Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.B10 (caspase-7)
 896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) may block apoptosis by inhibiting caspases via S-nitrosylation of cysteines. Here, we investigated whether effector caspases might cleave and thereby inhibit endothelial nitric oxide synthase (eNOS). Exposure of eNOS-transfected COS-7 cells and bovine aortic endothelial cells to staurosporine resulted in significant loss of 135-kDa eNOS protein and activity, and appearance of a 60-kDa eNOS fragment; effects were inhibited by the general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp[OMe]-fluoromethyl ketone (zVAD-fmk). In eNOS-transfected COS-7 cells, staurosporine-induced activation of caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage coincided with increased eNOS degradation and decreased activity. Loss of eNOS activity was greater than the degree of proteolysis. Incubation of immunoprecipitated eNOS with caspase-3, caspase-6 or caspase-7 resulted in eNOS cleavage. Staurosporine, a general protein kinase inhibitor, also reduced phosphorylation and decreased calmodulin binding, an effect that may explain the reduction in activity. eNOS, therefore, is both an inhibitor of apoptosis and a target of apoptosis-associated proteolysis.
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PMID:Effect of staurosporine-induced apoptosis on endothelial nitric oxide synthase in transfected COS-7 cells and primary endothelial cells. 1619 40

Paecilomyces tenuipes is a famous Chinese medicinal entomopathogenic fungus that grows within the larvae of silkworms. 4beta-acetoxyscirpendiol (4-MAS), a cytotoxic compound belonging to the scirpenol subfamily of trichothecene mycotoxin, was isolated from Paecilomyces tenuipes. To further elucidate the cytotoxic mechanism of 4-MAS, evidences of its induction of apoptosis, together with the structurally related acetoxyscirpenol moiety mycotoxins (ASMs) such as, 15-acetoxyscirpenol (15-MAS), 4,15-diacetoxyscirpenol (4,15-DAS), and 3alpha-acetyldiacetoxyscirpenol (TAS), in the human Jurkat T cell line were reported herein. In the MTT reduction and time-course cytotoxicity assays for monitoring cell viability, all the four ASMs that were tested exhibited cytotoxicity; single acetoxylation at C-4 of the scirpenol family resulted in relatively weak cytotoxicity, while acetoxylation at C-15 resulted in strong cytotoxicity regardless of the other acetoxylations at the C-3 and/or C-4 positions. Phosphatidylserine externalization was induced by all the ASMs that were treated at an early phase in a time-dependent manner, showing a typical apoptotic phenomenon, not a necrotic one. The ASMs also reduced the mitochondria's inner-membrane potential (deltaPsim) through flow cytometry analysis after staining these with DiOC6, a mitochondria-specific and voltage-dependent dye. Acetoxylation of ASM at C-15 increased deltaPsim disruption, but that at C-3 reduced the deltaPsim. The ASMs that were tested also cleaved 113 kDa PARP to an 89-kDa fragment through Western blot assay, suggesting the activation of caspase-3 and/or caspase-7 in the Jurkat T cell. DNA fragmentation was also observed to have been increased in a time-dependent manner by the ASMs that were tested in Jurkat T cells, resulting in the DNA fragmentation intensity order of 4,15-DAS>15-MAS>TAS>4-MAS. These data indicate that the Jurkat T cells that were treated with ASMs underwent typical cascades of apoptotic cell death.
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PMID:Induction of apoptosis by disturbing mitochondrial-membrane potential and cleaving PARP in Jurkat T cells through treatment with acetoxyscirpenol mycotoxins. 1659 95

Rocaglaol is a cytotoxic cyclopenta[b]benzofuran isolated from the bark of Aglaia crassinervia. It exhibited in vitro cytotoxic activity against Lu1, LNCaP and MCF-7 cells with ED50 values of 13.8, 23.0 and 9.2 nM, respectively. DAPI staining indicated that LNCaP cells treated with rocaglaol underwent apoptosis. In order to determine whether rocaglaol-induced apoptosis is mediated by the mitochondrial pathway, apoptosis-related mitochondrial-associated proteins were studied. Rocaglaol treatment induced Bax expression through 12 to 72 h of exposure, while Bcl-xl expression was slightly decreased through 48 h, and decreased more significantly by 72 h. Cleaved caspase-9 expression was detected at 72 h, and cleaved caspase-7 was increased through 48 to 72 h. Consequently, the large fragment (89 kDa) of PARP resulting from caspase cleavage was detected at 12, 24 and 48 h, and especially at 72 h. Cleaved PARP expression was also detected at 72 h. Since rocaglaol caused dose-dependent G2/M phase arrest of LNCaP cells as indicated by flow cytometric analysis, the protein levels of cell cycle-related genes were measured. Rocaglaol treatment (230 nM) did not change cyclin B after 24- to 60-h treatment. The expression of cdc2 was not changed and phospho-cdc2 (Tyr 15) increased after 36-, 48- and 60-h treatment. In addition, protein phosphatase Cdc25C, which functions as a mitotic activator by dephosphorylation of Cdc2, decreased in a time-dependent manner after rocaglaol treatment. Taken together, these results suggest that rocaglaol is a potent anticancer drug that induces apoptosis of LNCaP cells through the mitochondrial pathway and its G2/M-phase cell cycle arrest is associated with the down-regulation of Cdc25C and the dephosphorylation of Cdc2.
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PMID:Rocaglaol induces apoptosis and cell cycle arrest in LNCaP cells. 1661 91

Tumor cells with different origins have different threshold to apoptosis. Hematopoietic (Jurkat, NCI-H929) cells and non-hematopoietic (A549, MCF-7) cells were received hyperbaric oxygen (HBO(2)) treatment from 2.5 to 3.5 atmosphere absolute (ATA) of 100% oxygen for 6h, and a significant percentage of apoptosis were shown only in hematopoietic Jurkat and NCI-H929 cells by either Annexin V or TUNEL assay. Oxidative stress was illustrated higher in HBO(2)-treated hematopoietic cells by superoxide fluorochrome detectors. HBO(2) treatment leads to caspase-3, caspase-7 activation and further cleavage of PARP within cells. Furthermore, the increased phosphorylation of p38 MAPK was demonstrated in both Jurkat and NCI-H929 cells.
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PMID:Apoptosis of T-leukemia and B-myeloma cancer cells induced by hyperbaric oxygen increased phosphorylation of p38 MAPK. 1706 67

A novel small molecule inhibitor, 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB), competes with the Bak BH3 peptide to bind Bcl-2 protein with a binding affinity of IC(50) = 0.70 microM, as assessed by a fluorescence polarization based binding assay. HL-60 cells express the highest levels of Bcl-2 among the cell lines examined. Treated with 5 microM of MNB only for 6 h, 85% of HL-60 cells were detected to undergo apoptosis. Pan-caspase inhibitor, Z-VAD-FMK, blocks MNB-induced apoptosis in HL-60 cells. Caspase-2, caspase-3, caspase-7, caspase-8, caspase-9, and PARP activation were observed at as early as 4 to 6 h of MNB treatment. In addition, it has been confirmed that the caspase-3 specific inhibitor, Z-DEVD-FMK, blocks the activation of caspase-8 in MNB-treated HL-60 cells. MNB treatment does not change Bcl-2 or Bax expression level in HL-60 cells, but causes Bid cleavage. Further experiments have illustrated that MNB inhibits the heterodimerization of Bcl-2 with Bax or Bid, reduces the mitochondrial membrane potential (DeltaPsimt), and induces cytochrome c release from mitochondria in HL-60 cells. These results suggest that MNB induces apoptosis in HL-60 by inhibiting the heterodimerization of Bcl-2 with pro-apoptosis Bcl-2 members, resulting in a decrease in the mitochondrial membrane potential and cytochrome c release, activation of caspases and PARP; it is a caspase-dependent process in which the activation of caspase-8 is dependent on the mitochondrial apoptosis signal transduction pathway. MNB prolongs the life spans of HL-60 bearing mice, potently kills fresh AML and ALL cells, indicating that it has the potential to be developed to treat leukemia.
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PMID:A novel Bcl-2 small molecule inhibitor 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB)-induced apoptosis in leukemia cells. 1739 62

High-throughput subcellular imaging is a powerful tool for investigating the function of genes. In order to identify novel regulators of apoptosis we transiently transfected HeLa cells with 938 hypothetical genes of unknown function, and captured their nuclear images with an automated fluorescence microscope. We selected genes that induced greater than 3-fold increase in the percentage of apoptotic nuclei compared with vector-transfected cells. The full-length genes C10orf61, MGC 26717, and FLJ13855 were identified as candidate proapoptotic genes, and their apoptotic effects were confirmed by DNA fragmentation ELISAs and Western blotting for caspase-7 and PARP. We conclude that a subcellular image-based apoptotic screen is useful for identifying genes with proapoptotic activity.
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PMID:Identification of novel regulators of apoptosis using a high-throughput cell-based screen. 1746 93

The mechanism of acacetin-induced apoptosis of human breast cancer MCF-7 cells was investigated. Acacetin caused 50% growth inhibition (IC50) of MCF-7 cells at 26.4% 0.7% M over 24 h in the MTT assay. Apoptosis was characterized by DNA fragmentation and an increase of sub-G1 cells and involved activation of caspase-7 and PARP (poly-ADP-ribose polymerase). Maximum caspase 7 activity was observed with 100 microM acacetin for 24 h. Caspase 8 and 9 activation cascades mediated the activation of caspase 7. Acacetin caused a reduction of Bcl-2 expression leading to an increase of the Bax:Bcl-2 ratio. It also caused a loss of mitochondrial membrane potential that induced release of cytochrome c and apoptosis inducing factor (AIF) into the cytoplasm, enhancing ROS generation and subsequently resulting in apoptosis. Pretreatment of cells with N-acetylcysteine (NAC) reduced ROS generation and cell growth inhibition, and pretreatment with NAC or a caspase 8 inhibitor (Z-IETD-FMK) inhibited the acacetin-induced loss of mitochondrial membrane potential and release of cytochrome c and AIF. Stress-activated protein kinase/c-Jun NH4-terminal kinase 1/2 (SAPK/ JNK1/2) and c-Jun were activated by acacetin but extracellular-regulated kinase 1/2 (Erk1/2) nor p38 mitogen-activated protein kinase (MAPK) were not. Our results show that acacetin-induced apoptosis of MCF-7 cells is mediated by caspase activation cascades, ROS generation, mitochondria-mediated cell death signaling and the SAPK/JNK1/2-c-Jun signaling pathway, activated by acacetin-induced ROS generation.
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PMID:Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondria-mediated death signaling and SAPK/JNK1/2-c-Jun activation. 1784 3

The periodontopathic bacterium Actinobacillus actinomycetemcomitans has been implicated in the pathogenesis of periodontal diseases. It has been reported previously that infection with the organism induced apoptosis in the mouse macrophage cell line J774.1. In the present study, the role of caspases during apoptosis in A. actinomycetemcomitans-infected J774.1 cells was examined. A large number of apoptotic cells was detected by flow cytometric analysis in infected J774.1 cells; however, inhibitors of caspase-9, -6 and -3/7 completely blocked the induction of apoptosis. Expression of the cleaved forms of caspase-6 and -7 was detected during apoptosis in infected J774.1 cells. Immunoblot analysis revealed that the caspase-9 inhibitor blocked expression of the cleaved forms of caspase-6 and -7, whilst the caspase-3 inhibitor blocked expression of the cleaved form of caspase-7, but not caspase-6. It is known that lamin A/C and poly(ADP-ribose) polymerase (PARP) are essential nuclear components for maintaining normal cell function and viability, and both were found to be cleaved in the infected J774.1 cells. Immunoblot analysis also revealed that the caspase-6 inhibitor blocked the cleavage of lamin A/C, whilst the caspase-3/7 inhibitor blocked the cleavage of PARP. Taken together, these results suggest that activation of caspases and the subsequent cleavage of lamin A/C and PARP are involved in the morphological changes of apoptotic macrophages infected with A. actinomycetemcomitans.
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PMID:Role of caspases in cleavage of lamin A/C and PARP during apoptosis in macrophages infected with a periodontopathic bacterium. 1789 80

Phenethyl isothiocyanate (PEITC) is an isothiocyanate which is a major constituent of watercress and other cruciferous vegetables. Its chemopreventive potential has been previously shown in various rodent models of cancer. In this study, we investigated the chemopreventive efficacy of PEITC in the Apc(Min/+) mouse model. Apc(Min/+) mice were fed with diet supplemented with 0.05% of PEITC for 3-wk. Our results clearly demonstrated that Apc(Min/+) mice fed with PEITC supplemented diet developed significantly less (31.7% reduction) and smaller polyps in comparison to mice fed with the standard AIN-76A diet. Subsequent mechanistic study using Western blotting shows that inhibition of growth of adenomas by PEITC is associated with increase of apoptosis (cleaved-caspase-3, -caspase-7, and PARP). Treatments also led to the inhibition of cell cycle-related biomarkers such as the cyclins (D1, A, and E) and activation of p21. However, PEITC has no effect on the expression of p-Erk, p-JNK or p-p38. In conclusion, our results demonstrate that PEITC is a potent natural dietary compound for chemoprevention of gastrointestinal cancers. Its mechanism of actions may include induction of apoptosis and cell cycle arrest.
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PMID:Chemoprevention of familial adenomatous polyposis in Apc(Min/+) mice by phenethyl isothiocyanate (PEITC). 1793 52

The role of autophagy in cell death is under considerable debate. The process of autophagy has been shown to lead to either cell survival or cell death depending on cell type and stimulus. In the present study, we determined the contribution of ERK1/2 signalling to autophagy and cell death induced by tumour necrosis factor-alpha (TNF) in MCF-7 breast cancer cells. Treatment of MCF-7 cells with TNF caused a time-dependent increase in ERK1/2 activity. There was an induction of autophagy and cleavage of caspase-7, -8, -9 and PARP. Pharmacological inhibition of ERK1/2 phosphorylation with U0126 or PD98059 resulted in a decrease in TNF-induced autophagy that was accompanied by an increase in cleavage of caspase-7, -8, -9 and PARP Furthermore, inhibition of ERK1/2 signalling resulted in decreased clonogenic capacity of MCF-7 cells. These data suggest that TNF-induces autophagy through ERK1/2 and that inhibition of autophagy increases cellular sensitivity to TNF.
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PMID:Inhibition of ERK attenuates autophagy and potentiates tumour necrosis factor-alpha-induced cell death in MCF-7 cells. 1826 53


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