Microfilament-disrupting agents prevent the formation of apoptotic bodies in tumor cells undergoing apoptosis.
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Apoptosis is a form of cell death in which the cell "participates," such that metabolic energy and often protein synthesis are required for the death to occur. Once begun, the process of apoptosis proceeds in an ordered fashion. In the earliest phase DNA fragmentation occurs, accompanied by cell shrinkage and dilation of the endoplasmic reticulum. This is followed by cell fragmentation with the formation of sealed membrane vesicles, termed apoptotic bodies. In the present study we have demonstrated that the fungal metabolite cytochalasin B inhibits cell fragmentation and the formation of apoptotic bodies, probably by its ability to interfere with actin polymerization. This effect was seen when HL-60 cells were pretreated with cytochalasin B and then exposed to one of a number of apoptosis-inducing agents, including UV irradiation, camptothecin, aphidocholin, or PMA plus ionomycin. The observed effect was not peculiar to HL-60 cells, inasmuch as it was also seen for both Molt-4 and U-937 cell lines. Cytochalasin B had no effect on DNA fragmentation occurring in the earliest stage of apoptosis, and it appeared to have no inhibitory effects on nuclear fragmentation. Staurosporin had an effect similar to that seen with cytochalasin B, probably due to its ability to inhibit protein kinase C, which is a known potentiator of microfilament assembly. These data demonstrate that microfilament assembly is necessary for the formation of apoptotic bodies in the later stages of the apoptotic process.Keywords:
Fragmentation
Cytochalasin B
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Calcium ionophore (A23187)‐induced high molecular weight (HMW) and internucleosomal DNA fragmentation were investigated in human leukemia cell lines. An apoptosis‐sensitive cell line, HL‐60, showed HMW, internucleosomal DNA fragmentation and morphological changes of apoptosis by A23187. MOLT‐4, which is resistant to apoptosis, exhibited only HMW DNA fragmentation and died of necrosis under the same conditions. Autodigestion experiments suggested the endonucleolytic activity to cause HMW fragmentation in the cytoplasm of both cell lines. The activity was more dependent on Mg 2+ than Ca 2+ in HL‐60, whereas it was Ca 2+ ‐dependent in MOLT‐4. These results suggest that HMW DNA fragmentation is not specific to apoptosis.
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Apoptotic DNA fragmentation
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Exposure of HeLa cells to Cisplatin resulted in cell death characteristic of a suicide process known as apoptosis, as stated by morphologic features, extensive and specific DNA fragmentation and in situ end labeling of DNA breaks. The apoptotic cell death was induced timely in a dose-dependent manner, without any primary necrosis at the concentrations used. In contrast to other reports, the death in this cell line was accompanied by low-molecular weight DNA fragmentation. These results and their relevance to the apoptotic process are discussed.
HeLa
Apoptotic DNA fragmentation
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Cleavage (geology)
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Fragmentation
Apoptotic DNA fragmentation
Intrinsic apoptosis
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Zinc ions inhibit the morphological and DNA fragmentation features of apoptosis in a number of systems. HL-60 cells pretreated with zinc and exposed to UV irradiation maintained their normal morphology for up to 8 h, whereas non-zinc-treated cells underwent extensive apoptosis. Zinc pretreatment also inhibited both single and double-stranded DNA fragmentation, which is characteristic of apoptosis. The most effective zinc concentration that blocked apoptosis over short incubation periods (up to 8 h) was also the most toxic over extended time periods (⩾ 12 h). The mechanism of cell death at these longer time periods was akin to necrosis, but occurred in the absence of any DNA fragmentation. The effects of the nuclease inhibitor aurintricarboxylic acid (ATA) was also examined on UV-induced apoptosis in HL-60 cells. ATA had no toxic effects over the concentration range tested, but also failed to prevent DNA fragmentation in whole cells. Further analysis showed that it effectively inhibited DNA fragmentation in isolated nuclei.
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With a view to studying programmed cell death in plants at the molecular level, we report here for the first time that apoptotic‐like changes are induced by UV radiation in plant nuclei. In Arabidopsis thaliana seedlings a UV‐C dose of 10–50 kJ/m 2 induces an oligonucleosomal DNA fragmentation which is reminiscent of the apoptotic DNA ladder described in animal cells. This DNA fragmentation was also detected in situ in protoplast nuclei as soon as 2 h after UV‐C treatment. Moreover, UV‐C induced a nuclear morphology characteristic of animal apoptotic nuclei. We propose that UV‐C induction constitutes a powerful tool to compare the cellular response to irreversible UV damage in plants to that in animals and to study programmed cell death in A. thaliana .
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Nuclear DNA
Plant cell
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Thymus-derived lymphocytes undergo death after γ-irradiation via a pathway termed apoptosis, or programmed cell death. An early step in this pathway is the production of nucleosome-sized fragments of DNA. DNA fragmentation was used as the endpoint in these investigations to examine apoptosis in lymphocytes extracted from the rat thymus and irradiated in vitro. In unirradiated thymocytes the level of DNA fragmentation rose to 15% by the first hour of culture, where it remained approximately constant until the fifth hour. In contrast, thymocytes irradiated with a dose of 2·5 Gy exhibited a large and dramatic increase in DNA fragmentation beginning 2h postirradiation. DNA fragmentation measured 6h after irradiation was detected after as little as 0·25 Gy and reached a maximum of 90% with 10Gy. Metabolic control of DNA fragmentation after irradiation was evidenced by the suppression of DNA fragmentation when thymocytes were incubated with cyclohexamide or actinomycin D. When γ-irradiated thymocytes were incubated with the Ca2+ chelator EGTA, DNA fragmentation was reduced significantly. BAPTA-AM, a highly specific intracellular Ca2+ chelator, essentially eliminated DNA fragmentation in cells irradiated with 2·5Gy and, unlike EGTA, eliminated the background level of fragmentation in unirradiated samples. Therefore, our data are consistent with the possibility that Ca2+ serves as a second messenger to induce DNA fragmentation in irradiated thymocytes, suggesting a common pathway for cells prompted to enter apoptosis from seemingly dissimilar interval events.
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Apoptotic DNA fragmentation
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Thymocyte
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Fragmentation
Apoptotic DNA fragmentation
Intrinsic apoptosis
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Hematology
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