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)

Exposure of pancreatic beta-cells to cytokines, such as interleukin-1beta (IL-1beta), is thought to contribute to the beta-cell apoptosis that underlies the onset of type 1 diabetes. One important event triggered by IL-1beta is induction of nitric oxide synthase (iNOS), an enzyme that catalyzes intracellular generation of the cytotoxic free radical NO. We recently described a novel requirement for the protein kinase C (PKC) isozyme PKCdelta in this process. Our current aim, therefore, was to assess whether PKCdelta also plays a role in beta-cell apoptosis. As assessed by either annexin V staining or DNA fragmentation, IL-1beta caused INS-1 cells to undergo apoptosis. This was completely blocked by adenoviral overexpression of a dominant-negative, kinase-dead (KD) PKCdelta mutant. The corresponding PKCalpha virus was without effect. However, apoptosis caused by the cytotoxic agent streptozotocin (STZ), which acts independent of iNOS, was also inhibited by overexpression of PKCdeltaKD. STZ was additionally shown to activate the proteolytic enzyme caspase-3, a key biochemical effector of end-stage apoptosis. Moreover, STZ caused a caspase-dependent cleavage of PKCdelta, thereby releasing a COOH-terminal fragment corresponding to the kinase catalytic domain. Thus, proteolytic activation of PKCdelta seems to be important in the distal apoptotic pathway induced by STZ. That IL-1beta also activated caspase-3 and promoted PKCdelta cleavage suggests that this distal pathway also contributes in the apoptotic response to the cytokine. These data therefore support a dual role for PKCdelta in IL-1beta-mediated cell death: it is required for efficient NO generation through regulation of iNOS levels but also contributes to apoptotic pathways downstream of caspase activation.
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PMID:Inhibition of protein kinase C delta protects rat INS-1 cells against interleukin-1beta and streptozotocin-induced apoptosis. 1181 38

To examine whether the tumor microenvironment alters cytokine-induced cytotoxicity, human prostate adenocarcinoma DU-145 cells were exposed to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or glucose deprivation, a common characteristic of the tumor microenvironment. TRAIL alone reduced cell survival in a dose-dependent manner. Glucose deprivation alone induced no cytotoxicity within 4 h. However, the combination of TRAIL (50 ng/ml) and glucose deprivation for 4 h increased cell death and PARP cleavage by promoting activation of caspase-8 and caspase-3, relative to that of TRAIL alone. Similar results were observed in human colorectal carcinoma CX-1 cells. Data from immunoblotting analysis reveal that glucose deprivation-enhanced TRAIL cytotoxicity is inversely related to the intracellular level of FLICE inhibitory protein (FLIP) but not that of death receptor 5 (DR5). Results from mass spectrometry show that glucose deprivation elevates ceramide. The elevation of ceramide may cause dephosphorylation of Akt and maintain dephosphorylation of Akt in the presence of TRAIL and then subsequently down-regulate the expression of FLIP. Taken together, the present studies suggest that glucose deprivation enhances TRAIL-induced cytotoxicity through the ceramide-Akt-FLIP pathway.
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PMID:Low glucose-enhanced TRAIL cytotoxicity is mediated through the ceramide-Akt-FLIP pathway. 1182 46

Acute administration of cadmium results in hepatotoxicity. Recent reports indicate that Kupffer cells, the resident macrophages of the liver, participate in the manifestation of chemical-induced hepatotoxicity. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that is a major product of Kupffer cells and mediates the hepatotoxic effects of lipopolysaccharide (LPS). It has been speculated that cadmium also may exert its hepatotoxicity via the production of TNF-alpha by the Kupffer cells. Therefore, this study was undertaken to determine whether mice deficient in TNF-alpha are resistant to Cd-induced hepatotoxicity. TNF-alpha-null (TNF-KO) and wild-type (WT) mice were dosed ip with saline, LPS (0.1 mg/kg)/Gln (d-galactosamine, 700 mg/kg), or CdCl2 (2.2, 2.8, 3.4, and 3.9 mg Cd/kg). Serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities were quantified to assess liver injury. Caspase-3 activity was quantified to assess hepatocellular apoptosis. LPS/Gln treatment increased ALT (17-fold) and SDH (21-fold) in WT mice. In contrast, LPS/Gln-treatment did not significantly increase ALT or SDH in TNF-KO mice. LPS/Gln-treatment caused a 7.8-fold increase in caspase-3 activity in WT mice but did not increase caspase-3 in TNF-KO mice. Cadmium caused a dose-dependent increase in liver injury in both WT and TNF-KO mice. However, the liver injury produced by Cd in the TNF-KO mice was not different from that in WT at any dose. No significant increase in caspase-3 activity was detected in any of the Cd-treated mice. These data indicate that, in contrast to LPS/Gln-induced hepatotoxicity, TNF-alpha does not appear to mediate Cd-induced hepatotoxicity.
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PMID:Tumor necrosis factor-alpha-null mice are not resistant to cadmium chloride-induced hepatotoxicity. 1190 45

The involvement of p53, Bax, cytochrome C and CPP-32 (caspase-3) in the molecular mechanism ofTGF-beta1-induced apoptosis in HC11 mouse mammary epithelial cells (MEC) was examined. Laser scanning cytometry (LSC) was applied for the quantitative analysis of expression and distribution of examined apoptosis-related proteins in the cytoplasmic (Cf) and nuclear (Nf) area. Maximal pixel of fluorescence (MP) parameter corresponding to aggregation of molecules in the cell was also measured. Confocal and immunoelectron microscopy were used as a complementary methods. Apoptosis induced by TGF-beta1 (2 ng/ml) was associated with the increase of Bax MP observed within 60 min. after cytokine administration, indicating aggregation of Bax in the cell. Immunoelectron microscopy revealed Bax aggregation on mitochondrial membranes, rough endoplasmic reticulum, Golgi apparatus, cytoskeleton, nuclear envelope and inside of nucleus. The accumulation of Bax in the nucleus was confirmed by compartmental Bax analysis, showing the increase of cell number with elevated Bax Nf in 2 hr after TGF-beta1 administration to the culture. The redistribution of Bax within the cell was dependent on its activation occurring by the cleavage at N-terminal epitope and exposure of BH3 domain. Bax aggregation on organelles was completely abolished by prolactin or IGF-I. TGF-beta1 increased p53 MP, evidently after 4 hr of cell culture exposure to this cytokine. p53 was accumulated first of all in the nucleus, which was shown by significant increase of p53 Nf/Cf ratio and increase of p53-related nuclear fluorescence on confocal images. TGF-beta1 decreased cytochrome C MP, which corresponded to its release from mitochondria and dissipation in the cytosol. It was accompanied by the increase of CPP-32 MP and concentration of 89 kDa product of PARP degradation in the nucleus. In conclusion, TGF-beta1 triggers apoptosis in MEC through mitochondrial pathway involving: activation and translocation of Bax to mitochondrial membranes, release of cytochrome C from mitochondria, activation of CPP-32 and degradation of its substrate - PARP in the nucleus. Activation and subcellular redistribution of Bax is inhibited by lactogenic hormones: prolactin and IGF-I.
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PMID:Molecular mechanism of TGF-beta1-induced apoptosis in HC11 mouse mammary epithelial cells (MEC). 1193 68

The activation of the extracellular signal-regulated kinases (ERKs) by tumour necrosis factor-alpha (TNF) receptors (TNFRs) is an integral part of the cytokine's pleiotropic cellular responses. Here we report differences in the caspase sensitivity and TNFR subtype activation of members of the ERK family. Inhibition in HeLa cells of caspase function by pharmacological inhibitors or the expression of CrmA (cytokine response modifier A), a viral modifier protein, blocks TNF-induced apoptosis or caspase-dependent protein kinase Cdelta and poly(ADP-ribose) polymerase protein degradation. TNFR1- or TNFR2-stimulated c-Jun N-terminal kinase (JNK) activity was attenuated in cells in which caspase activity was inhibited either by pharmacological blockers or CrmA expression. Both TNFR1- and TNFR2-stimulated JNK activity was caspase-sensitive; however, only TNFR1 was capable of stimulating p42/44 mitogen-activated protein kinase (MAPK) and p38 MAPK activities. TNFR1-stimulated p42/44 MAPK and p38 MAPK activities were insensitive to pharmacological caspase inhibition or CrmA. These findings were supported when measuring TNF-induced cytosolic phospholipase A(2) activation, which is a downstream target for MAPK and p38 MAPK. Profiling caspase enzymes activated by TNF in HeLa cells showed sequential caspase-8, -3, -7, -6 and -9 activation, with their inhibition characteristics suggesting a role for caspase-3 and/or caspase-6 in modulating JNK activity. Taken together these results show delineated ERK-activation pathways employed by TNFR subtypes.
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PMID:Tumour necrosis factor-induced activation of c-Jun N-terminal kinase is sensitive to caspase-dependent modulation while activation of mitogen-activated protein kinase (MAPK) or p38 MAPK is not. 1199 67

Caspase-1 is responsible for processing inflammatory cytokines and is associated with the induction of apoptosis. Using RT-PCR, we found that caspase-1 mRNA transcripts from frozen brain extracts were significantly elevated in multiple sclerosis (MS) compared to controls. Immunohistochemical staining using a specific antiserum confirmed the marked up regulation of caspase-1 within acute and chronic MS plaques, while little staining was seen in control brains. In addition to the expected caspase-1 expression in microglia and infiltrating perivascular mononuclear cells, we found that cytoplasmic caspase-1 expression was sharply increased in the resident oligodendrocytes of MS lesions. The TUNEL reaction for fragmented DNA co-localized over an occasional caspase-1-expressing cell and large numbers of caspase-1-positive "corpses" were observed within phagocytic macrophages of an acute evolving MS lesion. Studies using an immortalized human oligodendroglial hybrid cell line exposed to cytokine challenge showed that death induction was blocked by the caspase-1-like inhibitor Z-YVAD-fmk, while the caspase-3-like inhibitor Z-DEVD-fmk was less effective. Cellular levels of procaspase-1 were reduced compared to controls in oligodendroglia induced to die by cytokine challenge, as judged by Western immunoblotting. Our results suggest that caspase-1 may play a role in the inflammatory and apoptotic processes associated with MS pathogenesis.
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PMID:Caspase-1 expression in multiple sclerosis plaques and cultured glial cells. 1199 61

Endothelial monocyte-activating polypeptide (EMAP) II is a unique cytokine, also known as p43, the active mature form of which exhibits antiangiogenic properties in vivo and in vitro. The proteolytic enzymes associated with the cleavage and release of the active mature form, however, remain unclear. Here we show that, in contrast to prior observations, purified pro-EMAP II is not cleaved by either caspase-3 or -7 in vivo or in vitro. Thus other proteolytic processes, which allow it to induce apoptosis via caspase-3 activation in migrating and dividing endothelium, may be involved in the release of the active mature EMAP II.
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PMID:Pro-EMAP II is not primarily cleaved by caspase-3 and -7. 1200 79

In addition to direct bactericidal activities, such as phagocytosis and generation of reactive oxygen species (ROS), neutrophils can regulate the inflammatory response by undergoing apoptosis. We found that infection of human neutrophils with Mycobacterium tuberculosis (Mtb) induced rapid cell death displaying the characteristic features of apoptosis such as morphologic changes, phosphatidylserine exposure, and DNA fragmentation. Both a virulent (H37Rv) and an attenuated (H37Ra) strain of Mtb were equally effective in inducing apoptosis. Pretreatment of neutrophils with antioxidants or an inhibitor of NADPH oxidase markedly blocked Mtb-induced apoptosis but did not affect spontaneous apoptosis. Activation of caspase-3 was evident in neutrophils undergoing spontaneous apoptosis, but it was markedly augmented and accelerated during Mtb-induced apoptosis. The Mtb-induced apoptosis was associated with a speedy and transient increase in expression of Bax protein, a proapoptotic member of the Bcl-2 family, and a more prominent reduction in expression of the antiapoptotic protein Bcl-x(L). Pretreatment with an inhibitor of NADPH oxidase distinctly suppressed the Mtb-stimulated activation of caspase-3 and alteration of Bax/Bcl-x(L) expression in neutrophils. These results indicate that infection with Mtb causes ROS-dependent alteration of Bax/Bcl-x(L) expression and activation of caspase-3, and thereby induces apoptosis in human neutrophils. Moreover, we found that phagocytosis of Mtb-induced apoptotic neutrophils markedly increased the production of proinflammatory cytokine TNF-alpha by human macrophages. Therefore, the ROS-dependent apoptosis in Mtb-stimulated neutrophils may represent an important host defense mechanism aimed at selective removal of infected cells at the inflamed site, which in turn aids the functional activities of local macrophages.
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PMID:Mycobacterium tuberculosis promotes apoptosis in human neutrophils by activating caspase-3 and altering expression of Bax/Bcl-xL via an oxygen-dependent pathway. 1205 53

Among the several changes that occur in the aged brain is an increase in the concentration of the proinflammatory cytokine interleukin-1beta that is coupled with a deterioration in cell function. This study investigated the possibility that treatment with the polyunsaturated fatty acid eicosapentaenoic acid might prevent interleukin-1beta-induced deterioration in neuronal function. Assessment of four markers of apoptotic cell death, cytochrome c translocation, caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and terminal dUTP nick-end staining, revealed an age-related increase in each of these measures, and the evidence presented indicates that treatment of aged rats with eicosapentaenoate reversed these changes as well as the accompanying increases in interleukin-1beta concentration and p38 activation. The data are consistent with the idea that activation of p38 plays a significant role in inducing the changes described since interleukin-1beta-induced activation of cytochrome c translocation and caspase-3 activation in cortical tissue in vitro were reversed by the p38 inhibitor SB203580. The age-related increases in interleukin-1beta concentration and p38 activation in cortex were mirrored by similar changes in hippocampus. These changes were coupled with an age-related deficit in long term potentiation in perforant path-granule cell synapses, while eicosapentaenoate treatment was associated with reversal of age-related changes in interleukin-1beta and p38 and with restoration of long term potentiation.
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PMID:Apoptotic changes in the aged brain are triggered by interleukin-1beta-induced activation of p38 and reversed by treatment with eicosapentaenoic acid. 1209 94

All human melanoma cell lines (assessed by annexin V and TUNEL assays) were resistant to apoptosis induction by TRAIL/Apo2L protein. TRAIL/Apo2L activated caspase-8 and caspase-3, but subsequent apoptotic events such as poly(ADP-ribose) polymerase cleavage and DNA fragmentation were not observed. To probe the molecular mechanisms of cellular resistance to apoptosis, melanoma cell lines were analyzed for expression of apoptosis regulators (apoptotic protease-associated factor-1, FLIP, caspase-8, caspase-9, caspase-3, cellular inhibitor of apoptosis, Bcl-2, or Bax); no correlation was observed. TRAIL/Apo2L was induced in melanoma cell lines by IFN-beta and had been correlated with apoptosis induction. Because IFN-beta induced other gene products that have been associated with apoptosis, it was postulated that one or more IFN-stimulated genes might sensitize cells to TRAIL/Apo2L. Melanoma cell lines were treated with IFN-beta for 16-24 h before treatment with TRAIL/Apo2L. Regardless of their sensitivity to either cytokine alone, >30% of cells underwent apoptosis in response to the combined treatment. Induction of apoptosis by IFN-beta and TRAIL/Apo2L in combination correlated with synergistic activation of caspase-9, a decrease in mitochondrial potential, and cleavage of poly(ADP-ribose) polymerase. Cleavage of X-linked inhibitor of apoptosis following IFN-beta and TRAIL/Apo2L treatment was observed in sensitive WM9, A375, or WM3211 cells but not in resistant WM35 or WM164 cells. Thus, in vitro IFN-beta and TRAIL/Apo2L combination treatment had more potent apoptotic and anti-growth effects when compared with either cytokine alone in melanoma cells lines.
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PMID:IFN-beta pretreatment sensitizes human melanoma cells to TRAIL/Apo2 ligand-induced apoptosis. 1209 88


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