UNIPROT:P42574 - FACTA Search

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Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in the intracellular reduced/oxidized glutathione ratio (GSH/GSSG) are crucial reduction-oxidation (redox) events that trigger downstream proliferation or death responses. We investigated the molecular mechanisms underlying redox-mediated cell signaling upon an oxidative insult by treating U937 cells with exogenous nonpermeable GSSG. This treatment results in a significant decrease of exofacial cell membrane thiol groups and intracellular decrement of GSH content, owing to its engagement in the formation of mixed disulfides. Changes in thioredoxin redox state were also observed, and they may be related to the activation of upstream ASK1 and selective induction of downstream p38 mitogen-activated protein kinase (MAPK) pathway, detectable by phosphorylation of MKK3/6 and p38 MAPK. Moreover, an increase in reactive oxygen species production was detected, and cells were committed to apoptosis along the mitochondrial pathway, evidenced by Bcl-2 down-regulation, cytochome c release from mitochondria, caspase-9 cleavage, and caspase-3 activation. GSH ethyl ester, a precursor of GSH, by counteracting intracellular mixed disulfide formation, canceled both p38 MAPK activation and GSSG-mediated apoptosis via inhibition of thioredoxin oxidation and stabilization of thioredoxin/ASK1 complex, whereas, blockage of p38 MAPK by specific inhibitor SB 203580 allowed apoptosis at a very reduced extent. Results suggest that kinase cascade may serve as a primary transducer of cytoplasmic oxidative signals to the nucleus before apoptosis-inducing signals are activated.
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PMID:Glutathione disulfide induces apoptosis in U937 cells by a redox-mediated p38 MAP kinase pathway. 1242 21

Chronic hyperglycemia and cytokines such as tumor necrosis factor alpha (TNF-alpha) cause oxidative stress leading to dysregulated cell growth or apoptosis that contributes to the development of inflammation and secondary complications of diabetes. However, the mechanisms regulating hyperglycemic or cytokine injury are not well understood. Herein we report that inhibition of the polyol pathway enzyme aldose reductase (AR) by two structurally unrelated inhibitors--sorbinil and tolrestat--prevents, in the human lens epithelial cell line B-3, the apoptosis and activation of caspase-3 caused by exposure to high glucose levels or TNF-alpha. Inhibition of AR attenuated TNF-alpha and hyperglycemia-induced activation of protein kinase C (PKC), phosphorylation of the inhibitory subunit of nuclear factor-kappaB (NF-kappaB), and stimulation of NF-kappaB, but it did not prevent the activation of NF-kappaB and PKC by phorbol ester. Inhibition of AR also attenuated the increase in p38 mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation. These signaling pathways were also inhibited in cells in which the expression of AR was reduced by antisense ablation. Collectively, these results identify a new participant in apoptotic signaling and suggest that AR is an obligatory mediator of the apoptotic events upstream of PKC. These observations could provide new insights into the pathophysiology of diabetes and the role of aberrant glucose metabolism in apoptotic cell death.
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PMID:Aldose reductase mediates cytotoxic signals of hyperglycemia and TNF-alpha in human lens epithelial cells. 1249 May 36

Nitric oxide (NO) is an important biological messenger in the regulation of tissue homeostasis and pathophysiological processes. Here, we investigated the effect of NO on gastric mucus glycoprotein (mucin) synthesis, apoptotic processes, and the involvement of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). Exposure of gastric mucosal cells to NO donor led to a dose-dependent decrease (up to 48%) in mucin synthesis, accompanied by a marked increase in caspase-3 activity and apoptosis. Inhibition of ERK with PD98059 accelerated (up to 23.8%) the NO-induced decrease in mucin synthesis, and cause further enhancement in caspase-3 activity and apoptosis. Blockade of p38 kinase with SB203580 produced reversal in the NO-induced reduction in mucin synthesis, and substantially countered the induced increase in caspase-3 activity and apoptosis. Moreover, caspase-3 inhibitor not only blocked the NO-induced increase in caspase-3 activity but also produced an increase in mucin synthesis. Thus, the detrimental influence of NO on mucin synthesis is closely linked to caspase-3 activation and apoptosis, and involves ERK and p38 kinase participation. Activation of p38 kinase leads to the upregulation of proapoptotic signal, while ERK activation stimulates the anti-apoptotic pathway.
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PMID:Nitric oxide as a modulator of gastric mucin synthesis: role of ERK and p38 mitogen-activated protein kinase activation. 1258 77

Creating conditions similar to those that occur during exposure of cells to microgravity induced a sixfold increase of apoptotic bodies and DNA fragments in human lymphocytes, paralleled by an early (within 2 h) fourfold increase in 5-lipoxygenase (5-LOX) activity and a fivefold decrease in mitochondrial membrane potential and increase in cytochrome c release (within 4 and 8 h, respectively). Similar membrane potential and cytochrome c release were observed in isolated mitochondria treated with physiological amounts of 5-LOX and were enhanced by creating conditions similar to those that occur during exposure of cells to microgravity. 5-LOX inhibitors, 5,8,11,14-eicosatetraynoic acid and caffeic acid, completely prevented apoptosis, whereas the phospholipase A(2) inhibitor methyl-arachidonoyl fluorophosphonate and the 5-LOX activating protein inhibitor MK886 reduced it to 65-70%. The intracellular calcium chelator EGTA-acetoxymethylester reduced 5-LOX activity and apoptosis to 30-40% of controls, whereas the p38 mitogen-activated protein kinase inhibitor SB203580 was ineffective. The caspase-3 and caspase-9 inhibitors Z-Asp(OCH(3))-Glu(OCH(3))-Val-Asp(OCH(3))-fluoromethylketone (FMK) and Z-Leu-Glu(OCH(3))-His-Asp(OCH(3))-FMK reduced apoptotic bodies to 25-30% of the control cells. Finally, creating conditions similar to those that occur during exposure of cells to microgravity did not induce apoptosis in human lymphoma U937 cells, which did not express an active 5-LOX.
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PMID:Creating conditions similar to those that occur during exposure of cells to microgravity induces apoptosis in human lymphocytes by 5-lipoxygenase-mediated mitochondrial uncoupling and cytochrome c release. 1266 Feb 22

Oxidative stress in the brain has been increasingly associated with the development of numerous human neurological diseases. Microglia, activated upon neuronal injury or inflammatory stimulation, are known to release superoxide anion (*O(2) (-)), hydrogen peroxide (H(2)O(2)), and nitric oxide (NO), thereby further contributing to oxidative neurotoxicity. The reaction of NO and *O(2) (-), forming the toxic peroxynitrite (ONOO(-)), has been proposed to play a pathogenic role in neuronal injury. However, the interactions between H(2)O(2) and NO during oxidative stress, which may promote or diminish cell death, is less clear. In this study, we explored oxidative neurotoxicity induced by H(2)O(2) plus NO in primary cultures of rat cerebral cortex neurons. As the mechanisms may involve reactions between H(2)O(2) and NO, we monitored the production of ONOO(-)and reactive oxygen species (ROS) throughout the experiments. Results indicated that the NO donor S-nitroso-N-acetyl-D, L-penicillamine (SNAP) and H(2)O(2) by themselves elicited neuronal death in a concentration- and time-dependent manner. Sublytic concentrations of H(2)O(2) plus SNAP were sufficient to induce neuronal apoptosis as determined by DNA laddering and fluorescent staining of apoptotic nuclei. Transient ONOO(-)increase was accompanied by rapid H(2)O(2) decay and NO production, whereas ROS slowly decreased following treatment. Furthermore, p38 mitogen-activated protein kinase (MAPK) activation and the cleavage of caspase-3 were observed. Conversely, inhibition of p38 MAPK and caspase-3 significantly reduced apoptotic death induced by H(2)O(2) plus SNAP. These data suggest that H(2)O(2) and NO act synergistically to induce neuronal death through apoptosis in which activation of p38 MAPK and caspase-3 is involved.
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PMID:Oxidative neurotoxicity in rat cerebral cortex neurons: synergistic effects of H2O2 and NO on apoptosis involving activation of p38 mitogen-activated protein kinase and caspase-3. 1270 12

Vascular smooth muscle cells (SMCs) generate carbon monoxide (CO) from the degradation of heme by the enzyme heme oxygenase. Because recent studies indicate that CO influences the properties of vascular SMCs, we examined whether this diatomic gas regulates apoptosis in vascular SMCs. Treatment of cultured rat aortic SMCs with a cytokine cocktail consisting of interleukin-1beta (5 ng/ml), tumor necrosis factor-alpha (20 ng/ml), and interferon-gamma (200 U/ml) for 48 hr stimulated apoptosis, as demonstrated by DNA laddering, caspase-3 activation, and annexin V staining. However, the exogenous addition of CO (200 ppm) completely blocked cytokine-mediated apoptosis. The antiapoptotic action of CO was partially reversed by the soluble guanylate cyclase inhibitor, H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 microM). In contrast, the p38 mitogen-activated protein kinase inhibitor, SB203580 (10 microM), had no effect on SMC apoptosis. These findings indicate that CO is a potent inhibitor of vascular SMC apoptosis and that it blocks apoptosis, in part, by activating the cGMP signaling pathway. The ability of CO to inhibit vascular SMC apoptosis may play a critical role in attenuating lesion formation at sites of arterial damage.
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PMID:Antiapoptotic action of carbon monoxide on cultured vascular smooth muscle cells. 1270 89

In this study, we have synthesized several compounds and examined their cytotoxic effects on human non-small cell lung cancer A549 cells. We found that GO-13 ((E,E)-2,5-bis[4-(3-dimethyl-aminopropoxy)styryl]-1,3,4-thiadiazole) is the most effective one by the MTT assay. Furthermore, the GO-13-induced apoptotic reaction was identified based on several criteria, such as negative release reaction of lactate dehydrogenase and positive labeling of annexin V and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) techniques. GO-13 induced the apoptosis in A549 cells in a concentration- and time-dependent manner. The data demonstrate that the regulations of p38 mitogen-activated protein kinase and protein kinase C was not involved in the GO-13-mediated mechanism. However, GO-13 significantly induced a down-regulation of Bcl-X(L) expression in a short-term treatment (less than 3hr), whereas stimulated up-regulation of Bax expression in a long-term treatment (24hr) indicating their involvement in GO-13 action. GO-13-mediated apoptosis is also positively correlated with the increase in caspase-3 activity. Worth noting is the fact that GO-13 did not modify the phosphorylation level of Akt/protein kinase B (PKB) until a 24-hr exposure was carried out indicating that the inhibition of Akt/PKB activation was involved in the late-phase apoptosis. Besides the anticancer activity, GO-13 also showed equivalent anti-angiogenic activity in the nude mice angiogenesis model. In summary, we conclude that GO-13 is the most effective anticancer compound in our screening tests. It induced the early-phase apoptosis in A549 cells via the Bcl-X(L) down-regulation, and that of the late-phase through up-regulation of Bax expression as well as inhibition of Akt/PKB activation.
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PMID:Investigation of anticancer mechanism of thiadiazole-based compound in human non-small cell lung cancer A549 cells. 1281 71

The temporal and spatial distribution of active c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in the brain was investigated in an experimental virus-mouse system in which neurovirulent influenza A virus caused lethal acute encephalitis. Following stereotaxic microinjection into the olfactory bulb, virus-infected neurons appeared in several midbrain structures, including the ventral tegmental area, amygdala and the pyramidal layer of the hippocampus. Infected neurons exhibited apoptosis on day 5, as demonstrated by in situ detection of DNA fragmentation and active caspase-3. The stress-responsive JNK signal transduction pathway was activated in virus-infected neurons. Activation of p38 MAPK was widespread and occurred in astrocytes on day 7 after infection. Active p38 MAPK in astrocytes showed no association with apoptosis but appeared to be involved in regulation of TNF-alpha production. These results indicate that these two stress-activated protein kinases may play distinct roles during the course of lethal acute influenza virus encephalitis.
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PMID:Differential activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 mitogen-activated protein kinase signal transduction pathways in the mouse brain upon infection with neurovirulent influenza A virus. 1291 61

Stable rat pituitary tumor cell lines expressing two isoforms of the dopamine D2 receptor, D2L (long) and D2S (short) (the GH3D2L and GH3D2S cell lines, respectively), were established, and the signaling pathway underlying the anti-proliferative and cell death effects of dopaminergic agonists was examined in these cells. After either dopamine or quinpirole treatment, the cell viability decreased significantly only in GH3D2L cells and GH3D2S cells, but not in GH3 cells where D2 receptors are absent. Treatment with haloperidol, a specific D2 receptor antagonist, rescued the dopamine-mediated decreased cell viability in both the GH3D2L and GH3D2S cells. Treatment of these cells with dopamine decreased the DNA synthesis rate, as demonstrated by the incorporation of 5-bromo-2'-deoxyuridine (BrdU). Dopamine-induced cell death was observed in the GH3D2L and GH3D2S cells, and was accompanied by DNA laddering and caspase-3 activation, which were blunted by haloperidol, indicating that dopamine-induced cell death in these cells is mediated by the dopamine D2 receptors. D2 receptor-mediated cell death in these cells correlated with the sustained and enhanced activation of p38 mitogen-activated protein kinase (MAPK) and the extracellular-signal regulated kinase (ERK)1/2 pathways. Treatment with SB203580, which is a specific p38 MAPK inhibitor and PD98059, which is an inhibitor of MEK1/ERK signaling, selectively abrogates dopamine-induced cell death. It was further shown that p38 MAPK and ERK activation was inhibited by the antioxidant, N-acetylcysteine (NAC), and that a treatment with haloperidol completely blocked the p38 and ERK activation induced by dopamine. These results suggest that dopamine induces an anti-proliferative effect and cell death via the dopamine D2 receptors, by means of the p38 MAPK and ERK pathways involving oxidative stress, in the pituitary tumor cells.
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PMID:Anti-proliferative effects and cell death mediated by two isoforms of dopamine D2 receptors in pituitary tumor cells. 1294 89

It is believed that bisphosphonates (BPs) induce apoptosis in cells such as myeloma cells, as they inhibit prenylation of G-proteins. However, the details of the apoptosis-inducing mechanism remain obscure. In the present study, we attempted to clarify the mechanism by which YM529, a new bisphosphonate, induces apoptosis. YM529 induced cell deaths in HL60 cells in a concentration-dependent manner. At that time, we observed an increase in Caspase-3 activity and morphological fragmentation of the nuclei. We could confirm that these cell deaths were evidence of apoptosis. The apoptosis induced by YM529 was not inhibited by the addition of farnesyl pyrophosphate (FPP), but was by the addition of geranylgeranyl pyrophosphate (GGPP). When we examined the survival signals at the time of apoptotic induction, we also observed that the administration of YM529 caused a remarkable decrease in the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). However, other survival signals such as nuclear factor kappa B (NF-kappaB), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38) exhibited no change. In addition, no quantitative change was observed in Bcl-2, which is an anti-apoptosis protein. It was also observed that apoptosis was induced when U0126, an MEK inhibitor, was added to the cells to inhibit ERK. These results suggest that YM529, the new bisphosphonate, induced apoptosis when inhibit GGPP synthase and consequently decreased the levels of phosphorylated ERK, which is a survival signal; moreover, during this process, there is no influence on NF-kappaB, Akt, p38, and Bcl-2. The results of this study also suggest that YM529 can be used as an anticancer agent, in addition to its use as a therapeutic agent to treat osteoporosis.
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PMID:A new bisphosphonate, YM529 induces apoptosis in HL60 cells by decreasing phosphorylation of single survival signal ERK. 1367 34

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