Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although there are several agents that induce neutrophil apoptosis, few are known as inducers of eosinophil apoptosis. As eosinophils are potent effector cells contributing to allergic inflammation and asthma, we investigated whether the pro-apoptotic agent Viscum album agglutinin-I (VAA-I) could induce eosinophil apoptosis. VAA-I was found to induce apoptosis in eosinophilic AML14.3D10 (3D10) cells and that these cells expressed caspases-1, -2, -3, -4, -7, -8, -9 and -10. VAA-I-induced gelsolin degradation was reversed by the pan-caspase inhibitor N-benzyloxycarbonyl-V-A-D-O-methylfluoromethyl ketone (z-VAD). Also, paxillin, vimentin and lamin B1 were cleaved by caspases in VAA-I-induced 3D10 cells. VAA-I activated caspase-3 and -8 in 3D10 cells but, unlike z-VAD, treatment with a caspase-8 inhibitor slightly reversed apoptosis. Treatment of purified human eosinophils with VAA-I was found to induce apoptosis, degradation of gelsolin and lamin B1, but unlike 3D10 cells, cleavage of lamin B1 and cell apoptosis was not reversed by z-VAD. We conclude that VAA-I is a potent inducer of eosinophil apoptosis and that proteases other than those inhibited by z-VAD in 3D10 cells are involved in VAA-I-induced peripheral blood eosinophil apoptosis and lamin B1 cleavage. Thus, VAA-I represents a potential candidate for the reduction of the number of eosinophils in diseases where they play important roles.
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PMID:Viscum album agglutinin-I induces apoptosis and degradation of cytoskeletal proteins via caspases in human leukaemia eosinophil AML14.3D10 cells: differences with purified human eosinophils. 1609 66

Viscum album agglutinin-I (VAA-I) is a potent inducer of cell apoptosis and possesses anti-tumoral activity. Using PLB-985 and chronic granulomatous disease (X-CGD) cells, which lack expression of gp91(phox), VAA-I was found to induce apoptosis in both cell lines as assessed by cytology, DNA laddering and degradation of the cytoskeletal protein gelsolin. Both cell lines expressed caspase-3 and -8 and VAA-I activated these caspases. We demonstrated that lamin B(1) is a novel target to VAA-I and its degradation was reversed by a pan-caspase inhibitor and by a caspase-6, but not a caspase-8, inhibitor.
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PMID:Viscum album agglutinin-I (VAA-I) induces apoptosis and degradation of cytoskeletal proteins in human leukemia PLB-985 and X-CGD cells via caspases: lamin B1 is a novel target of VAA-I. 1624 77

Apoptosis is a key mechanism underlying fulminant hepatic failure. The role of gelsolin in such apoptotic pathways is not well understood because both pro-apoptotic and anti-apoptotic effects have been reported in vitro, depending on the cell type and in vitro expression model used. Therefore, we studied an in vivo model of hepatic failure by analyzing expression of gelsolin; intrahepatic activation of caspase-3, -8, and -9; and the extent of apoptosis in gelsolin knockout (gsn(-/-)) versus wild-type mice (gsn(+/+)) after exposure to stimulatory Fas antibody Jo-2. Gelsolin was expressed exclusively in sinusoidal lining cells, including sinusoidal endothelial cells and Kupffer cells, of gsn(+/+) mice. Compared with wild-type mice, Jo2-exposed gsn(-/-) mice showed significantly higher numbers of apoptotic cells in the liver (22 +/- 9 versus 5 +/- 4% terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells, P = 0.002); shorter survival (P = 0.037); and enhanced activation of caspase-3 (P = 0.009), -8 (P = 0.004), and -9 (P = 0.004). Furthermore, inhibition of caspase-3 with z-DEVD-fmk blocked Jo2-induced liver failure in all mice. Thus, our data on Jo2-induced hepatic failure suggest that gelsolin exerts an overall anti-apoptotic effect in vivo. Moreover, selective expression of gelsolin in sinusoidal endothelial cells indicates a pivotal role for interactions between sinusoidal endothelial cells and liver parenchymal cells in Fas ligand-mediated liver failure.
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PMID:Anti-apoptotic function of gelsolin in fas antibody-induced liver failure in vivo. 1650 93

p21-activated protein kinase (PAK) 2 is a small GTPase-activated serine/threonine kinase regulating various cytoskeletal functions and is cleaved by caspase-3 during apoptosis. We demonstrate that the caspase-cleaved PAK2 C-terminal kinase fragment (C-t-PAK2) is posttranslationally myristoylated, although myristoylation is typically a cotranslational process. Myristoylation and an adjacent polybasic domain of C-t-PAK2 are sufficient to redirect EGFP from the cytosol to membrane ruffles and internal membranes. Membrane localization and the ability of C-t-PAK2 to induce cell death are significantly reduced when myristoylation is abolished. In addition, the proper myristoylation-dependent membrane localization of C-t-PAK2 significantly increased signaling through the stress-activated c-Jun N-terminal kinase signaling pathway, which often regulates apoptosis. Interestingly, C-t-PAK2 promoted cell death without compromising mitochondrial integrity. Posttranslational myristoylation of caspase-cleaved proteins involved in cytoskeletal dynamics (e.g., PAK2, actin, and gelsolin) might be part of a unique series of mechanisms involved in the regulation of the later events of apoptosis.
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PMID:Posttranslational myristoylation of caspase-activated p21-activated protein kinase 2 (PAK2) potentiates late apoptotic events. 1661 11

We have previously shown that the Ca(2+)-dependent actin-severing protein gelsolin plays an important role in regulated insulin secretion. The aim of this study was to determine the role of gelsolin in beta-cell survival as it has been shown to play a dual role in apoptosis in other cell types. MIN6 subclones B1 and C3, shown previously to express gelsolin at different levels (B1>>C3 cells), were used for this purpose. We demonstrate that B1 cells have lower levels of apoptosis and active caspase-3 when compared with C3 cells, in both standard (25 mmol/l glucose and 15% FCS) and deprived (5 mmol/l glucose and 1% FCS) conditions. Overexpression of gelsolin resulted in a decrease in the percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)(+) and active caspase-3(+) cells. Conversely, knockdown of gelsolin by RNA interference in B1 cells caused an increase in the number of TUNEL(+) and active caspase-3(+) cells. Finally, the anti-apoptotic role of gelsolin was confirmed in purified primary mouse beta-cells where overexpression of gelsolin resulted in a decrease in the percentage of TUNEL(+) cells. In summary, our results show for the first time that gelsolin plays a pro-survival role in pancreatic beta-cells.
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PMID:Pro-survival role of gelsolin in mouse beta-cells. 1719 68

The role of the anti-cancer agent Viscum album agglutinin-I (VAA-I) in leukaemia PLB-985 cells differentiated toward a neutrophil-like phenotype by dimethylsulphoxide (PLB-985D) has never been studied. This study investigated whether or not VAA-I can induce cytoskeletal breakdown in PLB-985D cells, as previously observed in undifferentiated PLB-985 cells. VAA-I was found to induce apoptosis in PLB-985D cells, as assessed by cytology and by degradation of gelsolin, an event known to occur via caspase-3 activation. VAA-I induced cytoskeletal breakdown based on the disruption of the F-actin network and cleavage of paxillin, vimentin and lamin B(1). In addition, we demonstrated, for the first time, that non-muscle myosin heavy chain IIA (NMHC-IIA) was cleaved by VAA-I treatment. Degradation of NMHC-IIA was reversed by the pan caspase inhibitor z-VAD-fmk in PLB-985D cells and neutrophils. However, unlike lamin B(1), no NMHC-IIA was detected on the cell surface of apoptotic neutrophils. In conclusion, PLB-985D cells responded in a similar manner to neutrophils regarding the degradation of the tested cytoskeletal. Therefore, PLB-985D cells may provide a suitable substitute for neutrophils in screening experiments, preventing extensive neutrophil cell isolation.
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PMID:Viscum album agglutinin-I induces degradation of cytoskeletal proteins in leukaemia PLB-985 cells differentiated toward neutrophils: cleavage of non-muscle myosin heavy chain-IIA by caspases. 1765 56

Glioblastomas, the most malignant of all brain tumors, are characterized by cellular resistance to apoptosis and a highly invasive growth pattern. These factors contribute to the poor response of glioblastomas to radiochemotherapy and prevent their complete neurosurgical resection. However, the driving force behind the distinct motility of glioma cells is only partly understood. Here, we report that in the absence of cellular stress and proapoptotic stimuli, human glioblastoma cells exhibit a constitutive activation of caspases in vivo and in vitro. The inhibition of caspases by various peptide inhibitors decreases the migration of cells in scrape motility assays and the invasiveness of cells in spheroid assays. Similarly, specific small interfering RNA- or antisense-mediated down-regulation of caspase-3 and caspase-8 results in an inhibition of the migratory potential of glioma cells. The constitutive caspase-dependent motility of glioblastoma cells is independent of CD95 activation and it is not mediated by mitogen-activated protein/extracellular signal-regulated kinase kinase signaling. The basal caspase activity is accompanied by a constant cleavage of the motility-associated gelsolin protein, which may contribute to the caspase-mediated promotion of migration and invasiveness in glioblastoma cells. Our results suggest that the administration of low doses of caspase inhibitors that block glioma cell motility without affecting the execution of apoptotic cell death may be exploited as a novel strategy for the treatment of glioblastomas.
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PMID:Basal caspase activity promotes migration and invasiveness in glioblastoma cells. 1817 80

Apoptosis--programmed cell death--has been implicated in a variety of cardiac diseases, including myocardial infarction and chronic heart failure. This study was conducted to quantify the amount of apoptotic markers in human end-stage heart failure and to correlate the results to clinical parameters of heart failure. Myocardial samples from 44 patients with end-stage heart failure and 5 controls were collected at the time of heart transplantation. Lysates of tissue samples were analysed for cleavage of alpha actin, alpha actinin, troponin T, tropomyosin, essential myosin light chain-1 (MLC-1v), and gelsolin. We observed cleavage of alpha actin, and alpha actinin. Troponin I, tropomyosin, and MLC-1v were not detectably cleaved. The amount of active caspase-3 was low in all samples (1.10+/-0.1 ng/ml). The same applied for DNA histone fragments (0.61+/-0.04). In patients with acutely decompensated heart failure we observed a striking increase in caspase-3 activity, but not DNA fragmentation. When calculated for the entire group there was no correlation between caspase-3 activity, DNA fragmentation and haemodynamic or echocardiographic variables. Relevant increases in apoptosis were only observed in patients with acute decompensated heart failure.
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PMID:Quantitative analysis of apoptotic markers in human end-stage heart failure. 1827 68

Calpain activation is linked to the cleavage of several cytoskeletal proteins and could be an important contributor to the loss of cardiomyocytes and contractile dysfunction during cardiac pressure overload (PO). Using a feline right ventricular (RV) PO model, we analyzed calpain activation during the early compensatory period of cardiac hypertrophy. Calpain enrichment and its increased activity with a reduced calpastatin level were observed in 24- to 48-h-PO myocardium, and these changes returned to basal level by 1 wk of PO. Histochemical studies in 24-h-PO myocardium revealed the presence of TdT-mediated dUTP nick-end label (TUNEL)-positive cardiomyocytes, which exhibited enrichment of calpain and gelsolin. Biochemical studies showed an increase in histone H2B phosphorylation and cytoskeletal binding and cleavage of gelsolin, which indicate programmed cardiomyocyte cell death. To test whether calpain inhibition could prevent these changes, we administered calpeptin (0.6 mg/kg iv) by bolus injections twice, 15 min before and 6 h after induction of 24-h PO. Calpeptin blocked the following PO-induced changes: calpain enrichment and activation, decreased calpastatin level, caspase-3 activation, enrichment and cleavage of gelsolin, TUNEL staining, and histone H2B phosphorylation. Although similar administration of a caspase inhibitor, N-benzoylcarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VD-fmk), blocked caspase-3 activation, it did not alleviate other aforementioned changes. These results indicate that biochemical markers of cardiomyocyte cell death, such as sarcomeric disarray, gelsolin cleavage, and TUNEL-positive nuclei, are mediated, at least in part, by calpain and that calpeptin may serve as a potential therapeutic agent to prevent cardiomyocyte loss and preserve myocardial structure and function during cardiac hypertrophy.
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PMID:In vivo administration of calpeptin attenuates calpain activation and cardiomyocyte loss in pressure-overloaded feline myocardium. 1848 34

Members of the caspase family of cysteine proteases play central roles in coordinating the stereotypical events that occur during apoptosis. Because the major executioner caspases, caspase-3 and caspase-7, exhibit almost indistinguishable activity toward certain synthetic peptide substrates, this has led to the widespread view that these proteases occupy functionally redundant roles within the cell death machinery. However, the distinct phenotypes of mice deficient in either of these caspases, as well as mice deficient in both, is at odds with this view. These distinct phenotypes could be related to differences in the relative expression levels of caspase-3 and caspase-7 in vivo, or due to more fundamental differences between these proteases in terms of their ability to cleave natural substrates. Here we show that caspase-3 and caspase-7 exhibit differential activity toward multiple substrate proteins, including Bid, XIAP, gelsolin, caspase-6, and cochaperone p23. Caspase-3 was found to be generally more promiscuous than caspase-7 and appears to be the major executioner caspase during the demolition phase of apoptosis. Our observations provide a molecular basis for the different phenotypes seen in mice lacking either caspase and indicate that these proteases occupy nonredundant roles within the cell death machinery.
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PMID:Executioner caspase-3 and caspase-7 are functionally distinct proteases. 1872 80


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