Caspases:  Keys in the Ignition of Cell Death

Denault, Jean‐Bernard; Salvesen, Guy S.

doi:10.1021/cr010183n

Cited by 276 publications

(177 citation statements)

References 89 publications

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“…1) (16). In the maturation of procaspase-3, the cleavage at Asp 175 separates the large and small subunits and results in a large increase in activity, whereas the cleavages at Asp 9 and Asp 28 remove the prodomain (17). We further showed that the uncleavable procaspase is ϳ200-fold less active than mature caspase-3 and that the lower activity is a result of a low catalytic efficiency rather than a difference in substrate binding (16).…”

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confidence: 74%

Reassembly of Active Caspase-3 Is Facilitated by the Propeptide

Feeney

Clark

2005

Journal of Biological Chemistry

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Changes in ionic homeostasis are early events leading up to the commitment to apoptosis. Although the direct effects of cations on caspase-3 activity have been examined, comparable studies on procaspase-3 are lacking. In addition, the effects of salts on caspase structure have not been examined. We have studied the effects of cations on the activities and conformations of caspase-3 and an uncleavable mutant of procaspase-3 that is enzymatically active. The results show that caspase-3 is more sensitive to changes in pH and ion concentrations than is the zymogen. This is due to the loss of both an intact intersubunit linker and the prodomain. The results show that, although the caspase-3 subunits reassemble to the heterotetramer, the activity return is low after the protein is incubated at or below pH 4.5 and then returned to pH 7.5. The data further show that the irreversible step in assembly results from heterotetramer rather than heterodimer dissociation and demonstrate that the active site does not form properly following reassembly. However, active-site formation is fully reversible when reassembly occurs in the presence of the prodomain, and this effect is specific for the propeptide of caspase-3. The data show that the prodomain facilitates both dimerization and active-site formation in addition to stabilizing the native structure. Overall, the results show that the prodomain acts as an intramolecular chaperone during assembly of the (pro)caspase subunits and increases the efficiency of formation of the native conformation.

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confidence: 74%

Reassembly of Active Caspase-3 Is Facilitated by the Propeptide

Feeney

Clark

2005

Journal of Biological Chemistry

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“…At the core of the death process is a family of cytosolic cysteine proteases, caspases, with a specificity for aspartic acid residues (reviewed in Refs. [1][2][3]. Stimuli from death receptor ligands (extrinsic pathway) or a variety of chemotherapeutic agents, drugs or cellular stresses (intrinsic pathway) cause the activation of apical (initiator) caspase-8, -9, or -10.…”

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confidence: 99%

Human Caspase-7 Activity and Regulation by Its N-terminal Peptide

Denault

Salvesen

2003

Journal of Biological Chemistry

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104

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Central to the execution phase of apoptosis are the two closely related caspase-3 and -7. They share common substrate specificity and structure, but differ completely in the sequence of their respective N-terminal regions including their N-peptides, a 23-28 residue segment that are removed during zymogen activation. We show that the N-peptide of caspase-7 plays no role in the fundamental activation or properties of the active protease in vitro. However, the N-peptide modifies the properties of caspase-7 in vivo. In ectopic expression experiments, caspase-7 constructs with no N-peptide are far more lethal than constructs that have an uncleavable peptide. Moreover, the N-peptide of caspase-7 must be removed before efficient activation of the zymogen can occur in vivo. These disparate requirements for the Npeptide argue that it serves to physically sequester the caspase-7 zymogen in a cytosolic location that prevents access by upstream activators (caspase-8, -9, and -10). The N-peptide must first be removed, probably by caspase-3, before efficient conversion and activation of the zymogen can occur in vivo.

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“…Western Blotting HL-60 cells (3×10 6 ) were plated in cell culture flasks, 25 cm 2 . After 1 h, the cells were treated with 20 µg/mL of crebanine at various times (0, 6, 12 and 24 h).…”

Section: Assay Of Mitochondrial Membrane Potential (δψ M )mentioning

confidence: 99%

“…Activated caspase-3 cleaves most substrates, including poly(ADP-ribose) polymerase (PARP), a DNA repair enzyme, and leads to cell death. 6,7) The link between the caspase cascade and the mitochondria is provided by the Bcl-2 family members, which guard mitochondrial integrity and control the release of mitochondrial proteins into the cytoplasm. 8) Cell cycle progression is a complex process that involved with numerous regulatory protein.…”

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Induction of G1 Arrest and Apoptosis in Human Cancer Cells by Crebanine, an Alkaloid from <i>Stephania venosa</i>

et al. 2012

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In this study, we focused the effects of crebanine, an alkaloid isolated from the tuber of Stephania venosa, on various human cancer cells. Crebanine treatment was found to significantly inhibit the proliferation of human leukemic cells (HL-60, U937 and K562), human fibrosarcoma cells (HT1080) and cervix cancer cell lines (KB-3-1 and KB-V1), of which HL-60 cells were the most sensitive to its treatment. In contrast, crebanine caused much less toxicity in human normal fibroblast cells. Our results demonstrated that crebanine mediated cell cycle arrest at G0/G1 phase and this was associated with down-regulation of cyclins A and D. In addition, crebanine induced apoptosis, which was detected by observation of the membrane phospholipid exposure in flow cytometry. Its induction of apoptosis was accompanied by an increase in cleavage of caspase-3, -8, -9 and poly(ADP-ribose) polymerase (PARP), and was attributable to the augmentation of Bax/Bcl proteins level. Crebanine also decreased mitochondrial membrane potential. Taken together, crebanine exerts anti-proliferative effects on human cancer cells through the induction of cell cycle arrest at the G1 phases and apoptosis. Our results suggest that crebanine is a promising new candidate as a chemotherapeutic agent for cancer therapy.

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Caspases: Keys in the Ignition of Cell Death

Cited by 276 publications

References 89 publications

Reassembly of Active Caspase-3 Is Facilitated by the Propeptide

Reassembly of Active Caspase-3 Is Facilitated by the Propeptide

Human Caspase-7 Activity and Regulation by Its N-terminal Peptide

Induction of G1 Arrest and Apoptosis in Human Cancer Cells by Crebanine, an Alkaloid from <i>Stephania venosa</i>

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