Caspases: the executioners of apoptosis

Cohen, Gerald M.

doi:10.1042/bj3260001

Cited by 4,320 publications

(3,159 citation statements)

References 149 publications

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“…The cysteine proteases of the caspase family are important regulators of the apoptotic process (Cohen, 1997). This report shows that TGFb-mediated B lymphocyte apoptosis is controlled through caspase activation.…”

Section: Discussionmentioning

confidence: 74%

“…Apoptosis is an active energy-dependent process which is characterized by morphological changes including loss of cell volume, plasma membrane blebbing and cell shrinkage, expression of phosphatidylserine on the outer lea¯et of the cell membrane, chromatin condensation, DNA fragmentation into oligo-nucleosomesized fragments and nuclear fragmentation (Cohen et al, 1992). There is growing evidence indicating that members of the ICE/CED-3 protease family play key roles in the execution phase of apoptosis (Cohen, 1997;Henkart, 1996;Salvesen and Dixit, 1997). These cysteine-related proteases, named caspases, are synthesized as inactive proenzymes which are activated following cleavage at speci®c aspartate cleavage sites (Alnemri, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Role of caspases and possible involvement of retinoblastoma protein during TGFβ-mediated apoptosis of human B lymphocytes

et al. 1999

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In this study, we investigated the involvement of caspases in TGFb-induced apoptosis in human B cells. Our results show that TGFb-mediated nuclear fragmentation, observed in the Epstein ± Barr virus-negative Burkitt's Lymphoma cell line BL41, was abolished in the presence of the tripeptide caspase inhibitor ZVAD-fmk or the speci®c caspase-3 inhibitor DEVD-fmk. Other apoptotic manifestations such as cell shrinkage, surface phosphatidylserine expression and chromatin condensation were strongly inhibited by ZVAD-fmk but only partially by DEVD-fmk. This suggests that other caspases in addition to caspase-3 control these apoptotis-associated features. Speci®c activation of caspase-3 during TGFbinduced apoptosis was demonstrated by the DEVD-fmksensitive expression of the active p17 subunit of caspase-3 and by in vivo cleavage of PARP. In addition, TGFb treatment of BL41 promoted the expression of both dephosphorylated and truncated forms of the retinoblastoma protein. Inhibition of caspase-3 activity abolished both nuclear fragmentation and expression of the truncated retinoblastoma protein, without modifying the G1 cell cycle arrest induced by TGFb. Our data thus demonstrate that TGFb-induced apoptosis of lymphoma B lymphocytes is dependent on caspase activation and involves caspase-dependent cleavage of the retinoblastoma protein.

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Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Role of caspases and possible involvement of retinoblastoma protein during TGFβ-mediated apoptosis of human B lymphocytes

et al. 1999

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“…Caspases exist in cells as catalytically inactive zymogens composed of three di erent subunits: a prodomain and two catalytic subdomains (Alnemri et al, 1996). Activation of procaspases generally requires cleavage after speci®c Asp residues (Cohen, 1997;Nicholson and Thornberry, 1997).…”

Section: Introductionmentioning

confidence: 99%

Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3

et al. 2000

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The release of mitochondrial cytochrome c by genotoxic stress induces the formation of a cytosolic complex with Apaf-1 (mammalian CED4 homolog) and thereby the activation of procaspase-3 (cas-3) and procaspase-9 (cas-9). Here we demonstrate that heat-shock protein 27 (Hsp27) inhibits cytochrome c (cyt c)-dependent activation of cas-3. Hsp27 had no e ect on cyt c release, Apaf-1 and cas-9 activation. By contrast, our results show that Hsp27 associates with cas-3, but not Apaf-1 or cas-9, and inhibits activation of cas-3 by cas-9-mediated proteolysis. Furthermore, the present results demonstrate that immunodepletion of Hsp27 depletes cas-3. Importantly, treatment of cells with DNA damaging agents dissociates the Hsp27/cas-3 complex and relieves inhibition of cas-3 activation. These ®ndings de®ne a novel function for Hsp27 and provide the ®rst evidence that a heat shock protein represses cas-3 activation.

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“…11 A wide range of cell signals of either extracellular or intracellular origin can positively (i.e., trigger) or negatively (i.e., repress, inhibit, or dampen) affect apoptosis, leading to its initiation or repression, respectively. Each of the two major apoptotic pathways (extrinsic and intrinsic) can be regulated at multiple levels.…”

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confidence: 99%

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

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It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.

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Caspases: the executioners of apoptosis

Cited by 4,320 publications

References 149 publications

Role of caspases and possible involvement of retinoblastoma protein during TGFβ-mediated apoptosis of human B lymphocytes

Role of caspases and possible involvement of retinoblastoma protein during TGFβ-mediated apoptosis of human B lymphocytes

Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

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