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)

Nitric oxide (NO) induces apoptotic cell death and cAMP has a significantly protective effect on NO-induced cytotoxicity in human osteoblasts, MG-63 cells. Treatment with S-nitroso-N-acetylpenicillamine (SNAP) (0.6 mM) resulted in genomic DNA fragmentation, characteristic of apoptosis. However, concomitant incubation of the cells with either DBcAMP or forskolin markedly inhibited SNAP-induced apoptosis in a dose-dependent manner. Furthermore, pretreatment of MG-63 cells with H-89 or KT5720, which is known to inhibit cAMP-dependent protein kinase (PKA), abolished the protective effect of DBcAMP and forskolin on SNAP-induced apoptosis. In this study, we explored the involvement of caspases in the regulatory mechanism of SNAP-induced apoptosis by cAMP. Our data show that DBcAMP or forskolin blocked SNAP-induced caspase-3-like cysteine protease activation and that H-89, a PKA inhibitor, reversed the cAMP-induced regulatory effect of caspase-3 like protease. Consistent with the results, cAMP inhibited the proteolytic cleavage of caspase-3, -6, -9 and cytochrome c release to cytoplasm. The inhibition of caspase-3 activation did not block SNAP-induced cytochrome c release to cytoplasm, suggesting that caspase-3 activation may occur downstream of cytochrome c release. In summary, these findings show that the exposure of MG-63 cells to cAMP analogs renders them more resistant to NO-induced damage and suggests the presence of regulatory mechanisms of the cell death pathway by cAMP in which caspase-3, -6, and -9 and cytochrome c release serves to mediate NO-induced apoptosis.
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PMID:Cyclic-AMP inhibits nitric oxide-induced apoptosis in human osteoblast: the regulation of caspase-3, -6, -9 and the release of cytochrome c in nitric oxide-induced apoptosis by cAMP. 1137 59

We measured the effects of stable thromboxane A2 (TXA2) analogues on signalling in cultured human myometrial cells. U46619 and/or IBOP stimulated total inositol phosphates (IPs) and cAMP production, RhoA-associated protein kinase (ROK) activity and elevated intracellular calcium [Ca2+]i. Pretreatment of the cells with pertussis toxin did not inhibit IPs or [Ca2+]i production but the thromboxane receptor (TP) antagonist SQ-29548 did inhibit IPs and cAMP production, the elevation of [Ca2+]i, and the increase in ROK activity. Pretreatment with thapsigargin inhibited [Ca2+]i elevation. TP receptor-stimulated ROK activity was inhibited by the ROK inhibitor Y27632 while ROK activity was enhanced by the caspase 3 inhibitor, Z-DEVD-FMK. TP receptor-stimulated IPs production is additive to prostaglandin F2alpha (FP) or prostaglandin E (EP) receptor-stimulated IPs production and neither FP nor EP receptor-stimulated IPs production is inhibited by SQ29548. Thus cultured human myometrial cells express at least two functional TP receptor subtypes; TPalpha-like (cAMP-stimulating) and TPbeta-like (IPs, [Ca2+] and ROK-stimulating).
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PMID:Thromboxane receptor signalling in human myometrial cells. 1178 96

The effects of different calcium-mobilizing agents on cell death were characterized in NG108-15 neuroblastoma x glioma hybrid cells. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) increased the cytosolic Ca(2+) concentration ([Ca(2+)](i)) and caused cell death. Thapsigargin (TG) not only increased the [Ca(2+)](i) and caused cell death but also induced neurite outgrowth via activation of phospholipase A(2) and cytochrome P450 epoxygenase. In contrast, bradykinin increased the [Ca(2+)](i), but had no effect on cell morphology or cell death. Cell death occurred by two different mechanisms, one of which was caspase-3-dependent and the other caspase-3-independent. Caspase-3 activation was Ca(2+)-dependent, whereas neurite outgrowth was Ca(2+)-independent. TG- or FCCP-induced caspase-3 activation occurred at the same time, but the cell death induced by TG was delayed. TG treatment did not enhance the generation of nitric oxide or cAMP or secretion of glial-derived neurotrophic factor or neurotrophin-3, but activated sphingosine kinase. Furthermore, inhibition of sphingosine kinase accelerated TG-induced cell death, and exogenous sphingosine 1-phosphate (S1P) protected cells from FCCP-induced cell death by about 60%. These results indicate that, in these cells, depletion of intracellular nonmitochondrial or mitochondrial Ca(2+) stores causes cell death, that TG activates phospholipase A(2) and sphingosine kinase, and that arachidonic acid induces neurite outgrowth, whereas S1P delays cell death.
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PMID:Distinct effects of different calcium-mobilizing agents on cell death in NG108-15 neuroblastoma X glioma cells. 1185 28

A number of cyclin-dependent protein kinase (CDK) inhibitors were tested for the ability to protect IPC-81 rat leukemic cells against cAMP-induced apoptosis. A near perfect proportionality was observed between inhibitor potency to protect against cAMP-induced apoptosis and to antagonize CDK5, and to a lesser extent, CDK2 and CDK1. Enforced expression of dominant negative CDK5 (but not CDK1-dn or CDK2-dn) protected against death, indicating that CDK5 activity was necessary for cAMP-induced apoptosis. The CDK inhibitors failed to protect the cells against daunorubicine-, staurosporine-, or okadaic acid-induced apoptosis. The inhibition of CDK5 prevented the cleavage of pro-caspase-3 in cAMP-treated cells. The cells could be saved closer to the moment of their onset of death by inhibitors of caspases than by inhibitors of CDK5. This suggested that the action of CDK5 was upstream of caspase activation. The cAMP treatment resulted in a moderate increase of the level of CDK5 mRNA and protein in IPC-81 wild-type cells. Such cAMP induction of CDK5 was not observed in cells expressing the inducible cAMP early repressor. The cAMP-induced increase of CDK5 contributed to apoptosis since cells overexpressing CDK5-wt were more sensitive for cAMP-induced death. These results demonstrate the first example of a proapoptotic CDK action upstream of caspase activation and of an extra-neuronal effect of CDK5.
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PMID:A novel, extraneuronal role for cyclin-dependent protein kinase 5 (CDK5): modulation of cAMP-induced apoptosis in rat leukemia cells. 1190 54

The elevation of intracellular cAMP content is accompanied by expression of genes whose promoter contains a Ca(2+)-cAMP responsive element. In vascular smooth muscle cells (VSMC), activation of cAMP signaling blocks apoptosis triggered by serum deprivation. In the present study we investigated the role of gene expression in the inhibition of apoptosis by cAMP. In VSMC transfected with E1A adenovirus, incubation in the absence of serum for 6 h led to 20-fold elevation of chromatin fragmentation and 10-fold activation of caspase-3 activity, these being employed as markers of apoptosis. Forskolin-induced activation of cAMP signaling was accompanied by 50% elevation of RNA synthesis and completely abolished the development of apoptosis during the initial 6 h incubation in growth factor-free medium. In 12 h apoptosis in forskolin-treated VSMC was slowly developed and after 24 h the content of chromatin fragments was 2-fold less than in control cells. Addition of actinomycin D and cycloheximide completely blocked RNA synthesis and decreased protein synthesis by 80%, respectively. Neither compound affected baseline apoptosis or its inhibition by forskolin. More than 70 newly phosphorylated proteins were observed by 2D-electrophoresis of VSMC after incubation with forskolin for 3 h; in 24 h the number of phosphoproteins triggered by forskolin was decreased by 2-3-fold. These results show that suppression of VSMC apoptosis under activation of cAMP signaling is mediated via posttranslational modification of pre-existing intermediates of the apoptotic machinery rather than by de novo synthesis of inhibitors of programmed cell death.
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PMID:Suppression of programmed cell death by intracellular cAMP is not mediated by expression of genes encoding an inhibitor of apoptosis. 1195 23

Sunghyangjungisan (SHJS) is a commonly prescribed drug for cerebrovascular diseases in Oriental medicine. The water extract of SHJS was found to be protective against neurotoxicity elicited by deprivation of tropic factors. SHJS inhibited the activation of caspase 3-like protease and nucleosome-sized DNA fragmentation in serum-deprived PC12 Pheochromocytoma cells. Interestingly, pretreatment with an inhibitor of protein kinase A, KT5720 inhibited the neuroprotective effects of SHJS via inhibition of capase 3-like protease activation. When PC12 cells were treated with SHJS, Ser133 phosphorylation of cAMP-responsive elements binding protein (CREB), a transcription factor, was also increased in a time- and dose-dependent manner. In addition, CRE DNA binding activity of CREB was also increased in a time-dependent manner. SHJS-induced CRE binding activity was blocked by KT5720. Taken together, we suggest the possibility that SHJS may provide a neuroprotective effects on serum-deprived apoptosis of PC12 cells in a CREB- and CRE-dependent manner.
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PMID:Sunghyangjungisan protects PC12 cells against neurotoxicity elicited by withdrawal of trophic support via CRE activation. 1202 48

Akt is a serine/threonine kinase that is believed to promote cell viability in many different cell types, including neurons. Here, we observed the state of Akt phosphorylation at several time points (1, 3, 6, 12, and 24 h) during permanent occlusion of the middle cerebral artery (MCA) in mice. We detected a transient upregulation of Akt phosphorylation at 1 h of MCA occlusion (MCAO) by Western blot analysis. Double immunostaining revealed that the enhanced phosphorylation of Akt occurred mainly in neurons located in the outer area of the MCA territory (ischemic penumbra). This phenomenon was accompanied by the nuclear translocation of Akt. We confirmed that Akt enzymatic activity is elevated in both the nuclear and cytosolic fractions of brain tissue subjected to 1 h of ischemia. cAMP-response-element-binding protein (CREB), an intranuclear target molecule of Akt, exhibited increased phosphorylation after 1 h of MCAO. In our ischemia model, caspase-3 was activated in the central part of the MCA territory as little as 1 h after MCAO. However, caspase-3 activation was not recognized at this time in the outer area of the MCA territory, where Akt activity was upregulated. These results suggest that prosurvival cell signaling is initiated in an active fashion before cell death pathways are activated in neurons situated in the ischemic penumbra at the early stage of ischemia.
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PMID:Upregulation of Akt phosphorylation at the early stage of middle cerebral artery occlusion in mice. 1203 47

We have previously shown that cAMP protects against bile acid-induced apoptosis in cultured rat hepatocytes in a phosphoinositide 3-kinase (PI3K)-dependent manner. In the present studies, we investigated the mechanisms involved in this anti-apoptotic effect. Hepatocyte apoptosis induced by glycodeoxycholate (GCDC) was associated with mitochondrial depolarization, activation of caspases, the release of cytochrome c from the mitochondria, and translocation of BAX from the cytosol to the mitochondria. cAMP inhibited GCDC-induced apoptosis, caspase 3 and caspase 9 activation, and cytochrome c release in a PI3K-dependent manner. cAMP activated PI3K in p85 immunoprecipitates and resulted in PI3K-dependent activation of the survival kinase Akt. Chemical inhibition of Akt phosphorylation with SB-203580 partially blocked the protective effect of cAMP. cAMP resulted in wortmannin-independent phosphorylation of BAD and was associated with translocation of BAD from the mitochondria to the cytosol. These results suggest that GCDC-induced apoptosis in cultured rat hepatocytes proceeds through a caspase-dependent intracellular stress pathway and that the survival effect of cAMP is mediated in part by PI3K-dependent Akt activation at the level of the mitochondria.
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PMID:cAMP inhibits bile acid-induced apoptosis by blocking caspase activation and cytochrome c release. 1218 Nov 89

Pituitary adenylate cyclase activating polypeptide (PACAP) modulates neurotransmission in the central and peripheral nervous systems. In vitro and in vivo studies have shown the protective effects of PACAP against neuronal damage induced by ischemia and agonists of NMDA-type glutamate receptors. Here, we demonstrated that PACAP also protected against neuronal toxicity induced by beta-amyloid (Abeta) peptide, aggregation of which is a causative factor for Alzheimer's disease. PACAP (10(-9)M) rescued 80% of decreased cell viability and 50% of elevated caspase-3 activity that resulted from exposure of PC12 cells to Abeta. PACAP was at least 10(4)-fold more effective than other neuropeptides including vasoactive intestinal peptide (VIP) and humanin, which correlated with the level of cAMP accumulation. Thus, our results suggested that PACAP attenuates Abeta-induced cell death in PC12 cells through an increase in cAMP and that caspase-3 deactivation by PACAP is involved in the signaling pathway for this neuroprotection.
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PMID:The neuropeptide PACAP attenuates beta-amyloid (1-42)-induced toxicity in PC12 cells. 1218 49

We previously reported that adrenomedullin produced by cardiac myocytes acts as a local modulator in some cardiac disorders. However, the role of adrenomedullin (AM) in cardiomyocyte apoptosis remains to be clarified. The present study investigated the effect of AM on doxorubicin-induced cardiac myocyte apoptosis. Doxorubicin increased the number of cells with pyknotic nuclei and lactate dehydrogenase release, and AM dose-dependently (10(-10)-10(-8)6 M) inhibited these increases produced by doxorubicin. Treatment with AM also suppressed doxorubicin-induced DNA fragmentation and caspase-3 activation. 8-Bromo-cAMP, a cAMP analog, mimicked these antiapoptotic effects of AM. An AM/calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) and a protein kinase A inhibitor H89 attenuated the antiapoptotic effect of AM. CGRP-(8-37) and H89 had no apoptotic effect alone, but accelerated doxorubicin-induced apoptosis. Under serum-free conditions, AM secretion into the culture medium and expression of AM mRNA were significantly increased after treatment with doxorubicin. Hydrogen peroxide scavenger catalase and antioxidant N-acetyl-L-cysteine inhibited the doxorubicin-mediated increase in AM secretion and its gene expression. These results indicate that AM inhibits doxorubicin-induced cardiac myocyte apoptosis through a cAMP-dependent mechanism and suggest that augmented production of AM by doxorubicin has an endogenous antiapoptotic effect. AM, as an autocrine factor, may play a protective role against cardiomyocyte injury by doxorubicin.
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PMID:Adrenomedullin inhibits doxorubicin-induced cultured rat cardiac myocyte apoptosis via a cAMP-dependent mechanism. 1219 65


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