Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is increasing evidence that a variety of natural substances derived from the diet may act as potent chemopreventive agents. In this work, we show that DAOY cells, a widely used model of metastatic medulloblastoma (MBL), are highly sensitive to sulforaphane, a naturally occurring isothiocyanate from Brassica vegetables. Sulforaphane induced DAOY cell death by apoptosis, as determined by DNA fragmentation and chromatin condensation. DAOY apoptosis correlates with the induction of caspase-3 and -9 activities, resulting in the cleavage of PARP and vimentin. Both the cytotoxic effect and apoptotic characteristics induced by sulforaphane were reversed by zVAD-fmk, a broad spectrum caspase inhibitor, demonstrating the important role of caspases in its cytotoxic effect. These results identify sulforaphane as a novel inducer of MBL cell apoptosis, supporting the potential clinical usefulness of diet-derived substances as chemopreventive agents.
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PMID:Induction of medulloblastoma cell apoptosis by sulforaphane, a dietary anticarcinogen from Brassica vegetables. 1467 Jun 15

Caspases are responsible for a cascade of events controlling the disassembly of apoptotic cells. We now demonstrate that caspase-9 is activated at an early stage of apoptosis in epithelial cells and all its detectable, catalytically active large subunits (both the p35 and p37) are concentrated on cytokeratin fibrils. Immunolabeling of distinctive neoepitopes, exposed by cleavage of procaspase-9 at either Asp315 or Asp330, was co-localized on these fibrils with active caspase-3, caspase-cleaved cytokeratin-18, death-effector-domain containing DNA-binding protein and ubiquitin. Cytokeratin filaments may thus provide a scaffold whereby active subunits of caspase-9 can activate caspase-3 which, in turn, can activate more caspase-9 so forming an amplification loop to facilitate cleavage of cytokeratin-18, disruption of the cytoskeleton and the ensuing formation of cytoplasmic inclusions. These inclusions, formed from the collapse of fibrils, together with their associated components, also contain ubiquitinated proteins, vimentin, heat-shock protein 72, and tumor necrosis factor receptor type-1-associated death domain protein. Many of their constituents, including active caspases, remain sequestered within these inclusions, even after detergent treatment and isolation. Thus, such inclusions do not merely accumulate disrupted cytokeratins but also sequestrate potentially noxious proteins that could injure healthy neighboring cells.
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PMID:Intermediate filaments control the intracellular distribution of caspases during apoptosis. 1474 46

Precision-cut rat lung slices have been employed in combination with an extensive immunohistochemistry of paraffin-embedded slices for monitoring of early pathohistological changes after exposure to CdCl(2)/TGF-beta(1). Three days of CdCl(2) exposure in combination with TGF-beta(1) seem to be sufficient to induce lung injury with alterations similar to changes observed in early lung fibrogenesis: (1) extracellular matrix accumulation and myofibroblast transdifferentiation (Sirius red staining, collagen type IV, alpha-smooth muscle actin), (2) type I cell injury with loss of type I cell antigens (T1alpha antigen, aquaporin-5, RAGE), (3) increased apoptosis of pulmonary cells (active caspase-3, vimentin cleavage product V1 of caspase-9), and (4) activation of microvascular endothelial cells (podocalyxin, caveolin-1). Western blot analysis confirmed the increasing amount of alpha-smooth muscle actin, the loss of T1alpha antigen, and the increase in caveolin-1 immunoreactivity. The explant culture using CdCl(2)/TGF-beta(1) provides a suitable tool for the study of other factors involved in pulmonary pathology including transcription factors, cytokines, and other metabolites involved in early stages of fibrogenesis.
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PMID:Early signs of lung fibrosis after in vitro treatment of rat lung slices with CdCl2 and TGF-beta1. 1475 65

Interleukin-15 (IL-15) induces the de novo protein synthesis of intracellular polypeptides and delays neutrophil apoptosis by a mechanism that is still unclear. Herein, we investigated the potential antiapoptotic role of newly synthesized proteins released into the external milieu in IL-15-induced neutrophils. We found that IL-15 induces the de novo synthesis of an approximately 23-kDa protein, representing the predominant protein detected in the milieu, and identified it as IL-1 receptor antagonist (IL-1Ra) by Western blot and immunoprecipitation. We quantified IL-1Ra, IL-1alpha, and IL-1beta concentrations by enzyme-linked immunosorbent assay in intracellular and extracellular fractions from IL-15-induced neutrophils and found that IL-15 does not increase IL-1alpha or IL-1beta production but induces IL-1Ra release. Also, we demonstrated that IL-1Ra does not modulate apoptosis, even at a concentration 250 times greater than that measured in the external milieu. In contrast to granulocyte macrophage-colony stimulating factor, the supernatant harvested from IL-15-induced neutrophils was devoid of antiapoptotic activity. Addition of cycloheximide demonstrates that IL-15 delays apoptosis via de novo synthesis of intracellular proteins and that it increases myeloid cell differentiation factor-1 stability. We demonstrated also that IL-15 decreases the activity of caspase-3 and caspase-8, resulting in an inhibition of vimentin cleavage. Our results indicate that IL-15 can activate an anti-inflammatory loop, based on its ability to induce the synthesis of IL-1Ra by neutrophils. We conclude that IL-15 delays human neutrophil apoptosis by intracellular events and not via extracellular factors.
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PMID:Interleukin-15 delays human neutrophil apoptosis by intracellular events and not via extracellular factors: role of Mcl-1 and decreased activity of caspase-3 and caspase-8. 1498 47

Diabetics suffer from both more frequent bacterial infections and greater consequences of infection. However, bacteria-induced tissue destruction and the subsequent response in diabetics have received relatively little attention. To investigate this issue, we inoculated the scalp of control or db/db diabetic mice, with the pathogen Porphyromonas gingivalis, which causes connective tissue destruction in humans. Both bacteria-induced cytokine expression and tissue loss were similar in diabetic and control mice. However, there was a significantly higher rate of fibroblast-specific apoptosis in the diabetic group, which was measured as cells that were double positive for the terminal deoxynucleotidyltransferase-mediated deoxy-UTP nick end labeling assay and expression of vimentin. The higher rate of fibroblast apoptosis could be explained in the diabetic group by enhanced levels of activated caspase-3. Apoptosis was evident during the peak healing period and coincided with reduced numbers of fibroblasts, diminished collagen I and III expression, and significantly reduced formation of new connective tissue matrix in diabetic mice. Thus, diabetes may impair the healing response to bacteria-induced connective tissue loss by increasing the number of caspase-3-activated fibroblasts, leading to greater apoptosis and reduced numbers of fibroblastic cells.
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PMID:Diabetes alters the response to bacteria by enhancing fibroblast apoptosis. 1503 11

Oxygen free radicals and nitric oxide (NO) participate in the pathogenesis of acute central nervous system (CNS) injury by forming peroxynitrite, which promotes oxidative damage and tyrosine nitration. Neuronal nitration is associated with cell death, but little is known of the characteristics and cell fate of nitrated astrocytes. In this study, we have used a postnatal excitotoxic lesion model (intracortical NMDA injection) and our aims were (i) to evaluate the temporal and spatial pattern of astroglial nitration in correlation with the neuropathological process and the sources of NO; and (ii) to establish, if any, the correlation among astrocyte nitration and other events such as expression of cytoskeletal proteins, antioxidant enzymes, and cell death markers to cope with nitration and/or undergo cell death. Our results show that after postnatal excitotoxic damage two distinct waves of nitration were observed in relation to astrocytes. At 24 h post-lesion, early-nitrated astrocytes were found within the neurodegenerating area, coinciding with the time of maximal cell death. These early-nitrated astrocytes are highly ramified protoplasmic cells, showing diffuse glial fibrillary acidic protein (GFAP) content and expressing inducible NOS. At later time-points, when astrogliosis is morphologically evident, nitrated hypertrophied reactive astrocytes are observed in the penumbra and the neurodegenerated area, displaying increased expression of GFAP and vimentin cytoskeletal proteins and of metallothionein I-II and Cu/Zn superoxide dismutase antioxidant proteins. Moreover, despite revealing activated caspase-3, they do not show TUNEL labeling. In summary, we show that nitrated astrocytes in vivo constitute a subpopulation of highly reactive astrocytes which display high resistance towards oxidative stress induced cell death.
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PMID:Astroglial nitration after postnatal excitotoxic damage: correlation with nitric oxide sources, cytoskeletal, apoptotic and antioxidant proteins. 1566 12

Accumulation of cytoplasmic inclusion bodies in many neurodegenerative diseases, including Alzheimer's disease (AD), might result from dysfunction of the ubiquitin-proteasome system. This system degrades many cellular proteins, including beta-catenin, a member of the Wnt signaling pathway, and a presenilin-1-interacting protein. Phosphorylation of beta-catenin marks it for ubiquitination and rapid proteasomal degradation. We found phospho-beta-catenin accumulated as detergent-insoluble, punctate, cytoplasmic inclusions in hippocampal pyramidal neurons more abundantly in AD than in aged controls. In AD, beta-catenin was ubiquitin conjugated, thus suggesting impaired proteasome-dependent degradation. Phospho-beta-catenin was partially sequestered within granulovacuolar degeneration bodies but not in lysosomes, indicating sequestration within autophagosomes. Exposure of neuronal cultures to proteasome inhibitors induced formation of detergent-insoluble, phospho-beta-catenin-positive cytoplasmic inclusions that coalesced into aggresomes and colocalized with gamma-tubulin and vimentin. These aggregates were associated with apoptotic cell death and with activation of caspase-3, c-Jun-N-terminal kinases, and c-Jun. These findings suggest that phospho-beta-catenin accumulation in AD might result from impaired proteasome function.
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PMID:Phospho-beta-catenin accumulation in Alzheimer's disease and in aggresomes attributable to proteasome dysfunction. 1578 69

Membrane-type 1 matrix metalloproteinase (MT1-MMP) has been suggested to play an essential role in angiogenesis. Based on recent evidence suggesting that the sprouting and branching of capillaries during angiogenesis involves apoptosis, we investigated the involvement of this process in MT1-MMP-dependent morphogenic differentiation of EC into capillary-like structures. We found that MT1-MMP sensitizes EC to apoptosis, since reduction of MT1-MMP expression abolished vimentin fragmentation in apoptotic HUVECs while overexpression of the enzyme induced caspase-3 activity in BAECs subjected to pro-apoptotic treatments. MT1-MMP-mediated caspase-3 activation likely occurs through the mitochondrial pathway since it was abrogated by Bcl-2, but not by CrmA overexpression. Reduction of MT1-MMP expression in HUVECs reduced morphogenic differentiation that was correlated with diminished vimentin fragmentation, whereas its overexpression in BAECs stimulated both processes. Inactivation of the catalytic activity or removal of the cytoplasmic domain of MT1-MMP markedly reduced its ability to induce both morphogenic differentiation and caspase-3 activation. The inhibitory effects of the anti-apoptotic protein Bcl-2 and the caspase inhibitor zVAD-fmk further suggested the involvement of apoptosis during MT1-MMP-mediated morphogenic differentiation. Our results show that the ability of MT1-MMP to induce EC morphogenic differentiation involves its activation of a caspase-dependent mechanism.
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PMID:Membrane type 1-matrix metalloproteinase induces endothelial cell morphogenic differentiation by a caspase-dependent mechanism. 1588 63

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

Vimentin is an intermediate filament that regulates cell attachment and subcellular organization. In this study, vimentin filaments were morphologically altered, and its soluble subunits were rapidly reduced via cadmium chloride treatment. Cadmium chloride stimulated three major mitogen-activated protein kinases (MAPKs): extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, and led apoptotic pathway via caspase-9 and caspase-3 activations. In order to determine whether MAPKs were involved in this cadmium-induced soluble vimentin disappearance, we applied MAPK-specific inhibitors (PD98059, SP600125, SB203580). These inhibitors did not abolish the cadmium-induced soluble vimentin disappearance. Caspase and proteosome degradation pathway were also not involved in soluble vimentin disappearance. When we observed vimentin levels in soluble and insoluble fractions, soluble vimentin subunits shifted to an insoluble fraction. As we discovered that heat-shock protein 27 (HSP27) was colocalized and physically associated with vimentin in unstressed cells, the roles of HSP27 with regard to vimentin were assessed. HSP27-overexpressing cells prevented morphological alterations of the vimentin filaments, as well as reductions of soluble vimentin, in the cadmium-treated cells. Moreover, HSP27 antisense oligonucleotide augmented these cadmium-induced changes in vimentin. These findings indicate that HSP27 prevents disruption of the vimentin intermediate filament networks and soluble vimentin disappearance, by virtue of its physical interaction with vimentin in cadmium-treated SK-N-SH cells.
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PMID:Heat shock protein 27 interacts with vimentin and prevents insolubilization of vimentin subunits induced by cadmium. 1626 67


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