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)

Glutamate receptor stimulation reportedly activates NF-kappaB in vitro and in vivo, although underlying mechanisms remain to be elucidated. Here we evaluated the role of proteases in mediating N-methyl-D-aspartate (NMDA) receptor agonist-induced NF-kappaB activation and apoptosis in rat striatum. The intrastriatal infusion of quinolinic acid (QA, 60 nmol) had no effect on levels of NF-kappaB family proteins, including p65, p50, p52, c-Rel and Rel B. In contrast, QA decreased IkappaB-alpha protein levels by 60% (P<0. 05); other members of the IkappaB family, including IkappaB-beta, IkappaB-gamma, IkappaB-epsilon and Bcl-3, were not altered. The QA-stimulated degradation of IkappaB-alpha was completely blocked by the NMDA receptor antagonist MK-801. QA-induced IkappaB-alpha degradation and NF-kappaB activation were not affected by the proteasome inhibitor MG-132 (1-4 microg). On the other hand, the caspase-3 inhibitor Ac-DEVD.CHO (2-8 microgram) blocked QA-induced IkappaB-alpha degradation in a dose-dependent manner (P<0.05). Ac-DEVD.CHO (4 microgram) also substantially reduced QA-induced NF-kappaB activation (P<0.05), but had no effect on QA-induced AP-1 activation. Furthermore, Ac-DEVD.CHO, but not MG-132, dose-dependently attenuated QA-induced internucleosomal DNA fragmentation. These findings suggest that NF-kappaB activation by NMDA receptor stimulation involves IkappaB-alpha degradation by a caspase-3-like cysteine protease dependent mechanism. Caspase-3 thus appears to contribute to the excitotoxin-induced apoptosis in rat striatal neurons occurring at least partially as a consequence of NF-kappaB activation.
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PMID:A caspase-3-like protease is involved in NF-kappaB activation induced by stimulation of N-methyl-D-aspartate receptors in rat striatum. 1103 44

We previously demonstrated that 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) induced apoptosis in primary cultured rat hepatocytes. In this study, we investigated apoptotic biomarkers in rat liver after perfusion with 30 microM Trp-P-1 as preliminary experiments for in vivo study. Induction of c-Myc and p53 protein and the activities of caspase-3, -6, and -8 were detected in Trp-P-1-perfused liver. In addition, Trp-P-1 modulated the DNA binding activity of the apoptosis-related transcription factors, NF-kappaB and AP-1. These results imply a possibility that Trp-P-1 would induce apoptosis in vivo.
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PMID:Detection of biomarkers for apoptosis in rat liver after perfusion with 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1). 1105 18

Methylazoximethanol (MAM) acetate-induced cell death in the external granule cell layer of the developing cerebellum affects clusters of cells with morphological features of apoptosis. This is accompanied by selective induction of active caspase-3 expression and increased c-Jun/AP-1 (N) immunoreactivity in dying cells, as revealed with immunohistochemistry. Since the antibody to cJun/AP-1 (N) cross-reacts with epitopes emerging after caspase-mediated proteolysis during apoptosis, these results indicate that MAM-induced cell death is associated with active caspase-3 expression and function in dying cells. In order to investigate the involvement of tissue-type plasminogen activator (tPA), which has been implicated in certain forms of neuronal cell death, MAM-induced cell death has been examined in tPA-/- and tPA+/+ mice. No differences in the number of dying cells, as seen with haematoxylin and eosin staining and in situ end-labelling of fragmented nuclear DNA-processed sections, were seen between tPA-/- and tPA+/+ mice. These results indicate that tPA is not involved in MAM-induced cell death in the developing brain.
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PMID:Methylazoximethanol acetate-induced cell death in the granule cell layer of the developing mouse cerebellum is associated with caspase-3 activation, but does not depend on the tissue-type plasminogen activator. 1116 42

Curcumin, in addition to its role as a spice, has been used for centuries to treat inflammatory disorders. Although the mechanism of action remains unclear, it has been shown to inhibit the activation of NF-kappaB and AP-1, transcription factors required for induction of many proinflammatory mediators. Due to its low toxicity it is currently under consideration as a broad anti-inflammatory, anti-tumor cell agent. In this study we investigated whether curcumin inhibited the response of gammadelta T cells to protease-resistant phosphorylated derivatives found in the cell wall of many pathogens. The results showed that curcumin levels > or =30 microM profoundly inhibited isopentenyl pyrophosphate-induced release of the chemokines macrophage inflammatory protein-1alpha and -1beta and RANTES. Curcumin also blocked isopentenyl pyrophosphate-induced activation of NF-kappaB and AP-1. Commencing around 16 h, treatment with curcumin lead to the induction of cell death that could not be reversed by APC, IL-15, or IL-2. This cytotoxicity was associated with increased annexin V reactivity, nuclear expression of active caspase-3, cleavage of poly(ADP-ribose) polymerase, translocation of apoptosis-inducing factor to the nucleus, and morphological evidence of nuclear disintegration. However, curcumin led to only large scale DNA chromatolysis, as determined by a combination of TUNEL staining and pulse-field and agarose gel electrophoresis, suggesting a predominantly apoptosis-inducing factor-mediated cell death process. We conclude that gammadelta T cells activated by these ubiquitous Ags are highly sensitive to curcumin, and that this effect may contribute to the anti-inflammatory properties of this compound.
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PMID:Curcumin inhibits activation of Vgamma9Vdelta2 T cells by phosphoantigens and induces apoptosis involving apoptosis-inducing factor and large scale DNA fragmentation. 1154 38

The involvement of MAPK pathways in differentiation, proliferation and survival was investigated by comparing Epo and GM-CSF signalling in human factor-dependent myeloerythroid TF-1 cells with abnormal Epo-R. GM-CSF withdrawal induced cell-cycle arrest and apoptosis accompanied by increased caspase-3 activity, DNA degradation and reduced expression of the antiapoptotic Bcl-2 and Bcl-xl proteins. Readministration of GM-CSF but not Epo reversed these processes and induced proliferation. The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. In contrast, Epo failed to activate the Raf-1/ERK1/2 MAPK pathway or to induce Egr-1 and/or c-Fos expression, while it induced erythroid differentiation in GM-CSF-deprived cells. In addition, the Epo-induced haemoglobin production was inhibited in the presence of GM-CSF. These results demonstrate that the activation of MAPK cascade is not necessary for Epo-induced haemoglobin production in TF-1 cells and suggest a negative cross-talk between the signalling of GM-CSF-stimulated cell proliferation and Epo-induced erythroid differentiation.
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PMID:Activation of Raf/ERK1/2 MAP kinase pathway is involved in GM-CSF-induced proliferation and survival but not in erythropoietin-induced differentiation of TF-1 cells. 1160 85

Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome.
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PMID:Retinoic acid prevents experimental Cushing syndrome. 1160 19

Caspases and c-Jun N-terminal kinase (JNK) are activated in tumor cells during induction of apoptosis. We investigated the signaling cascade and function of these enzymes in cisplatin-induced apoptosis. Treatment of Jurkat T-cells with cisplatin induced cell death with DNA fragmentation and activation of caspase and JNK. Bcl-2 overexpression suppressed activation of both enzymes, whereas p35 and CrmA inhibited only the DEVDase (caspase-3-like) activity, indicating that the activation of these enzymes may be differentially regulated. Cisplatin induced apoptosis with the cytochrome c release and caspase-3 activation in both wild-type and caspase-8-deficient JB-6 cells, while the Fas antibody induced these apoptotic events only in wild-type cells. This indicates that caspase-8 activation is required for Fas-mediated apoptosis, but not cisplatin-induced cell death. On the other hand, cisplatin induced the JNK activation in both the wild-type and JB-6 cells, and the caspase-3 inhibitor Z-DEVD-fmk did not inhibit this activation. The JNK overexpression resulted in a higher JNK activity, AP-1 DNA binding activity, and metallothionein expression than the empty vector-transfected cells following cisplatin treatment. It also partially protected the cells from cisplatin-induced apoptosis by decreasing DEVDase activity. These data suggest that the cisplatin-induced apoptotic signal is initiated by the caspase-8-independent cytochrome c release, and the JNK activation protects cells from cisplatin-induced apoptosis via the metallothionein expression.
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PMID:Signaling and function of caspase and c-jun N-terminal kinase in cisplatin-induced apoptosis. 1201 40

The exposure of mammalian cells to UV irradiation induces the expression of immediate early genes such as c-jun and c-fos and activates the transcription factors AP-1 and NF-kappaB. JunD is one of the three members of the Jun family and shares some functional characteristics with c-Jun. In the present study, we found that the exposure of myeloblastic leukemia ML-1 cells to UV light (UVC) caused a significant increase in junD mRNA expression within 5 min that persisted for a period of 3 h. The activation of protein kinase C (PKC) with 12-O-tetradecaoylphorbol-13-acetate (TPA) also induced increases in junD expression similar to those of UV irradiation. In addition, UV irradiation- and TPA-induced increases in junD expression were completely abolished by GF-109203X, a PKC-specific inhibitor. UV irradiation activated intracellular signaling pathways including extracellular regulated kinase-2 (Erk-2), c-Jun N-terminal kinases-1 (JNK-1), and p38. However, TPA-induced activation of PKC affected only Erk-2 activity, and GF-109203X (a PKC inhibitor) markedly suppressed UV-induced Erk-2 activation. To further investigate the effect of UV-induced Erk-2 activation on the expression of junD mRNA, cDNA encoding mitogen-activated protein kinase kinase (MEK1) was overexpressed in ML-1 cells. The overexpression of MEK1 enhanced substantially junD expression in response to UV or TPA. In contrast, the suppression of Erk activation with PD98059, a specific inhibitor of MEK1, inhibited UV- and TPA-induced junD mRNA expression, UV-induced increases in caspase-3 activities, and cell death. In addition, the overexpression of junD enhanced the UV irradiation-induced increases in caspase-3 activity and cell death. We conclude that UV irradiation-induced increases in junD expression in ML-1 cells are mediated through activation of the PKC-coupled Erk-2 signaling pathway and play an important role in ML-1 cell apoptosis.
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PMID:Ultraviolet-induced junD activation and apoptosis in myeloblastic leukemia ML-1 cells. 1208 1

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), a contaminant in our daily diet, induces apoptosis in cultured immunocytes. In this study, Trp-P-1 (1 mg/kg) was injected intraperitoneally into male Wistar rats to investigate whether Trp-P-1 induces apoptosis in immune tissues in vivo. In the thymus, Trp-P-1 induced DNA fragmentation and morphological changes. Trp-P-1 also activated the initiator and executioner caspases, caspase-8 and -3, respectively, and activated caspase-3 in turn cleaved its intracellular substrate poly(ADP-ribose) polymerase 1 hr after injection. On the other hand, Trp-P-1 upregulated anti-apoptotic factors Bcl-2 and Bcl-XL and downregulated pro-apoptotic factor Bax in mitochondria 1 hr after injection, indicating that Trp-P-1 also stimulated anti-apoptotic signals. Trp-P-1 activated the serine-threonine protein kinase Akt, which is known to be an anti-apoptotic protein, and increased the DNA binding activities of apoptosis-associated transcription factors NF-kappaB and AP-1. In addition to the thymus, increases in the activities of these transcription factors were also observed in the spleen and in mononuclear cells from the blood. Therefore, Trp-P-1 activates both pro- and anti-apoptotic signals in vivo in the immune system, particularly in the thymus, and the former signal overcomes the latter.
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PMID:Apoptosis in the thymus after intraperitoneal injection of rats with Trp-P-1. 1235 51

Chronic treatment with calcium ionophore A23187 in NGF-differentiated cells results in cell death that is time- and concentration-dependent. Additionally, PC12 cells codifferentiated with NGF and dBcAMP become dependent on these factors for survival and undergo apoptosis when both factors are withdrawn. We show that in both cases there is a prolonged induction of c-Fos which correlates with cell death. Its continual activation in PC12 cells overexpressing c-FosER results in caspase-3 cleavage and rapid cell death. Specific phosphorylation of CREB/CREM(tau) transactivators or their binding to CRE of c-fos was observed. Our results indicate that prolonged c-Fos induction activates p53. There is increased nuclear localization of p53, p21 and Bax levels are induced in NGF/dBcAMP-deprived c-FosER cells, and dominant negative p53 inhibits cell death induced either by serum deprivation or by c-Fos. Overall these data implicate AP-1 as a nuclear target of signal transduction pathways which plays a role in the activation of apoptosis.
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PMID:Molecular mechanisms of neuronal cell death: implications for nuclear factors responding to cAMP and phorbol esters. 1235 47


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