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)

Inflammatory processes and cytokine expression have been implicated in the pathogenesis of several neurodegenerative disorders. Chronic ethanol intake induces brain damage, although the mechanisms involved in this effect are not well understood. We tested the hypothesis that activation of glial cells by ethanol would induce stimulation of signaling pathways and inflammatory mediators in brain, and would cause neurotoxicity. We used cerebral cortex from control and chronic ethanol-fed rats, which received ethanol-liquid diet for 5 months and cultured of astrocytes exposed to 75 mM ethanol for 7 days. Our results demonstrate that chronic ethanol treatment up-regulates iNOS, COX-2 and IL-1beta in rat cerebral cortex and in cultured astrocytes. Under both experimental conditions, up-regulation of these inflammatory mediators and IL-1RI concomitantly occurs with the stimulation of IRAK and MAP kinases, including ERK1/2, p-38 and JNK, which trigger the downstream activation of oxidant-sensitive transcription factors NF-KB and AP-1. These effects were associated with an increased in both caspase-3 and apoptosis in ethanol-fed rats and in astrocytes exposed to ethanol. In conclusion, chronic ethanol treatment stimulates glial cells, up-regulating the production and the expression of inflammatory mediators in the brain, and activating signalling pathways and transcription factors involved in inflammatory damage and cell death.
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PMID:Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. 1560 83

The oncogenic transcription factor c-Jun plays an important role in cell proliferation, transformation and differentiation. All identified c-Jun-interacting proteins are localized to the nucleus or cytoplasm and function in their intact forms. Here we show that the pleckstrin homology domain-containing protein CKIP-1 (casein kinase 2-interacting protein-1) functions as a plasma membrane-bound AP-1 regulator. During apoptosis, CKIP-1 is cleaved by caspase-3 and translocated to the cytoplasm and then to the nucleus. C-terminal fragments of cleaved CKIP-1 strongly repress AP-1 activity. Importantly, CKIP-1 overexpression promotes apoptosis by forming a positive feedback loop between CKIP-1 and caspase-3. RNA interference of CKIP-1 or overexpression of c-Jun attenuates the sensitivity to apoptosis, indicating a novel role of CKIP-1 in apoptosis. CKIP-1 is the first case of a c-Jun-interacting protein that regulates AP-1 activity via caspase-3-dependent cleavage and translocation.
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PMID:Role for the pleckstrin homology domain-containing protein CKIP-1 in AP-1 regulation and apoptosis. 1570 51

We describe cyclic hydrostatic pressure of 200/100 mmHg with a frequency of 85/min as a hemodynamically relevant pathological condition enforcing apoptosis in endothelial cells (EC) after 24 h of treatment. This went along with an increase of CD95 and CD95L surface expression, shedding of CD95L into the supernatant, cleavage of caspase-3 and caspase-8, and elevated JNK-2, c-Jun, and CD95L mRNA expression. Furthermore, increased DNA-binding activity of the AP-1 transcription factor family members FRA-1 and c-Jun was observed. This activation was reduced by inhibition of JNK, which subsequently prevented elevated CD95L mRNA expression. Caspase inhibitors and a CD95L-neutralizing antibody also reduced EC apoptosis. Most of the pressure-induced events were most prominent at 24 and 48 h. However, after 48 h, the CD95/CD95L expression pattern switched back to CD95-/CD95L+ and the specific death rate decreased. Cyclic pathological hydrostatic pressure is a novel type of stress to EC that renders them susceptible to CD95/CD95L-mediated autoapoptosis and/or paracrine apoptosis accompanied by upregulation of intracellular molecules known to trigger both apoptosis and survival.
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PMID:Pathologically elevated cyclic hydrostatic pressure induces CD95-mediated apoptotic cell death in vascular endothelial cells. 1577 24

Trichothecene mycotoxins and other translational inhibitors activate mitogen-activated protein kinase (MAPKs) by a mechanism called the "ribotoxic stress response," which drives both cytokine gene expression and apoptosis in macrophages. The purpose of this study was to identify upstream kinases involved in the ribotoxic stress response using the trichothecene deoxynivalenol (DON) and the RAW 264.7 macrophage as models. DON (100 to 1000 ng/ml) dose-dependently induced phosphorylation of c-Jun N-terminal protein kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 MAPKs. MAPK phosphorylation in response to DON exposure occurred as early as 5 min, was maximal from 15 to 30 min, and lasted up to 8 h. Preincubation with inhibitors of protein kinase C, protein kinase A, or phospholipase C had no effect on DON-induced MAPK phosphorylation. In contrast, the Src family tyrosine kinase inhibitors, PP1 (4-amino-5-[4-methylphenyl)]-7-[t-butyl]pyrazolo[3,4-d]-pyrimidine) and, PP2 (4-amino-5-[4-chlorophenyl]-7-[t-butyl]pyrazolo[3,4-d]-pyrimidine) concentration-dependently impaired phosphorylation of all three MAPK families. PP1 suppressed DON-induced phosphorylation of the MAPK substrates c-jun, ATF-2, and p90(Rsk). MAPK phosphorylation by two other translational inhibitors, anisomycin and emetine, were similarly Src-dependent. PP1 reduced DON-induced increases in nuclear levels and binding activities of several transcription factors (NF-kappaB, AP-1, and C/EBP), which corresponded to decreases in TNF-alpha production, caspase-3 activation, and apoptosis. Tyrosine phosphorylation of hematopoeitic cell kinase (Hck), a Src found in macrophages, was detectable within 1 to 5 min after DON addition, and this was suppressed by PP1. Knockdown of Hck expression with siRNAs confirmed involvement of this Src in DON-induced TNF-alpha production and caspase activation. Taken together, activation of Hck and possibly other Src family tyrosine kinases are likely to be critical signals that precede both MAPK activation and induction of resultant downstream sequelae by DON and other ribotoxic stressors.
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PMID:Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. 1577 66

Elderly lung cancer patients and those with poor performance status/co-morbid conditions are deprived of chemotherapy because of high toxicity of multidrug regimens. Human squamous cell lung carcinoma H520 cells treated with Curcumin were sensitized to the cytotoxicity caused by chemotherapeutic agent, Vinorelbine. Both caused apoptosis by increasing the protein expression of Bax and Bcl-xs while decreasing Bcl-2 and Bcl-X(L), releasing apoptogenic cytochrome c, and augmenting the activity of caspase-9 and caspase-3. Expression of Cox-2, NF-kappaB, and AP-1 was also affected. 23.7% apoptosis was induced in the H520 cells by treatment with Curcumin while Vinorelbine caused 38% apoptosis. Pre-treatment with Curcumin enhanced the Vinorelbine induced apoptosis to 61.3%. The findings suggest that Curcumin has the potential to act as an adjuvant chemotherapeutic agent and enhance chemotherapeutic efficacy of Vinorelbine in H520 cells in vitro. Thus, Curcumin offers the prospect of being beneficial in the above-mentioned patient groups.
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PMID:Curcumin enhances Vinorelbine mediated apoptosis in NSCLC cells by the mitochondrial pathway. 1588 9

Development of age-related macular degeneration (AMD) is associated with functional abnormalities and cell death in retinal pigment epithelial (RPE) cells attributable to oxidative stress. To minimize the adverse effects of oxidative stress, cells activate their defence systems, e.g., via increased expression of heat shock protein (Hsp), activation of stress sensitive AP-1 and NF-kappaB transcription factors. In this study, we examined the accumulation of Hsp70 protein, activation of AP-1 and NF-kappaB transcription factors in human ARPE-19 cells subjected to a 4-hydroxynonenal (HNE)-induced oxidative stress. In addition, the influence of Hsp90 inhibitor geldanamycin (GA) was studied in HNE-treated cells. Mitochondrial metabolic activity and apoptosis were determined to evaluate cell death in the ARPE-19 cells. The ARPE-19 cells showed increased accumulation of Hsp70 protein before of the cytotoxic hallmarks appearing in response to HNE. In contrast, increased DNA-binding activities of AP-1 or NF-kappaB transcription factors were not seen under HNE insults. Interestingly, GA significantly increased cell death in the HNE-treated cells, which was involved in caspase-3 independent apoptosis. This study reveals that the Hsps have an important role in the cytoprotection of RPE cells subjected to HNE-derived oxidative stress.
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PMID:Geldanamycin increases 4-hydroxynonenal (HNE)-induced cell death in human retinal pigment epithelial cells. 1591 Nov 46

CD40 is critically involved in Fas-mediated cholangiocyte apoptosis during liver inflammation, but the underlying signalling events are poorly understood. Our recent work implicated AP-1 in CD40-induced cholangiocyte apoptosis, but suggested involvement of other signalling pathways. Because STAT3 has been implicated in liver regeneration we investigated this signalling pathway during CD40 mediated cholangiocyte apoptosis. Western immunoblotting, electrophoretic mobility gel shift assays, In situ DNA end labelling and caspase-3 activity were used to investigate intracellular signalling and apoptosis in primary human cholangiocytes following CD40 activation. CD40-activation induced caspase-3 dependent cholangiocyte apoptosis and 3-fold increases in JNK/ERK phosphorylation (concomitant with increased AP-1 binding activity) and 4-fold increases in pSTAT3, which were sustained for up to 24 h. Protein levels of c-Jun, c-Fos and pSTAT3 confirmed the upregulation. Phosphorylation of p38 remained unchanged suggesting that this MAP kinase was not involved in CD40 mediated apoptosis. Increased JAK2 phosphorylation accompanied increased STAT3 phosphorylation after CD40 ligation. Cholangiocytes were also shown to express JAK1 and 3 which was phosphorylated following control stimulation with TNFalpha or IL2 respectively but not after CD40 ligation. JNK, ERK and JAK2 inhibitors partially abrogated apoptosis and when used in combination reduced it to basal levels. In conclusion, induction of CD40-mediated cholangiocyte apoptosis requires JAK2-mediated phosphorylation of STAT3 as well as sustained JNK1/2, ERK1/2 activation. This study demonstrates that STAT3 can function as a proapoptotic factor in primary human liver epithelial cells.
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PMID:CD40 mediated human cholangiocyte apoptosis requires JAK2 dependent activation of STAT3 in addition to activation of JNK1/2 and ERK1/2. 1597 Apr 30

Toll-like receptor (TLR) 2 functions as a sensor for detecting various microbial components conserved in bacteria or fungi in innate immunity. TLR2 induces several signalling pathways linking to activation of the transcriptional factors NF-kappaB and AP-1 as well as induction of cell death. In human embryonic kidney 293 cells expressed human TLR2, mycoplasmal lipoproteins (MLP) or staphylococcal peptidoglycans (PGN) induced sustained phosphorylation of p38 mitogen-activated protein kinase (MAPK), accompanied by generation of reactive oxygen species. This observation encouraged us to examine roles of apoptosis signal-regulating kinase 1 (ASK1) in TLR2 signalling, because ASK1 is an upstream activator of p38 MAPK during exposure to oxidative stress and other stressful stimuli. A kinase-inactive mutant of ASK1 greatly impaired the sustained phosphorylation of p38 MAPK induced by MLP or PGN. This mutant also attenuated MLP- or PGN-induced transcriptional activities of NF-kappaB and AP-1 via inhibition of p38 MAPK activation. MLP- or PGN-induced cell death reactions, including DNA fragmentation and caspase-3/7 activation, were also down-regulated by the ASK1 mutant via p38 MAPK inhibition. Furthermore, TLR2 signalling had a potential to phosphorylate and dephosphorylate ASK1 at Ser83 residue. Thus, MLP and PGN have capabilities to induce ASK1-dependent signalling pathways which regulate p38 MAPK activation through TLR2, leading to activation of NF-kappaB and AP-1 as well as induction of cell death.
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PMID:Apoptosis signal-regulating kinase 1-mediated sustained p38 mitogen-activated protein kinase activation regulates mycoplasmal lipoprotein- and staphylococcal peptidoglycan-triggered Toll-like receptor 2 signalling pathways. 1609 18

Apoptotic and inflammatory processes occur in human arteriosclerotic lesions. We examined the hypothesis whether both processes are possibly associated by studying the colocalization of corresponding markers. In 11 human arteriosclerotic carotid arteries, proapoptotic markers (CPP32 (caspase-3), poly(ADP-ribose) polymerase, apoptosis-inducing factor, c-Jun/AP-1, and p53) and proinflammatory markers (macrophage migration inhibitory factor (MIF) and cyclooxygenase-2) were found in macrophages (MPhi) evaluated by computer-assisted immunohistomorphometry. Double-labeling studies demonstrated a colocalization of, both, proapoptotic and proinflammatory markers in these MPhi. Moreover, these MPhi also contained oxidized low-density lipoproteins (oxLDL). Exposure of cultured human MPhi to oxLDL, C6-ceramide, and tumor necrosis factor-alpha or H2O2 resulted in a significant increase of the apoptosis rate as well as of the MIF protein expression. Our study of MPhi in arteriosclerotic carotid arteries and in vitro experiments provide evidence that markers of apoptosis and inflammation are not only significantly increased but are also coexpressed. We conclude there are reciprocal modulatory interactions between apoptotic and inflammatory pathways in human plaque MPhi, which might importantly modify plaque progression or stability.
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PMID:Colocalization of oxidized low-density lipoprotein, caspase-3, cyclooxygenase-2, and macrophage migration inhibitory factor in arteriosclerotic human carotid arteries. 1613 50

In the present study we have studied the effect of resveratrol in signal transduction mechanisms leading to apoptosis in 3T3 fibroblasts when exposed to 4-hydroxynonenal (HNE). In order to gain insight into the mechanisms of apoptotic response by HNE, we followed MAP kinase and caspase activation pathways; HNE induced early activation of JNK and p38 proteins but downregulated the basal activity of ERK (1/2). We were also able to demonstrate HNE-induced release of cytochrome c from mitochondria, caspase-9, and caspase-3 activation. Resveratrol effectively prevented HNE-induced JNK and caspase activation, and hence apoptosis. Activation of AP-1 along with increased c-Jun and phospho-c-Jun levels could be inhibited by pretreatment of cells with resveratrol. Moreover, Nrf2 downregulation by HNE could also be blocked by resveratrol. Overexpression of dominant negative c-Jun and JNK1 in 3T3 fibroblasts prevented HNE-induced apoptosis, which indicates a role for JNK-c-Jun/AP-1 pathway. In light of the JNK-dependent induction of c-Jun/AP-1 activation and the protective role of resveratrol, these data may show a critical potential role for JNK in the cellular response against toxic products of lipid peroxidation. In this respect, resveratrol acting through MAP kinase pathways and specifically on JNK could have a role other than acting as an antioxidant-quenching reactive oxygen intermediate.
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PMID:Resveratrol protects against 4-hydroxynonenal-induced apoptosis by blocking JNK and c-JUN/AP-1 signaling. 1632 78


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