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:4.1.1.6 (CAD)
4,420 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecules participating in apoptosis induced by T-2 toxin in human leukemia HL-60 cells were investigated. The rank order of the potency of trichothecene mycotoxins to induce internucleosomal DNA fragmentation was found to be T-2, satratoxin G, roridin A >> diacetoxyscirpenol > baccharin B-5 >> nivalenol, deoxynivalenol, 3-acetyldeoxynivalenol, fusarenon-X, baccharin B-4=vehicle control. Western blot analysis of caspase-3 in T-2-treated cells clearly indicated the appearance of its catalytically active fragment of 17-kDa. Increased caspase-3 activity was also detected by using a fluorogenic substrate, DEVD-AMC. Next, cells exposed to T-2 led to cleavage of PARP from its native 116-kDa form to the 85-kDa product. Moreover, DFF-45/ICAD were cleaved to give a 12.5-kDa fragment via T-2 treatment. T-2 caused the release of cytochrome c from mitochondria into the cytosol. Increased enzymic activity of caspase-9 on LEHD-AMC was shown. These data indicate that T-2-induced apoptosis involves activation of caspase-3 and DFF-40/CAD through cytosolic accumulation of cytochrome c along with caspase-9 activation.
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PMID:Apoptosis induction by T-2 toxin: activation of caspase-9, caspase-3, and DFF-40/CAD through cytosolic release of cytochrome c in HL-60 cells. 1157 12

Satratoxins have been recognized as potential immunomodulatory agents in outbreaks of building-related illness. Here we report that satratoxin G-treated human leukemia HL-60 cells underwent apoptosis through the action of caspase-3 which was activated by both caspase-8 and caspase-9. Western blot analysis of caspase-3 in the satratoxin G-treated cells apparently indicated the appearance of a catalytically active fragment of 17 kDa. Increased caspase-3 activity was also detected by using a fluorogenic substrate, DEVD-AMC. Next, exposure to satratoxin G led to cleavage of PARP from its native 116 kDa form to a 85 kDa product. Moreover, DFF-45/ICAD were cleaved into a 12.5 kDa fragment via satratoxin G treatment. Enzymic assay on IETD-AMC revealed that caspase-8 is strongly activated by exposure to satratoxin G while T-2 toxin (T-2) could not activate caspase-8 at an early stage of apoptosis. Furthermore, satratoxin G caused a release of cytochrome c from mitochondria into the cytosol and increased the activity of caspase-9 against LEHD-AMC. These findings indicate that satratoxin G-induced apoptosis involves activation of caspase-3 and DFF-40/CAD through both activation of caspase-8 and cytosolic accumulation of cytochrome c along with activation of caspase-9.
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PMID:Molecular mechanism of satratoxin-induced apoptosis in HL-60 cells: activation of caspase-8 and caspase-9 is involved in activation of caspase-3. 1216 Dec 80

Acrolein is a highly reactive alpha,beta-unsaturated aldehyde, which is a product of lipid peroxidation. It is an environmental pollutant that has been implicated in multiple respiratory diseases. Acrolein is produced by the enzymatic oxidative deamination of spermine by amine oxidase. Oxidation products of polyamines have been involved in the inhibition of cell proliferation, apoptosis, and the inhibition of DNA and protein synthesis. The present study investigates the mechanism of cell death induced by acrolein. Acrolein induced apoptosis through a decrease in mitochondrial membrane potential, the liberation of cytochrome c, the activation of initiator caspase-9, and the activation of the effector caspase-7. However, acrolein inhibited enzymatic activity of the effector caspase-3, although a cleavage of pro-caspase-3 occurred. The activation of caspases-9 and -7 was confirmed by the cleavage of their pro-enzyme form by acrolein. Apoptosis was inhibited by an inhibitor of caspase-9, but not by an inhibitor of caspase-3. The induction of apoptosis by acrolein was confirmed morphologically by the condensation of nuclear chromatin and by the cleavage of the inhibitor of caspase activated DNase (ICAD), which leads to the liberation of CAD that causes DNA fragmentation. These results demonstrate that acrolein causes apoptosis through the mitochondrial pathway.
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PMID:The aldehyde acrolein induces apoptosis via activation of the mitochondrial pathway. 1584 39

Cisplatin [cis-diamminedichloroplatinum (II)]-treated murine peritoneal macrophages interact with L929 cells in vitro in a sequential manner, resulting in the formation of contact between the two cells. This interaction leads to the death of L929 cells by the process of apoptosis. The detailed investigations have suggested the involvement of two different pathways in macrophage-mediated L929 cell apoptosis. It is observed that the induction of apoptosis in L929 cells by cisplatin-treated macrophages is contact dependent and is mediated through Fas-Fas ligand and tumor necrosis factor-tumor necrosis factor receptor 1 pathways. This conclusion was based on the Western blot and immunoprecipitation analysis of Fas-Fas ligand, tumor necrosis factor-tumor necrosis factor receptor 1, Fas-associated death domain and tumor necrosis factor receptor-associated death domain. The Fas-Fas ligand interaction between macrophages and L929 cells increased the expression of Fas-associated death domain, and tumor necrosis factor-tumor necrosis factor receptor 1 interaction between macrophages and L929 cells increased the expression of tumor necrosis factor receptor-associated death domain in L929 cells. The induction of apoptosis in L929 cells was investigated by DNA fragmentation, Annexin V staining and Western blot analysis of Bax, Bcl-2, Bid, cytochrome c, poly(ADP ribose) polymerase, CAD, caspase-8 and caspase-3.
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PMID:Cisplatin-treated murine peritoneal macrophages induce apoptosis in L929 cells: role of Fas-Fas ligand and tumor necrosis factor-tumor necrosis factor receptor 1. 1715 5

In this study we report that, imidazole derivatives can induce apoptosis in Ehrlich ascites tumor (EAT) cells, which is clearly evident from annexin-V staining, flow cytometric analysis of cell cycle phase distribution and DNA fragmentation. Delineating further into molecular mechanisms leading to apoptosis of EAT cells, we observed that imidazole derivatives induce tumor cell death by the up-regulation of proto-oncoprotein Bax, release of cytochrome c from the mitochondria which activates caspase-3 and activated caspase-3 activates CAD (Caspase Activated DNase) causes DNA fragmentation. The status of Bcl-2 remains unaltered in EAT cells, and the under expression of Bcl-2 and up-regulation of Bax resulted in the increase of Bax: Bcl-2 ratio suggesting that Bcl-2 family involved in the control of apoptosis. These results suggest a further possible clinical application of imidazole derivatives as pro-apoptotic agent in association with conventional chemotherapeutic agents.
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PMID:Pro-apoptotic activity of imidazole derivatives mediated by up-regulation of Bax and activation of CAD in Ehrlich Ascites Tumor cells. 1737 79

Natural killer (NK) cells are the effectors of innate immunity to act as the first line of defense against viruses and tumors. Granzyme H (GzmH) is predicted to evolve from GzmB and constitutively expressed at a high level in human NK cells. It indicates GzmH plays a pivotal role in NK cell mediated cytolysis. However GzmH is defined as an orphan granzyme and its function has less been defined. Here we demonstrate GzmH can induce rapid apoptosis of target cells, which is dependent on caspase activation and mitochondrial damage. GzmH-induced death is characterized by phophatidylserine externalization, nuclear condensation, DNA fragmentation, caspase activation and cytochrome c release that are hallmarks of typical apoptosis. GzmH can directly cleave ICAD to unleash CAD for DNA fragmentation. Moreover, GzmH directly processes Bid to produce the active form tBid leading to cytochrome c release. Therefore, GzmH may play an essential role in caspase-dependent pathogen clearance in the innate immunity that may complement the proapoptotic function of GzmB in human NK cells.
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PMID:Granzyme H induces apoptosis of target tumor cells characterized by DNA fragmentation and Bid-dependent mitochondrial damage. 1776 74

Cellular ionic homeostasis, fundamentally K(+) homeostasis, has been implicated as a critical regulator of apoptosis. The intracellular K(+) efflux on apoptotic insult and suppression of apoptosis by high concentration of extracellular K(+) or after inhibition of this efflux by K(+) channel blockers have established the crucial role of K(+) in turning on the apoptotic machinery. Several contrasting observations have reported the antiapoptotic effect of intracellular K(+) concentration to be the result of inhibition of cytochrome c release from mitochondria, but the exact inhibitory mechanism remains obscure. However, here we show the blockage of K(+) efflux during apoptosis did not affect cytochrome c release from the mitochondria, still completely inhibited the formation of the apoptosome comprising Apaf-1, cytochrome c, caspase-9 and other accessories. As a consequence of this event, procaspase-9, -3, -8 and other death-related proteins were not processed. Furthermore, physiological concentrations of K(+) also inhibited the processing of procaspase-3 by purified caspase-8 or -9, the nucleosomal DNA fragmentation by purified DFF40/CAD and the nuclear fragmentation to varying extents. Altogether, these findings suggest that the efflux of K(+) is prerequisite not only for the formation of the apoptosome but also for the downstream apoptotic signal-transduction pathways.
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PMID:Intracellular K(+) inhibits apoptosis by suppressing the Apaf-1 apoptosome formation and subsequent downstream pathways but not cytochrome c release. 1788 67

We hypothesized that induction of differentiation with retinoid could increase sensitivity to microtubule-binding drug taxol (TXL) for apoptosis in human glioblastoma T98G and U87MG cells. Treatment of cells with 1 microM all-trans retinoic acid (ATRA) or 1 microM 13-cis retinoic acid (13-CRA) for 7 days induced astrocytic differentiation, overexpression of glial fibrillary acidic protein (GFAP), and also down regulated telomerase expression and activity, thereby increased sensitivity to TXL for apoptosis. Treatment of glioblastoma cells with TXL triggered production of reactive oxygen species (ROS), induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), and activated the redox-sensitive c-Jun NH(2)-terminal kinase 1 (JNK1) pathway. Moreover, TXL activated Raf-1 kinase for phosphorylation and inactivation of anti-apoptotic Bcl-2 protein. The events of apoptosis included increase in expression of Bax, down regulation of Bcl-2 and baculoviral inhibitor-of-apoptosis protein (IAP) repeat containing (BIRC) proteins, mitochondrial release of cytochrome c and Smac into the cytosol, increase in intracellular free [Ca(2+)], and activation of calpain, caspase-9, and caspase-3. Increased activity of caspase-3 cleaved inhibitor of caspase-activated DNase (ICAD) to release and translocate CAD to the nucleus for DNA fragmentation. Involvement of stress signaling kinases and proteolytic activities of calpain and caspase-3 in apoptosis was confirmed by pretreating cells with specific inhibitors. Taken together, our results suggested that retinoid (ATRA or 13-CRA) induced astrocytic differentiation with down regulation of telomerase activity to increase sensitivity to TXL to enhance apoptosis in glioblastoma cells. Thus, combination of retinoid and TXL could be an effective therapeutic strategy for controlling the growth of glioblastoma.
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PMID:Retinoids induced astrocytic differentiation with down regulation of telomerase activity and enhanced sensitivity to taxol for apoptosis in human glioblastoma T98G and U87MG cells. 1798 64

Cell-free systems have been instrumental in the identification of several important components of the cell death machinery such as cytochrome c, APAF-1, ICAD/CAD (DFF45/DFF40) and Smac/Diablo. Such systems have also proved invaluable for the detailed analysis of caspase activation mechanisms, caspase activation cascades, proteolysis of caspase substrates, apoptosis-associated chromatin condensation and internucleosomal DNA fragmentation. Here, we describe a cell-free system that we have used routinely in our laboratory for the analysis of caspase activation and associated events. Caspase activation in this system can be triggered either through assembly of the APAF-1 apoptosome by addition of cytochrome c/dATP, or alternatively, by addition of the cytotoxic lymphocyte protease, granzyme B. In both cases, the order of caspase activation events has been established and the relative importance of individual caspases to apoptosis-associated nuclear events, as well as substrate proteolysis, is known. Cell-free systems are therefore very useful for screening potential caspase-inhibitory compounds or other agents that may positively or negatively affect caspase-dependent events in apoptosis.
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PMID:Analysis of apoptosis in cell-free systems. 1831 59

We have previously demonstrated the effectiveness of simultaneous RNA interference (RNAi)-mediated downregulation of urokinase-type plasminogen activator receptor (uPAR) and matrix metalloproteinase-9 (MMP-9) in inhibiting tumor invasion in vitro and in vivo. In particular, we have shown that the downregulation of uPAR and MMP-9 inhibits intracranial tumor growth. The mechanism of the inhibition of tumor growth has not yet been determined. In this study, we have attempted to explain the mechanisms involved in the inhibition of invasiveness and tumor growth in vitro. SNB19 glioma cells were transfected with scrambled vector plasmid (pSV) and a siRNA-expressing plasmid targeting either uPAR (pU) or MMP-9 (pM) singly or in combination (pUM). Untransfected cells were also used as a control. Western blotting and RT-PCR analyses showed the downregulation of uPAR in pU-transfected cells and MMP-9 in pM-transfected cells. In cells transfected with pUM, we observed down-regulation of both uPAR and MMP-9, thereby indicating the specificity of the siRNA-expressing plasmids. An increase in caspase 9 expression was observed in cells transfected with pUM whereas no change in the level of caspase 9 was observed in pU or pM-transfected cells. Additionally, no change in the expression level of caspase 8 was observed. However, an increase in the expression level of cleaved PARP was observed in the case of cells transfected with pU, pM and pUM. Cells transfected with pUM showed the highest levels of cleaved PARP expression. Expression levels of APAF-1 were also higher in pUM-transfected cells with no change in expression levels of controls and in pU and pM-transfected cells. Total CAD expression levels did not change under any of the transfection conditions. However, immunohistochemical studies demonstrated that CAD was translocated to the nucleus, thereby indicating DNA damage. As determined by Western blot analysis of subcellular fractions, cytoplasmic levels of cytochrome c were also increased. We determined the extent of DNA damage using the TUNEL assay (poly-A termination of free -OH ends of degraded nuclear DNA). Based on our results we conclude that the simultaneous downregulation of uPAR and MMP-9 induces apoptosome-mediated apoptosis.
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PMID:Simultaneous downregulation of uPAR and MMP-9 induces overexpression of the FADD-associated protein RIP and activates caspase 9-mediated apoptosis in gliomas. 1881 92


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