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:3.1.22.1 (DNase II)
429 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lovastatin, an HMG-CoA reductase inhibitor, was found to suppress growth and induce apoptosis in culture human promyelocytic leukaemic cell, HL-60. However, the mechanisms of lovastatin-induced apoptosis are still unclear. In this study, we attempted to elucidate the signal transduction pathway for lovastatin-induced apoptosis in HL-60 cells in a dose- and time-dependent manner. The features of this apoptosis were attenuated by the presence of mevalonate, a metabolic intermediate of cholesterol synthesis. Treatment of lovastatin caused a rapid release of mitochondrial cytochrome c into cytosol and subsequent induction of caspase-3, but not caspase-1 activity. Lovastatin also stimulated proteolytic cleavage of poly-(ADP-ribose) polymerase (PARP), and followed by the appearance of caspase activity and DNA fragmentation. Pretreatment with caspase-3 inhibitors, Ac-DEVD-CHO and Z-VAD-FMK, inhibited lovastatin induced caspase-3 activity and DNA fragmentation. Furthermore, we demonstrated that DNase II was involved in the DNA fragmentation induced by lovastatin. These results suggested that the mechanism of lovastatin induced HL-60 cells apoptosis through activation of caspase-3 and DNase II activities.
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PMID:Induction of apoptosis by lovastatin through activation of caspase-3 and DNase II in leukaemia HL-60 cells. 1072 20

The exact molecular mechanism of ischemic neuronal death still remains unclear from rodents to primates. A number of studies using lower species animals have suggested implication of apoptosis cascade, while using monkeys the authors recently claimed necrosis cascade by calpain-induced leakage of lysosomal cathepsins (calpain-cathepsin hypothesis). This paper is to study implications of apoptotic versus necrotic cascades for the development of hippocampal CA1 neuronal death in the primate brain undergoing complete global ischemia. Here, we focused on two terminal cell death effectors; caspase-activated DNase (CAD) and lysosomal enzyme DNase II, in the monkey CA1 sector undergoing 18 min ischemia. The expressions of their mRNA and proteins, and the subcellular localizations as well as ultrastructure and specific DNA gel electrophoresis were examined. Expression of CAD was much less in the normal brain, compared with the lymph node or heart tissues. On day 1 after ischemia, however, CAD mRNA and protein were significantly increased in the CA1 sector, and then CAD protein immunohistochemically showed a translocation from the perikarya into the nucleus. Activated DNase II protein was significantly increased on days 2 and 3 after ischemia, and also showed a similar translocation indicating lysosomal leakage. Although the post-ischemic CA1 neurons showed positive terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining on days 3-5, they showed eosinophilic coagulation necrosis on light microscopy, and frank membrane disruption and mild chromatin condensation on electron microscopy. Furthermore, DNA smear pattern typical for necrosis was observed instead of DNA laddering. These data altogether suggest that the post-ischemic CA1 neuronal death of the monkey occurs not by apoptosis but by necrosis with participations of lysosomal enzymes DNase II and cathepsins as well as CAD. The interactions between apoptotic (caspase-3 and CAD) and necrotic (calpain, cathepsin and DNase II) cascades should be studied further.
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PMID:Implications of CAD and DNase II in ischemic neuronal necrosis specific for the primate hippocampus. 1175 60

Vitamin C (VC) and vitamin K(3) (VK(3)) administered in a VC:VK(3) ratio of 100:1 exhibit synergistic antitumor activity and preferentially kill tumor cells by autoschizis, a novel type of necrosis characterized by exaggerated membrane damage and progressive loss of organelle-free cytoplasm through a series of self-excisions. During this process, the nucleus becomes smaller, cell size decreases one-half to one-third of its original size, and most organelles surround an intact nucleus in a narrow rim of cytoplasm. While the mitochondria are condensed, tumor cell death does not result from ATP depletion. However, vitamin treatment induces a G(1)/S block, diminishes DNA synthesis, increases H(2)O(2) production, and decreases cellular thiol levels. These effects can be prevented by the addition of catalase to scavenge the H(2)O(2). There is a concurrent 8- to 10-fold increase in intracellular Ca(2+) levels. Electrophoretic analysis of DNA reveals degradation due to the caspase-3-independent reactivation of deoxyribonuclease I and II (DNase I, DNase II). Redox cycling of the vitamins is believed to increase oxidative stress until it surpasses the reducing ability of cellular thiols and induces Ca(2+) release, which triggers activation of Ca(2+)-dependent DNase and leads to degradation of DNA. Recent experiments indicate that oral VC:VK(3) increases the life-span of tumor-bearing nude mice and significantly reduces the growth rate of solid tumors without any significant toxicity by reactivating DNase I and II and inducing autoschizis. This report discusses the mechanisms of action employed by these vitamins to induce tumor-specific death by autoschizis.
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PMID:Autoschizis: a novel cell death. 1203 62

Deficiency of alkaline and acid DNase is a hallmark in all non-necrotic cancer cells in animals and humans. These enzymes are reactivated at early stages of cancer cell death by vitamin C (acid DNase) and vitamin K(3) (alkaline DNase). Moreover, the coadministration of these vitamins (in a ratio of 100:1, for C and K(3), respectively) produced selective cancer cell death. Detailed morphological studies indicated that cell death is produced mainly by autoschizis, a new type of cancer cell death. Several mechanisms are involved in such a cell death induced by CK(3), they included: formation of H(2)O(2) during vitamins redox cycling, oxidative stress, DNA fragmentation, no caspase-3 activation, and cell membrane injury with progressive loss of organelle-free cytoplasm. Changes in the phosphorylation level of some critical proteins leading to inactivation of NF-kappaB appear as main intracellular signal transduction pathways. The increase knowledge in the mechanisms underlying cancer cells death by CK(3) may ameliorate the techniques of their in vivo administration. The aim is to prepare the introduction of the association of vitamins C and K(3) into human clinics as a new, non-toxic adjuvant cancer therapy.
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PMID:The association of vitamins C and K3 kills cancer cells mainly by autoschizis, a novel form of cell death. Basis for their potential use as coadjuvants in anticancer therapy. 1276 95

Neural progenitor cells play an essential role in both the developing embryonic nervous system and in the adult brain, where the capacity for self-renewal would be important for normal brain functions. In the present study, we used embryonic cortical neural progenitor cells to investigate the effects of trimethyltin chloride (TMT) on the survival of neural progenitor cells. In cultures of cortical neural progenitor cells, the formation of round neurospheres was observed in the presence of epidermal growth factor and basic fibroblast growth factor within 9 days in vitro. The neurospheres were then harvested for subsequent replating and culturing for assessment of cell viability in either the presence or absence of TMT at the concentration of 5microM. Lasting exposure to TMT produced not only nuclear condensation in the cells in a time-dependent manner over a period of 6-24h, but also the release of lactate dehydrogenase into the culture medium. Immunoblot and immunocytochemical analyses revealed that TMT had the ability to activate both caspase-3 and calpain, as well as to cause nuclear translocation of deoxyribonuclease II, which is located within cytoplasm in intact cells. Additionally, treatment with a calpain inhibitor [trans-epoxysuccinyl-l-leucylamido-(4-guanidino) butane] and a caspase inhibitor [Z-Val-Ala-Asp(OMe)-CH2F] produced a significant reduction in damaged cells induced by TMT. Taken together, our data indicate that neural progenitor cells are highly susceptible to TMT in undergoing cell death via the activation of 2 parallel pathways, ones involving calpain and the other, caspase-3.
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PMID:High susceptibility of cortical neural progenitor cells to trimethyltin toxicity: involvement of both caspases and calpain in cell death. 1952 17

In recent times, Cr(III)(picolinate)(3) [Cr(III)(pic)(3)] a nutritional supplement, is gaining attention because of its clastogenic and mutagenic properties. Earlier studies of ours indicated that Cr(III)(pic)(3) is cytotoxic to lymphocytes with ROS and mitochondrial events playing a role in bringing about apoptosis. Now, we report that, autoschizis is induced in lymphocytes in a concentration and time dependent manner which is confirmed through TEM and SEM. Lymphocytes treated with concentrations of 100microM of Cr(III)(pic)(3) exhibit features such as cytoplasmic bleb, self excision of cytoplasm, cytoplasmic leakage and membrane bound bodies formed from the excised pieces apart from apoptosis and necrosis. Though autoschizis has been described in tumor cell lines treated with menadione and ascorbate, occurrence of this cell death in normal T-lymphocytes is reported here. The cellular events that accompany autoschizis are found to be increase in intracellular Reactive Oxygen Species (ROS) and cytoplasmic lactate dehydrogenase, loss of mitochondrial membrane potential (MMP) and depletion of ATP. Further, autoschizis is effected through increases in DNase I and DNase II activity with a concomitant decrease in caspase-3 activity which leads to a random cleavage of the DNA as demonstrated by a smear like pattern after electrophoresis on agarose gel.
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PMID:Autoschizis of T-cells is induced by the nutritional supplement, Cr(III)picolinate. 1985 52

Many cells die during mammalian development and are engulfed by macrophages. In DNase II(-/-) embryos, the TUNEL-positive DNA of apoptotic cells is left undigested in macrophages, providing a system for studying programmed cell death during mouse development. Here, we showed that an Apaf-1-null mutation in the DNase II(-/-) embryos greatly reduced the number of macrophages carrying DNA at E11.5. However, at later stages of the embryogenesis, a significant number of macrophages carrying undigested DNA were present in Apaf-1(-/-) embryos, indicating that cells died and were engulfed in an Apaf-1-independent manner. In most tissues of the Apaf-1(-/-) embryos, no processed caspase-3 was detected, and the DNA of dead cells accumulated in the macrophages appeared intact. Many nonapoptotic dead cells were found in the tail of the Apaf-1(-/-) embryos, suggesting that the Apaf-1-independent programmed cell death occurred, and these dead cells were engulfed by macrophages. In contrast, active caspase-3 was detected in E14.5 thymus of Apaf-1(-/-) embryos. Treatment of fetal thymocytes with staurosporine, but not etoposide, induced processing of procaspases 3 and 9, indicating that the E14.5 thymocytes have the ability to undergo caspase-dependent apoptosis in an Apaf-1-independent manner. Thus, programmed cell death in mouse development, which normally proceeds in an efficient Apaf-1-depenent mechanism, appears to be backed up by Apaf-1-independent death systems.
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PMID:Apaf-1-independent programmed cell death in mouse development. 1996 21

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