Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upon activation, cell surface death receptors, Fas/APO-1/CD95 and tumor necrosis factor receptor-1 (TNFR-1), are attached to cytosolic adaptor proteins, which in turn recruit caspase-8 (MACH/FLICE/Mch5) to activate the interleukin-1 beta-converting enzyme (ICE)/CED-3 family protease (caspase) cascade. However, it remains unknown whether these apoptotic proteases are generally involved in apoptosis triggered by other stimuli such as Myc and p53. In this study, we provide lines of evidence that a death protease cascade consisting of caspases and serine proteases plays an essential role in Myc-mediated apoptosis. When Rat-1 fibroblasts stably expressing either s-Myc or c-Myc were induced to undergo apoptosis by serum deprivation, a caspase-3 (CPP32)-like protease activity that cleaves a specific peptide substrate, Ac-DEVD-MCA, appeared in the cell lysates. Induction of s-Myc- and c-Myc-mediated apoptotic cell death was effectively prevented by caspase inhibitors such as Z-Asp-CH2-DCB and Ac-DEVD-CHO. Furthermore, exposing the cells to a serine protease inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), also significantly inhibited s-Myc- and c-Myc-mediated apoptosis and the appearance of the caspase-3-like protease activity in vivo. However, AEBSF did not directly inhibit caspase-3-like protease activity in the apoptotic cell lysates in vitro. Together, these results indicate that caspase-3-like proteases play a critical role in both s-Myc- and c-Myc-mediated apoptosis and that caspase-3-like proteases function downstream of the AEBSF-sensitive step in the signaling pathway of Myc-mediated apoptosis.
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PMID:A functional role for death proteases in s-Myc- and c-Myc-mediated apoptosis. 934 38

Calcineurin, a Ca(2+)/calmodulin-dependent Ser/Thr phosphatase (protein phosphatase 2B), plays a critical role in IL-2 production during T cell activation. It has been previously reported that IL-2 release in activated Jurkat T requires caspase-like activity (Posmantur et al. (1998) Exp. Cell. Res. 244, 302-309). We report here that the 60-kDa catalytic subunit of calcineurin A (Cn A) was partially cleaved to a 45-kDa form in phytohemagglutinin A (PHA) or phorbol ester + ionomycin (P + I)-activated Jurkat cells. In parallel, proteolytic activation of upstream caspases (caspase-8 and -9) as well as effector caspase-3 was also observed. Cn A cleavage was caspase mediated, since it was inhibitable by pan-caspase inhibitor Cbz-Asp-CH(2)OC(O)-2,6-dichlorobenzene (Z-D-DCB). Cn A cleavage was also observed when purified calcineurin was digested in vitro with caspase-3. Truncated Cn A was associated with enhanced phosphatase activity and reduced calmodulin sensitivity. Furthermore, in PHA or P + I-activated Jurkat cells, dephosphorylation of calcineurin substrate NFATc (a transcription factor known to be involved in transactivation of the IL-2 gene), was also suppressed by Z-D-DCB. Taken together, our results suggest that caspase-mediated cleavage of Cn A contributes to IL-2 production during T cell activation.
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PMID:Caspase-mediated calcineurin activation contributes to IL-2 release during T cell activation. 1147 81

Some diterpenoids show various biological activities, including anti-inflammatory, anti-HIV and anti-tumor activity. Previously, we have focused our research on the apoptosis-inducing properties of diterpenoids and found that some ent-kaurene-type diterpenoids induced apoptosis in human leukemia HL-60 cells. In this study, we have investigated the induction of apoptosis in HL-60 cells by the novel ent-kaurene-type diterpenoids, jungermannenones A (JA), B (JB), C (JC) and D (JD), isolated from the New Zealand liverwort Jungermannia species. Treatment of the cells with each compound for 12 h resulted in cytotoxicity (IC (50) values: A, 1.3; B, 5.3; C, 7.8; D, 2.7 microM) and caused DNA fragmentation and nuclear condensation, both biochemical markers of the induction of apoptosis. Treatment with the compounds resulted in activation of caspases, including caspase-3 and caspase-8. A broad-spectrum inhibitor of caspases, Z-Asp-CH (2)-DCB, attenuated the cytotoxicity induced by these compounds, suggesting that JA, JB, JC and JD induced apoptosis through a caspase-dependent pathway. JA and JD inhibited the activity of nuclear factor-kappaB, which is a transcriptional factor of anti-apoptotic factors. Thus, some of these new ent-kaurene-type diterpenoids may be promising candidates for anti-tumor agents.
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PMID:Induction of apoptosis by new ent-kaurene-type diterpenoids isolated from the New Zealand liverwort Jungermannia species. 1632 Feb

The toxicology of benzo[a]pyrene (BaP) has been mainly studied with regard to the carcinogenicity of its metabolites, but its phototoxicity is not well understood. Although some studies have indicated the lethal phototoxicity of BaP, there have been no reports regarding the pattern of cell death induced by this agent. In this study, we investigated the pattern and mechanism of cell death induced by coexposure to BaP plus ultraviolet A (UVA) in Jurkat cells. Coexposure to BaP plus UVA showed dose-dependent cytotoxicity. The pattern of cell death was apoptotic as determined by cell shrinkage, chromatin condensation, appearance of subdiploid apoptotic nuclei and translocation of phosphatidylserine to the outer membrane leaflet. Coexposure also strongly increased caspase-3/7 activity and slightly elevated those of caspase-8/6 and -9. The pan caspase inhibitor Z-VAD-CH(2)-DCB partially inhibited the phototoxicity of BaP. Cytochrome c release was observed 6 h after coexposure, but not after 1 h. Furthermore, the phototoxicity was inhibited by NaN(3) (quencher of singlet oxygen), but not by mannitol (quencher of hydroxy radicals). Chromatin condensation and translocation of phosphatidylserine were also inhibited by NaN(3), suggesting that the induction of apoptosis by coexposure to BaP plus UVA was due to singlet oxygen production.
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PMID:Phototoxicity of benzo[a]pyrene by ultraviolet A irradiation: induction of apoptosis in Jurkat cells. 2178 91

The irradiation of fat-containing food forms 2-dodecylcyclobutanone (2-DCB) from palmitic acid (PA). In this study, we investigated whether 2-DCB and PA induce apoptosis in human lymphoma U937 cells. We found that cell viability decreased by 2-DCB and apoptosis was induced by 2-DCB and PA. 2-DCB and PA significantly enhanced the formation of intracellular reactive oxygen species (ROS). Apoptosis induced by 2-DCB and PA was strongly prevented by an antioxidant, N-acetyl-L: -cysteine. The treatment with 2-DCB and PA resulted in the loss of mitochondrial membrane potential, and Fas, caspase-8 and caspase-3 activation. Pretreatment with a pan-caspase inhibitor (z-VAD) significantly inhibited apoptosis induced by 2-DCB and PA. Moreover, 2-DCB and PA also induced Bax up-regulation, the reduction in Bcl-2 expression level, Bid cleavage and the release of cytochrome c from the mitochondria to the cytosol. In addition, an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) was observed after the treatment with 2-DCB and PA. Our results indicated that intracellular ROS generation, the modulation of the Fas-mitochondrion-caspase-dependent pathway and the increase in [Ca(2+)](i) involved in apoptosis are induced by 2-DCB and PA in U937 cells.
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PMID:Molecular mechanisms of apoptosis induction by 2-dodecylcyclobutanone, a radiolytic product of palmitic acid, in human lymphoma U937 cells. 2231 71

TNF has been reported to induce caspase-independent necroptosis in the presence of Z-VAD-fmk, a pan-caspase inhibitor. We examined whether necroptosis was induced by caspase inhibitors other than Z-VAD-fmk. TNF-induced necroptosis was detected in the presence of Z-DEVD-fmk, which is commonly used as a caspase-3-specific inhibitor, but not in the presence of Z-Asp-CH2-DCB, which was reported to be a pan-caspase inhibitor. TNF-induced caspase-3 activity was completely inhibited by Z-VAD-fmk, Z-DEVD-fmk, or Z-Asp-CH2-DCB. Although TNF-induced proteolytic activation of procaspase-3 was completely prevented by Z-VAD-fmk or Z-DEVD-fmk, the partial proteolysis of procaspase-3 was induced in the presence of Z-Asp-CH2-DCB. Furthermore, although TNF-induced proteolytic activation of procaspase-8 was completely inhibited by Z-VAD-fmk or Z-DEVD-fmk, the partial proteolysis of procaspase-8 to the p43/41 intermediate and p18 active fragment was detected in the presence of Z-Asp-CH2-DCB. The cleavage of RIP1, which plays a crucial role in TNF-induced necroptosis and is cleaved by caspase-8, was completely inhibited by Z-VAD-fmk or Z-DEVD-fmk, whereas the partial degradation of RIP1 was detected in the presence of Z-Asp-CH2-DCB. These results suggest that the partial activation of caspase-8 in the presence of Z-Asp-CH2-DCB may suppress TNF-induced necroptosis via the cleavage of RIP1, and also suggest that Z-Asp-CH2-DCB, but not Z-DEVD-fmk, may be used as a caspase-3-specific inhibitor in cells.
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PMID:Differential effects of caspase inhibitors on TNF-induced necroptosis. 2341 Jul 48

It has been shown that necroptosis-caspase-independent programmed necrotic cell death-can be induced by treatment with tumor necrosis factor (TNF) in the L929 murine fibrosarcoma cell line, even in the absence of a caspase inhibitor. Although it was reported that necrostatin-1-a specific inhibitor of necroptosis-inhibited TNF-induced necroptosis in L929 cells, it has not been elucidated whether the cells eventually die by apoptosis in the presence of necrostatin-1. In this paper, induction of apoptosis was demonstrated in TNF-treated L929 cells in the presence of necrostatin-1. Co-treatment with cycloheximide expedited apoptosis induction in necrostatin-1/TNF-treated L929 cells: typical apoptotic morphological changes, including membrane blebbing and nuclear fragmentation, induction of caspase-3 activity, proteolytic activation of caspases-3, -8, and -9, and cleavage of poly(ADP-ribose) polymerase (PARP) (a well-known substrate of caspase-3) were observed. Moreover, co-treatment with Z-VAD-fmk (a pan-caspase inhibitor) inhibited apoptosis by completely inhibiting caspases, resulting in a shift from apoptosis to necroptosis. In contrast, co-treatment with Z-Asp-CH2-DCB (a caspase inhibitor preferential to caspase-3) inhibited apoptosis without expediting necroptosis. These results indicate that apoptosis can be induced in TNF-treated L929 cells when the cells are protected from necroptosis, and support the notion that partial activation of caspase-8 in the presence of a caspase inhibitor preferential to caspase-3 suppresses both apoptosis and necroptosis.
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PMID:Induction of Apoptosis in TNF-Treated L929 Cells in the Presence of Necrostatin-1. 2773 12