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)

Glucocorticoid hormones kill immature thymocytes through the induction of a suicide process commonly referred to as "apoptosis." A characteristic marker for this process is the stimulation of endogenous endonuclease activity which results in the extensive cleavage of cell chromatin. In an attempt to characterize the biochemical events involved in this process, we studied the role of Ca2+ in glucocorticoid-induced DNA fragmentation and cell killing in thymocytes. Treatment of thymocytes from immature rats with the synthetic glucocorticoid methylprednisolone resulted in extensive DNA fragmentation which was preceded by an early, sustained increase in cytosolic Ca2+ concentration. This increase in Ca2+ level was blocked by cycloheximide and actinomycin D, inhibitors of de novo protein and mRNA synthesis, respectively. Prevention of the Ca2+ increase by buffering cytosolic Ca2+ with quin-2, or through incubation of the thymocytes in a "Ca2+-free" medium, prevented endonuclease activation and cell killing. Inhibitors of calmodulin also prevented DNA fragmentation without inhibiting the glucocorticoid-stimulated elevation of cytosolic Ca2+ concentration. The Ca2+ increase appeared to be due to the action of a heat-labile cytosolic factor, synthesized in response to glucocorticoids, which facilitated the influx of extracellular Ca2+. Our findings suggest that glucocorticoids induce thymocyte suicide through an elevation of cytosolic Ca2+ concentration resulting in endonuclease activation, DNA fragmentation, and cell death.
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PMID:Glucocorticoids activate a suicide process in thymocytes through an elevation of cytosolic Ca2+ concentration. 253 63

The effect of in vivo exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on glucocorticoid- and calcium ionophore-induced DNA fragmentation in rat thymocytes was investigated. TCDD dose-dependently abolished DNA fragmentation in response to both agents after 7 days of exposure. Analysis of the time dependence of the effect revealed that after 1 or 2 days TCDD potentiated DNA fragmentation in untreated and glucocorticoid-treated thymocyte suspensions relative to controls. The DNA fragmentation in untreated thymocyte suspensions from TCDD-treated rats was completely prevented by inhibitors that block glucocorticoid-induced thymocyte suicide. Our results suggest that TCDD-induced thymic atrophy is due to Ca2+-dependent endonuclease activation.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) kills glucocorticoid-sensitive thymocytes in vivo. 254 82

The 163-kilobase-pair (kb) plasmid pMOL28, which determines inducible resistance to nickel, cobalt, chromate, and mercury salts in its native host Alcaligenes eutrophus CH34, was transferred to a derivative of A. eutrophus H16 and subjected to cloning procedures. After Tn5 transposon mutagenesis, restriction endonuclease analysis, and DNA-DNA hybridization, two DNA fragments, a 9.5-kb KpnI fragment and a 13.5-kb HindIII fragment (HKI), were isolated. HKI contained EK1, the KpnI fragment, as a subfragment flanked on both sides by short regions. Both fragments were ligated into the suicide vector pSUP202, the broad-host-range vector pVK101, and pUC19. Both fragments restored a nickel-sensitive Tn5 mutant to full nickel and cobalt resistance. The hybrid plasmid pVK101::HKI expressed full nickel resistance in all nickel-sensitive derivatives, either pMOL28-deficient or -defective, of the native host CH34. The hybrid plasmid pVK101::HKI also conferred nickel and cobalt resistance to A. eutrophus strains H16 and JMP222, Alcaligenes hydrogenophilus, Pseudomonas putida, and Pseudomonas oleovorans, but to a lower level of resistance. In all transconjugants the metal resistances coded by pVK101::HKI were expressed constitutively rather than inducibly. The hybrid plasmid metal resistance was not expressed in Escherichia coli. DNA sequences responsible for nickel resistance in newly isolated strains showed homology to the cloned pMOL28-encoded nickel and cobalt resistance determinant.
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PMID:Cloning of pMOL28-encoded nickel resistance genes and expression of the genes in Alcaligenes eutrophus and Pseudomonas spp. 254 12

In the IL-2-dependent T cell clone CTLL-2, dexamethasone, a synthetic glucocorticoid, induces a suicide program characterized by the early degradation of chromatin in oligonucleosome-length fragments which precedes the loss of cell viability by 2 to 4 h. These effects are most likely mediated through the interaction with a specific glucocorticoid receptor as suggested by the structure-activity relationship of the various steroids tested. Incubation of nuclei of glucocorticoid-untreated cells in the presence of calcium and magnesium ions induces the cleavage of DNA in the linker region between nucleosomes, suggesting that fragmentation of chromatin in intact cells by glucocorticoids may involve the activation of a preexisting endonuclease. Interestingly, the presence of a saturating dose of IL-2 during the treatment of CTLL-2 cells with glucocorticoids completely blocks the cell death program.
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PMID:IL-2 protects T lymphocytes from glucocorticoid-induced DNA fragmentation and cell death. 255 79

The effect of phorbol esters on the proliferation and survival of interleukin-2(IL-2)-dependent cells was studied using an IL-2-dependent T cell line (CTLL-2) and blasts of BALB/c mouse spleen cells stimulated with Concanavalin A. Addition of phorbol 12,13-dibutyrate (PDBu) to CTLL-2 or ConA blasts induces a mitogenic response which is 25-40% of that elicited by IL-2. Interleukin 2 deprivation leads to a marked decline in the number of viable cells (50% of CTLL-2 cells have died after 8-10 hours incubation in IL-2-free medium). The mechanism of cell death seems to correspond to the suicide process known as apoptosis since an early degradation of DNA into oligonucleosome-size fragments could be observed after removal of the growth factor. When present, PDBu inhibits both the activation of the endonuclease and the development of the cell death process in CTLL-2 cells and ConA-blasts deprived of IL-2. Taken together, our results suggest that the tumor promoters phorbol esters inactivate in T cells the mechanism of cell elimination triggered by IL-2 deprivation and may help to explain why transformation of T cells decreases or even abolishes their requirements of IL-2 for survival and growth.
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PMID:Phorbol esters inhibit apoptosis in IL-2-dependent T lymphocytes. 259 Jan 87

IL-2-dependent T effector cells usually die when deprived of growth factor. Cell death (as measured by plasma membrane breakdown) requires protein synthesis because it is inhibited by cycloheximide or emetine. When the DNA in several IL-2-dependent cell lines was examined following removal of IL-2, it was found that extensive chromatin cleavage precedes plasma membrane breakdown by several hours. The DNA fragments observed were not randomly generated but consisted of oligonucleosomes. This suggests that IL-2 deprivation led to activation of an endonuclease with specificity for linker DNA. DNA fragmentation, like cell death, did not occur in the presence of protein synthesis inhibitors. The protein(s) synthesized in response to IL-2 deprivation may, therefore, be the endonuclease or its activator; none of the IL-2-dependent T cells examined contain detectable endogenous endonuclease prior to IL-2 removal. DNA fragments were also found in vivo in lymph node cells draining a site of antigen administration. These results suggest that one aspect of the termination of immune responses involves activation of a cell suicide program in the expanded effector T cell clones. In this program an endonuclease is activated and chromatin is cleaved; as a result macromolecular synthesis begins to wind down so that repair synthesis stops; within a few hours, the cell lyses.
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PMID:IL-2 addiction: withdrawal of growth factor activates a suicide program in dependent T cells. 294 3

Restriction-modification (RM) systems are believed to have evolved to protect cells from foreign DNA. However, this hypothesis may not be sufficient to explain the diversity and specificity in sequence recognition, as well as other properties, of these systems. We report that the EcoRI restriction endonuclease-modification methylase (rm) gene pair stabilizes plasmids that carry it and that this stabilization is blocked by an RM of the same sequence specificity (EcoRI or its isoschizomer, Rsr I) but not by an RM of a different specificity (PaeR7I) on another plasmid. The PaeR7I rm likewise stabilizes plasmids, unless an rm gene pair with identical sequence specificity is present. Our analysis supports the following model for stabilization and incompatibility: the descendants of cells that have lost an rm gene pair expose the recognition sites in their chromosomes to lethal attack by any remaining restriction enzymes unless modification by another RM system of the same specificity protects these sites. Competition for specific sequences among these selfish genes may have generated the great diversity and specificity in sequence recognition among RM systems. Such altruistic suicide strategies, similar to those found in virus-infected cells, may have allowed selfish RM systems to spread by effectively competing with other selfish genes.
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PMID:Restriction-modification systems as genomic parasites in competition for specific sequences. 747 44

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

Although there are different ways in which cells may die, it is now thought that in a developmental context cells are induced to positively commit suicide whilst in a homeostatic context the absence of certain survival factors may provide the impetus for suicide. There appears to be some variation in the morphology and indeed the biochemistry of these suicide pathways; some treading the path of "apoptosis", others following a more generalized pathway to deletion, but both usually being genetically and synthetically motivated. There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade, however, presumably true apoptosis and programmed cell death must be genetically mediated. It is also becoming clear that mitosis and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors.
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PMID:Apoptosis or programmed cell death? 831 48

Apoptosis is a mechanism for eliminating unwanted cells from the cell community of multicellular organisms. Abnormalities in the regulation of apoptosis may play a part in the aetiology of cancer, autoimmune diseases, AIDS, degenerative nerve diseases and malformation. On of the hallmarks of apoptosis is the enzymatic cleavage of genomic DNA into nucleosomal oligomers. The identification of an endonuclease responsible for apoptosis might help to explain how this cell suicide is regulated and why DNA is cleaved. Here, we found that gamma type of DNase was retained in apoptotic rat thymocyte nuclei. The mode of DNA cleavage, 3'-hydroxyl (OH)/5'-phosphoryl (P) ends, by homogeneously purified DNase gamma (Mr = 33 kDa) and its Zn2+ sensitivity match those observed in apoptosis in thymocytes induced by irradiation or glucocorticoid treatment, indicating that this endonuclease is a central component of the thymic apoptosis machinery.
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PMID:[Apoptosis: its molecular mechanisms and biological roles]. 857 68


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