Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Nitric oxide (NO) causes apoptosis and dedifferentiation of articular chondrocytes by the modulation of extracellular signal-regulated kinase (ERK), p38 kinase, and protein kinase C (PKC) alpha and -zeta. In this study, we investigated the effects and mechanisms of non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, ketoprofen, ibuprofen, sulindac sulfide, and flurbiprofen, in NO-induced apoptosis and dedifferentiation of articular chondrocytes. We found that all of the examined NSAIDs inhibited apoptosis and dedifferentiation. NO production in chondrocytes caused activation of ERK-1/2 and p38 kinase, which oppositely regulate apoptosis and dedifferentiation. NO production also caused inhibition of PKCalpha and -zeta independent of and dependent on, respectively, p38 kinase, which is required for apoptosis and dedifferentiation. Among the signaling molecules modulated by NO, NSAIDs blocked NO-induced activation of p38 kinase, potentiated ERK activation, and blocked inhibition of PKCalpha and -zeta. NSAIDs also inhibited some of the apoptotic signaling that is downstream of p38 kinase and PKC, such as NFkappaB activation, p53 accumulation, and caspase-3 activation. The inhibitory effects of NSAIDs on apoptosis and dedifferentiation were independent of the inhibition of cyclooxygenase (COX)-2 and prostaglandin E(2) (PGE(2)) production, as evidenced by the observation that specific inhibition of COX-2 activity and PGE(2) production or exogenous PGE(2) did not affect NO-induced apoptosis and dedifferentiation. Taken together, our results indicate that NSAIDs block NO-induced apoptosis and dedifferentiation of articular chondrocytes by the modulation of ERK, p38 kinase, and PKCalpha and -zeta in a manner independent of their ability to inhibit COX-2 and PGE(2) production.
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PMID:Non-steroidal anti-inflammatory drugs inhibit nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes independent of cyclooxygenase activity. 1258 66

Erythropoietin (EPO) can rescue erythroid cells from apoptosis during erythroid development, leading to red cell production. However, the detailed mechanism of how EPO protects erythroid cells from apoptosis is still open to question. To address this problem, we used a human EPO-dependent leukemia cell line UT-7/EPO and normal erythroid progenitor cells. After deprivation of EPO, UT-7/EPO cells underwent apoptosis, accompanied by down-regulation of the Bcl-xL protein. In addition, the cleaved products of caspase-3, p11 and p21, and a few cleaved forms of inhibitor of caspase-activated DNase (ICAD) were detected in these cells. When the cells were pre-treated with the pancaspase inhibitor Z-VAD-FMK, the ratio of apoptotic cells was significantly reduced, suggesting that EPO protects the UT-7/EPO cells from apoptosis via inhibition of caspase activities. When an MEK 1/2 inhibitor U0126 inhibited activities of extracellular signal-regulated kinases (ERKs), the expression of Bcl-xL protein was down-regulated and subsequently apoptosis was induced. Interestingly, Z-VAD-FMK blocked U0126-induced down-regulation of Bcl-xL protein and apoptosis, strongly suggesting that Bcl-xL expression is regulated by caspases which lies downstream of ERK activation pathway in EPO signaling. Importantly, these findings were also observed in normal erythroid progenitor cells. In conclusion, the activation of ERKs by EPO up-regulates Bcl-xL expression via inhibition of caspase activities, resulting in the protection of erythroid cells from apoptosis.
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PMID:Activation of extracellular signal-regulated kinases ERK1 and ERK2 induces Bcl-xL up-regulation via inhibition of caspase activities in erythropoietin signaling. 1265 55

Monocytes are important components of the innate immune response. The number of circulating monocytes is controlled in part by apoptosis. We have previously shown that monocyte apoptosis requires the activation of caspase-3, a central component of the apoptotic machinery, and that several stimulatory signals, including endotoxin (lipopolysaccharide [LPS]), induce monocyte survival, by the inhibition of caspase-3. We hypothesized that the Th2 anti-inflammatory cytokine, interleukin (IL)-4, may also influence monocyte life span by modulating the apoptotic cascade and the kinases known to be activated by LPS. Here, we show that the IL-4-dependent killing of LPS-treated monocytes reactivates the apoptotic cascade blocked by endotoxin, evidenced by the activity of the effector caspase-3 and the upstream caspases-8 and -9. IL-4 did not affect the activity of caspase-3 or the fragmentation of DNA in nonstimulated monocytes, suggesting that the induction of the apoptotic cascade by IL-4 is specific for stimulated monocytes. In addition, we show that the ability of IL-4 to induce apoptosis is associated with the dephosphorylation of the extracellular signal-regulated kinase, but not with changes in TLR4 expression. Together, these findings suggest a molecular mechanism by which the anti-inflammatory cytokine IL-4 modulates the life span of monocytes at least in part by an extracellular signal-regulated kinase-dependent pathway.
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PMID:Interleukin-4-induced apoptosis entails caspase activation and suppression of extracellular signal-regulated kinase phosphorylation. 1266 28

Aplidine is a promising antitumor agent derived from the Mediterranean tunicate Aplidium albicans. We have found that Aplidine at nM concentrations (10-100 nM) induced apoptosis in human leukemic cell lines and primary leukemic cell cultures from leukemic patients. Inhibition of the Fas (CD95)/Fas ligand (CD95L) signaling pathway with an antagonistic anti-Fas antibody partially inhibited Aplidine-induced apoptosis. L929 cells were resistant to Aplidine action but underwent apoptosis after transfection with human Fas cDNA. Aplidine induced a rapid and sustained c-Jun NH(2)-terminal kinase activation, and pretreatment with curcumin or SP600125 inhibited Aplidine-induced c-Jun NH(2)-terminal kinase activation and apoptosis. However, inhibition of extracellular signal-regulated kinase and p38 kinase signaling pathways did not affect Aplidine-induced apoptosis. Aplidine induced caspase-3 activation, and caspase inhibition prevented Aplidine-induced apoptosis. Aplidine failed to induce apoptosis in MCF-7 breast cancer cells, defective in caspase-3, additionally implicating caspase-3 in its proapoptotic action. Aplidine also triggered an early release of cytochrome c from mitochondria, and overexpression of bcl-2 by gene transfer abrogated mitochondrial cytochrome c release and apoptosis. Aplidine rapidly induced cleavage of Bid, a mediator that connects the Fas/CD95 cell death receptor to the mitochondrial apoptosis pathway. Primary cultures of normal human cells, including hepatocytes and resting peripheral blood lymphocytes, were spared or weakly affected after Aplidine treatment. Nevertheless, mitogen (phytohemagglutinin/interleukin-2)-activated T lymphocytes resulted sensitively to the apoptotic action of Aplidine. Thus, Aplidine is an extremely potent and rapid apoptotic inducer on leukemic cells that triggers Fas/CD95- and mitochondrial-mediated apoptotic signaling routes, and shows a rather selective apoptotic action on cancer cells and activated T cells.
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PMID:Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism. 1268 30

Arsenic trioxide (As(2)O(3)) has been found to be remarkably effective in the treatment of patients with acute promyelocytic leukemia (APL). Although evidences for the proapoptotic activity of As(2)O(3) have been suggested in leukemic and other solid cancer cells, the nature of intracellular mechanisms is far from clear. In the present study, we investigated As(2)O(3) affect on the stress-responsive signaling pathways and pretreatment with antioxidants using HepG2 cells. When treated with micromolar concentrations of As(2)O(3), HepG2 cells became highly apoptotic paralleled with activation of caspase-3 and members of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK) and c-jun NH(2)-terminal kinase (JNK) but not p38 MAP kinase. However, inhibition of each kinase activity failed to inhibit apoptosis by As(2)O(3). Addition of n-acetyl cysteine (NAC) or diphenyleneiodonium (DPI) effectively protected cells from apoptosis and significantly lowered As(2)O(3)-induced activation of caspase-3. However, neither NAC nor DPI was able to effect ERK or JNK activation induced by As(2)O(3). Guanidinoethyldisulfide dihydrochloride (GED) and 2-ethyl-2-thiopseudourea (ETU), known inhibitors of the inducible nitric oxide synthase (iNOS), also suppressed the apoptotic activity of As(2)O(3). These results suggest that As2O3 induces caspase-mediated apoptosis involving a mechanism generating oxidative stress. However, activation of some stress-responsive signaling pathways by As(2)O(3) may not be the major determinant in the course of apoptotic processes.
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PMID:Arsenic trioxide-induced apoptosis is independent of stress-responsive signaling pathways but sensitive to inhibition of inducible nitric oxide synthase in HepG2 cells. 1275 11

The epidermal growth factor receptor (EGFR) is an important novel target for anticancer therapy. In this study, we examined the molecular mechanisms that underlie the antitumor effects of the anti-EGFR monoclonal antibody C225 (Cetuximab) and the selective EGFR tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca) in non-small cell lung cancer (NSCLC) cell lines. Cell growth, assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, was inhibited at low concentrations of ZD1839 and C225 in control A431 cells, whereas the NSCLC cell lines were comparatively more resistant. In A431 cells, but not in the NSCLC cells, ZD1839 treatment resulted in a modest increase in DNA fragmentation, the externalization of phosphatidyl serine, and the activation of caspase-3, known markers of apoptotic cell death. However, poly(ADP-ribose) polymerase cleavage was not detected, and caspase inhibition by carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone partially reduced ZD1839-generated DNA fragmentation. Overexpression of the antiapoptotic protein Bcl-2 in A431 cells suppressed the cytotoxicity upon anti-EGFR treatment. These results thus demonstrate that the toxic effect of ZD1839 in A431 cells is caused by a form of cell death that involves a mitochondrial step and is, at least in part, dependent on caspase activation. EGFR expression levels showed no significant correlation with sensitivity to ZD1839 and C225. Evaluation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and phosphatidylinositol 3'-kinase/Akt pathways showed considerable inhibition of these pathways by ZD1839 and C225 in A431 cells, whereas one or both of these pathways remained active upon anti-EGFR treatment in NSCLC cells. In addition, treatment with specific inhibitors of mitogen-activated protein kinase kinase or phosphatidylinositol 3'-kinase resulted in a smaller effect on proliferation than simultaneous treatment with both inhibitors, whereas induction of apoptosis was observed only when both pathways were blocked. Together, these data suggest that persistent activity of either of these signaling pathways is involved in the lack of sensitivity of NSCLC cell lines to EGFR inhibitors.
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PMID:Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. 1279 1

The SK-N-MC neuroblastoma cell line, which expresses surface tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors TRAIL-R2 and TRAIL-R4, was used as a model system to examine the effect of TRAIL on key intracellular pathways involved in the control of neuronal cell survival and apoptosis. TRAIL induced distinct short-term (1-60 min) and long-term (3-24 h) effects on the protein kinase B (PKB)/Akt (Akt), extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), nuclear factor kappa B (NF-kappaB) and caspase pathways. TRAIL rapidly (from 20 min) induced the phosphorylation of Akt and ERK, but not of c-Jun NH2-terminal kinase (JNK). Moreover, TRAIL increased CREB phosphorylation and phospho-CREB DNA binding activity in a phosphatidylinositol 3-kinase (PI 3K)/Akt-dependent manner. At later time points (from 3 to 6 h onwards) TRAIL induced a progressive degradation of inhibitor of kappaB (IkappaB)beta and IkappaBepsilon, but not IkappaBalpha, coupled to the nuclear translocation of NF-kappaB and an increase in its DNA binding activity. In the same time frame, TRAIL started to activate caspase-8 and caspase-3, and to induce apoptosis. Remarkably, caspase-dependent cleavage of NF-kappaB family members as well as of Akt and CREB proteins, but not of ERK, became prominent at 24 h, a time point coincident with the peak of caspase-dependent apoptosis.
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PMID:Tumour necrosis factor-related apoptosis-inducing ligand sequentially activates pro-survival and pro-apoptotic pathways in SK-N-MC neuronal cells. 1280 32

The clinically relevant polyamine analogue N(1),N(11)-diethylnorspermine (DENSPM) inhibits cell growth by down-regulating polyamine biosynthesis, up-regulating polyamine catabolism at the level of spermidine/spermine N(1)-acetyltransferase (SSAT), and depleting intracellular polyamine pools. Among human melanoma cell lines, the analogue causes rapid apoptosis in SK-MEL-28 cells and a sharp G(1) arrest in MALME-3M cells. This study reveals that DENSPM potently activates the mitogen-activated protein kinase (MAPK) pathways in melanoma cells and investigates the role of this response in determining cellular outcomes. Onset of apoptosis was preceded by an intense phosphorylation of the MAPKs, including extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase, and p38 in both SK-MEL-28 and MALME-3M cells. A panel of DENSPM analogues differing only in their ability to induce SSAT was used to show that MAPK activation was causally linked to induction of SSAT activity and related oxidative events. The latter was confirmed with the polyamine oxidase inhibitor MDL-75275 and the antioxidant N-acetyl-L-cysteine, which when used in combination with DENSPM, decreased MAPK activation and as previously shown, reduced apoptosis. The MAP/extracellular signal-regulated kinase-1 inhibitor PD 98059 reduced activation of all three kinases but failed to alter apoptosis in DENSPM-treated SK-MEL-28 cells. By contrast, the inhibitor prevented p21(waf1/cip1) induction and enhanced apoptosis in MALME-3M cells as indicated by accelerated caspase-3 activation and positive annexin V staining. The generality of this effect was demonstrated in DENSPM-treated A375 and LOX human melanoma cells. Taken together, the importance of the MAPK pathways in determining the biological response to DENSPM treatment is dependent on the genetic environment of the cell.
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PMID:The role of mitogen-activated protein kinase activation in determining cellular outcomes in polyamine analogue-treated human melanoma cells. 1283 50

To elucidate the role of mitogen-activated protein kinases (MAPKs) and Akt kinase in leukemogenesis caused by the breakpoint cluster region (BCR)-Abelson (ABL) tyrosine kinase oncoprotein, we examined the activities of MAPKs and Akt kinase and their roles in the action of STI571, a specific inhibitor of BCR-ABL tyrosine kinase, in chronic myelogenous leukemia (CML) cells. We found that extracellular signal-regulated kinase (ERK) 1/2 and Akt kinase are constitutively active in the chronic phase of CML, blast crisis of CML, and the CML-derived K562 cell line. Both interferon-alpha and STI571 suppressed ERK1/2 activity in K562 cells. In contrast, Akt kinase activity was inhibited only by STI571. K562 cell proliferation was markedly suppressed by LY294002, a specific inhibitor of PI3K/Akt kinase, and STI571 but not by PD98059, a specific inhibitor of MEK1/2. In addition, caspase-3 was activated by treatment of cells with STI571 and LY294002 but not with PD98059. These data indicate that Akt kinase may play a role in the proliferation of CML leukemia cells and the action of STI571. Primary leukemia cells from patients with CML blast crisis did not show inhibition of ERK1/2 or Akt kinase activity and were resistant to caspase-3-associated apoptosis after treatment with STI571. These findings suggest that STI571 does not effectively block signaling molecules downstream of the BCR-ABL tyrosine kinase in some cases of CML blast crisis.
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PMID:Involvement of Akt kinase in the action of STI571 on chronic myelogenous leukemia cells. 1285 Apr 78


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