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)

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

The linked polymorphic loci 5' to the insulin gene and 3' to the c-Harvey-ras-1 (c-Ha-ras) gene, both localised to the short arm of chromosome 11, have been studied in 14 type I diabetic pedigrees. The use of a cloned gene probe corresponding to the polymorphic locus adjacent to the insulin gene, in combination with the restriction endonuclease PvuII, has permitted an improvement in the resolution of sizes of insert at this locus. An MspI restriction fragment length polymorphism at the c-Ha-ras proto-oncogene locus (4 cM upstream from the insulin gene) was used to identify parental insulin gene related alleles unambiguously, and subsequently a pedigree analysis was performed to determine whether subclasses of inserts at this locus track with insulin dependent diabetes. Segregation analysis demonstrated no linkage between the polymorphic loci 5' to the insulin gene, nor 3' to the c-Ha-ras, and type I diabetes. However, a similar analysis confirmed an association between the HLA locus chromosome 6 and insulin dependent diabetes.
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PMID:DNA polymorphic haplotypes on the short arm of chromosome 11 and the inheritance of type I diabetes mellitus. 301 47

Restriction endonuclease analysis was used to determine the methylation status of collagen, c-Ha-ras, and thymidine kinase genes in human fibroblasts and tumor cell lines. When digested with the methylation sensitive enzymes HpaII or HhaI, the DNA of each cell line generated a unique banding pattern for each gene examined. No generalized trend of gene hypomethylation or decreases in overall cytosine methylation were observed in tumor cell lines when compared to fibroblasts. Collagen biosynthetic profiles were also determined, and no correlations could be made between patterns of type I and type III collagen gene methylation and expression. Our findings support those of a previous report in which methylation and expression of the chick alpha 2(I) collagen gene were examined, and this represents the first such analysis of the pro-alpha 1 (III) collagen gene. MspI restriction fragment length polymorphisms were detected within c-Ha-ras, pro-alpha 2(I) collagen, pro-alpha 1(III) collagen, and thymidine kinase genes. The ras gene polymorphisms can be attributed to variation in the number of tandem repeats within a MspI fragment at the 3' end of the gene. The other gene polymorphisms may be due to base pair mutations at methylated cytosine residues within CCGG sequences.
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PMID:Patterns of DNA methylation and gene expression in human tumor cell lines. 369 18

Harvey and Kirsten murine sarcoma viruses each encode a structurally and functionally related 21-kilodalton protein (p21), which is the transforming protein of each virus. Using probes from the 0.9-kilobase (kb) p21-coding region of each virus (called v-Ha-ras and v-Ki-ras, respectively), we have molecularly cloned from normal human genomic DNA the sequences that hybridize to these probes. Four evolutionarily divergent restriction endonuclease fragments were isolated. Two hybridized preferentially to v-Ha-ras and were designated human c-Ha-ras1 and c-Ha-ras2; two hybridized preferentially to v-Ki-ras and were called c-Ki-ras1 and c-Ki-ras2. Human c-Ha-ras1 contained 0.9 kb of sequence homologous with v-Ha-ras interspersed with three intervening sequences; this gene was closely related to a previously cloned rat c-Ha-ras gene that also contained intervening sequences. Human c-Ha-ras2 was more divergent from v-Ha-ras and also hybridized poorly to human c-Ha-ras1. One c-Ki-ras gene contained 0.9 kb homologous to v-Ki-ras and had one intervening sequence, whereas the other contained only 0.3 kb homologous to v-Ki-ras. The results indicated that human DNA contains several copies of the c-ras family and that c-Ha-ras1 (with intervening sequences) was more highly conserved evolutionarily than was c-Ha-ras2.
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PMID:Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. 628 20

Mouse-Chinese hamster somatic cell hybrids containing various combinations of mouse chromosomes were analyzed for the presence of the mouse c-Ha-ras (1) sequences after restriction endonuclease digestion and hybridization with a 32P-labeled Ha-ras specific probe according to the procedure of Southern (2). The presence of the mouse c-Ha-ras containing fragment was correlated with the presence of mouse chromosome 7 in the hybrids.
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PMID:Assignment of murine cellular Harvey ras gene to chromosome 7. 631 74

Sequence specific ethylation damage and repair of ethyl-adducts in selected restriction endonuclease recognition sites within p220-ras plasmid DNA was assessed by a modified Southern blotting coupled immunoprobing technique. In situ UV irradiation of DNA in gels clearly ameliorated the immunodetection of minute amounts of facultative fragments generated due to inhibition of enzyme cleavage site by covalent alkylation modification of the cognate sites. Specific and quantitative localization of induced facultative fragments was achieved in as low as 1 ng of DNA digest corresponding to a peak intensity below 0.1 absorbance unit upon laser scanning. An ENU dose dependent increase in the intensity of representative 7.1 and 7.7 kb facultative fragments was observed as a result of cleavage block at EcoRI (G/ATTC) and BamHI (G/GATCC) restriction endonuclease sites, respectively. To determine the repair in prokaryotic cells, the half-life of repairable alkyl-adducts was assessed in plasmid DNA established in various Escherichia coli strains as a function of post-treatment incubation time in the recovery medium. The repair is indicated by the gradual disappearance of the 7.1, 7.7, 11.9 and 5.5 kb facultative fragments within the wild-type and mutant E. coli strains. The ethyl-adducts within EcoRI and BamHI restriction sites were effectively lost from the target DNA in repair-proficient E. coli with an estimated t1/2 of approximately 40 min. However, decreased overall rate and at least 2.2-times lesser extent of repair was observed in the repair-deficient (ada+ogt-) and (ada-ogt+) cells. No measurable repair was noticed in alkyltransferase defective double mutant (ada-ogt-) even after 2 h of post-treatment incubation. The repair of ethyl-adducts at NotI site (GC/GGCCGC) in 5.5 kb facultative fragment occurred at a relatively faster rate (t1/2 of 27 min) in wild-type bacteria. A 1.5-fold slower repair of ethyl-adducts in BamHI and EcoRI sequences containing G/G and A/G at their cleavage sites was observed compared to C/G in NotI sequence. These results demonstrate the regioselective induction of alkyl-adducts in ethylated DNA and their differential repair in E. coli due to varied efficiency of the repair enzymes for promutagenic DNA base lesions present in different sequence context.
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PMID:Repair of base alkylation damage in targeted restriction endonuclease sequences of plasmid DNA. 754 6

Cell suicide, or apoptosis, is now recognized as an essential regulatory step in such diverse developmental processes as embryogenesis, thymocyte restriction, and hematopoiesis. One of the major features of apoptosis is the activation of an endogenous nuclease that cleaves DNA into nucleosomal fragments. Little is known about the activation or specificity of the apoptotic endonuclease. In this study, we investigated signalling pathways and the specificity of the apoptotic nuclease. We found that forced over-expression of activated H-ras inhibited activation of the apoptotic endonuclease. Since a high percentage of myelodysplasias and leukemias have mutations that activate ras, this finding lends insight into how ras might be leukemogenic. In addition, the phorbol ester TPA and a cyclic AMP analogue also slowed activation of this endonuclease. Interestingly, protein synthesis inhibition stimulated the endonuclease activity. In addition, by cloning and sequencing apoptotic fragments we found that the apoptotic nuclease has no sequence specificity. Thus, the apoptotic nuclease inhibited by H-ras over-expression was random in nature.
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PMID:Mutant H-ras over-expression inhibits a random apoptotic nuclease in myeloid leukemia cells. 768 29

Transfection of a murine fibroblast cell line with an activated form of the Harvey ras oncogene conferred sensitivity to apoptosis induced by various agents. This intrinsic sensitivity to apoptosis correlated with the expression of endogenous endonuclease activity in isolated nuclei that was undetectable in the untransfected parental cell line. Subsequent transfection with the human bcl-2 oncogene prevented the morphological and biochemical features of apoptosis in whole cells, although it failed to confer complete protection against cell death. Furthermore, transfection of the bcl-2 oncogene also inhibited the enhanced endonuclease activity in isolated nuclei. Our results indicate that some of the effects of Ha-ras and bcl-2 and potentially other oncogenes, are exerted on the biochemical machinery of apoptosis at the level of the nucleus.
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PMID:Differential regulation of endogenous endonuclease activation in isolated murine fibroblast nuclei by ras and bcl-2. 786 55

To date, apoptosis has been characterized biochemically by the production of 180-200 bp internucleosomal DNA fragments resulting from the activation of an endonuclease(s). The principal morphological feature of apoptosis is the condensation of chromatin and it has been assumed that this may reflect the oligonucleosomal fragmentation pattern. We have re-examined this dogma by comparing the biochemical and morphological features of cell death in several epithelial cell types (HT-29-I1 colon adenocarcinoma, CC164 mink lung, DU-145 human prostatic carcinoma and MCF-7 human breast adenocarcinoma) and one mesenchymal cell line (H11ras-R3 ras-transformed rat fibroblasts). Cell death was induced either by serum deprivation, TGF-beta 1 or etoposide, or by leaving cells to reach confluence. Cell death was assessed with respect to detachment from monolayers, morphological changes and DNA integrity. The DNA-binding fluorophore Hoechst 33258 revealed chromatin condensation patterns consistent with apoptotic cell death in all cell types except MCF-7 cells. Using field inversion gel electrophoresis in conjunction with conventional 2% agarose gel electrophoresis, cleavage of DNA to 50 kbp fragments was observed in all cases except MCF-7 cells. This preceded the appearance of oligonucleosomal fragments in HT-29-I1, CC164 and H11ras-R3 cells. Although the DNA of DU-145 cells fragmented into 50 kbp units, and although the cells exhibited classical apoptotic morphology, no subsequent internucleosomal cleavage was observed. These results suggest that changes in the integrity of DNA indicative of the release of chromatin loop domains occur before cleavage at internucleosomal sites is initiated and that the latter is not an essential step in the apoptotic process.
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PMID:Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. 825 89

Oncogenes and oncosuppressors can deregulate cell replication in tumours, and recently have been shown to influence the probability of apoptosis. The effects of human c-myc and mutated (T24) Ha-ras oncogenes on susceptibility to apoptosis were investigated by introducing them into immortalised rat fibroblasts. The resulting family of transfectants showed closely similar measures of proliferation, but widely divergent rates of apoptosis, differing by up to fifteen-fold, that correlated inversely with population expansion rates in vitro. T24-ras transfectants with moderate or high p21ras expression showed reduced apoptosis, and this was reversed by pharmacological inhibition of membrane localisation of p21ras by mevinolin. In contrast, c-myc stimulated apoptosis, and this was further enhanced by serum deprivation. Inducibility of effector proteins represents one possible mechanism of genetic control of the susceptibility to apoptosis, and its investigation showed that c-myc was associated with expression by viable cells of latent calcium/magnesium sensitive endonuclease activity characteristic of apoptosis. In contrast, endonuclease activity was not detected in viable cells of a T24-ras transfectant expressing high levels of p21ras. Thus, there appeared to be differential regulation of susceptibility to apoptosis, positively by c-myc and negatively by activated ras, and this was associated with availability of endonuclease activity. Genetic modulation of apoptosis in human neoplasms is likely to influence net growth rate, retention of cells acquiring new mutations and response to certain chemotherapeutic agents.
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PMID:Susceptibility to apoptosis is differentially regulated by c-myc and mutated Ha-ras oncogenes and is associated with endonuclease availability. 826 Mar 64


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