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)

The B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a potent immunomodulatory molecule capable of treating and preventing autoimmune disease. These properties result from its ability to bind to glycolipid receptors, principally G(M1) ganglioside, and modulate immune cell function. EtxB receptor binding causes B cell activation, modulates monocyte cytokine secretion and triggers apoptosis of CD8+ T cells. These wide-ranging effects suggest that B subunit receptor interaction triggers signaling events affecting cellular differentiation. We have investigated the processes by which EtxB induces CD8+ T cell apoptosis. We show that receptor interaction by EtxB activates caspase-3 in CD8+ but not in CD4+ T cells. Inhibition of caspase-3 blocks the apoptotic process. EtxB induces the activation of NF-kappaB in both CD8+ and CD4+ T cells. The findings that (i) SN50, a peptide inhibitor of NF-kappaB nuclear translocation, prevents caspase-3 activation and subsequent apoptosis, and (ii) CD8+CD4- thymocytes from transgenic mice expressing a dominant-negative form of the IkappaBalpha protein were markedly less susceptible to EtxB-induced apoptosis than cells from wild-type mice, indicate that NF-kappaB is important in the induction of the apoptotic pathway. Further investigations revealed that while caspase-8 activity is detected concomitant to caspase-3, caspase-9 activation, following mitochondrial cytochrome c release, is detectable later on. These observations are consistent with death receptor-mediated signaling, however, experiments using lpr/lpr and p55 TNFR -/- mice rule out the involvement of Fas and the p55 TNF receptor, respectively. The data therefore indicate that EtxB-mediated apoptosis occurs via a novel pathway involving NF-kappaB.
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PMID:CD8+ T cell apoptosis induced by Escherichia coli heat-labile enterotoxin B subunit occurs via a novel pathway involving NF-kappaB-dependent caspase activation. 1211 57

Inhaled nitric oxide (iNO) is used clinically to treat pulmonary hypertension in newborns, often in conjunction with hyperoxia (NO/O2). Prolonged exposure to NO/O2 causes synergistic lung injury and death of lung epithelial cells. To explore the mechanisms involved, oxygen-resistant HeLa-80 cells were exposed to NO +/- O2. Exposure to NO and O2 induced a synergistic cytotoxicity, accompanied with apoptotic characteristics, including elevated caspase-3-like activity, Annexin V incorporation, and nuclear condensation. This apoptosis was associated with a synergistic suppression of NF-kappaB activity. Cells lacking functional NF-kappaB p65 subunit were more sensitive to NO/O2 than their wild type counterparts. This injury was partially rescued by transfection with a p65 expression construct, suggesting an inverse relationship between NF-kappaB and susceptibility to the cytotoxicity of NO/O2. Despite the reduced NF-kappaB activity in cells exposed to NO +/- O2, IkappaBalpha was degraded, suggesting that pathways regulating the steady-state levels of IkappaB were not involved. However, exposure to NO/O2 caused a marked reduction in nuclear localization and an increase in protein carbonyl formation of NF-kappaB p65 subunit. These results suggest that NO/O2-induced apoptosis occurs by suppressing NF-kappaB activity.
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PMID:Suppression of nuclear factor-kappa B activity by nitric oxide and hyperoxia in oxygen-resistant cells. 1221 28

TNF family receptors can lead to the activation of NF-kappaB and this can be a prosurvival signal in some cells. Although activation of NF-kappaB by ligation of Fas (CD95/Apo-1), a member of the TNFR family, has been observed in a few studies, Fas-mediated NF-kappaB activation has not previously been shown to protect cells from apoptosis. We examined the Fas-induced NF-kappaB activation and its antiapoptotic effects in a leukemic eosinophil cell line, AML14.3D10, an AML14 subline resistant to Fas-mediated apoptosis. EMSA and supershift assays showed that agonist anti-Fas (CH11) induced nuclear translocation of NF-kappaB heterodimer p65(RelA)/p50 in these cells in both a time- and dose-dependent fashion. The influence of NF-kappaB on the induction of apoptosis was studied using pharmacological proteasome inhibitors and an inhibitor of IkappaBalpha phosphorylation to block IkappaBalpha dissociation and degradation. These inhibitors at least partially inhibited NF-kappaB activation and augmented CH11-induced cell death. Stable transfection and overexpression of IkappaBalpha in 3D10 cells inhibited CH11-induced NF-kappaB activation and completely abrogated Fas resistance. Increases in caspase-8 and caspase-3 cleavage induced by CH11 and in consequent apoptotic killing were observed in these cells. Furthermore, while Fas-stimulation of resistant control 3D10 cells led to increases in the antiapoptotic proteins cellular inhibitor of apoptosis protein-1 and X-linked inhibitor of apoptosis protein, Fas-induced apoptosis in IkappaBalpha-overexpressing cells led to the down-modulation of both of these proteins, as well as that of the Bcl-2 family protein, Bcl-x(L). These data suggest that the resistance of these leukemic eosinophils to Fas-mediated killing is due to induced NF-kappaB activation.
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PMID:Fas resistance of leukemic eosinophils is due to activation of NF-kappa B by Fas ligation. 1224 43

Neutrophils are among the first circulating leukocytes involved in acute inflammatory processes. Transcription factor NF-kappaB plays a key role in the inflammatory response, regulating the expression of proinflammatory and anti-apoptotic genes. Recently we have shown that human neutrophils contain a significant amount of NF-kappaB inhibitor, IkappaBalpha, in the nucleus of unstimulated cells. The present objective was to examine the mechanisms controlling the nuclear content of IkappaBalpha in human neutrophils and to determine whether increased accumulation of IkappaBalpha in the nucleus is associated with increased neutrophil apoptosis. We show for the first time that neutrophil stimulation with pro-inflammatory signals results in degradation of IkappaBalpha that occurs in both cytoplasm and nucleus. Prolonged (2-h) stimulation with TNF and LPS induces resynthesis of IkappaBalpha that is again translocated to the nucleus in human neutrophils, but not in monocytic cells. Leptomycin B, a specific inhibitor of nuclear export, increases nuclear accumulation of IkappaBalpha in stimulated neutrophils by blocking the IkappaBalpha nuclear export, and this is associated with inhibition of NF-kappaB activity, induction of caspase-3 activation, and apoptosis. Based on our data we present a new model of NF-kappaB regulation in human neutrophils by nuclear IkappaBalpha. Our results demonstrate that the NF-kappaB activity in human neutrophils is regulated by mechanisms clearly different from those in monocytes and other human cells and suggest that the increased nuclear content of IkappaBalpha in human neutrophils might represent one of the underlying mechanisms for the increased apoptosis in these cells.
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PMID:NF-kappa B regulation in human neutrophils by nuclear I kappa B alpha: correlation to apoptosis. 1224 95

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a wide range of malignant cells. However, several cancers, including human hepatoma, are resistant to TRAIL. In this study, we analyzed TRAIL-induced pro- and antiapoptotic signaling pathways in human hepatoma cells. Nuclear factor kappa B (NF-kappaB) was found to be a critical TRAIL-induced antiapoptotic factor in the PLC/PRF/5, HepG2, and Hep3B cell lines. TRAIL-induced NF-kappaB activation was preceded by IkappaBalpha kinase (IKK) activation and IkappaBalpha degradation and depended on TRAF2, NF-kappaB-inducing kinase (NIK), IKK1, and IKK2. Accordingly, inhibition of NF-kappaB by adenoviral dominant negative (dn) TRAF2, NIKdn, IKK1dn, IKK2dn, or IkappaBsr sensitized PLC/PRF/5 cells to rhTRAIL, resulting in 40% to 50% cell death after 48 hours as compared with <10% with rhTRAIL alone. Agonistic anti-TRAIL receptor 1 and anti-TRAIL receptor 2 antibodies or combinations of both were equally efficient in inducing apoptosis as rhTRAIL, indicating that decoy receptors did not contribute to resistance toward TRAIL under the conditions of our study. TRAIL-mediated apoptosis depended on FADD, caspase 8 and 3 as demonstrated by the ability of FADDdn, CrmA, and pharmacologic caspase inhibitors to prevent apoptosis. Confocal microscopy showed the onset of the mitochondrial permeability transition (MPT) 5 hours after rhTRAIL plus actinomycin D, which was followed by cytochrome c release. The MPT was critical for TRAIL-induced apoptosis as demonstrated by the ability of pharmacologic MPT inhibitors to completely protect PLC/PRF/5 cells. In conclusion, NF-kappaB prevents TRAIL-induced apoptosis in human hepatoma through a TRAIL-activated TRAF2-NIK-IKK pathway. Inhibition of NF-kappaB unmasks a TRAIL-induced apoptotic signaling cascade that involves FADD, caspase 8, the MPT, and caspase 3.
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PMID:TRAIL-mediated apoptosis requires NF-kappaB inhibition and the mitochondrial permeability transition in human hepatoma cells. 1244 76

Tumour necrosis factor-alpha (TNF) is capable of activating many downstream signaling molecules via its two receptors TNFR1 and TNFR2. TNF can stimulate the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) as well as the stress induced kinase c-Jun N-terminal kinase (JNK) through mechanisms that are not fully delineated. NF-kappaB becomes activated mainly through TNFR1 while JNK can be stimulated by either TNF receptor subtype. TNF can also induce apoptosis within cells due to its ability to recruit procaspase-8 to TNFR1, which in turn induces the caspase proteolytic cascade. We provide evidence here in human cells, that TNF-induced JNK activation is under the influence of caspases while NF-kappaB activity is not. By using pharmacological inhibitors of caspases, we have shown that JNK activity is reduced following caspase inhibition, especially when caspase-3 is targeted. NF-kappaB activity, as assessed by IkappaBalpha or IkappaBbeta degradation, electrophoretic mobility shift assay and NF-kappaB gene reporter assays, is shown to be unaffected by caspase inhibition. Therefore, downstream TNF receptor signaling events are differentially influenced by caspases.
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PMID:Modulation by caspases of tumor necrosis factor-stimulated c-Jun N-terminal kinase activation but not nuclear factor-kappaB signaling. 1247 83

Tumor necrosis factor-alpha (TNFalpha) induces apoptosis in hepatocytes only under transcriptional arrest induced by galactosamine (GalN). In this study we demonstrated the shuttle of the transcription factor NFkappaB (nuclear factor-kappa B) in the liver tissue of mice within 30 min-4.5 hr hours after GalN/TNFalpha treatment. NFkappaB translocation from cytoplasm to the nucleus is initiated by its separation from the inhibitory IkappaB proteins which include IkappaBalpha, IkappaBbeta, and IkappaB. Thirty minutes after GalN/TNFalpha administration, NFkappaBp65 in hepatocellular nuclei becomes increasingly detectable and reaches its highest level after 2.5 hr. Then export back into cytoplasm begins but, surprisingly, approximately 30% of NFkappaB remains in the nuclear fraction and appears as an immunoprecipitate in the nuclei of apoptotic hepatocytes. Non-apoptotic hepatocytes do not show any reaction product in the nuclei 4.5 hr after treatment. Correspondingly, the amount of dissociated IkappaBbeta decreases in the cytoplasm up to 2.5 hr and increases again afterwards, although it does not reach the level of the control samples. No evidence of IkappaBbeta in the nuclei was found either immunocytochemically or biochemically. Caspase-3 activity, which is responsible for apoptosis, increases significantly after 3.5 hr. At that time, apoptotic hepatocytes can occasionally be observed and, 4.5 hr after GalN/TNFalpha treatment, constitute approximately 30% of the hepatocytes.
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PMID:NFkappaB and caspase-3 activity in apoptotic hepatocytes of galactosamine-sensitized mice treated with TNFalpha. 1248 82

Osteoclasts are the sole bone-resorbing cells. Heightened activity of these cells under pathological conditions leads to the development of bone loss diseases, such as osteolysis, osteoporosis, and rheumatoid arthritis. We have shown previously that tumor necrosis factor alpha-(TNF) strongly induces osteoclastogenesis of preosteoclasts and do so through activation of the transcription factor, NF-kappaB. Most importantly, recent studies have shown that NF-kappaB is required for the development of osteoclasts. This transcription factor has also been proven as an essential mediator of inflammatory diseases including those related to bone. In this regard, we have shown that various mutated forms of IkappaBalpha are potent inhibitors of osteoclastogenesis. In this study, we examined the direct effect of DN-IkappaB on mature and preosteoclast development in the presence of TNF. Our findings indicate that once committed to the osteoclastogenic pathway, preosteoclasts form giant and hyperactive osteoclasts in response to TNF. However, administration of DN-IkappaB to cultures prior to TNF exposure averts the osteoclastogenic effect of TNF into apoptosis. Screening potential mediators of DN-IkappaB and TNF-induced apoptosis shows that caspase 3, caspase 9, poly(ADP-ribose)polymerase, and Bax are activated, whereas levels of Bcl-XL, cIAP-1, and TRAF6 were reduced. Taken together, these findings suggest that under conditions of NF-kappaB inactivity levels of pro-survival factors are diminished, which in turn facilitates TNF induction of pro-apoptotic factors leading to apoptosis.
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PMID:Dominant-negative IkappaB facilitates apoptosis of osteoclasts by tumor necrosis factor-alpha. 1263 73

In oncogenic therapies, apoptosis seems to be the important mechanism of deciding chemotherapy effect. NF-kappaB transcription factors are implicated in the control of cell proliferation and apoptosis. NF-kappaB is activated by chemotherapy and by irradiation, and this pathway has been shown to protect cells potently from their stimuli-induced apoptosis. Furthermore, inhibition of NF-kappaB leads to enhanced apoptosis in response to various stimuli. However, because the role of NF-kappaB as a modifier of the intrinsic chemosensitivity of cancer cells is less clear, we have studied the impact of IkappaBalpha (an inhibitor of NF-kappaB) on the chemosensitivity of human lung cancer cells. We used adenoviral vectors expressing human IkappaBalpha (AdIkappaBalpha) and investigated the effects of IkappaBalpha gene transfer in combination with 6 anticancer agents on a human pulmonary adenocarcinoma cell line, A549. Solutions containing anticancer agents at various concentrations were added followed by the addition of recombinant adenovirus solutions, and each IC50 was calculated based on the dose-response curves. The gene transfer of AdIkappaBalpha decreased IC50 from 12.0 to 2.2 nM on paclitaxel and increased IC50 from 0.27 to 16.0 microM on SM5887 compared with the transfer of control gene, AdLacZ. The IC50 did not change clearly on the other anticancer drugs. To investigate this molecular mechanism, we measured caspase 3 activity by the transfer of IkappaBalpha gene. On result, paclitaxel increased caspase 3 activity and SM5887 decreased the activity. These results indicate that the cell killing effect of anticancer drug is influenced by the inhibition of NF-kappaB activity and may, at least in part, depend on the regulation of caspase 3 activation. Adenovirus mediated IkappaBalpha gene transfer improve the anti-cancer effect of paclitaxel to lung cancer cells through the regulation of caspase 3 activation.
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PMID:Transfer of IkappaBalpha gene increase the sensitivity of paclitaxel mediated with caspase 3 activation in human lung cancer cell. 1272 25

Ceramides are important intracellular second messengers that play a role in the regulation of cell growth, differentiation, and programmed cell death. To determine whether ceramides can mediate the apoptosis of HCT116 and OVCAR-3 cancer cells, exogenous C2-, C6-, and C16-ceramides were used to mimic the endogenous lipid increase that follows a large variety of stresses. C2- and C6-ceramides (cell-permeable ceramide analogs), but not C16-ceramide, induced nuclear factor-kappaB (NF-kappaB) DNA-binding, caspase-3 activation, poly(ADP-ribose) polymerase degradation, and mitochondrial cytochrome c release, indicating that apoptosis occurs through the caspase cascade and the mitochondrial pathway. No difference in survival was observed between control cells and cells expressing mutated IkappaBalpha and treated with the permeable ceramides. This suggests that, at least in these cell lines, stable NF-kappaB inhibition did not modify the ceramide-induced cytotoxicity pathway. C6-ceramide also induced a double block in G1 and G2, thus emptying the S phase.
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PMID:Mechanisms involved in exogenous C2- and C6-ceramide-induced cancer cell toxicity. 1275 99


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