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)

Lymphocytes from a common human leukemia, chronic lymphocytic leukemia, chronic lymphocytic leukemia, have a greatly enhanced capability of DNA repair and a concomitantly prolonged survival in vitro after damage to DNA. From these lymphocytes, we isolated and purified a DNA-binding protein with a molecular weight of 24,000. It binds tightly to both ultraviolet light (UV)-irradiated and single-stranded DNA. At 35 degrees it enhances the helix-coil transition of poly[d(A-T)] AND the UV-irradiated calf thymus DNA but is inefficient in ordinary native DNA. This protein also facilitates the rate of UV-endonuclease incision of UV DNA but does not induce any nicks by itself. This finding suggests that the protein may be involved in DNA repair by enhancing such activity, and also offers an explanation for our observation of increased DNA repair in chronic lymphocytic leukemia cells. When human metaphase chromosomes are exposed to the protein, it induces marked lengthening of chromatids suggesting that this protein may also act on complex chromosomes. By quantitative immunochemical determinations, such protein could not be found in lymphocyte extracts of three normal individuals.
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PMID:Some properties of a DNA-unwinding protein unique to lymphocytes from chronic lymphocytic leukemia. 111 55

Ca2+/Mg(2+)-dependent endonuclease has been implicated in the extensive internucleosomal DNA fragmentation that accompanies apoptosis (gene-directed cell death). We present further evidence that this enzyme is involved in apoptosis. Ca2+/Mg2+ nuclease activity was increased about 6-fold during colchicine-induced apoptosis in human chronic lymphocytic leukaemia cells. The increase in activity coincided with onset of DNA fragmentation. Spleen, liver, kidney and thymus expressed high levels of this enzyme while lung, brain, heart and testis contained little activity. Cells from tissues with high Ca2+/Mg2+ nuclease activity underwent rapid DNA fragmentation in response to a Ca2+ flux. Physiological concentrations of Zn2+ known to inhibit both apoptosis and DNA fragmentation also inhibited Ca2+/Mg2+ nuclease activity.
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PMID:Ca2+/Mg(2+)-dependent nuclease: tissue distribution, relationship to inter-nucleosomal DNA fragmentation and inhibition by Zn2+. 166 94

Ca, Mg-dependent endonuclease is one of the main DNAses of lymphocyte chromatin. It's activity is known to increase in the immune response and to decrease in spontaneous and experimental CLL. These observations became a basis for analysis of possible clinical meaning of it's enzymatic activity assay. Donors' peripheral blood lymphocytes being tested, normal level of endonucleolysis for men and children was defined. Except that patients with different clinical forms of lymphoproliferative diseases such as chronic lympholeukemia, non-Hodgkin lymphomas, Hodgkin's disease were observed. The results showed that Ca, Mg-dependent endonucleolysis activity was decreased in comparison to donors' one. Ca, Mg-dependent endonucleolysis activity was the same in the group of patients with non-malignant pathology and in donors' one. Successful treatment and remission state of our patients was associated with alteration of the Ca, Mg-dependent endonucleolysis activity to normal level as well as immunological parameters. That is why the activity of Ca, Mg-dependent endonucleolysis is suggested to be a new criterion of immune state and lymphocyte malignant transformation.
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PMID:[Changes in Ca, Mg-dependent endonuclease of DNA in isolated nuclei of human lymphocytes in lymphoproliferative diseases]. 239 89

The methylation state of CCGG sites in and around the human ornithine decarboxylase gene, oncogenes c-myc and erb-A1, and actin genes were determined in human malignant leucocytes from patients with acute and chronic myeloid leukemia, chronic lymphatic leukemia, polycythemia vera, and multiple myeloma by means of isoschizomeric restriction endonuclease analysis. When compared with DNA from leucocytes of healthy controls, the ornithine decarboxylase and erb-A1 genes were substantially hypomethylated in all samples obtained from patients with chronic lymphatic leukemia. Hypomethylation of genes, particularly growth-related sequences, might be a crucial fact in the malignant transformation of human leucocytes. Its relatively simple detection from blood samples may prove clinically applicable in monitoring patients with chronic lymphatic leukemia.
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PMID:Hypomethylation of ornithine decarboxylase gene and erb-A1 oncogene in human chronic lymphatic leukemia. 290 92

Peripheral blood mononuclear cells from five patients with IgG+ B-type chronic lymphocytic leukemia (B-CLL) were analyzed for the presence of clone-specific Ig H chain variable region gene mRNA transcripts linked to C mu and/or C alpha. This was assessed by (1) comparing the lengths of portions of the VHDJH of the IgG+ CLL clones with those of the mu and alpha isotype-expressing B cells, (2) performing clone-specific endonuclease digestion studies, and (3) determining the DNA sequences of the mu and alpha isotype-expressing cDNA. Thus, when B-cell mRNA from these five patients were reverse transcribed with C gamma-specific primers and then amplified by polymerase chain reaction, dominant cDNA were found with lengths corresponding to those of the IgG+ CLL B cell. In addition, in four cases, cDNA of lengths identical to those of the CLL B cell were detected when mRNA was reverse transcribed and amplified using c mu- and/or C alpha-specific primers, strongly suggesting clonal relatedness. These CLL-related mu- and alpha-expressing cDNA were present in greater amounts that unrelated (non-CLL) mu- and alpha-expressing cDNA from normal B cells that used genes of the same VH family. When the sequences of these CLL-related C mu- and C alpha-expressing cDNA were compared with those of the IgG+ CLL clones, it was clear that they were derived from the same ancestral gene as the IgG-expressing CLL B cell, thus documenting their common origin. Finally, nucleotide point mutations were observed in the mu- and alpha-expressing cDNA of certain patients, indicating divergence with the CLL. These data suggest that IgM+ B cells, which are precursors of the leukemic B cells, exist in increased numbers in the blood of most patients with IgG+ B-CELL and that these cells may differentiate, accumulate V genes mutations, and undergo isotype switching in vivo. In addition, the data are consistent with a sequential-hit model for the evolution of CLL.
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PMID:Evidence for progenitors of chronic lymphocytic leukemia B cells that undergo intraclonal differentiation and diversification. 860 51

Therapeutic agents used in the treatment of chronic lymphocytic leukemia (CLL) are capable of inducing apoptosis in some (but not all) patient isolates. It is not yet clear whether cells that are resistant to one agent will also be resistant to others, and the mechanisms contributing to differential apoptosis sensitivity are not known. Here we report that glucocorticoid hormone and a clinically relevant chemotherapy combination (fludarabine plus mitoxantrone) fail to induce apoptosis in four of 24 CLL patient isolates. Apoptosis resistance was associated with elevated BCL-2 and BAX expression. Interestingly, incubation in vitro led to down-regulation of BCL-2 expression in both apoptosis-sensitive and apoptosis-resistant cells, whereas parallel down-regulation of BAX occurred only in the resistant samples. Evaluation of nuclear endonuclease content indicated that all of the apoptosis-sensitive samples contained appreciable levels of activity, whereas the endonuclease was not detected in the four populations of resistant cells. Our results indicate that nuclear endonuclease activity represents an excellent prognostic indicator of CLL apoptosis sensitivity that may be controlled by differential BCL-2 family polypeptide expression and signals from the in vivo microenvironment.
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PMID:Apoptosis sensitivity in chronic lymphocytic leukemia is determined by endogenous endonuclease content and relative expression of BCL-2 and BAX. 878 28

A case of CLL with two different cellular populations is reported. A 50-year-old man was evaluated for persistent absolute lymphocytosis. A peripheral blood smear revealed numerous small lymphocytes (83% of white blood cells counted). Frequent Grumpecht shadows were present, too. On bone marrow aspirate smears lymphocytes comprised 85% of the total cells counted, and the bone marrow biopsy showed a mixed nodular-interstitial infiltration pattern. The immunophenotypic study showed two different leukemic populations. The first one (comprising 79% leukemic cells) was CD5+, CD19+, CD10-, CD20+, CD18-, CD22-, CD23+ +, lambda dim, and FMC7-. The second population (comprising 21% leukemic cells) was CD5+, CD19+, CD10-, CD20+, CD18+, CD22+, CD23+, lambda+ +, and FMC7+. Gene rearrangement studies detected the germline and one rearranged band in Jk blot with each restriction endonuclease. In the Jh blot the germline and two rearranged bands were detected with EcoRI and BamHI and three rearranged bands with HindIII. The JBI/JBII blot detected only the germline band. The detection of three rearranged bands was interpreted as evidence of the presence of at least two monoclonal populations of cells with the same light chain restriction.
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PMID:Chronic lymphocytic leukemia with two cellular populations: a biphenotypic or biclonal disease. 920 Sep 98

Two flow cytometric apoptosis assays, the terminal deoxynucleotidyl transferase (TdT) assay and in situ nick translation (ISNT) assay, were assessed for their ability to quantitate drug-induced apoptosis in CLL lymphocytes. In contrast to HL60 cells, biotinylated dUTP could not be effectively incorporated into apoptotic CLL lymphocytes using exogenous TdT. This suggested that CLL lymphocytes possess a different type of endonuclease that cleaves DNA, leaving blunt or 3' recessed DNA breaks, which are poor substrates for TdT. This possibility was tested using lambda exonuclease, which can convert a blunt or 3' recessed DNA break into a 3' overhang. Apoptotic CLL lymphocytes pre-treated with lambda exonuclease demonstrated increased nucleotide incorporation with TdT. Single-strand DNA breaks are also present in apoptotic CLL lymphocytes, as labelled nucleotides could be incorporated using the in situ nick translation assay. This study suggests that the efficiency of tailing reactions may be limited by the nature of the endonuclease activity in certain cell types and that validation with other parameters is an essential prerequisite to their quantitative use.
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PMID:Flow cytometric apoptosis assays indicate different types of endonuclease activity in haematopoietic cells and suggest a cautionary approach to their quantitative use. 948 82

Cleavage of DNA into internucleosomal fragments is one of the characteristics of apoptosis. However, searches for in vivo evidence of nucleosomal DNA fragmentation in leukemia cells freshly obtained from patients during chemotherapy frequently failed to reveal nucleosomal multimers (DNA ladders). It is not clear whether this type of DNA cleavage is an essential event in drug-induced apoptosis and thus a denominator of cell killing, or whether the internucleosomal DNA fragments are merely the by-products of the apoptotic process. Here, we report our investigation into the role of DNA fragmentation in apoptotic cell death induced by anticancer nucleoside analogues, both in cell culture and in leukemia patients undergoing chemotherapy. Using a 5'-end DNA-labeling technique and pulsed field gel electrophoresis, we detected fragmentation of DNA in two distinct size classes, internucleosomal and high molecular weight (predominantly 50 kb) DNA fragments, in a human leukemia cell line exposed to the nucleoside analogues fludarabine and gemcitabine. We further demonstrated that the two types of DNA fragmentation were separate events, distinguishable by their requirements for Ca2+ and responses to phorbol ester treatment. The drug-treated cells underwent morphological changes of apoptosis even after internucleosomal DNA fragmentation was selectively inhibited by intracellular Ca2+ chelation, or by treatment with phorbol ester. In contrast, neither apoptotic morphology nor internucleosomal DNA fragmentation was observed when the high molecular weight DNA fragmentation was blocked by inhibition of nucleoside analogue incorporation into DNA. These results suggest that cleavage of DNA into large fragments may be an initial event that is critical for drug-induced apoptosis, whereas activation of a Ca2+-dependent endonuclease to cleave DNA at internucleosomal sites is not an absolute requirement for the execution of the apoptotic cell death program. Further studies of leukemic lymphocytes obtained from 9 patients with chronic lymphocytic leukemia during therapy with fludarabine revealed high molecular weight DNA fragmentation, which was correlated with a decrease of peripheral lymphocytes in 6 patients, whereas only 1 of the 15 patients evaluated for nucleosomal DNA fragments showed the DNA ladders. These results indicate that high molecular weight DNA fragmentation occurs in vivo, and may be correlated with the cytotoxic action of the anticancer drugs. Further study of the association of high molecular weight DNA fragmentation with clinical response to chemotherapy is warranted.
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PMID:High molecular weight DNA fragmentation: a critical event in nucleoside analogue-induced apoptosis in leukemia cells. 981 73

Fludarabine monophosphate is a purine nucleoside antimetabolite with efficacy in the treatment of lymphoproliferative disorders and chronic lymphocytic leukemia. It is the 2-fluoro, 5' phosphate derivative of 9-beta-D-arabinofuranosyl adenine (ara-A, vidarabine) and the mechanism of action is through inhibition of DNA synthesis and the cytolytic effects through the induction of endonuclease-independent apoptosis.
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PMID:Corticosteroid responsive fludarabine pulmonary toxicity. 1215 60


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