Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The apoptosome, a heptameric complex of Apaf-1, cytochrome c, and caspase-9, has been considered indispensable for the activation of caspase-9 during apoptosis. By using a large panel of genetically modified murine embryonic fibroblasts, we show here that, in response to tumor necrosis factor (TNF), caspase-8 cleaves and activates caspase-9 in an apoptosome-independent manner. Interestingly, caspase-8-cleaved caspase-9 induced lysosomal membrane permeabilization but failed to activate the effector caspases whereas apoptosome-dependent activation of caspase-9 could trigger both events. Consistent with the ability of TNF to activate the intrinsic apoptosis pathway and the caspase-9-dependent lysosomal cell death pathway in parallel, their individual inhibition conferred only a modest delay in TNF-induced cell death whereas simultaneous inhibition of both pathways was required to achieve protection comparable to that observed in caspase-9-deficient cells. Taken together, the findings indicate that caspase-9 plays a dual role in cell death signaling, as an activator of effector caspases and lysosomal membrane permeabilization.
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PMID:Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. 2928 51

Although benzene, a well-known human carcinogen, has been shown to induce apoptosis in vitro, no studies have been carried out to confirm and characterize its role in activating apoptosis in vivo. The present study investigated the effects of benzene inhalation on the epithelial cells lining the respiratory tract including bronchioles, terminal bronchioles, respiratory bronchioles and alveoli of male Sprague-Dawley rats. Inhalation of benzene 300 ppm for 7 days induced apoptotic changes in the parenchymal components in the lung that significantly exceeded the events of programmed cell death in normal control tissues. Apoptosis was confirmed by the electrophoretic analysis of internucleosomal DNA fragmentation of benzene-exposed lung tissues, which exhibited 180-200 bp laddering subunits indicative of genomic DNA degradation. Furthermore, semi-quantitative analysis of intracellular localization of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling TUNEL) showed a significant (p < 0.001) increase in the apoptotic index calculated for bronchiolar 73.5%, terminal bronchiolar (65%), and respiratory bronchiolar 60.8% segmental epithelial components as well as alveolar (55%) epithelia. Analysis of immunohistochemical expression of apoptosis-related gene products also supported the hypothesis that benzene can induce apoptosis in chemosensitive target cells in the lung parenchyma. Quantitative immunhistochemistry showed a statistically significant increase p < 0.001 in the immunoreactive staining index for cytochrome c, Apaf-1 (apoptosis activating factor-1), DNA fragmentation factor, and representative cysteine proteases including caspase-1, caspase-2L, caspase-8 and caspase-9. Thus this is the first study of the respiratory system that demonstrates that benzene inhalation induces lung cell apoptosis as confirmed by DNA electrophoresis, in situ nick end labeling, and the upregulation of apoptosis-related gene products that facilitate caspase-cleaved enzymes which lead to cell degradation via programmed cell death. These responses may represent an important defense mechanism within the parenchymal cells of the respiratory system that reduce mutational hazard and the potential carcinogenic effects of benzene-initiated pathogenesis.
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PMID:The effects of benzene exposure on apoptosis in epithelial lung cells: localization by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and the immunocytochemical localization of apoptosis-related gene products. 1717 16

Both Caspase-3 and Caspase-9 play critical roles in the execution of mitochondria-mediated apoptosis. Caspase-9 binds to Apaf-1 in the presence of cytochrome c and dATP/ATP, and is activated by self-cleavage. Caspase-3 is activated by cleavage of caspase-8 and caspase-9. Over hundred direct caspase-3 substrates are identified whereas only few direct caspase-9 substrates are known. Here, we demonstrate that Ring1B, a component of polycomb protein complex that plays important roles in modulating chromatin structures, is a direct substrate of active caspase-3 and caspase-9 both in vitro and in vivo. The specific cleavage sites for caspase-3 and caspase-9 were mapped to Asp(175) and Asp(208), respectively. Importantly, cleavage of Ring1B by active caspases-3 and caspase-9 triggers the redistribution of Ring1B, from exclusive nuclear localization to even distribution throughout the entire cell. The transcriptional repression activity of Ring1B was also disrupted by caspase cleavage. Our data suggest that caspases-3 and caspase-9 play novel roles in transcription by regulating polycomb protein function through direct cleaving of Ring1B.
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PMID:Polycomb group protein RING1B is a direct substrate of Caspases-3 and -9. 1737 27

Taxane derivatives such as paclitaxel elicit their antitumor effects at least in part by induction of apoptosis, but the underlying mechanisms are incompletely understood. Here, we used different cellular models with deficiencies in key regulators of apoptosis to elucidate the mechanism of paclitaxel-induced cell death. Apoptosis by paclitaxel was reported to depend on the activation of the initiator caspase-10; however, we clearly demonstrate that paclitaxel kills murine embryonic fibroblasts (MEFs) devoid of caspase-10 as well as human tumor cell lines deficient in caspase-10, caspase-8, or Fas-associating protein with death domain. In contrast, the lack of Apaf-1 or caspase-9, key regulators of the mitochondrial pathway, not only entirely protected against paclitaxel-induced apoptosis but could even confer clonogenic survival, depending on the cell type and drug concentration. Thus, paclitaxel triggers apoptosis not through caspase-10, but via caspase-9 activation at the apoptosome. This conclusion is supported by the fact that Bcl-2-overexpressing cells and Bax/Bak doubly-deficient MEFs were entirely resistant to paclitaxel-induced apoptosis. Interestingly, also the single knockout of Bim or Bax, but not that of Bak or Bid, conferred partial resistance, suggesting a particular role of these mediators in the cell-death pathway activated by paclitaxel.
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PMID:Apaf-1 and caspase-9 deficiency prevents apoptosis in a Bax-controlled pathway and promotes clonogenic survival during paclitaxel treatment. 1765 22

The novel protein RGPR-p117 was discovered as a regucalcin gene promoter region-related protein that binds to the TTGGC motif using a yeast one-hybrid system. The role of RGPR-p117 in cell function has not been fully clarified. This study was undertaken to determine whether overexpression of RGPR-p117 regulates various types of signaling factor-induced apoptotic cell death in the cloned normal rat kidney proximal tubular epithelial NRK52E cells. NRK52E cells (wild-type) or stable RGPR-p117/phCMV2-transfected cells (transfectant) were cultured in Dulbecco's modified Eagle's medium containing 5% bovine serum (BS). NRK52E cells with subconfluent monolayers were cultured for 24-72 h in a medium without BS. The presence of tumor necrosis factor-alpha (TNF-alpha; 1.0 or 10 ng/ml of medium), lipopolysaccharide (LPS; 0.1 or 1.0 microg/ml), Bay K 8644 (10(-6) or 10(-5) M), or thapsigargin (10(-8) or 10(-7) M) caused a significant decrease in the number of NRK52E wild-type cells or phCMV2-transfected (mock-type) cells. The effect of TNF-alpha, LPS, Bay K 8644, or thapsigargin in decreasing cell number was significantly suppressed in the presence of the caspase-3 inhibitor (10(-8) M) in wild-type cells cultured for 48 h. The effect of TNF-alpha, LPS, or Bay K 8644 in decreasing cell number was significantly inhibited in the transfectants, while the effect of thapsigargin on cell death was not inhibited in the transfectants. Culture with TNF-alpha or LPS caused DNA fragmentation in wild-type cells. These effects were significantly suppressed in the transfectants. The result of reverse transcription-polymerase chain reaction analysis using specific primers for the genes of apoptotic cell death-related proteins showed that IAP-1, FADD, caspase-8, caspase-9, and caspase-3 mRNA levels were significantly decreased in the transfectants, while Akt-1, Bid, Apaf-1, and glyceroaldehyde-3-phosphate dehydrogenase mRNA levels were not significantly altered in the transfectants. Culture with TNF-alpha, LPS, Bay K 8644, or thapsigargin caused a significant increase in Apaf-1 or caspase-3 mRNA levels. Such an effect was not seen in the transfectants. This study demonstrates that overexpression of RGPR-p117 has a suppressive effect on cell death and apoptosis induced by TNF-alpha, LPS, or Bay K 8644 whose actions are mediated through intracellular signaling pathways. This study also demonstrates that RGPR-p117 regulates the gene expression of apoptosis-related proteins.
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PMID:Overexpression of RGPR-p117 suppresses apoptotic cell death and its related gene expression in cloned normal rat kidney proximal tubular epithelial NRK52E cells. 1778 89

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

Mitochondrial proteins function as essential regulators in apoptosis. Here, we show that mitochondrial adenylate kinase 2 (AK2) mediates mitochondrial apoptosis through the formation of an AK2-FADD-caspase-10 (AFAC10) complex. Downregulation of AK2 attenuates etoposide- or staurosporine-induced apoptosis in human cells, but not that induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) or Fas ligand (FasL). During intrinsic apoptosis, AK2 translocates to the cytoplasm, whereas this event is diminished in Apaf-1 knockdown cells and prevented by Bcl-2 or Bcl-X(L). Addition of purified AK2 protein to cell extracts first induces activation of caspase-10 via FADD and subsequently caspase-3 activation, but does not affect caspase-8. AFAC10 complexes are detected in cells undergoing intrinsic cell death and AK2 promotes the association of caspase-10 with FADD. In contrast, AFAC10 complexes are not detected in several etoposide-resistant human tumour cell lines. Taken together, these results suggest that, acting in concert with FADD and caspase-10, AK2 mediates a novel intrinsic apoptotic pathway that may be involved in tumorigenesis.
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PMID:AK2 activates a novel apoptotic pathway through formation of a complex with FADD and caspase-10. 1795 61

Myrtucommulone (MC) is a unique, nonprenylated acylphloroglucinol contained in the leaves of myrtle (Myrtus communis). Here, we addressed the potential of MC to induce apoptosis of cancer cells. MC potently induced cell death of different cancer cell lines (EC(50) 3-8 microM) with characteristics of apoptosis, visualized by the activation of caspase-3, -8 and -9, cleavage of poly(ADP-ribose)polymerase (PARP), release of nucleosomes into the cytosol, and DNA fragmentation. MC was much less cytotoxic for non-transformed human peripheral blood mononuclear cells (PBMC) or foreskin fibroblasts (EC(50) cell death = 20-50 microM), and MC up to 30 microM hardly caused processing of PARP, caspase-3, -8 and -9 in human PBMC. MC-induced apoptosis was mediated by the intrinsic rather than the extrinsic death pathway. Thus, MC caused loss of the mitochondrial membrane potential in MM6 cells and evoked release of cytochrome c from mitochondria. Interestingly, Jurkat cells deficient in caspase-9 were resistant to MC-induced cell death and no processing of PARP or caspase-8 was evident. In cell lines deficient in either CD95 (Fas, APO-1) signalling, FADD or caspase-8, MC was still able to potently induce cell death and PARP cleavage. Conclusively, MC induces apoptosis in cancer cell lines, with marginal cytotoxicity for non-transformed cells, via the mitochondrial cytochrome c/Apaf-1/caspase-9 pathway.
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PMID:Myrtucommulone from Myrtus communis induces apoptosis in cancer cells via the mitochondrial pathway involving caspase-9. 1795 73

Increased population with hepatic diseases and apoptosis were found in patients with SLE and implicated in the pathogenesis of SLE. Since cystamine has been demonstrated to be beneficial to NZB/W F1 mice in our previous report, this study intends to investigate the effects of cystamine in liver from NZB/W F1 mice. Decreased apoptosis was detected in liver from NZB/W F1 mice given cystamine as compared to those given PBS by TUNEL and caspase-3 activity assay. Fas-dependent apoptotic proteins including Fas, cleaved caspase-8 and tBid were reduced in liver from NZB/W F1 mice given cystamine as compared to those given PBS. Additionally, the mitochondria-dependent apoptotic proteins including cytochrome c and Apaf-1 were reduced in liver from NZB/W F1 mice given cystamine as compared to those given PBS. Moreover, increased BCL-2 protein was observed in liver from both mice. Notably, increased NF-kappaB protein was detected in liver from NZB/W F1 mice given cystamine as compared to those given PBS. These experimental results suggest the effect of cystamine in reducing apoptosis in liver from NZB/W F1 mice through Fas-dependent and mitochondrial-dependent pathways. The phosphorylation of NF-kappaB (p65) could be a possible mechanism involving anti-apoptotic effects of cystamine in liver from NZB/W F1 mice.
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PMID:Treatment with cystamine reduces apoptosis in liver from NZB/W F1 mice. 1832 51

The purpose of this study was to investigate the occurrence and possible mechanisms of apoptosis in skeletal muscles after burn injury. After a 40% body surface area burn to rats, TA muscles were examined for apoptosis at varying times by TEM, TUNEL and cell death ELISA assay. Thermal injury was found to induce apoptosis in skeletal muscle on the first day and maximal apoptosis appeared 4 days post-injury. Apoptotic ligands in serum assessed by ELISA revealed rapidly increase of TNF-alpha and subsequent increase of sFasL to sFas ratio after burn injury. It implied TNF-alpha induced apoptosis in early stage and FasL induced apoptosis in later stage after burn injury. Apoptosis-related genes/proteins in skeletal muscles examined by real-time PCR array and Western blotting showed pro-apoptotic genes/proteins, including Tnfrsf1a, Tnfrsf1b and Tnfsf6 in TNF ligand and receptor family, Bax and Bid in Bcl-2 family, caspase-3 and caspase-6 in caspase family, Dapk1, FADD and Cidea in death and CIDE domain family, Apaf-1 in CARD family, and Gadd45a were up-regulated, while anti-apoptotic gene Bnip1 was down-regulated compared with that of time-matched controls. In addition, increment of caspase-3, caspase-8 and caspase-9 activity provided further evidence for their role in apoptosis in skeletal muscle. Significant increase in expression in pro-apoptotic genes/proteins and activity of caspases suggested that death receptor-mediated signaling pathways and other apoptotic related pathways participated in apoptosis in skeletal muscle after burn injury. However, it was found that some anti-apoptotic genes such as Bcl2l1, Mcl-1, Nol-3, Il-10 and Prok2 were also up-regulated, which might imply the co-existence of protective response of the body after burns. In conclusion, the data suggest that apoptosis and pro-apoptotic signaling are enhanced in muscles of burned rats. To further elucidate the underlying apoptotic mechanisms mediating the atrophic response is important in establishing potential therapeutic interventions that could prevent and/or reduce skeletal muscle wasting and preserve its physiological function.
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PMID:Effect of burn injury on apoptosis and expression of apoptosis-related genes/proteins in skeletal muscles of rats. 1900 50


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