DNA cleavage in rat liver nuclei activated by Mg2+ or Ca2+ + Mg2+ is inhibited by a variety of structurally unrelated inhibitors

Cain, Kelvin; Inayat-Hussain, Salmaan H.; Kokileva, Ludmilla; Cohen, Gerald M.

doi:10.1139/o94-083

Cited by 18 publications

(10 citation statements)

References 24 publications

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“…Similar effects have been described earlier (45)(46)(47)(48), although the protective effects of TPCK, DCI, or LLnL on cell survival noted in these studies were attributed to inhibition of an unidentified serine protease or of calpain. These observations seem at first glance to be contradictory to previous results (14) and to the findings reported here, but they can be explained on the basis of cell-specific differences in cell cycle regulation and the proliferative status of the cell, as manifested, for instance, by the expression of c-Myc.…”

supporting

confidence: 85%

Activation of the cell death program by inhibition of proteasome function

Drexler

1997

Proc. Natl. Acad. Sci. U.S.A.

454

324

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Activation of proteolytic enzymes, including cysteine proteases of the ced-3͞ICE family, is a characteristic feature of the apoptotic program. In contrast, the role of the proteasome as the major nonlysosomal machinery to degrade or process proteins by ATP͞ubiquitin-dependent proteolysis in this process is less clear. In human leukemic HL60 cells, inhibition of proteasome-mediated proteolysis by specific proteasomal inhibitors leads to the rapid induction of apoptosis as judged by morphological changes as well as by nuclear condensation and DNA fragmentation. HL60 apoptosis is due to activation of CPP32, a member of the ced-3͞ICE family of cysteine proteases, and appears to occur independently from ICE activity. HL60 apoptosis is accompanied by an increase in the concentration of the cyclin-dependent kinase inhibitor p27 Kip1 . Labeling of the cells by the TUNEL technique demonstrates that HL60 cells undergoing apoptosis are primarily in the G 1 phase of the cell cycle. Proteasomal activity therefore appears to be required in proliferating, but not in quiescent, HL60 cells for cell survival as well as normal progression through the cell cycle.Apoptosis has been recognized as a distinct form of cell death that has an essential function in the regulation of cell turnover during development, tissue homeostasis, and cancer (1, 2). For a long time the characteristic cleavage of DNA into oligonucleosomal fragments has been regarded as a hallmark of apoptosis and was the only biochemical marker available. Recently the focus of interest has shifted toward proteolytic events during apoptotic cell death, and it has become apparent that activation of proteolytic enzymes, culminating in the disintegration of the cell, is a characteristic feature of apoptosis. In particular, cysteine proteases of the ced-3͞ICE family have been implicated as central components of this proteolytic machinery (3). However, in contrast to the intense research efforts spent on the ced-3͞ICE family of proteases, much less attention has been paid so far to the multicatalytic protease complex (MCP) or proteasome, which represents the cell's major nonlysosomal tool to rapidly degrade or process proteins by ATP͞ubiquitin-dependent proteolysis and its potential role in apoptotic cell death. In higher eukaryotic cells the MCP is involved in the degradation of most of the cytosolic proteins and in particular of short-lived proteins critical for cell proliferation and cell cycle regulation. Examples include the tumor suppressor protein p53 (4) and various cyclins (5), as well as the cyclin-dependent kinase inhibitor p27 Kip1 (6). The proteasome in addition has a direct impact on transcriptional regulation by processing and degradation of NF B and I B respectively, as well as by proteolysis of transcription factors such as c-Fos (7, 8) and c-Jun (9). Finally, studies performed in two developmental systems, regression of the intersegmental muscles in the hawkmoth Manduca sexta and thyroxininduced apoptosis in the tadpole tail, suggest a link between...

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supporting

confidence: 85%

Activation of the cell death program by inhibition of proteasome function

Drexler

1997

Proc. Natl. Acad. Sci. U.S.A.

454

324

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“…Ca 2+ is one of the most significant intracellular messengers in modulating cell growth and differentiation, and plays an essential role in the induction of apoptosis. However, the role of Ca 2+ as an intracellular messenger is incomplete without the coexistence of internal Mg 2+ ions (33). Consistent with the above implication, the experiment showed that SeMoV markedly increased intracellular Ca 2+ and Mg 2+ concentrations.…”

Section: Discussionsupporting

confidence: 80%

“…Ca 2+ and Mg 2+ play a crucial role in governing the morphological and biochemical changes attributed to apoptotic cell death (33). Therefore, the perturbations of intracellular ion homeostasis, pH value and MMP may be a conspicuous manifestation of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The novel selenium heteropoly compound (NH4)4H4[Se2Mo2V4O24]ï¿½7H2O induces apoptosis of K562 cells

Yang

Fan

et al. 2011

Mol Med Report

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Abstract. The purpose of this study was to investigate the antitumor effects and mechanism of the selenium heteropoly compound (NH 4 ) 4 H 4 [Se 2 Mo 2 V 4 O 24 ]·7H 2 O (SeMoV) in K562 cells. The results showed that 0.313-10 mg/l SeMoV significantly inhibited the proliferation of K562 cells in vitro in a time-and concentration-dependent manner as determined by a micro culture tetrazolium assay; the IC 50 values were 7.69 and 4.06 mg/l following 48 and 72 h of treatment with SeMoV, respectively. Analysis of the cell cycle indicated that the proportion of cells in the G0/G1 phase was decreased at 48 h whereas the proportion of cells in the S phase was increased following treatment for 24 and 48 h. A significant sub-G1 peak was observed at 5 mg/l for 24 h. Morphological observation revealed typical apoptotic features. SeMoV signifi cantly caused the accumulation of Ca 2+ , Mg 2+ and ROS, and a reduction in the pH value and the mitochondrial membrane potential (MMP) in the K562 cells compared with the control (p<0.01), as shown by confocal laser scanning microscopy. Experiments also showed that the expression of Bcl-2 was significantly inhibited by 20 mg/l SeMoV, while Bax expression increased. Meanwhile, the amount of cytochrome C and IκB in K562 cells was increased, while NF-κB expression was significantly decreased, following treatment with SeMoV for 24 h. The experiment implied that SeMoV had antitumor activity and its mechanism was attributed partially to apoptosis, which was induced by the elevation of the intracellular Ca 2+ , Mg 2+ and ROS concentration, a reduction in the pH value and MMP, and the NF-κB/IκB signaling pathway.

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“…However, we and others (29), have shown caspase-11 is not expressed in caspase-1-deficient mice and, although caspase-12 is expressed, we found no evidence that it is up-regulated, at least at the mRNA level. Alternatively, neutrophil apoptosis may be initiated independently of upstream caspases, perhaps via mitochondrial factors (35) or involvement of serine proteases (9,36).…”

Section: Discussionmentioning

confidence: 99%

Caspase-1-Deficient Mice Have Delayed Neutrophil Apoptosis and a Prolonged Inflammatory Response to Lipopolysaccharide-Induced Acute Lung Injury

Rowe¹,

Allen

Ridger

et al. 2002

The Journal of Immunology

104

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Caspase-1, the prototypic caspase, is known to process the cytokines IL-1β and IL-18 to mature forms but it is unclear whether, like other caspases, it can induce apoptosis by activation of downstream protease cascades. Neutrophils are known to express caspase-1, to release IL-1β and to undergo rapid, caspase-dependent apoptosis. We examined apoptosis and IL-1β production in peripheral blood neutrophils of caspase-1-deficient and wild-type mice. Constitutive apoptosis of caspase-1-deficient neutrophils was delayed compared with wild-type neutrophils and LPS-mediated inhibition of apoptosis was absent, but caspase-1-deficient neutrophils were susceptible to Fas-mediated apoptosis. LPS-stimulated IL-1β production was absent from caspase-1-deficient neutrophils. To ascertain whether these differences in apoptosis and IL-1β production would alter the response to acute lung injury, we studied pulmonary neutrophil accumulation following intratracheal administration of LPS. Caspase-1-deficient mice showed increased, predominantly neutrophilic pulmonary inflammation, but inflammation had resolved in both wild-type and deficient animals by 72 h after LPS instillation. IL-1β production was increased in wild-type lungs but was also detected in caspase-1-deficient mice. We conclude that caspase-1 modulates apoptosis of both peripheral blood and inflammatory neutrophils, but is not essential for IL-1β production in the lung.

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DNA cleavage in rat liver nuclei activated by Mg²⁺ or Ca²⁺ + Mg²⁺ is inhibited by a variety of structurally unrelated inhibitors

Cited by 18 publications

References 24 publications

Activation of the cell death program by inhibition of proteasome function

Activation of the cell death program by inhibition of proteasome function

The novel selenium heteropoly compound (NH4)4H4[Se2Mo2V4O24]ï¿½7H2O induces apoptosis of K562 cells

Caspase-1-Deficient Mice Have Delayed Neutrophil Apoptosis and a Prolonged Inflammatory Response to Lipopolysaccharide-Induced Acute Lung Injury

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