ concentration and was not detected in cells pretreated with intracellular Ca2+ chelators, calmodulin antagonists, or activators of protein kinase C. Image analysis of fura-2-loaded BT-20 cells treated with tumor necrosis factor alpha revealed that, in many cells, the initial increase in Ca2+ level occurred in a cellular region that corresponded to the localization of the nucleus. Our findings suggest that tumor necrosis factor alpha can promote an increase in intranuclear free Ca2+ which, in turn, may stimulate Ca(2+)-dependent endonuclease activity, resulting in DNA fragmentation and apoptosis.
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PMID:Tumor necrosis factor alpha induces apoptosis in mammary adenocarcinoma cells by an increase in intranuclear free Ca2+ concentration and DNA fragmentation. 173 95

A novel lentivirus was isolated from South African sheep with experimentally transmitted lung adenocarcinoma. Similar to visna virus and caprine arthritis encephalitis virus, this new strain induced cytopathic effects on ovine plexus choroid cultures. In contrast to a recent Israeli isolate from sheep with adenocarcinoma, the South African lentivirus could not transform fibroblast cultures. The antigenic relatedness between the new isolate and visna virus was assessed by immunoprecipitation of radiolabeled viral proteins, using monospecific antisera against visna virus proteins. The results indicate that the new virus contains four major structural proteins of sizes similar to those of visna virus (i.e., gp135, p30, p16, and p14) and have some common antigenic determinants (about 90% in the major core antigen p30). However, the nucleotidic sequences of the novel lentivirus were found to be only 16.5 to 27.4% homologous to visna virus and 8.3 to 15% homologous to caprine arthritis encephalitis virus, by means of liquid hybridization under stringent conditions. The genetic divergence indicated by this last result was confirmed by the dissimilar restriction endonuclease cleavage map of the new virus in comparison to those of visna virus and three caprine arthritis encephalitis virus strains. The demonstration of a third type of ovine lentivirus supports the concept of an important genetic variation among the lentiviruses infecting one animal species.
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PMID:Characteristics of a novel lentivirus derived from South African sheep with pulmonary adenocarcinoma (jaagsiekte). 243 95

Chromosome 5 allele loss is a genetic alteration occurring during the multistep progression of colon carcinogenesis. To determine whether a similar genetic alteration occurs in other gastrointestinal malignancies, the authors have analyzed DNA extracted from freshly frozen normal and neoplastic tissue from nineteen patients who underwent radical resections for gastric, ampullary and pancreatic adenocarcinomas at the University of Chicago. Loss of heterozygosity for alleles on the long arm of chromosome 5 was detected in tumor DNA compared to normal tissue DNA from the same patient using restriction fragment length polymorphisms (RFLPs). Eleven patients were informative using the restriction endonuclease TaqI to generate RFLPs for chromosome 5 probes C11 P11 and pTP5E. Loss of heterozygosity was found in one of eight informative gastric carcinomas (12.5%) and in one of two informative ampullary carcinomas. The only informative pancreatic adenocarcinoma was heterozygous. It is concluded that chromosome 5 allele loss occurs in a variety of gastrointestinal malignancies and suggest that common genetic origins may underlie these different tumors.
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PMID:Chromosome 5 allele loss in human gastric, ampullary and pancreatic carcinomas. 257 24

Genomic DNA and mRNA from the adenocarcinoma cell line LoVo were used to generate L-cell transfectants and a bacteriophage lambda gt11 cDNA clone that express epitopes of carcinoembryonic antigen (CEA). Primary and secondary L-cell transfectants expressing CEA were selected with a fluorescence-activated cell sorter (FACS). These transfectants, including some clones that were selected for high-level CEA expression by multiple rounds of FACS sorting, express a surface protein of 150 kDa that reacts with all anti-CEA antibodies tested. In parallel, a cDNA library of LoVo poly(A)+ RNA was constructed in lambda gt11 and fusion proteins were screened with polyclonal antisera against CEA. One positive clone, lambda cLV7, was identified that hybridized specifically to transfectant DNA. The nucleic acid sequence of the cDNA insert (cLV7) contained two regions of extensive internal homology, with greater than 70% identity at the amino acid level. cLV7 hybridized to three mRNA species of LoVo cells and to a predominant mRNA of the CEA-expressing transfectants. Hybridization of cLV7 to restriction endonuclease-digested genomic DNA of colon carcinoma cells, normal human cells, and human-mouse somatic cell hybrids revealed the presence of multiple hybridizing bands, one of which was present in transfectant cells. These CEA-related sequences are not rearranged in tumors and, by somatic cell hybrid analysis, were mapped to human chromosome 19.
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PMID:Carcinoembryonic antigen family: expression in a mouse L-cell transfectant and characterization of a partial cDNA in bacteriophage lambda gt11. 295 15

Activated c-Ki-ras with a point mutation (GGT to CGT) at codon 12, resulting in the substitution of arginine for glycine, was found in DNA from metastatic pancreatic adenocarcinoma in a lymph node. By means of restriction endonuclease length polymorphism with SacI digestion, we were able to demonstrate that the same point mutation of c-Ki-ras was present in the primary tumor and in metastases in lymph nodes. DNA from the normal spleen of the patient did not have this type of point mutation. Moreover, amplifications of 3- to 6-fold of the activated c-Ki-ras and 50-fold of c-myc were found in the primary tumor and the metastases in the two lymph nodes, indicating that point mutation had occurred at a relatively early stage of the tumor development, before amplification of the gene. This is the first clear demonstration of amplification of activated c-Ki-ras accompanied by amplification of c-myc in both primary and metastatic human tumors in vivo.
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PMID:Amplifications of both c-Ki-ras with a point mutation and c-myc in a primary pancreatic cancer and its metastatic tumors in lymph nodes. 300 77

In ongoing studies, we have tested resected lung cancers from 41 men and 49 women; of those with primary lung cancer, 46 patients are free of disease and 35 have died of cancer or have persistent disease. Measurements and studies were as follows: total cellular deoxyribonucleic acid content by image analysis (n = 77); total genomic deoxyribonucleic acid methylation state and banding patterns from probed Southern blots (n = 36); radioimmunoassay for motilin, bombesin, gastrin, vasoactive intestinal peptide, and cholecystokinin (n = 18); and cytogenetic analysis (n = 39). All lung cancers were hyperploid. Adenocarcinomas and epidermoid carcinomas were generally hexaploid to nearly septaploid; comparisons by stage and histologic features suggested potential prognostic correlations. There was general hypomethylation of deoxyribonucleic acid (p less than 0.001). Deoxyribonucleic acid digests from restriction endonuclease Hpa II, when probed with deoxyribonucleic acid homologous to KPN, showed banding patterns that separated histologically indistinguishable primary adenocarcinomas and metastatic adenocarcinomas from one another. Cancers studied with radioimmunoassay were all negative for polypeptide hormones. Five cancers grew adequately in vitro to permit study of 190 detailed karyotypes (20 to 50 per tumor). Chromosome modal numbers ranged from 49 to 109. There were from 4 to 20 clearly abnormal marker chromosomes per tumor; abnormality derived from chromosome 1 was prevalent. Ten of 19 tumors xenotransplanted to nude mice were carried through two to five transplant generations without a change in histologic patterns.
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PMID:Biochemical and cytogenetic studies of human lung cancers. 319 97

Current evidence suggests that the complex nature of mammalian chromatin can result in the concealment of DNA damage from repair enzymes and their co-factors. Recently it has been proposed that the acetylation of histone proteins in chromatin may provide a surveillance system whereby damaged regions of DNA become exposed due to changes in chromatin accessibility. This hypothesis has been tested by: (i) using n-butyrate to induce hyperacetylation in human adenocarcinoma (HT29) cells; (ii) monitoring the enzymatic accessibility of chromatin in permeabilised cells; (iii) measuring u.v. repair-associated nicking of DNA in intact cells and (iv) determining the effects of n-butyrate on cellular sensitivity to DNA damaging agents. The results indicate that the accessibility of chromatin to Micrococcus luteus u.v. endonuclease is enhanced by greater than 2-fold in n-butyrate-treated cells and that there is a corresponding increase in u.v. repair incision rates in intact cells exposed to the drug. Non-toxic levels of n-butyrate induce a block to G1 phase transit and there is a significant growth delay on removal of the drug. Resistance of HT29 cells to u.v.-radiation and adriamycin is enhanced in n-butyrate-treated cells whereas X-ray sensitivity is increased. Although changes in the responses of cells to DNA damaging agents must be considered in relation to the effects of n-butyrate on growth rate and cell-cycle distribution, the results are not inconsistent with the proposal that increased enzymatic-accessibility/repair is biologically favourable for the resistance of cells to u.v.-radiation damage. Overall the results support the suggested operation of a histone acetylation-based chromatin surveillance system in human cells.
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PMID:n-Butyrate alters chromatin accessibility to DNA repair enzymes. 375 5

Tumor specimens from patients with adenocarcinoma of the colon or rectum were examined for the presence of cytomegalovirus (CMV), and specimens of normal mucosa from the same patients were studied in parallel. Frozen sections of 14 specimens were made and the presence of CMV mRNA assayed by in situ hybridisation using 3H-labelled CMV-DNA as a probe. Nine of these sections were also tested for cytomegalovirus antigens by immunofluorescence. No viral nucleic acids or antigens were detected. In addition to these direct approaches, the specimens were disaggregated and 19 were successfully cultured in various media over several months without yielding virus on any occasion. Areas containing epithelial cells were found in some cultures, foci of bipolar cells in others, while, in several, fibroblastic cells predominated. To ensure that any virus-containing cells were not lost by this method, the disaggregated tumour and normal intestinal cells were directly co-cultivated and also fused with human embryo lung cells, which are permissive for cytomegalovirus replication. The resulting cultures were examined over two to three months for the presence of cytomegalovirus, and in no instance was virus found, despite attempted induction by iododeoxyuridine. Two fusion cultures became contaminated with cytomegalovirus, strain AD-169, which was being handled in the laboratory at the same time. The strain was identified by the pattern of viral DNA fragments produced by restriction endonuclease cleavage. Thus the accidental passage of virus in the heterokaryons did not alter its DNA and would further indicate the absence of any cytomegalovirus genomes in the adenocarcinoma cells.
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PMID:Lack of association of cytomegalovirus with adenocarcinoma of the colon. 627 66


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