The proteolytic procaspase activation network: an in vitro analysis

Craen, Marc Van de; Declercq, Wim; Brande, Ilse van den; Fiers, Walter; Vandenabeele, Peter

doi:10.1038/sj.cdd.4400589

Cited by 182 publications

(157 citation statements)

References 37 publications

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“…The small subunit was subsequently processed by caspase-3 at D330 to yield a p12 form. 15,18,22,37,38 In agreement with an earlier study, 12 caspase-2 was not processed in caspase-9 deficient Jurkat cells (Figure 2). Both z-VAD.fmk and caspase-7 but not caspase-6 siRNA (Figures 4 and 5) inhibited the processing of caspase-2.…”

Section: Discussionsupporting

confidence: 92%

“…24 Furthermore, recombinant caspase-7 can also cleave both caspase-2 and -6. 15 To resolve this discrepancy, we examined the hierarchical ordering of caspases in intact cells after activation of the intrinsic pathway under physiological conditions using M-791, a caspase-3 specific inhibitor and siRNA of caspases in caspase-3-deficient MCF-7 cells. After initial mitochondrial perturbation, activated caspase-9 activates both effector caspase -3 and -7.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14] Using recombinant proteins, caspase-3, -8 and to a lesser extent caspase-7 can process caspase-2. 15 The physiological role of caspase-2 is not known and no marked phenotype is observed in caspase-2 À/À mice. Caspase-6 is generally considered to be an effector caspase.…”

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confidence: 99%

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Ordering of caspases in cells undergoing apoptosis by the intrinsic pathway

et al. 2009

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Caspases are a family of aspartate-specific cysteine proteases responsible for the biochemical and morphological changes that occur during the execution phase of apoptosis. The hierarchical ordering of caspases has been clearly established using dATPactivated cell lysates to model the intrinsic pathway induced by initial mitochondrial perturbation. In this model, caspase-9, the apical caspase, directly processes and activates the effector caspases, caspase-3 and -7, and then active caspase-3 but not caspase-7, processes caspase-2 and -6, and subsequently the activated caspase-6 processes caspase-8 and -10. To address the possibility that this model in vitro system might not reflect the precise ordering of caspases in intact cells, we have examined this possibility in cells induced to undergo apoptosis by activation of the intrinsic pathway. We have used caspase deficient cells, small interference RNA for caspase-6 and -7, and a specific caspase-3 inhibitor. In contrast to the earlier in vitro studies, we now show that in intact cells caspase-7 can also directly process and activate caspase-2 and -6. The processing of caspase-2 and -6 occurs within the cytoplasm and active caspase-6 is then responsible for both the processing of caspase-8 and the cleavage of caspase-6 substrates, including lamin A/C. Apoptosis, a major form of cell death used to remove unwanted or excess cells, is characterized by a plethora of morphological and biochemical changes resulting primarily from the activation of a family of cysteine proteases, which cleave their substrates at specific aspartate residues. 1-4 Two major apoptotic pathways have been described, the intrinsic pathway involving initial mitochondrial perturbation resulting from cellular stress or cytotoxic insults and the extrinsic pathway, which is triggered by the activation of death receptors of the TNF family. 5-7 Caspase-8 and -9, the apical caspases in the extrinsic and intrinsic pathways, possess a protein interaction prodomain, which result in their recruitment and subsequent activation within cellular complexes, namely the death-inducing signaling complex (DISC) and the Apaf-1 apoptosome, respectively, and the subsequent activation of effector caspases, such as caspase-3, -6 and -7. 5,[8][9][10] Caspases are synthesized as single-chain zymogens, containing an N-terminal prodomain, as well as large (B20 kDa) and small (B10 kDa) subunits, with the basic catalytic domain forming from a large and small subunits. 1,3,4 Caspase-2 also has a sizeable prodomain, but it is unclear whether it should be considered an initiator or an effector caspase. 3 Although caspase-2 has been proposed to act upstream of mitochondria and to be activated within the PIDDosome, it may also be activated downstream of caspase-3. 11-14 Using recombinant proteins, caspase-3, -8 and to a lesser extent caspase-7 can process caspase-2. 15 The physiological role of caspase-2 is not known and no marked phenotype is observed in caspase-2 À/À mice. Caspase-6 is generally considered to be an effector casp...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Ordering of caspases in cells undergoing apoptosis by the intrinsic pathway

et al. 2009

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“…Caspase-2 is known as a substrate for both caspase-3 and caspase-8 [43,44]. Caspase-2 activation comprises the formation of PIDDosome complex including RIP-associated ICH-1/ ECD3 homologous protein with death domain (RAIDD) that have CARD and death domain (DD) and p53-induced protein with death domain (PIDD) [45].…”

Section: Caspase Family Membersmentioning

confidence: 99%

Major apoptotic mechanisms and genes involved in apoptosis

et al. 2016

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As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.

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“…In various settings it has been found to be processed by caspase 3, situating it at a downstream point in the apoptotic pathway. [4][5][6][7] On the other hand, caspase 2 interacts through its prodomain with the adaptor molecules RAIDD/CRADD and ARC, [8][9][10][11] is processed early in certain apoptotic pathways 12 and upon overexpression activates the caspase 9/3 cascade. 13,14 More recent studies have suggested that caspase 2 acts upstream of cytochrome c release.…”

Section: Introductionmentioning

confidence: 99%

RAIDD aggregation facilitates apoptotic death of PC12 cells and sympathetic neurons

et al. 2004

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In human cell lines, the caspase 2 adaptor RAIDD interacts selectively with caspase 2 through its caspase recruitment domain (CARD) and leads to caspase 2-dependent death. Whether RAIDD induces such effects in neuronal cells is unknown. We have previously shown that caspase 2 is essential for apoptosis of trophic factor-deprived PC12 cells and rat sympathetic neurons. We report here that rat RAIDD, cloned from PC12 cells, interacts with rat caspase 2 CARD. RAIDD overexpression induced caspase 2 CARD-and caspase 9-dependent apoptosis of PC12 cells and sympathetic neurons. Apoptosis correlated with the formation of discrete perinuclear aggregates. Both death and aggregates required the expression of full-length RAIDD. Such aggregates may enable more effective activation of caspase 2 through close proximity. Following trophic deprivation, RAIDD overexpression increased death and aggregate formation. Therefore, RAIDD aggregation is important for its death-promoting effects and may play a role in trophic factor withdrawal-induced neuronal apoptosis.

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The proteolytic procaspase activation network: an in vitro analysis

Cited by 182 publications

References 37 publications

Ordering of caspases in cells undergoing apoptosis by the intrinsic pathway

Ordering of caspases in cells undergoing apoptosis by the intrinsic pathway

Major apoptotic mechanisms and genes involved in apoptosis

RAIDD aggregation facilitates apoptotic death of PC12 cells and sympathetic neurons

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