Requirement for Caspase-2 in Stress-Induced Apoptosis Before Mitochondrial Permeabilization

Lassus, Patrice; Opitz-Araya, Ximena; Lazebnik, Yuri

doi:10.1126/science.1074721

Cited by 674 publications

(630 citation statements)

References 18 publications

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“…13 Interestingly, the antagonist MX781 induced caspase 2 cleavage in Bcl-2-and C9DN-expressing cells to levels comparable to those seen in Jurkat-pcDNA cells (Figure 5a), suggesting an apical role for caspase 2 in MX781-induced apoptosis. 17 Slightly higher levels of procaspase 2 were observed in untreated Jurkat-Bcl-2 cells, which were not due to differences in protein loading (see Figure 4a and data not shown).…”

Section: Expression Of Bcl-2 and Bcl-x L In Jurkat Cells Prevents Rrmmentioning

confidence: 83%

“…17 This contrasts with the requirement of caspase 9 activity for the efficient cleavage of procaspase 2 by MX2870-1 and Fas signals. The latter resembles the activation of caspase 2 by effector caspases upon activation of the mitochondrial pathway, 13 as observed in UV-and TNF-dependent apoptosis.…”

Section: Discussionmentioning

confidence: 97%

“…Recent evidence suggests that caspase 2 activation upstream of the mitochondria can provoke the release of mitochondrial proapoptotic factors and is essential for UV-and stress-induced apoptosis. [15][16][17] A second mechanism of apoptosis initiation is triggered by extracellular signals that bind to cell surface death receptors, such as Fas/CD95, TNFR1, or DR-5, which activate the extrinsic pathway. Upon ligand binding, death receptors dimerize and engage in the formation of the deathinducing signaling complex (DISC), which contains at least the receptor, initiator procaspases 8 or 10, and the protein adaptor Fas-associated death domain or TNFR1-associated death domain.…”

Section: Introductionmentioning

confidence: 99%

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Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

López-Hernández¹,

Ortiz²,

Bayón³

et al. 2003

Cell Death Differ

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Certain retinoid-related molecules (RRMs) with agonist or antagonist activities have been described to induce apoptosis in a variety of cancer cell lines and show promise for the treatment of cancer. Similar to other chemotherapeutic drugs, these retinoid analogs have been suggested to induce apoptosis through the intrinsic pathway, which requires the release of cytochrome c from the mitochondria for the effective activation of caspase 9. Expression of a catalytically inactive form of caspase 9, which functions as a dominant negative mutant, inhibits the induction of DEVDase activity and nuclear fragmentation by selective RRMs. Whereas the RRMs could induce the release of cytochrome c in the absence of caspase 9 activity, the later is necessary for the effective release of Smac/Diablo from the mitochondria. Furthermore, overexpression of Bcl-2 or Bcl-X L also inhibits RRM-induced apoptosis. We demonstrate that activation of caspase 2 by the agonist MX2870-1 requires caspase 9 activity and is inhibited by Bcl-2 overexpression. In contrast, the antagonist MX781 induces cleavage of procaspase 2 upstream of mitochondria and independently of caspase 9. Thus, two retinoid analogs with unique characteristics activate two distinct apical caspases (2 or 9) to initiate apoptosis. In addition to caspase-mediated cell death, sustained exposure to the RRMs can also lead to loss of cell viability in cells lacking caspase 9 activity or in cells stimulated in the presence of the caspase inhibitor Z-VADfmk. Moreover, MX2870-1 and MX781 produce cell cycle arrest independently of caspase activity and the retinoid receptors.

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Section: Expression Of Bcl-2 and Bcl-x L In Jurkat Cells Prevents Rrmmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

López-Hernández¹,

Ortiz²,

Bayón³

et al. 2003

Cell Death Differ

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“…32 Recently, caspase-2 has been identified as an initiator caspase for apoptotic signaling induced by DNA damage in some cell lines. 33 Whether c-Abl functions up-or downstream of caspase-2 is presently the subject of intensive research in our laboratory. Yet another possibility includes unknown factors that interact with fragments of the cleaved kinase.…”

Section: Discussionmentioning

confidence: 99%

Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis

2003

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c-Abl protein tyrosine kinase plays an important role in cell cycle control and apoptosis. Furthermore, induction of apoptosis correlates with the activation of c-Abl. Here, we demonstrate the cleavage of c-Abl by caspases during apoptosis. Caspases separate c-Abl into functional domains including a Src-kinase, a fragment containing nuclear import sequences, a fragment with an actin-binding domain and nuclear export sequence. Caspase cleavage increases the kinase activity of c-Abl as demonstrated by in vitro kinase assays as well as by auto-and substrate phosphorylation. Cells in which c-Abl expression was knocked down by RNA interference resisted cisplatin-but not TNFa-induced apoptosis. A similar selective resistance against cisplatin-induced apoptosis was observed when cleavage resistant c-Abl was overexpressed in treated cells. Our data suggest the selective requirement of c-Abl cleavage by caspases for stressinduced, but not for TNFa-induced apoptosis.

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“…Braga et al [52] recently found an increased caspase-2 expression in the skeletal muscle of old mice. This caspase is thought to cooperate with MOMP during stress-induced apoptosis [81]. However, it is still unclear whether caspase-2 is an initiator or an effector caspase and how it is activated.…”

Section: The Involvement Of Apoptosis In the Pathogenesis Of Sarcopeniamentioning

confidence: 99%

Multiple Pathways to the Same End: Mechanisms of Myonuclear Apoptosis in Sarcopenia of Aging

Marzetti

Privitera

Simili

et al. 2010

The Scientific World JOURNAL

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Sarcopenia, the age-related decline in muscle mass and function, represents a significant health issue due to the high prevalence of frailty and disability associated with this condition. Nevertheless, the cellular mechanisms responsible for the loss of muscle mass in old age are still largely unknown. An altered regulation of myocyte apoptosis has recently emerged as a possible contributor to the pathogenesis of sarcopenia. Studies in animal models have shown that the severity of skeletal muscle apoptosis increases over the course of aging and correlates with the degree of muscle mass and strength decline. Several apoptotic pathways are operative in aged muscles, with the mitochondria- and TNF-α-mediated pathways likely being the most relevant to sarcopenia. However, despite the growing number of studies on the subject, a definite mechanistic link between myocyte apoptosis and age-related muscle atrophy has not yet been established. Furthermore, the evidence on the role played by apoptosis in human sarcopenia is still sparse. Clearly, further research is required to better define the involvement of myocyte apoptosis in the pathogenesis of muscle loss at advanced age. This knowledge will likely help in the design of more effective therapeutic strategies to preserve muscle mass into old age, thus fostering independence of the elderly population and reducing the socioeconomic burden associated with sarcopenia.

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Requirement for Caspase-2 in Stress-Induced Apoptosis Before Mitochondrial Permeabilization

Cited by 674 publications

References 18 publications

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

Retinoid-related molecules require caspase 9 for the effective release of Smac and the rapid induction of apoptosis

Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis

Multiple Pathways to the Same End: Mechanisms of Myonuclear Apoptosis in Sarcopenia of Aging

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