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)

In articular chondrocytes, nitric oxide (NO) production triggers dedifferentiation and apoptotic cell death that is regulated by the converse functions of two mitogen-activated protein kinase subtypes, extracellular signal-regulated kinase (ERK) and p38 kinase. Since protein kinase C (PKC) transduces signals that influence differentiation, survival, and apoptosis of various cell types, we investigated the roles and underlying molecular mechanisms of action of PKC isoforms in NO-induced dedifferentiation and apoptosis of articular chondrocytes. We report here that among the expressed isoforms, activities of PKCalpha and -zeta were reduced during NO-induced dedifferentiation and apoptosis. Inhibition of PKCalpha activity was independent of NO-induced activation of ERK or p38 kinase and occurred due to blockage of expression. On the other hand, PKCzeta activity was inhibited as a result of NO-induced p38 kinase activation and was observed prior to proteolytic cleavage by a caspase-mediated process to generate enzymatically inactive fragments. Inhibition of PKCalpha or -zeta activities potentiated NO-induced apoptosis, whereas ectopic expression of these isoforms significantly reduced the number of apoptotic cells and blocked dedifferentiation. Ectopic expression of PKCalpha or -zeta did not affect p38 kinase or ERK but inhibited the p53 accumulation and caspase-3 activation that are required for NO-induced apoptosis of chondrocytes. Therefore, our results collectively indicate that p38 kinase-independent and -dependent inhibition of PKCalpha and -zeta, respectively, regulates NO-induced apoptosis and dedifferentiation of articular chondrocytes.
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PMID:p38 kinase-dependent and -independent Inhibition of protein kinase C zeta and -alpha regulates nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes. 1204 19

Helicobacter pylori is a primary factor in the etiology of gastric disease, and its early pathogenic effects are manifested by up-regulation of inflammatory processes and the loss of mucus coat continuity. We investigated the role of extracellular signal-regulated kinase (ERK) and p38 mitogen activated protein kinase (MAPK) in the disturbances in gastric mucin synthesis and apoptotic processes evoked by H. pylori lipopolysaccharide (LPS). Exposure of gastric mucosal cells to the LPS led to a dose-dependent decrease (up to 59.5%) in mucin synthesis, accompanied by a marked increase in caspase-3 activity and apoptosis. Inhibition of ERK with PD98059 accelerated (up to 36.1%) the LPS-induced decrease in mucin synthesis, and caused further enhancement in caspase-3 activity and apoptosis. Blockade of p38 kinase with SB203580 produced reversal in the LPS-induced reduction in mucin synthesis, and substantially countered the LPS-induced increases in caspas-3 activity and apoptosis. Moreover, inhibition of caspase-3 blocked the LPS-induced increase in caspse-3 activity and produced an increase in mucin synthesis. Thus the detrimental influence of H. pylori LPS on gastric mucin synthesis is closely linked to caspase-3 activation and apoptosis, and involves ERK and p38 kinase participation.
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PMID:Disruption in gastric mucin synthesis by Helicobacter pylori lipopolysaccharide involves ERK and p38 mitogen-activated protein kinase participation. 1205 97

Heat shock proteins (HSPs) have been shown to act as inhibitors of apoptosis, but this anti-apoptotic effect is not known in the central nervous system. Prior heat shock has been demonstrated to protect astrocytes from cell death in a model of reperfusion injury (Brain Res. 735 (1996) 265). The present study examines the mechanism underlying the protective effect of the heat shock. Preincubation of astrocytes at 40 degrees C for 10 min attenuated the hydrogen peroxide (H(2)O(2))-induced decrease in cell viability, DNA ladder formation and nuclear condensation, and these effects were blocked by the protein synthesis inhibitor cycloheximide. The thermal stress inhibited the H(2)O(2)-induced increase in caspase-3 like protease activity, but it did not affect the H(2)O(2)-induced loss of mitochondrial membrane potential. The cytosol prepared from preheated cells did not affect Ca(2+)-induced swelling of mitochondria, a marker of the permeable transition pore. The protective effect of the thermal stress on the H(2)O(2)-induced decrease in cell viability was not affected by the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor 2'-amino-3'-methoxyflavone, the phosphatidylinositol-3 kinase inhibitor wortmannin and the NF-kappaB inhibitor pyrrolidinedithiocarbamate. These findings suggest that HSPs inhibit apoptosis via an inhibition of caspase-3 activation without effect on mitochondrial dysfunction.
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PMID:Heat shock inhibits hydrogen peroxide-induced apoptosis in cultured astrocytes. 1213 26

Imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate (NAMI-A) is a new ruthenium compound active against lung metastasis in vivo and tumor cell invasion in vitro. Since angiogenesis was recognized as a key event in the metastasizing process, the manipulation of neo-vessel formation has been developed as a new therapeutic approach. Within this context, a pivotal role for apoptosis in regulating cellular growth has been proposed. In the present study, we exposed to NAMI-A the spontaneously transformed human endothelial cell line ECV304 and assessed a number of apoptosis-related features, including the DNA degradation rate, the activation of caspase-3 protease, the expression of Hsp27, and the release of cytochrome c. Cell treatment with NAMI-A elicited a significant increment in the apoptotic response, as indicated by DNA fragmentation and caspase-3 activation, two classical hallmarks of cellular suicide. Furthermore, NAMI-A was able to down-regulate Hsp27 protein expression and provoke the release of mitochondrial cytochrome c in the cytosol. Here, we analyze the involvement of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signal transduction pathway in the induction of apoptosis elicited by NAMI-A. Such a response was associated with a marked inhibition of MAPK/ERK kinase (MEK) and ERK phosphorylation with a time course and dose dependency overlapping those observed throughout NAMI-A-induced apoptosis. In addition, we report that PD98059, a selective MEK inhibitor, is able to induce apoptosis by itself in the ECV304 cell line. These results suggest that inhibition of MEK/ERK signaling by NAMI-A may have an important role in modulating an apoptotic event in ECV304.
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PMID:The anti-metastatic agent imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate induces endothelial cell apoptosis by inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway. 1213 70

The authors used cultured mouse cortical neurons to study mechanisms of DNA damage-induced apoptosis in immature and mature neurons. Neurons were maintained viably for 60 days in vitro (DIV60). The increased levels of glutamate receptors, synaptic proteins, and glycolytic enzyme were used to track maturation. Exposure of neurons to the DNA-damaging agent camptothecin induced apoptosis in immature (DIV5) and mature (DIV25-30) neurons. Internucleosomal fragmentation of DNA emerged more rapidly in mature neurons than in immature neurons. Immunoblotting revealed that cleaved caspase-3 increased in apoptotic DIV5 neurons but not in DIV30 neurons, but immunolocalization showed accumulation of cleaved caspase-3 in DIV5 and DIV30 neurons. A reversible caspase-3 inhibitor blocked apoptosis in DIV5 neurons but not in DIV30 neurons. Phosphorylation of extracellular signal-regulated kinase/mitogen-activated protein kinase (Erk/MAP kinase)-42/44 occurred preapoptotically in mature but not immature neurons, while Erk54 nuclear translocation and MAP kinase kinase kinase-1 cleavage into putative caspase-3-generated proapoptotic fragments occurred in DIV5 but not DIV30 neurons. Inhibition of Erk activation with MAP kinase kinase inhibitor blocked apoptosis at both ages. The results show that immature and mature cortical neurons engage different signaling mechanisms in MAP kinase and caspase pathways during apoptosis; thus, neuron age influences the mechanisms and progression of apoptosis.
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PMID:Immature and mature cortical neurons engage different apoptotic mechanisms involving caspase-3 and the mitogen-activated protein kinase pathway. 1217 79

Human neutrophil granulocytes die rapidly, and their survival is contingent upon rescue from programmed cell death by signals from the environment. Here we report that a novel signal for delaying neutrophil apoptosis is the classic acute phase reactant, C-reactive protein (CRP). However, this anti-apoptotic activity is expressed only when the cyclic pentameric structure of CRP is lost, resulting in formation of modified or monomeric CRP (mCRP), which may be formed in inflamed tissues. By contrast, native pentameric CRP and CRP peptides 77-82, 174-185, and 201-206 failed to affect neutrophil apoptosis. The apoptosis delaying action of mCRP was markedly attenuated by an antibody against the low affinity IgG immune complex receptor (CD16) but not by an anti-CD32 antibody. mCRP evoked a transient concurrent activation of the extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt signaling pathways, leading to inhibition of caspase-3 and consequently to delaying apoptosis. Consistently, pharmacological inhibition of either ERK or Akt reversed the anti-apoptotic action of mCRP; however, they did not produce additive inhibition. Thus, mCRP, but not pentameric CRP or peptides derived from CRP, promotes neutrophil survival and may therefore contribute to amplification of the inflammatory response.
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PMID:Loss of pentameric symmetry of C-reactive protein is associated with delayed apoptosis of human neutrophils. 1219 21

A number of highly virulent, intracellular bacteria are known to induce cell death by apoptosis in infected host cells. In this work we demonstrate that phagocytosis of bacteria from the Escherichia coli laboratory strain K12 DH5alpha is a potent cell death stimulus for mouse macrophages. RAW264.7 mouse macrophages took up bacteria and digested them within 2-4 h as investigated with green fluorescent protein-expressing bacteria. No evidence of apoptosis was seen at 8 h postexposure, but at 24 h approximately 70% of macrophages displayed an apoptotic phenotype by a series of parameters. Apoptosis was blocked by inhibition of caspases or by forced expression of the apoptosis-inhibiting protein Bcl-2. Processing of caspase-3 and caspase-9 but not caspase-8 was seen suggesting that the mitochondrial branch of the apoptotic pathway was activated. Active effector caspases could be detected in two different assays. Because the adapter molecule myeloid differentiation factor 88 (MyD88) has been implicated in apoptosis, involvement of the Toll-like receptor pathway was investigated. In RAW264.7 cells, heat-treated bacteria were taken up poorly and failed to induce significant apoptosis. However, cell activation was almost identical between live and heat-inactivated bacteria as measured by extracellular signal-regulated kinase activation, generation of free radicals, and TNF secretion. Furthermore, primary bone marrow-derived macrophages from wild-type as well as from MyD88-deficient mice underwent apoptosis upon phagocytosis of bacteria. These results show that uptake and digestion of bacteria leads to MyD88-independent apoptosis in mouse macrophages. This form of cell death might have implications for the generation of the immune response.
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PMID:Caspase-9/-3 activation and apoptosis are induced in mouse macrophages upon ingestion and digestion of Escherichia coli bacteria. 1221 35

Ceramide is implicated in the regulation of various signaling pathways leading to proliferation, differentiation or apoptotic cell death, but there have been few investigations about the effects of ceramide on the cell growth and the melanogenesis of melanocytes. In the present study, we investigated the effects of cell-permeable ceramide on Malme-3M human melanoma cell line. MTT proliferation assay showed that C2-ceramide inhibited the growth of Malme-3M cells in a dose-dependent manner. Cell cycle analysis confirmed the inhibition of DNA synthesis by a reduction in the S phase and an increase in the G0/G1 phase. Flow cytometric analysis for apoptotic cells and morphological observations indicated that the antiproliferative effect of C2-ceramide was not due to apoptosis. We next investigated the effects of C2-ceramide on the pigmentation of Malme-3M melanoma cells. The results showed that C2-ceramide induced only a slight decrease of tyrosinase activity and melanin synthesis. To investigate the ceramide signaling pathway, we studied the influence of C2-ceramide on extracellular signal-regulated kinase (ERK) and Akt activation by Western blot. We demonstrated that the amount of phosphorylated Akt was decreased by C2-ceramide, whereas ERK was activated transiently. Because of a well-known involvement of ceramide in apoptosis, we further investigated the level of caspase-3 and HSP70 after treatment of C2-ceramide. We found that the caspase-3 was not activated and the expression of HSP70 increased moderately. In conclusion, C2-ceramide inhibited the cell growth of Malme-3M cells without the induction of apoptosis. We suggest that increased HSP70 may be related to the resistance against apoptosis.
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PMID:Effects of C2-ceramide on the Malme-3M melanoma cell line. 1235 15

Porphyromonas gingivalis is a Gram-negative periodontopathic bacterium colonizing the oral cavity and its lipopolysaccharide (LPS) is a key factor in the development of periodontitis. We investigated the effect of P. gingivalis LPS on the cellular responses associated with mucin synthesis in sublingual salivary gland acinar cells. Exposure of the acinar cells to the LPS led to a dose-dependent decrease in mucin synthesis and was accompanied by a massive induction in inducible nitric oxide synthase (NOS-2) activity and the increase in NO production, caspase-3 activity and apoptosis. Inhibition of extracellular signal-regulated kinase (ERK) with PD98059 accelerated the LPS-induced decrease in the glycoprotein synthesis and caused further increase in apoptosis and NOS-2 activity, while the blockade of p38 mitogen-activated kinase (MAPK) with SB203580 countered the LPS-induced reduction in the glycoprotein synthesis and obviated the induced increases in NOS-2 and apoptosis. Introduction of NOS-2 inhibitor, L-NAME, not only countered the LPS-induced increase in NO generation, caspase-3 activity and apoptosis, but caused the impedance of the LPS inhibition on mucin synthesis. The findings point to the upregulation in NOS-2 expression by P. gingivalis LPS as a key detrimental culprit affecting salivary mucin synthesis.
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PMID:Porphyromonas gingivalis lipopolysaccharide interferes with salivary mucin synthesis through inducible nitric oxide synthase activation by ERK and p38 kinase. 1237 6

EB1089, a novel vitamin D3 analog, has been shown to have cytotoxic and antiproliferative properties in a variety of malignant cells. However, its potential as a treatment for B-cell chronic lymphocytic leukemia (B-CLL) has not been evaluated. EB1089 induced apoptosis in all of the 102 B-CLL samples tested with a mean LD(50) (the concentration of EB1089 required to kill 50% of cells) value (+/- SD) of 2.1 x 10(-8) M (+/- 1.4 x 10(-8) M). Furthermore, no significant difference was found in the cytotoxicity of EB1089 in B-CLL samples from previously treated and untreated patients (P =.1637). Induction of apoptosis was associated with a reduction in Bcl-2 and Mcl-1 protein expression, but this was evident only in the apoptotic cells. In contrast, the expression of Bax, p21, and p53 was not altered in the viable or apoptotic cells from either B- or T-lymphocyte lineages. EB1089-induced apoptosis was preceded by activation of p38 mitogen-activated protein (MAP) kinase and suppression of extracellular signal-regulated kinase (ERK) activity, and this was associated with downstream activation of caspase-3. The pancaspase inhibitor (Z-VAD-FMK) and the caspase-9 inhibitor (Z-LEHD-FMK) were able to partially abrogate the apoptotic effects of EB1089 but did not affect the phosphorylation of p38 MAP kinase or the suppression of ERK. The B-CLL cells in the study were shown to highly express vitamin D receptor, but an additional receptor-independent mechanism of cell killing cannot be ruled out at this stage. These findings show that EB1089 is a potent apoptosis-inducing agent in B-CLL cells and may be useful in the treatment of B-CLL patients, particularly those with p53 mutations or drug-resistant disease.
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PMID:The vitamin D3 analog EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro. 1244 53


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