Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis was inhibited in rat cardiomyocytes pretreated with the aspartic protease inhibitor pepstatin A and subsequently exposed to naphthazarin (5,8-dihydroxy-1,4-naphthoquinone). Cathepsin D was released from lysosomes to the cytosol upon exposure to naphthazarin, and the enzyme activity decreased simultaneously. Later, cathepsin D reappeared in granules of increased size, and enzyme activity was restored. Activation of caspase-3-like proteases was detected, and the number of cells showing apoptotic morphology increased with time. Pepstatin A pretreatment did not prevent release of cathepsin D from lysosomes but did significantly inhibit subsequent naphthazarin-induced caspase activation and apoptotic morphology. This suggests that cathepsin D exerts its apoptosis-stimulating effect upstream of caspase-3-like activation.
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PMID:Inhibition of cathepsin D prevents free-radical-induced apoptosis in rat cardiomyocytes. 1062 Mar 58

We investigated whether retinal pigment epithelial (RPE) responds to ceramide, a known second messenger of apoptosis. RPE cells were isolated by 6-8 day old Long Evans rat eye. We used MTS assay for viability test, and used Hoechst 33552 and propidium iodide for apoptotic cell staining. In cultured rat RPE cells, the addition of membrane-permeable ceramide induced apoptosis-like cell death rapidly. RPE cell death was dependent on C2-ceramide concentration. The effective dose (ED50) of C2-ceramide was 23.64 microM. Ceramide-induced RPE cell death was inhibited by zVAD-fmk, a CPP32-like protease inhibitor. Our findings indicated that ceramide in RPE cell death functions upstream of CPP32-like proteases.
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PMID:Ceramide-induced cell death in cultured rat retinal pigment epithelial cells. 1077 6

Epidemiological studies have demonstrated that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of and mortality from colon cancer. In addition, NSAIDs reduce the number and the size of polyps in patients with familial adenomatous polyposis. The mechanisms responsible for the antineoplastic effect of NSAIDs are not yet completely understood, but one of the possible mechanisms is an induction of apoptosis. We explored the role of caspase-3, a major apoptosis-executing enzyme, in NSAID-induced apoptosis of colon cancer cell line HT-29. Treatment of HT-29 cells with indomethacin induced a dramatic increase in caspase-3-like protease activity measured by a cleavage of the fluorogenic substrate Ac-DEVD-AMC. Western blot analysis showed that indomethacin treatment led both to decrease in procaspase-3 and to cleavage of its substrate poly(ADP-ribose) polymerase (PARP). Furthermore, the caspase-3-like protease inhibitor Ac-DEVD-CHO attenuated indomethacin-induced DNA fragmentation dose dependently. However, mRNA expression of CASP genes was not affected by the addition of indomethacin, highlighting the importance of posttranslational modification of this enzyme for the activation. These results suggest that NSAIDs, including indomethacin, induce apoptosis in colon cancer cells through a caspase-3 dependent mechanism which may contribute to the chemopreventive functions of these agents.
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PMID:Role of caspase-3 in apoptosis of colon cancer cells induced by nonsteroidal anti-inflammatory drugs. 1085 54

The recombinant immunotoxins anti-Tac(Fv)-PE38 (LMB-2), targeting the interleukin-2 receptor alpha subunit (IL-2Ralpha, Tac or CD25), and RFB4(dsFv)-PE38 (BL22), targeting CD22, are being evaluated in clinical trials as treatment for hematologic malignancies. The toxin moiety Pseudomonas exotoxin A (PE) of these recombinant molecules leads to the arrest of protein synthesis due to inactivation of elongation factor 2. Here, we provide evidence that cell lines derived from patients with hematologic malignancies react to immunotoxins not only with inhibition of protein synthesis but also with characteristic hallmarks of apoptosis such as caspase activation, cleavage of the "death substrate poly(ADP)-ribose polymerase and DNA laddering. Anti-Tac(Fv)-PE38 leads to a 10-fold increase in the cleavage of the fluorescent substrate DEVD-AFC, suggesting that a caspase-3-like enzyme is involved. This was verified by cleavage of caspase-3 (CPP32). MT1 cells exhibited DNA laddering after treatment with immunotoxin, which was reversed by pre-treatment with the protease inhibitor zVAD-fmk. This caspase inhibitor led to an at least 5-fold improvement in cell viability without altering inhibition of protein synthesis. Interestingly, HUT-102 cells did not undergo programmed cell death after exposure to immunotoxins that kill these cells. We conclude that immunotoxins may be valuable in the treatment of cancers that are resistant toward apoptosis because their targeted killing is often facilitated by, but not completely dependent on, programmed cell death. Int. J. Cancer 87:86-94, 2000. Published 2000 Wiley-Liss, Inc.
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PMID:Apoptosis induced by immunotoxins used in the treatment of hematologic malignancies. 1086 57

Methylmercury (MeHg) has been implicated to induce massive neurodegeneration by disruption of neuron-glia interactions besides a direct potent neurotoxicity. In the present study, we examined potential cytotoxic effects of MeHg on primary cultured rat microglia. Following treatment with a relatively low concentration (0.5 microM) of MeHg, microglia had induced cell death accompanied by DNA fragmentation and an activation of caspase-3-like protease. MeHg-induced microglial death was significantly suppressed by the caspase-3-like protease inhibitor benzyloxycarbonyl-Try-Val-Ala-Asp-fluoromethyl-ketone indicating the occurrence of caspase-3-like protease-executed apoptosis. The aspartic protease inhibitor pepstatin A had a partial but significant inhibitory effect on MeHg-induced microglial apoptosis. These results indicate that a relatively low concentration of MeHg predominantly induces caspase-3-like protease-executed apoptosis of microglia, while the endosomal/lysosomal system is also partially involved in the cell death pathway.
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PMID:Involvement of caspase 3-like protease in methylmercury-induced apoptosis of primary cultured rat cerebral microglia. 1088 96

We have attempted to elucidate the precise mechanism of nitric oxide (NO)-induced apoptotic neuronal cell death. Enzymatic cleavages of DEVD-AFC, VDVAD-AFC, and LEHD-AFC (specific substrates for caspase-3-like protease (caspase-3 and -7), caspase-2, and caspase-9, respectively) were observed by treatment with NO. Western blot analysis showed that pro-forms of caspase-2, -3, -6, and -7 are decreased during apoptosis. Interestingly, Ac-DEVD-CHO, a caspase-3-like protease inhibitor, blocked not only the decreases in caspase-2 and -7, but also the formation of p17 from p20 in caspase-3 induced by NO, suggesting that caspase-3 exists upstream of caspase-2 and -7. Bongkrekic acid, a potent inhibitor of mitochondrial permeability transition, specifically blocked both the loss of mitochondrial membrane potential and subsequent DNA fragmentation in response to NO. Thus, NO results in neuronal apoptosis through the sequential loss of mitochondrial membrane potential, caspase activation, and degradation of inhibitor of caspase-activated DNase (CAD) (CAD activation).
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PMID:Mechanism of nitric oxide-induced apoptosis in human neuroblastoma SH-SY5Y cells. 1107 88

Apoptosis plays an important role in heat-induced cell death. However, the mechanism of heat-induced apoptosis has not yet been elucidated. In the present study, the signal transduction pathway underlying heat-induced apoptosis was investigated in heat-resistant HeLa cells carrying mutant p53 gene and heat sensitive HeLa cells that had been transduced with an antisense TNF gene. Induction of mutant p53, but not p21/WAF-1, was observed after heat treatment of both the resistant and sensitive cells. Heat-induced cytotoxicity was not inhibited in either cells with interleukin-1beta-converting enzyme (ICE: caspase-1) like protease inhibitor Ac-YVAD-CHO. In contrast, there was 48% and 63% inhibition of cytotoxicity in HeLa and transfectants, respectively, with a caspase-3 inhibitor (Ac-DEVD-CHO). Heat-induced apoptosis was also prevented by administration of Ac-DEVD-CHO in both cells. In addition, an augmentation of heat-induced cytotoxicity in transfectants was almost completely inhibited by Ac-DEVD-CHO. Further, caspase-3 mRNA expression was increased remarkably in heat-treated HeLa cells and transfectants. Taken together, these results suggest that activation of caspase-3 is involved in the signal transduction pathway of heat-induced apoptosis of the tumour cells carrying mutant p53.
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PMID:Heat-induced apoptosis via caspase-3 activation in tumour cells carrying mutant p53. 1112 59

In the previous studies, we have demonstrated that the tumor suppressor gene p53 is required for DNA strand break-induced neuronal apoptosis in organotypic slice cultures of cerebellum as well as in dissociated cerebellar neuron cultures. In this study, we further investigated the role of p53 in neuronal apoptosis, by examining whether caspases and c-Jun N-terminal kinase (JNK) are involved in the DNA strand break-induced apoptosis. The protein level of phospho-JNK increased in p53 wild-type mouse cerebellar granule neurons after exposure to bleomycin. On the other hand, the response was not observed in cerebellar granule neurons of p53-deficient mice. Caspase-3-like protease was activated and poly(ADP-ribose) polymerase (PARP) was cleaved in the bleomycin-induced apoptosis. Caspase-3-like protease inhibitor decreased the number of TUNEL-positive but not p53- or c-Jun-positive neurons in bleomycin-induced death. These results suggest that JNK and caspase-3-like protease are involved in the signaling cascade of DNA strand break-induced, p53-dependent apoptosis.
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PMID:Involvement of c-Jun N-terminal kinase and caspase 3-like protease in DNA damage-induced, p53-mediated apoptosis of cultured mouse cerebellar granule neurons. 1140 25

YC-1, a benzyl indazole derivative, is an NO-independent direct activator of soluble guanylyl cyclase (sGC), which presents a synergistic action with NO in stimulating cGMP synthesis. These properties have served to suggest YC-1 as an attractive therapeutic agent by permitting the reduction of nitrovasodilator dosage and regulating endogenous cGMP metabolism. Here we studied the effect of prolonged exposure of adrenomedullary endothelial and chromaffin cells to YC-1. We found that YC-1 increased cGMP in the two types of cells and this action was blocked by the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Cells underwent apoptotic death in association with increased caspase-3-like activity, DNA fragmentation, cytoskeletal disorganization and changes in membrane permeability after prolonged incubation with YC-1. Caspase-3-like protease activity and DNA fragments in the cytoplasm were increased in a dose-dependent manner by 16 h YC-1 treatment. The specific and cell permeable caspase-3-like protease inhibitor DEVD-CHO effectively inhibited YC-1-mediated caspase-3-like activation and DNA fragmentation. Moreover, YC-1 also induced cell shape changes accompanied by actin filament disorganization and alterations in membrane permeability. Cells incubated for 24h with YC-1 showed damaged membranes by binding to nucleic acid of a dye excluded by the intact plasma membrane of live cells. YC-1 also induced a decrease in the intracellular non-specific esterase activity, another indication of cell toxicity. Apoptotic phenomena were not prevented by the presence of ODQ although it effectively inhibited the YC-1-elicited cGMP increases. These findings indicate that YC-1 induces apoptosis by activating caspase-3-like protease through a mechanism independent of sGC activation.
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PMID:Prolonged exposure to YC-1 induces apoptosis in adrenomedullary endothelial and chromaffin cells through a cGMP-independent mechanism. 1168 54

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to attenuate proliferation of vascular smooth muscle cells (VSMCs) by mechanisms independent of lipid reduction. In the current study, we investigated the effect of lipophilic and hydrophilic statins (fluvastatin and pravastatin) on apoptosis in unstimulated or cytokine-stimulated VSMCs. The presence of apoptosis in rat VSMCs was evaluated by electrophoresis of DNA fragments and 4'6'-diamidine-2'-phenylindole staining and quantified by flow cytometry. Fluvastatin but not pravastatin enhanced apoptosis in interleukin-1beta-stimulated VSMCs. The proapoptotic effect of fluvastatin was fully reversed by mevalonate and geranylgeranyl-pyrophosphate, and partially by farnesyl-pyrophosphate, but not by squalene. Inhibition of the extracellular signal-regulated protein kinase (ERK1/2) pathway significantly increased fluvastatin-enhanced apoptosis, whereas inhibition of the p38-mitogen-activated protein kinase (MAPK) pathway significantly prevented this increase. However, fluvastatin showed no effect on the activity of ERK1/2 and p38-MAPK. Furthermore, fluvastatin-induced apoptosis was inhibited by YVAD-FMK (a caspase-1/interleukin-1beta-converting enzyme-like protease inhibitor) and DEVD-FMK (a caspase-3/CPP32 inhibitor), indicating involvement of an important segment in the apoptosis signaling pathway. These findings suggest that fluvastatin enhances apoptosis in cytokine-stimulated VSMCs and that protein prenylation, MAPK (ERK1/2 and p38-MAPK), and caspases are critically involved in the pathways of fluvastatin-enhanced apoptosis.
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PMID:Fluvastatin enhances apoptosis in cytokine-stimulated vascular smooth muscle cells. 1179 Oct 17


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