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)

During heart development, cell hyperplasia and hypertrophy are the main mechanisms by which cardiac mass grows. Both these processes along with programmed cell death lead to complete growth and function. In addition, since the establishment of cardiac function depends on the relationship between oxygen supply and demand, we investigated some of the molecular mechanisms at the basis of rat myocardial cell response to hypoxic stress at different times of neonatal life. In particular, the role played by hypertrophic and survival factors like NF-kB and IAP-1 (Inhibiting Apoptosis Protein) and by death factors ASK-1 (Apoptosis Signal Regulating Kinase), JNK/SAPK (Jun-N-Terminal-Kinase/Stress-Activated Protein Kinase) pathways in regulating caspase-3 expression and activity has been evaluated by immunohistochemical and Western blotting analyses, respectively. Level of phosphorylation of IkBalpha and IAP-1 expression were substantial in 8-day-old hypoxic hearts, suggesting the persistence of NF-kB driven hypertrophic signal along with a rescue attempt against hypoxic stress. In contrast, ASK-1 mediated JNK/SAPK activation, regulating Bcl(2) levels, allows Bax homodimerization and caspase-3 activation in the same experimental conditions. Thus, a regulation carried out by NF-kB and JNK/SAPK pathways on caspase-3 activation at day 8 of neonatal life can be suggested as the main factor for the heart 'adaptive' response to hypoxia.
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PMID:Balance between hypertrophic and hypoxic stimulus in caspase-3 activation during rat heart development. 1590 Apr 13

The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. Recently, we have demonstrated that treatment with a G-quadruplex-interactive agent, telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines. In the present study, we investigated the mechanisms of apoptosis induced by telomerase inhibition in acute leukemia. We have found the activation of caspase-3 and poly-(ADP-ribose) polymerase in telomestatin-treated U937 cells (PD20) and dominant-negative DN-hTERT-expressing U937 cells (PD25). Activation of p38 mitogen-activated protein (MAP) kinase and MKK3/6 was also found in telomestatin-treated U937 cells (PD20) and dominant-negative DN-hTERT-expressing U937 cells (PD25); however, activation of JNK and ASK1 was not detected in these cells. To examine the effect of p38 MAP kinase inhibition on growth properties and apoptosis in telomerase-inhibited cells, we cultured DN-hTERT-expressing U937 cells with or without SB203580. Dominant-negative-hTERT-expressing U937 cells stopped proliferation on PD25; however, a significant increase in growth rate was observed in the presence of SB203580. Treatment of SB203580 also reduced the induction of apoptosis in DN-hTERT-expressing U937 cells (PD25). These results suggest that p38 MAP kinase has a critical role for the induction of apoptosis in telomerase-inhibited leukemia cells. Further, we evaluated the effect of telomestatin on the growth of U937 cells in xenograft mouse model. Systemic intraperitoneal administration of telomestatin in U937 xenografts decreased tumor telomerase levels and reduced tumor volumes. Tumor tissue from telomestatin-treated animals exhibited marked apoptosis. None of the mice treated with telomestatin displayed any signs of toxicity. Taken together, these results lay the foundations for a program of drug development to achieve the dual aims of efficacy and selectivity in vivo.
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PMID:Telomerase inhibition with a novel G-quadruplex-interactive agent, telomestatin: in vitro and in vivo studies in acute leukemia. 1665 54

Several recent studies have demonstrated that thioredoxin (Trx) is an important antiapoptotic/cytoprotective molecule. The present study was designed to determine whether Trx activity is altered in the aging heart in a way that may contribute to increased susceptibility to myocardial ischemia/reperfusion (MI/R). Compared to young animals, MI/R-induced cardiomyocyte apoptosis and infarct size were increased in aging animals (p<0.01). Trx activity was decreased in the aging heart before MI/R, and this difference was further amplified after MI/R. Trx expression was moderately increased and Trx nitration, a posttranslational modification that inhibits Trx activity, was increased in the aging heart. Moreover, Trx-aptosis-regulating kinase-1 (Trx-ASK1) complex formation was reduced and activity of p38 mitogen-activated protein kinase (MAPK) was increased. Treatment with FP15 (a peroxynitrite decomposition catalyst) reduced Trx nitration, increased Trx activity, restored Trx-ASK1 interaction, reduced P38 MAPK activity, attenuated caspase 3 activation, and reduced infarct size in aging animals (p<0.01). Our results demonstrated that Trx activity is decreased in the aging heart by posttranslational nitrative modification. Interventions that restore Trx activity in the aging heart may be novel therapies to attenuate MI/R injury in aging patients.
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PMID:Nitrative thioredoxin inactivation as a cause of enhanced myocardial ischemia/reperfusion injury in the aging heart. 1756 Oct 92

Apoptosis signal-regulating kinase 2 (ASK2) is an interaction partner of the highly related ASK1. Here, we describe a regulatory function of ASK2 in stress signaling-induced cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Increased cleavage of caspase-3 and PARP was demonstrated by overexpression as well as knockdown of ASK2 after stress-induction by serum-starvation. We show that ectopically expressed ASK2 homo-oligomerized while endogenous ASK2 and ASK1 formed hetero-oligomers, which decreased upon serum-starvation. Co-expression of ASK2 and ASK1 stabilized these two proteins and reduced starvation-induced caspase-3 activation and degradation of PARP. Analysis of the intracellular localization of ASK2 exhibited a similar localization compared with ASK1 in the nucleus, cytoplasm, and in mitochondria. We propose that ASK2 regulates stress-induced caspase-3 and PARP cleavage in a dose-dependent manner by heteromeric complex formation with ASK1.
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PMID:Heteromeric complex formation of ASK2 and ASK1 regulates stress-induced signaling. 1771 88

Previously, we have shown that 4-hydroxynonenal (4-HNE) induces Fas-mediated apoptosis in HLE B-3 cells through a pathway which is independent of FasL, FADD, procaspase 8, and DISC (Li, J., et al. (2006) Biochemistry 45, 12253-12264). The involvement of Daxx has also been suggested in this pathway, but its role is not clear. Here, we report that Daxx plays an important regulatory role during 4-HNE-induced, Fas-mediated apoptosis in Jurkat cells. 4-HNE induces Fas-dependent apoptosis in procaspase 8-deficient Jurkat cells via the activation of ASK1, JNK, and caspase 3, and the apoptosis can be inhibited by masking Fas with the antagonistic anti-Fas antibodies. We demonstrate that 4-HNE exposure to Jurkat cells leads to the induction of both Fas and Daxx. 4-HNE binds to both Fas and Daxx and promotes the export of Daxx from the nucleus to the cytosol, where it binds to Fas and inhibits apoptosis. Depletion of Daxx results in an increase in the activation of ASK1, JNK, and caspase 3 along with exacerbation of 4-HNE-induced apoptosis, suggesting that Daxx inhibits apoptosis by binding to Fas. 4-HNE-induced translocation of Daxx is also accompanied by the activation of the transcription factor HSF1. The results of these studies are consistent with a model in which, by interacting with Fas, 4-HNE promotes proapoptotic signaling via ASK1, JNK, and caspase 3. In parallel, 4-HNE induces Daxx and promotes its export from the nucleus to the cytosol, where it interacts with Fas to self-limit the extent of apoptosis by inhibiting the downstream proapoptotic signaling. Cytoplasmic translocation of Daxx also results in up-regulation of HSF1-associated stress-responsive genes.
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PMID:4-Hydroxynonenal self-limits fas-mediated DISC-independent apoptosis by promoting export of Daxx from the nucleus to the cytosol and its binding to Fas. 1806

In recent years there has been an increasing interest in the azinomycin epoxide (2S, 3S)-benzyl 3,4-epoxy-2-(3-methoxy-5-methyl-1-naphthoyloxy)-3-methylbut anamide (EA), a potent cytotoxic and anti-tumour antibiotic. However, the molecular mechanisms of its cytotoxic activity have not yet been investigated. Here we report that exposure of the THP-1 human myeloid leukaemia cells to EA leads to the activation of apoptosis signal-regulating kinase 1 via a redox-dependent mechanism in a concentration and time-dependent manner. Accumulation of p53 and activation of caspase 3 were also seen. This was consistent with EA concentration-dependent accumulation of HIF-1alpha protein peaking after 4 h of stimulation with EA. Experiments with THP-1 cells, where the activity of ASK1 was blocked by transfection with the dominant-negative form of ASK1 demonstrated the importance of this enzyme for EA-dependent activation of caspase 3. Accumulated HIF-1alpha protein did not, however, promote EA-induced activation of caspase 3 or accumulation of p53. The experiments with p53 knockdown THP-1 cells demonstrated that this protein is not important for EA-induced activation of ASK1, caspase 3 or accumulation of HIF-1alpha protein. This is consistent with previous results indicating a reduced activity of p53 in THP-1 cells.
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PMID:Azinomycin epoxide induces activation of apoptosis signal-regulating kinase 1 (ASK1) and caspase 3 in a HIF-1alpha-independent manner in human leukaemia myeloid macrophages. 1907 71

Oxidized LDL is highly atherogenic, as it stimulates foam cell formation and promotes inflammatory and thrombotic processes. The present study elucidated whether the antioxidants quercetin and its rutinoside rutin exert antiapoptosis in endothelial cells exposed to Cu(2+)-oxidized LDL. Quercetin and rutin inhibited the oxidized LDL-induced endothelial toxicity at nontoxic doses of </=25 muM with an inhibition of intracellular oxidant accumulation. These effects accompanied disappearance of apoptotic bodies and suppression of caspase-3 activation. Additionally, condensed nuclei vanished in oxidized LDL-exposed cells treated with quercetin and rutin. This study further explored whether such effects were achieved by redox manipulation via JAK2-STAT3-responsive death/survival signaling pathways involving multiple MAPK. Unlike quercetin, rutin blocked the activation of oxidized LDL-induced JNK and p38 MAPK as well as the upstream ASK1 phosphorylation. Quercetin dose-dependently attenuated the JAK2 phosphorylation evoked by oxidized LDL, whereas rutin abolished the JAK signaling accompanying nuclear transactivation of STAT3 and enhanced the JAK activity-inhibiting SOCS3 expression. Conversely, oxidized LDL-induced IL-6 release was minimal for the JAK2 activation, although this effect was counteracted by quercetin and rutin. These results suggest that quercetin and rutin inhibit Cu(2+)-oxidized LDL-induced endothelial apoptosis through modulating JAK2-STAT3 pathways and that rutin may modulate a signaling crosstalk between JAK2 and MAPK.
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PMID:Blockade of oxidized LDL-triggered endothelial apoptosis by quercetin and rutin through differential signaling pathways involving JAK2. 1919

Japanese encephalitis virus (JEV) causes severe neurological diseases with a high fatality rate. Clinical, neurophysiological and radiological features of Japanese encephalitis JE patients showed that JEV infection resulted in widespread involvement of the nervous system, including thalamus, basal ganglia, brainstem, cerebellum, cerebral cortex and spinal cord. In this study, we characterized the apoptotic effect of JEV infection and its viral proteins on the TE671 human medulloblastoma cells. JEV replicated in TE671 cells, inducing caspase 3-mediated apoptosis in MOI- and time-dependent manners. Of viral proteins, co-expression of JEV NS3 protease with NS2B cofactor significantly induced higher degrees of apoptosis and triggered higher caspase 3 activities than single expression of E, NS1, NS2B or NS3 protease in human medulloblastoma cells. Moreover, JEV NS2B-NS3 protease induced reduction of mitochondrial membrane potential and release of mitochondrial cytochrome C, which were responsible for the mitochondria-mediated apoptosis. In addition, the production of reactive oxygen species production and activation of ASK1-p38 MAPK signaling pathway might be associated with JEV NS2B-NS3 protease-induced mitochondria-mediated apoptosis. The results demonstrated that the JEV infection and the co-expression of JEV NS3 protease with NS2B cofactor induced caspase 3 activation and mitochondria-mediated apoptosis in human medulloblastoma cells, being valuable insight for cellular and molecular levels of JEV pathogenesis.
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PMID:Japanese encephalitis virus NS2B-NS3 protease induces caspase 3 activation and mitochondria-mediated apoptosis in human medulloblastoma cells. 1946 24

Several signaling pathways are differentially activated during apoptotic cell death. We have previously found that during apoptotic death of cerebellar granule neurons (CGN) induced by potassium deprivation (K5) and staurosporine there is an increase in the generation of reactive oxygen species (ROS). The inhibition of ROS generation reduces the extent of cell death. However, remain to be elucidated the mechanisms by which ROS participate in this apoptotic process. On the other hand, it is well known that c-Jun amino-terminal kinase (JNK) pathway plays a pivotal role in cell death of several cell types. In the present study we found that K5 activated the JNK pathway and that its inhibition with SP600125 markedly prevented caspase 3 activation, nuclear condensation and cell death induced by K5. In contrast, JNK pathway was not activated by staurosporine and the JNK inhibitor did not affect cell death induced by this stimulus. We also found that JNK inhibition did not affect ROS levels induced by K5 or staurosporine, suggesting that ROS are upstream of JNK pathway activation. Antioxidants increased ASK1 phosphorylation and decreased JNK1/2 and c-Jun phosphorylation induced by K5. According to these results, we suggest that apoptosis induced by K5 is JNK-dependent and mediated by ROS, but apoptosis induced by staurosporine is not dependent on JNK and that the observed ROS generation by staurosporine seems not to be involved in the activation of this signaling pathway.
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PMID:Role of oxidative stress and JNK pathway in apoptotic death induced by potassium deprivation and staurosporine in cerebellar granule neurons. 1948 16

Epidemiologic and laboratory studies suggest that paraquat can be an environmental etiologic factor in Parkinson's disease (PD). One mechanism by which paraquat may mediate cell death of dopaminergic neurons is by inducing endoplasmic reticulum (ER) stress, as suggested in a recent report. In this study, we further investigated this linkage by examining ER stress cascades. To this aim, human neuroblastoma cells (SH-SY5Y cells) were treated with paraquat and the signaling cascades through which ER stress results in apoptosis were examined. Then, it was examined whether ER stress is produced by paraquat. Paraquat increased ER stress biomarker proteins, glucose-regulated protein 78 (GRP78), ER degradation-enhancing alpha-mannosidae-like protein (EDEM), and C/EBP homologous protein (CHOP). Then, it was investigated which ER stress cascades are affected by paraquat. Paraquat activated inositol-requiring enzyme 1 (IRE1), apoptosis signal regulating kinase 1 (ASK1), and c-jun kinase (JNK). Also, paraquat activated calpain and caspase 3, but did not affect the levels of intracellular calcium and the activity of caspase 12. Finally, apoptotic DNA damage by paraquat was investigated and this damage was attenuated by salubrinal (ER stress inhibitor), thioredoxin (ASK1 inhibitor) and SP600125 (JNK inhibitor). Therefore, current data indicate that paraquat activates the IRE1/ASK1/JNK cascade associated with apoptosis in SY5Y cells.
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PMID:Paraquat activates the IRE1/ASK1/JNK cascade associated with apoptosis in human neuroblastoma SH-SY5Y cells. 1973 4


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