The Experts below are selected from a list of 200928 Experts worldwide ranked by ideXlab platform
John D Robertson - One of the best experts on this subject based on the ideXlab platform.
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bh3 only protein bim mediates heat shock induced apoptosis
PLOS ONE, 2014Co-Authors: John D Robertson, Indra M Mahajan, Miao Der Chen, Israel Muro, Casey W Wright, Shawn B BrattonAbstract:Acute heat shock can induce apoptosis through a canonical pathway involving the upstream activation of Caspase-2, followed by BID cleavage and stimulation of the intrinsic pathway. Herein, we report that the BH3-only protein BIM, rather than BID, is essential to heat shock-induced cell death. We observed that BIM-deficient cells were highly resistant to heat shock, exhibiting short and long-term survival equivalent to Bax−/−Bak−/− cells and better than either Bid−/− or dominant-negative Caspase-9-expressing cells. Only Bim−/− and Bax−/−Bak−/− cells exhibited resistance to mitochondrial outer membrane permeabilization and loss of mitochondrial inner membrane potential. Moreover, while dimerized Caspase-2 failed to induce apoptosis in Bid−/− cells, it readily did so in Bim−/− cells, implying that Caspase-2 kills exclusively through BID, not BIM. Finally, BIM reportedly associates with MCL-1 following heat shock, and Mcl-1−/− cells were indeed sensitized to heat shock-induced apoptosis. However, pharmacological inhibition of BCL-2 and BCL-XL with ABT-737 also sensitized cells to heat shock, most likely through liberation of BIM. Thus, BIM mediates heat shock-induced apoptosis through a BAX/BAK-dependent pathway that is antagonized by antiapoptotic BCL-2 family members.
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requirement of apaf 1 for mitochondrial events and the cleavage or activation of all proCaspases during genotoxic stress induced apoptosis
Biochemical Journal, 2007Co-Authors: Emily E Franklin, John D RobertsonAbstract:Sequential activation of Caspases is critical for the execution of apoptosis. Recent evidence suggests Caspase 2 is a significant upstream Caspase capable of initiating mitochondrial events, such as the release of cytochrome c. In particular, in vitro studies using recombinant proteins have shown that cleaved Caspase 2 can induce mitochondrial outer membrane permeabilization directly or by cleaving the BH3-only protein BID (BH3 interacting domain death agonist). However, whether interchain cleavage or activation of proCaspase 2 occurs prior to Apaf-1-mediated proCaspase 9 activation under more natural conditions remains unresolved. In the present study, we show that Apaf-1-deficient Jurkat T-lymphocytes and mouse embryonic fibroblasts were highly resistant to DNA-damage-induced apoptosis and failed to cleave or activate any apoptotic proCaspase, including Caspase 2. Significantly, drug-induced cytochrome c release and loss of mitochondrial membrane potential were inhibited in cells lacking Apaf-1. By comparison, proCaspase proteolysis and apoptosis were only delayed slightly in Apaf-1-deficient Jurkat cells upon treatment with anti-Fas antibody. Our data support a model in which Apaf-1 is necessary for the cleavage or activation of all proCaspases and the promotion of mitochondrial apoptotic events induced by genotoxic drugs.
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Caspase 2 acts upstream of mitochondria to promote cytochrome c release during etoposide induced apoptosis
Journal of Biological Chemistry, 2002Co-Authors: John D Robertson, Boris Zhivotovsky, Mari Enoksson, Minna Suomela, Sten OrreniusAbstract:Abstract DNA damage induced by the cancer chemotherapeutic drug etoposide triggers the onset of a series of intracellular events characteristic of apoptosis. Among the early changes observed is the release of cytochrome c from mitochondria, although the mechanism responsible for this effect is unclear. We demonstrate here a role for Caspase-2 in etoposide-induced cytochrome crelease. In particular, Jurkat T-lymphocytes treated with an irreversible Caspase-2 inhibitor, benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethyl ketone (z-VDVAD-fmk), or stably transfected with pro-Caspase-2 antisense (Casp-2/AS) are refractory to cytochrome crelease stimulated by etoposide. Experiments performed using a reconstituted cell-free system indicate that etoposide-induced cytochrome c release by way of Caspase-2 occurs independently of cytosolic factors, suggesting that the nuclear pool of pro-Caspase-2 is critical to this process. Apart from inhibiting cytochrome c release, undermining Caspase-2 activity results in an attenuation of downstream events, such as pro-Caspase-9 and -3 activation, phosphatidylserine exposure on the plasma membrane, and DNA fragmentation. Taken together, our data indicate that Caspase-2 provides an important link between etoposide-induced DNA damage and the engagement of the mitochondrial apoptotic pathway.
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Caspase 2 acts upstream of mitochondria to promote cytochrome c release during etoposide induced apoptosis
Journal of Biological Chemistry, 2002Co-Authors: John D Robertson, Boris Zhivotovsky, Mari Enoksson, Minna Suomela, Sten OrreniusAbstract:Abstract DNA damage induced by the cancer chemotherapeutic drug etoposide triggers the onset of a series of intracellular events characteristic of apoptosis. Among the early changes observed is the release of cytochrome c from mitochondria, although the mechanism responsible for this effect is unclear. We demonstrate here a role for Caspase-2 in etoposide-induced cytochrome crelease. In particular, Jurkat T-lymphocytes treated with an irreversible Caspase-2 inhibitor, benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethyl ketone (z-VDVAD-fmk), or stably transfected with pro-Caspase-2 antisense (Casp-2/AS) are refractory to cytochrome crelease stimulated by etoposide. Experiments performed using a reconstituted cell-free system indicate that etoposide-induced cytochrome c release by way of Caspase-2 occurs independently of cytosolic factors, suggesting that the nuclear pool of pro-Caspase-2 is critical to this process. Apart from inhibiting cytochrome c release, undermining Caspase-2 activity results in an attenuation of downstream events, such as pro-Caspase-9 and -3 activation, phosphatidylserine exposure on the plasma membrane, and DNA fragmentation. Taken together, our data indicate that Caspase-2 provides an important link between etoposide-induced DNA damage and the engagement of the mitochondrial apoptotic pathway.
Sten Orrenius - One of the best experts on this subject based on the ideXlab platform.
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Caspase-2 promotes cytoskeleton protein degradation during apoptotic cell death
Cell Death & Disease, 2013Co-Authors: H Vakifahmetoglu-norberg, E Norberg, A B Perdomo, Fabiola Ciccosanti, Gian Maria Fimia, Maria Piacentini, M. Olsson, Sten Orrenius, Boris ZhivotovskyAbstract:The Caspase family of proteases cleaves large number of proteins resulting in major morphological and biochemical changes during apoptosis. Yet, only a few of these proteins have been reported to selectively cleaved by Caspase-2. Numerous observations link Caspase-2 to the disruption of the cytoskeleton, although it remains elusive whether any of the cytoskeleton proteins serve as bona fide substrates for Caspase-2. Here, we undertook an unbiased proteomic approach to address this question. By differential proteome analysis using two-dimensional gel electrophoresis, we identified four cytoskeleton proteins that were degraded upon treatment with active recombinant Caspase-2 in vitro. These proteins were degraded in a Caspase-2-dependent manner during apoptosis induced by DNA damage, cytoskeleton disruption or endoplasmic reticulum stress. Hence, degradation of these cytoskeleton proteins was blunted by siRNA targeting of Caspase-2 and when Caspase-2 activity was pharmacologically inhibited. However, none of these proteins was cleaved directly by Caspase-2. Instead, we provide evidence that in cells exposed to apoptotic stimuli, Caspase-2 probed these proteins for proteasomal degradation. Taken together, our results depict a new role for Caspase-2 in the regulation of the level of cytoskeleton proteins during apoptosis.
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Caspase 2 acts upstream of mitochondria to promote cytochrome c release during etoposide induced apoptosis
Journal of Biological Chemistry, 2002Co-Authors: John D Robertson, Boris Zhivotovsky, Mari Enoksson, Minna Suomela, Sten OrreniusAbstract:Abstract DNA damage induced by the cancer chemotherapeutic drug etoposide triggers the onset of a series of intracellular events characteristic of apoptosis. Among the early changes observed is the release of cytochrome c from mitochondria, although the mechanism responsible for this effect is unclear. We demonstrate here a role for Caspase-2 in etoposide-induced cytochrome crelease. In particular, Jurkat T-lymphocytes treated with an irreversible Caspase-2 inhibitor, benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethyl ketone (z-VDVAD-fmk), or stably transfected with pro-Caspase-2 antisense (Casp-2/AS) are refractory to cytochrome crelease stimulated by etoposide. Experiments performed using a reconstituted cell-free system indicate that etoposide-induced cytochrome c release by way of Caspase-2 occurs independently of cytosolic factors, suggesting that the nuclear pool of pro-Caspase-2 is critical to this process. Apart from inhibiting cytochrome c release, undermining Caspase-2 activity results in an attenuation of downstream events, such as pro-Caspase-9 and -3 activation, phosphatidylserine exposure on the plasma membrane, and DNA fragmentation. Taken together, our data indicate that Caspase-2 provides an important link between etoposide-induced DNA damage and the engagement of the mitochondrial apoptotic pathway.
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Caspase 2 acts upstream of mitochondria to promote cytochrome c release during etoposide induced apoptosis
Journal of Biological Chemistry, 2002Co-Authors: John D Robertson, Boris Zhivotovsky, Mari Enoksson, Minna Suomela, Sten OrreniusAbstract:Abstract DNA damage induced by the cancer chemotherapeutic drug etoposide triggers the onset of a series of intracellular events characteristic of apoptosis. Among the early changes observed is the release of cytochrome c from mitochondria, although the mechanism responsible for this effect is unclear. We demonstrate here a role for Caspase-2 in etoposide-induced cytochrome crelease. In particular, Jurkat T-lymphocytes treated with an irreversible Caspase-2 inhibitor, benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethyl ketone (z-VDVAD-fmk), or stably transfected with pro-Caspase-2 antisense (Casp-2/AS) are refractory to cytochrome crelease stimulated by etoposide. Experiments performed using a reconstituted cell-free system indicate that etoposide-induced cytochrome c release by way of Caspase-2 occurs independently of cytosolic factors, suggesting that the nuclear pool of pro-Caspase-2 is critical to this process. Apart from inhibiting cytochrome c release, undermining Caspase-2 activity results in an attenuation of downstream events, such as pro-Caspase-9 and -3 activation, phosphatidylserine exposure on the plasma membrane, and DNA fragmentation. Taken together, our data indicate that Caspase-2 provides an important link between etoposide-induced DNA damage and the engagement of the mitochondrial apoptotic pathway.
Jitka Fucikova - One of the best experts on this subject based on the ideXlab platform.
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Caspase 2 and oxidative stress underlie the immunogenic potential of high hydrostatic pressure induced cancer cell death
OncoImmunology, 2017Co-Authors: Irena Moserova, Abhishek D Garg, Patrizia Agostinis, Radek Spisek, Iva Truxova, Jakub Tomala, Pierre Francois Cartron, Sarka Vosahlikova, Marek Kovar, Jitka FucikovaAbstract:High hydrostatic pressure (HHP) promotes key characteristics of immunogenic cell death (ICD), in thus far resembling immunogenic chemotherapy and ionizing irradiation. Here, we demonstrate that cancer cells succumbing to HHP induce CD4+ and CD8+ T cell-dependent protective immunity in vivo. Moreover, we show that cell death induction by HHP relies on the overproduction of reactive oxygen species (ROS), causing rapid establishment of the integrated stress response, eIF2α phosphorylation by PERK, and sequential Caspase-2, -8 and -3 activation. Non-phosphorylatable eIF2α, depletion of PERK, Caspase-2 or -8 compromised calreticulin exposure by cancer cells succumbing to HHP but could not inhibit death. Interestingly, the phagocytosis of HHP-treated malignant cells by dendritic cells was suppressed by the knockdown of Caspase-2 in the former. Thus, Caspase-2 mediates a key function in the interaction between dying cancer cells and antigen presenting cells. Our results indicate that the ROS→PERK→eIF2α→Caspase-2 signaling pathway is central for the perception of HHP-driven cell death as immunogenic.
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abstract a039 Caspase 2 and oxidative er stress crosstalk regulates the exposure of eat me signal calreticulin by high hydrostatic pressure treated cancer cells
Cancer immunology research, 2016Co-Authors: Irena Moserova, Patrizia Agostinis, Radek Spisek, Iva Truxova, Pierre Francois Cartron, Sarka Vosahlikova, Garg Abhishek G, Jitka FucikovaAbstract:Immunogenic cell death (ICD) is a type of cell death induced by various chemotherapeutics, physical modalities such as photodynamic therapy, radiotherapy and high hydrostatic pressure (HHP). HHP induces immunogenic cell death of cancer cell is currently tested in running II. and III. phase of clinical trial for preparation of active cellular cancer immunotherapy (DCVAC). Previous studies have shown that the immunogenicity of ICD mainly relies on surface exposed calreticulin (ecto-CRT); CRT is normally located in the lumen of the endoplasmic reticulum (ER) and may translocate to the cell surface within hours after treatment. Although ICD can be triggers by HHP, underlying danger signaling pathways remain unclear. Therefore ovarian (OV90) cancer cell line was treated by HHP, UV-B and anthracycline (Idarubicin). The kinetics of ICD markers and key components of ER stress-mediated apoptotic pathway were analyzed by flow cytometry, western blotting and confocal microscopy. In this work we described the ability of HHP triggers oxidative ER-stress (the production of reactive oxygen species (ROS) together with ER stress response) which results in phosphorylation of PERK and eIF2α. We also observed a rapid Caspase-8 activation subsequently followed by BAP31 cleavage, Bid activation and Caspase-3 activation. While Caspase-8 activation was necessary for cell surface exposure of calreticulin (ecto-CRT) after HHP treatment, proapoptotic proteins Bax and Bak were dispensable for this process. Moreover, we identified that HHP treatment leads to Caspase-2 activation. Whereas Idarubicin treatment has no effect on ecto-CRT exposure in Caspase-2 knockdown tumor cells, ecto-CRT was significantly decreased in these cells after HHP treatment. In addition, phagocytosis of HHP-treated Caspase-2 knockdown tumor cells was compromised in contrast to Idarubicin-treated knockout tumor cells. In conclusion, we characterized the molecular mechanism of ecto-CRT exposure pathway induced by HHP which is analogous to that induced by anthracycline treatment. For the first time we provide evidence that Caspase-2 might play an important role in the HHP-mediated ecto-CRT exposure. Citation Format: Irena Kusova Moserova, Iva Truxova, Abhishek G, Garg, Patrizia Agostinis, Piere Francois Cartron, Sarka Vosahlikova, Radek Spisek, Jitka Fucikova. Caspase-2 and oxidative-ER stress crosstalk regulates the exposure of “eat me” signal calreticulin by high hydrostatic pressure treated cancer cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A039.
Boris Zhivotovsky - One of the best experts on this subject based on the ideXlab platform.
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A Caspase-2-RFXANK interaction and its implication for MHC class II expression
Nature Publishing Group, 2018Co-Authors: Jeremy Forsberg, Boris Zhivotovsky, Birce Akpinar, Roger Salvatori, Martin Ott, Magnus OlssonAbstract:Abstract Despite recent achievements implicating Caspase-2 in tumor suppression, the enzyme stands out from the apoptotic Caspase family as a factor whose function requires further clarification. To specify enzyme characteristics through the definition of interacting proteins in apoptotic or non-apoptotic settings, a yeast 2-hybrid (Y2H) screen was performed using the full-length protein as bait. The current report describes the analysis of a captured prey and putative novel Caspase-2 interacting factor, the regulatory factor X-associated ankyrin-containing protein (RFXANK), previously associated with CIITA, the transactivator regulating cell-type specificity and inducibility of MHC class II gene expression. The interaction between Caspase-2 and RFXANK was verified by co-immunoprecipitations using both exogenous and endogenous proteins, where the latter approach suggested that binding of the components occurs in the cytoplasm. Cellular co-localization was confirmed by transfection of fluorescently conjugated proteins. Enhanced Caspase-2 processing in RFXANK-overexpressing HEK293T cells treated with chemotherapeutic agents further supported Y2H data. Yet, no distinct differences with respect to MHC class II expression were observed in plasma membranes of antigen-presenting cells derived from wild type and Caspase-2−/− mice. In contrast, increased levels of the total MHC class II protein was evident in protein lysates from Caspase-2 RNAi-silenced leukemia cell lines and B-cells isolated from gene-targeted mice. Together, these data identify a novel Caspase-2-interacting factor, RFXANK, and indicate a potential non-apoptotic role for the enzyme in the control of MHC class II gene regulation
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Caspase-2 promotes cytoskeleton protein degradation during apoptotic cell death
Cell Death & Disease, 2013Co-Authors: H Vakifahmetoglu-norberg, E Norberg, A B Perdomo, Fabiola Ciccosanti, Gian Maria Fimia, Maria Piacentini, M. Olsson, Sten Orrenius, Boris ZhivotovskyAbstract:The Caspase family of proteases cleaves large number of proteins resulting in major morphological and biochemical changes during apoptosis. Yet, only a few of these proteins have been reported to selectively cleaved by Caspase-2. Numerous observations link Caspase-2 to the disruption of the cytoskeleton, although it remains elusive whether any of the cytoskeleton proteins serve as bona fide substrates for Caspase-2. Here, we undertook an unbiased proteomic approach to address this question. By differential proteome analysis using two-dimensional gel electrophoresis, we identified four cytoskeleton proteins that were degraded upon treatment with active recombinant Caspase-2 in vitro. These proteins were degraded in a Caspase-2-dependent manner during apoptosis induced by DNA damage, cytoskeleton disruption or endoplasmic reticulum stress. Hence, degradation of these cytoskeleton proteins was blunted by siRNA targeting of Caspase-2 and when Caspase-2 activity was pharmacologically inhibited. However, none of these proteins was cleaved directly by Caspase-2. Instead, we provide evidence that in cells exposed to apoptotic stimuli, Caspase-2 probed these proteins for proteasomal degradation. Taken together, our results depict a new role for Caspase-2 in the regulation of the level of cytoskeleton proteins during apoptosis.
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Caspase 2 acts upstream of mitochondria to promote cytochrome c release during etoposide induced apoptosis
Journal of Biological Chemistry, 2002Co-Authors: John D Robertson, Boris Zhivotovsky, Mari Enoksson, Minna Suomela, Sten OrreniusAbstract:Abstract DNA damage induced by the cancer chemotherapeutic drug etoposide triggers the onset of a series of intracellular events characteristic of apoptosis. Among the early changes observed is the release of cytochrome c from mitochondria, although the mechanism responsible for this effect is unclear. We demonstrate here a role for Caspase-2 in etoposide-induced cytochrome crelease. In particular, Jurkat T-lymphocytes treated with an irreversible Caspase-2 inhibitor, benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethyl ketone (z-VDVAD-fmk), or stably transfected with pro-Caspase-2 antisense (Casp-2/AS) are refractory to cytochrome crelease stimulated by etoposide. Experiments performed using a reconstituted cell-free system indicate that etoposide-induced cytochrome c release by way of Caspase-2 occurs independently of cytosolic factors, suggesting that the nuclear pool of pro-Caspase-2 is critical to this process. Apart from inhibiting cytochrome c release, undermining Caspase-2 activity results in an attenuation of downstream events, such as pro-Caspase-9 and -3 activation, phosphatidylserine exposure on the plasma membrane, and DNA fragmentation. Taken together, our data indicate that Caspase-2 provides an important link between etoposide-induced DNA damage and the engagement of the mitochondrial apoptotic pathway.
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Caspase 2 acts upstream of mitochondria to promote cytochrome c release during etoposide induced apoptosis
Journal of Biological Chemistry, 2002Co-Authors: John D Robertson, Boris Zhivotovsky, Mari Enoksson, Minna Suomela, Sten OrreniusAbstract:Abstract DNA damage induced by the cancer chemotherapeutic drug etoposide triggers the onset of a series of intracellular events characteristic of apoptosis. Among the early changes observed is the release of cytochrome c from mitochondria, although the mechanism responsible for this effect is unclear. We demonstrate here a role for Caspase-2 in etoposide-induced cytochrome crelease. In particular, Jurkat T-lymphocytes treated with an irreversible Caspase-2 inhibitor, benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethyl ketone (z-VDVAD-fmk), or stably transfected with pro-Caspase-2 antisense (Casp-2/AS) are refractory to cytochrome crelease stimulated by etoposide. Experiments performed using a reconstituted cell-free system indicate that etoposide-induced cytochrome c release by way of Caspase-2 occurs independently of cytosolic factors, suggesting that the nuclear pool of pro-Caspase-2 is critical to this process. Apart from inhibiting cytochrome c release, undermining Caspase-2 activity results in an attenuation of downstream events, such as pro-Caspase-9 and -3 activation, phosphatidylserine exposure on the plasma membrane, and DNA fragmentation. Taken together, our data indicate that Caspase-2 provides an important link between etoposide-induced DNA damage and the engagement of the mitochondrial apoptotic pathway.
Leta K Nutt - One of the best experts on this subject based on the ideXlab platform.
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janus faced pidd a sensor for dna damage induced cell death or survival
Molecular Cell, 2012Co-Authors: Francis Mccoy, Laura Eckard, Leta K NuttAbstract:In this issue of Molecular Cell , an activator of the PIDDosome (a complex comprising of PIDD, RAIDD, and Caspase-2) is described in experiments detailing endogenous PIDDosome assembly and Caspase-2 function after DNA damage in the presence of Chk1 suppression (Ando et al., 2012).
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metabolic control of oocyte apoptosis mediated by 14 3 3ζ regulated dephosphorylation of Caspase 2
Developmental Cell, 2009Co-Authors: Leta K Nutt, Christopher D Freel, Marisa R Buchakjian, Rashid Darbandi, Sook Young Yoon, Judy Wu, Yuko J Miyamoto, Jennifer A Gibbon, Josh L Andersen, Wanli TangAbstract:Summary Xenopus oocyte death is partly controlled by the apoptotic initiator Caspase-2 (C2). We reported previously that oocyte nutrient depletion activates C2 upstream of mitochondrial cytochrome c release. Conversely, nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3ζ, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2. Although C2 dephosphorylation is responsive to metabolism, neither PP1 activity nor binding is metabolically regulated. Rather, release of 14-3-3ζ from C2 is controlled by metabolism and allows for C2 dephosphorylation. Accordingly, a C2 mutant unable to bind 14-3-3ζ is highly susceptible to dephosphorylation. Although this mechanism was initially established in Xenopus , we now demonstrate similar control of murine C2 by phosphorylation and 14-3-3 binding in mouse eggs. These findings provide an unexpected evolutionary link between 14-3-3 and metabolism in oocyte death.
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metabolic regulation of oocyte cell death through the camkii mediated phosphorylation of Caspase 2
Cell, 2005Co-Authors: Leta K Nutt, Seth S Margolis, Mette V Jensen, Catherine E Herman, William G Dunphy, Jeffrey C Rathmell, Sally KornbluthAbstract:Summary Vertebrate female reproduction is limited by the oocyte stockpiles acquired during embryonic development. These are gradually depleted over the organism's lifetime through the process of apoptosis. The timer that triggers this cell death is yet to be identified. We used the Xenopus egg/oocyte system to examine the hypothesis that nutrient stores can regulate oocyte viability. We show that pentose-phosphate-pathway generation of NADPH is critical for oocyte survival and that the target of this regulation is Caspase-2, previously shown to be required for oocyte death in mice. Pentose-phosphate-pathway-mediated inhibition of cell death was due to the inhibitory phosphorylation of Caspase-2 by calcium/calmodulin-dependent protein kinase II (CaMKII). These data suggest that exhaustion of oocyte nutrients, resulting in an inability to generate NADPH, may contribute to ooctye apoptosis. These data also provide unexpected links between oocyte metabolism, CaMKII, and Caspase-2.