Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The serine/threonine glycogen synthase kinase 3beta (GSK-3beta) is abundant in the central nervous system, particularly in the hippocampus, and plays a pivotal role in the pathophysiology of a number of diseases, including neurodegeneration. This study was designed to investigate the effects of GSK-3beta inhibition against I/R injury in the rat hippocampus. Transient cerebral ischemia (30 min) followed by 1 h of reperfusion significantly increased generation of reactive oxygen species and modulated superoxide dismutase activity; 24 h of reperfusion evoked apoptosis (determined as mitochondrial cytochrome c release and Bcl-2 and caspase-9 expression), resulted in high plasma levels of TNF-alpha and increased expression of cyclooxygenase-2, inducible nitric oxide synthase, and intercellular adhesion molecule-1. The selective GSK-3beta inhibitor, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), was administered before and after ischemia or during reperfusion alone to assess its potential as prophylactic or therapeutic strategy. Prophylactic or therapeutic administration of TDZD-8 caused the phosphorylation (Ser(9)) and hence inactivation of GSK-3beta. Infarct volume and levels of S100B protein, a marker of cerebral injury, were reduced by TDZD-8. This was associated with a significant reduction in markers of oxidative stress, apoptosis, and the inflammatory response resulting from cerebral I/R. These beneficial effects were associated with a reduction of I/R-induced activation of the mitogen-activated protein kinases JNK1/2 and p38 and nuclear factor-kappaB. The present study demonstrates that TDZD-8 protects the brain against I/R injury by inhibiting GSK-3beta activity. Collectively, our data may contribute to focus the role of GSK-3beta in cerebral I/R.
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PMID:Treatment with the glycogen synthase kinase-3beta inhibitor, TDZD-8, affects transient cerebral ischemia/reperfusion injury in the rat hippocampus. 1832 34

Endostatin (ES) was reported to stimulate apoptosis in endothelial cells, but the exact mechanism remains controversial. In the present study, we elucidate the mechanism of ES-induced endothelial cell apoptosis. Our results indicate that ES induces cytochrome c release and caspase-9 activation in human microvascular endothelial cells (HMECs) at the concentration of 1 microM for 24 h, which initiates the apoptosis process. Further, ATP production, mitochondrial membrane potential, and tubule formation assays showed that ES promotes the mitochondrial permeability transition pore (mPTP) opening via voltage-dependent anion channel 1 (VDAC1), a major component of mitochondrial outer membrane. Knocking down VDAC1 by small interfering RNA attenuates ES-induced apoptosis, while overexpression of VDAC1 enhances the sensitivity of endothelial cells to ES. Moreover, we reveal that ES induces the reduction of hexokinase 2 (HK2), which, in turn, promotes VDAC1 phosphorylation and accumulation. Data from two-dimensional electrophoresis, immunoprecipitation, mPTP opening, and caspase-3 activation assays indicate that two serine residues of VDAC1, Ser-12 and Ser-103, can modulate VDAC1 protein level and thus the sensitivity to apoptosis stimuli. On the basis of these findings, we conclude that VDAC1 plays a vital role in modulating ES-induced endothelial cell apoptosis.
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PMID:Voltage-dependent anion channel 1 is involved in endostatin-induced endothelial cell apoptosis. 1838 14

Costunolide, isolated from the stem bark of Magnolia sieboldii, is a sesquiterpene lactone that exhibits various biological and immunological actions. We investigated the induction mechanism of apoptosis by costunolide in a human B cell leukemia NALM-6 cell culture system. Costunolide (10 microM)-induced apoptosis time-dependently increased, estimated by nuclear damage observation and flow cytometric analysis. Costunolide did not change Fas-associated factor 1 (FAF1), but the phosphorylation of Fas-associated death domain (FADD) at serine 194 increased from early treatment. The activation of caspase-8 and -9 and degradation of poly-(ADP-ribose) polymerase (PARP) was time-dependently detected by incubation with costunolide. Pretreatment of cells with caspase-3, -8 and broad spectrum caspase inhibitors significantly blocked costunolide-induced apoptosis, but caspase-9 inhibitor failed to block apoptosis. Telomerase activity was significantly suppressed after treatment with costunolide, and human telomerase reverse transcriptase (hTERT), a critical determinant of the enzyme activity of telomerase, decreased the expression of both mRNA and protein levels by costunolide. Costunolide-induced repression of telomerase was prevented by pretreatment of cells with caspase-3, -8 and broad spectrum caspase inhibitors, but caspase-9 inhibitor was no effect. These data suggest that one of the costunolide-induced apoptotic mechanisms is that the receptor-mediated pathway precedes the mitochondria-dependent pathway, caused by the inhibition of telomerase activity via suppression of hTERT in NALM-6 cells.
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PMID:Costunolide-induced apoptosis is caused by receptor-mediated pathway and inhibition of telomerase activity in NALM-6 cells. 1845 40

Previous studies from our laboratory had indicated that cytochrome c-independent processing and activation of caspase-9 by caspase-8 contributed to early amplification of the caspase cascade in tumor necrosis factor (TNF)-alpha-treated murine cells. Here we show that murine caspase-9 is phosphorylated by casein kinase 2 (CK2) on a serine near the site of caspase-8 cleavage. CK2 has been shown to regulate cleavage of the pro-apoptotic Bid protein by phosphorylating serine residues near its caspase-8 cleavage site. Similarly, CK2 modification of Ser(348) on caspase-9 appears to render the protease refractory to cleavage by active caspase-8. This phosphorylation did not affect the ability of caspase-9 to autoprocess. Substitution of Ser(348) abolished phosphorylation but not cleavage, and a phospho-site mutant promoted apoptosis in TNF-alpha-treated caspase-9 knock-out mouse embryo fibroblasts. Furthermore, inhibition of CK2 activity and RNA interference-mediated knockdown of the kinase accelerated caspase-9 activation, whereas phosphatase inhibition delayed both caspase-9 activation and death in response to TNF receptor occupation. Taken together, these studies show that TNF receptor cross-linking promotes dephosphorylation of caspase-9, rendering it susceptible to processing by activated caspase-8 protein. Thus, our data suggest that modification of procaspase-9 to protect it from inappropriate cleavage and activation is yet another mechanism by which the oncogenic kinase CK2 promotes survival.
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PMID:Phosphorylation of murine caspase-9 by the protein kinase casein kinase 2 regulates its cleavage by caspase-8. 1846 26

Bioassay directed fractionation and purification led to the successful isolation of a furano sesquiterpene, Methyl 5-[(1E,5E)-2,6-Dimethyl octa-1,5,7-trienyl] furan-3-carboxylate (MDTFC), a bioactive component from a soft coral, Sinularia kavarittiensis. Its structure was determined by analyzing (1)H, (13)C NMR and FAB-MS. The results show that MDTFC could efficiently and selectively inhibit the proliferation of several human cancer cell lines. Among all the cell lines, THP-1 was found to be most sensitive (IC(50) 29.59 microM), whereas the peripheral blood mononuclear cells were least effected (IC(50) 464.16 microM). The molecular mechanism of MDTFC mediated apoptosis was investigated for the first time. Induction of apoptosis in THP-1 cells was characterized by cell membrane blebbing, chromatin condensation, DNA fragmentation, and decrease in level of pro-caspases 3, 9 and increase in Bax/Bcl-2 ratio. Our results were further strengthened through cleavage of poly (ADP-ribose) polymerase, reduction of mitochondrial membrane potential (Psim) and cytosolic release of cytochrome c, which are key events during apoptosis. Moreover, phosphatidyl serine exposure and appearance of sub-G1 peak also demonstrated cell death, when analyzed by flow cytometry. DNA fragmentation was prevented moderately when pretreated with caspase-9 inhibitor (Z-LEHD-FMK) and largely with caspase-3 inhibitor (Z-DEVD-FMK). In summary, MDTFC mediated apoptosis involves mitochondria-dependent pathway and the present compound of marine origin might have a therapeutic value against human cancer cell lines and especially on leukemia cells.
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PMID:Furano-sesquiterpene from soft coral, Sinularia kavarittiensis: induces apoptosis via the mitochondrial-mediated caspase-dependent pathway in THP-1, leukemia cell line. 1928 88

Drak2 is a member of the death-associated protein family and a serine threonine kinase. In this study, we investigated its role in beta cell survival and diabetes. Drak2 mRNA and protein were rapidly induced in islet beta cells after stimulation by inflammatory lymphokines known to be present in type 1 diabetes. Drak2 up-regulation was accompanied by increased beta cell apoptosis. beta cell apoptosis caused by the said stimuli was inhibited by Drak2 knockdown using small interfering RNA. Conversely, transgenic Drak2 overexpression led to aggravated beta cell apoptosis triggered by the stimuli. Further in vivo experiments demonstrated that Drak2 transgenic islets were more vulnerable to streptozocin insult. We established that inducible NO synthase was upstream and caspase-9 was downstream of Drak2 in its signaling pathway. Purified Drak2 could phosphorylate ribosomal protein S6 (p70S6) kinase in an in vitro kinase assay. Drak2 overexpression in NIT-1 cells led to enhanced p70S6 kinase phosphorylation, whereas Drak2 knockdown in these cells reduced it. These mechanistic studies proved that p70S6 kinase was a bona fide Drak2 substrate.
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PMID:Drak2 is upstream of p70S6 kinase: its implication in cytokine-induced islet apoptosis, diabetes, and islet transplantation. 1934 53

The laminin tyrosine-isoleucine-glycine-serine-arginine (YIGSR) peptide, corresponding to the 929-933 sequence of beta1 chain, is known to inhibit tumor growth and metastasis. In the present study, we observed that YIGSR not only inhibited the growth and migration of prostate cancer cells in a dose-dependent manner but also decreased mitochondrial membrane potential, inhibited ATP synthesis and increased caspase-9 activity. Investigation into the interaction of YIGSR with 67LR, the receptor for laminin and polyphenol (-) epigallocatechin-3-gallate (EGCG) employing MVD (Molegro Virtual Docker, an integrated platform for predicting protein ligand interactions), revealed that the binding site of YIGSR was the same as that of EGCG that explains as to why YIGSR is able to inhibit the cytotoxicity of EGCG against PC-3 cells.
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PMID:Effect of laminin tyrosine-isoleucine-glycine-serine-arginine peptide on the growth of human prostate cancer (PC-3) cells in vitro. 1957 62

This study is the first to investigate the anticancer effect of tricetin in human breast adenocarcinoma MCF-7 cells. Results reveal that tricetin inhibits MCF-7 cells by blocking cell cycle progression in the G2/M phase and inducing apoptosis. Cell cycle blockade is associated with increased activation of ataxia telangiectasia-mutated (ATM). Activation of ATM by tricetin phosphorylated p53 at serine 15, resulting in increased stability of p53 by decreasing p53 and murine double minute-2 (MDM2) interaction. In addition, tricetin-mediated G2/M phase arrest was also associated with decreases in the amounts of cyclin B, cyclin A, cdc2 and cdc25C, and increases in the phosphorylation of Chk2, cdc25C and cdc2. The specific ATM inhibitor caffeine significantly decreased tricetin-mediated G2/M arrest by inhibiting the phosphorylation of p53 (serine 15) and Chk2. Tricetin-induced apoptotic cell death is associated with changes in the expression of Bax and Bak, decreasing levels of Bcl-2 and Bcl-X(L), and subsequently triggering the mitochondrial apoptotic pathway. In addition, pretreatment of cells with caspase-9 inhibitor blocked tricetin-induced apoptosis, indicating that caspase-9 activation is involved in tricetin-mediated MCF-7 cell apoptosis. These findings suggest that tricetin may be a promising chemopreventive agent against human breast cancer.
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PMID:Tricetin, a dietary flavonoid, inhibits proliferation of human breast adenocarcinoma mcf-7 cells by blocking cell cycle progression and inducing apoptosis. 1970 44

Nimesulide, a popular nonsteroidal anti-inflammatory drug, has been associated with serious hepatotoxicity. Reactive oxygen species (ROS) and mitochondrial perturbations have been implicated in drug induced hepatotoxicity, although their role in the pathway needs exploration. Study was undertaken to elucidate the effect of Fumaria parviflora Lam. (Fp) on nimesulide induced cell death in primary rat hepatocyte cultures. Fp extract treated cells showed increased viability as compared to nimesulide stressed cells as assessed by MTT assay. LDH leakage increased significantly at 500microM nimesulide, and the data suggested that apoptosis was the predominant mechanism responsible for cell death. Nimesulide induced apoptosis was further confirmed by DNA fragmentation and chromatin condensation. Nimesulide exposure increased intracellular ROS, translocation of Bax and Bcl2 followed by mitochondrial depolarization and cytochrome c (Cyt c) release along with caspase-9/-3 activity confirming involvement of mitochondria in nimesulide induced apoptosis. Events like membrane depolarization of mitochondria, expression of Bax, Bcl2, externalization of phosphatidyl serine are substantially reversed by the pre-treatment of Fp extract. Thus, the study indicates that Fp extract modulates critical events regulating pro and anti-apoptotic proteins in mitochondria dependent apoptosis induced by nimesulide.
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PMID:Involvement of mitochondria mediated pathways in hepatoprotection conferred by Fumaria parviflora Lam. extract against nimesulide induced apoptosis in vitro. 1977 12

It has been previously reported that treatment of CHP-100 human neuroepithelioma cells with N-hexanoylsphingosine (C6-Cer) induces intracellular accumulation of long-chain ceramide (LC-Cer) and apoptosis. Herein, we investigated the existence of any causal relationship between the two phenomena. We report that C6-Cer-evoked LC-Cer accumulation is potently attenuated by the ceramide synthase inhibitor fumonisin B1; however, fumonisin B1 neither affects the apoptotic response evoked by C6-Cer administration, nor is toxic by itself to CHP-100 cells. Different to fumonisin B1, the serine-palmitoyltransferase inhibitor L: -cycloserine does not attenuate C6-Cer-evoked LC-Cer accumulation, thus suggesting that LC-Cer is produced via the sphingosine salvage pathway. Consistently, CHP-100 cells accumulate LC-Cer in response to sphingosine administration; however, their viability is not affected. The above-reported results indicate that, in the cell system investigated, C6-Cer, but not LC-Cer, is involved in apoptosis induction. As this finding is discussed in the light of the evidence that C6-Cer-induced apoptosis associates with cytochrome c release into the cytosol and caspase-9 activation, thus calling for an involvement of the mitochondrial pathway, it also lends support to the notion that caution must be exercised when investigating the biological effects of endogenous ceramide by use of exogenously administered short-chain analogues.
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PMID:Long-chain ceramide produced in response to N-hexanoylsphingosine does not induce apoptosis in CHP-100 cells. 1978 83


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