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: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family and has recently been shown to exert tumoricidal activity in vivo in the absence of any observable toxicity. The signaling pathways triggered by TRAIL stimulation and the mechanisms involved in resistance against TRAIL-mediated apoptosis are still poorly defined. We show here that TRAIL-induced apoptosis involves late dissipation of mitochondrial membrane potential (delta psi(m)) and cytochrome c release. These events follow activation of caspase-8 and caspase-3 and induction of DNA fragmentation. In addition, caspase-8-deficient cells are resistant against TRAIL-induced apoptosis, and inhibition of caspase-8 but not caspase-9 prevents mitochondrial permeability transition and apoptosis. In contrast, various Bcl-2- or Bcl-xL-overexpressing tumor cell lines are sensitive to TRAIL-induced apoptosis; however, they show a delay in TRAIL-induced mitochondrial permeability transition compared with control transfectants. This indicates that TRAIL-induced apoptosis depends on caspase-8 activation rather than on the disruption of mitochondrial integrity. Because most chemotherapeutic drugs used in the treatment of malignancies lead to apoptosis primarily by engagement of the mitochondrial proapoptotic machinery, we tested whether drug-resistant tumor cells retain sensitivity for TRAIL-induced apoptosis. Tumor cells overexpressing Bcl-2 or Bcl-xL become resistant to apoptosis induced by the chemotherapeutic drug etoposide. However, these cells are not protected or are only marginally protected against TRAIL-induced apoptosis. Thus, TRAIL may still kill tumors that have acquired resistance to chemotherapeutic drugs by overexpression of Bcl-2 or Bcl-xL. These data will influence future treatment strategies involving TRAIL.
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PMID:Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2- or Bcl-xL-overexpressing chemotherapy-resistant tumor cells. 1085 Apr 56

Bcl-2 and related proteins are key regulators of apoptosis or programmed cell death implicated in human disease including cancer. We recently showed that cell-permeable Bcl-2 binding peptides could induce apoptosis of human myeloid leukemia in vitro and suppress its growth in severe combined immunodeficient mice. Here we report the discovery of HA14-1, a small molecule (molecular weight = 409) and nonpeptidic ligand of a Bcl-2 surface pocket, by using a computer screening strategy based on the predicted structure of Bcl-2 protein. In vitro binding studies demonstrated the interaction of HA14-1 with this Bcl-2 surface pocket that is essential for Bcl-2 biological function. HA14-1 effectively induced apoptosis of human acute myeloid leukemia (HL-60) cells overexpressing Bcl-2 protein that was associated with the decrease in mitochondrial membrane potential and activation of caspase-9 followed by caspase-3. Cytokine response modifier A, a potent inhibitor of Fas-mediated apoptosis, did not block apoptosis induced by HA14-1. Whereas HA14-1 strongly induced the death of NIH 3T3 (Apaf-1(+/+)) cells, it had little apoptotic effect on Apaf-1-deficient (Apaf-1(-/-)) mouse embryonic fibroblast cells. These data are consistent with a mechanism by which HA14-1 induces the activation of Apaf-1 and caspases, possibly by binding to Bcl-2 protein and inhibiting its function. The discovery of this cell-permeable molecule provides a chemical probe to study Bcl-2-regulated apoptotic pathways in vivo and could lead to the development of new therapeutic agents.
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PMID:Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. 1086 Sep 79

Cytogenetic and molecular analyses have shown that the chromosome band 12q22 is recurrently deleted in male germ cell tumors (GCTs), indicating the presence of a candidate tumor suppressor gene (TSG) in this region. To identify the TSG, we mapped the APAF1 gene, a proapoptotic mammalian homologue of ced-4, to chromosomal band 12q22, that suggested that this might be the candidate deleted gene in GCTs. We further localized the gene between the polymorphic markers D12S1671 and D12S1082 at 12q22 to determine the role of APAF1 in the pathogenesis of GCT, and we characterized its normal genomic structure and analyzed its alterations in GCTs. The APAF1 gene comprises 27 exons, with the coding region spanning 26. The region containing APAF1 was found to be deleted in GCT by fluorescence in situ hybridization analysis, but without evidence of coding sequence alterations. RT-PCR and Western blot analysis showed APAF1 gene expression at detectable levels in all GCT cell lines analyzed. An aberrant-sized APAF1 protein was seen in one cell line. This and 2 other cell lines carrying APAF1 deletions also exhibited defects in dATP-mediated caspase-3 activation. Caspase-3 activity was effectively restored by addition of recombinant caspase-9 and APAF1 proteins, and to a lesser extent by caspase-9 alone, but not by APAF1 alone. These data do not support a TSG role for APAF1, but defects in other components of the apoptotic pathway that may be related to 12q22 deletion cannot be ruled out. Genes Chromosomes Cancer 28:258-268, 2000.
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PMID:Genetic analysis of the APAF1 gene in male germ cell tumors. 1086 31

We previously reported that exposure of DiFi human colon cancer cells to the anti-epidermal growth factor (EGF) receptor monoclonal antibody (mAb) 225 resulted in apoptosis, but the mechanisms remain to be elucidated. In the present study, we investigated the effects of a panel of four anti-EGF receptor mAbs, each of which binds to different epitopes of the EGF receptor in DiFi cells, on the induction of apoptosis. We found that each of these mAbs induced apoptosis in DiFi cells. Exposure of DiFi cells to mAb 225 activated the initiation caspase-8, which was detectable between 8 and 16 h after exposure of the cells to the antibody. There was also an activation of the initiation caspase-9, which lagged a few hours behind the activation of caspase-8. Exposure of DiFi cells to mAb 225 also activated the execution caspase-3, which was accompanied temporally by evidence of cleavage of a well-characterized caspase-3 substrate, poly(ADP)ribosepolymerase (PARP). Pre-exposure of the cells to the caspase-3-specific inhibitor DEVD-CHO partially reduced the mAb 225-induced PARP cleavage and apoptosis, whereas pre-exposure of the cells to the caspase pan-inhibitor z-VAD-fmk completely inhibited mAb 225-induced apoptosis. Caspases-3, -8 and -9 were not activated in the cell lines in which mAb 225 only induced G1 phase arrest of the cell cycle. In contrast to the apoptosis of DiFi cells induced by ultraviolet irradiation, which strongly activated the c-jun N-terminal kinase-1 (JNK1) and the caspase cascade, mAb 225-induced apoptosis and activation of the caspase cascade in DiFi cells were not associated with activation of JNK1.
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PMID:Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. 1086 8

Granulocytopenia, a hematological hallmark of classical swine fever, is partially responsible for the suppression of innate immune defenses during classical swine fever. The present report demonstrates that this depletion was apparent as early as 3 days postinfection (p.i.). Both mature peripheral and bone marrow neutrophils were affected, whereas immature neutrophils increased absolutely in the periphery and coincidentally immature myeloid progenitors in the bone marrow. These data suggest that a pathogenic relationship exists between these compartments. The central event was not the arrest of hematopoietic cell proliferation or of the mobilization process, but instead apoptosis and possibly also necrosis were shown to play a role. This increase in apoptotic and dead cells was detected as early as 1-3 days p.i. In contrast, viral RNA in bone marrow hematopoietic cells (BMHC) was first detected 5 days p.i., and significant amounts of infected BMHC were detected only 7 days p.i., with the major target being the myeloid compartment. The increased caspase-3 activity observed supported a role for apoptotic cell death. Furthermore, the elevated caspase-9 activity indicated the involvement of the mitochondrial apoptotic pathway. Taken together, the results demonstrate that granulocytopenia and bone marrow atrophy are mediated by hematopoietic cell death and that indirect virus-host-mediated mechanisms are likely to be responsible.
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PMID:Pathogenesis of granulocytopenia and bone marrow atrophy during classical swine fever involves apoptosis and necrosis of uninfected cells. 1087 48

Caspases are aspartate-specific proteases that are specifically activated by numerous death stimuli. Caspase activation is thought to play a major role for the execution of apoptosis. Inactive caspase-9 zymogen is known to be localized within the mitochondrial intermembrane space where it is involved in monitoring mitochondrial damage-associated cytochrome c release and subsequent activation of procaspase-3. Here we show that in mammary epithelial cell lines a significant fraction of caspase-9 proform is associated with discrete structures in the nucleus. Stimulation of cells with chemotherapeutic agents leads to the processing of nuclear procaspase-9 and to the accumulation of nuclear and cytoplasmic caspase activity. Using cell-free extracts from caspase-3-deficient MCF-7 cells we show that caspase-8-mediated processing of nuclear procaspase-9 requires caspase-3. In caspase-3-expressing breast cancer cells, cytochrome c-induced processing of nuclear procaspase-9 is blocked by the caspase inhibitors z-VAD and DEVD but not by YVAD. Purified active caspase-3 is sufficient to cleave nuclear caspase-9 zymogen. These results suggest that, in addition to the mitochondrial localization, caspase-9 proform is found within the nucleus and its processing can be regulated by caspase-3.
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PMID:Nuclear localization of procaspase-9 and processing by a caspase-3-like activity in mammary epithelial cells. 1088 67

Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults and is invariably fatal. We have investigated the effect of cyclo-(Arg-Gly-Asp-D-Phe-Val) (cRGDfV) peptide on survival of human malignant glioma cells in vitro and in vivo. Immunofluorescent analyses revealed the presence of alpha(v)beta3 integrin on U-87MG and U-373MG cells, but minimal expression on U-251MG cells. Treatment of U-87MG and U-373MG cells in vitro with cRGDfV (20 microg/ml), but not the linear peptide, resulted in the appearance of rounded and loosely attached cells with subsequent cell death. By comparison, neither this cyclic peptide nor its linear homolog had any significant effect on growth and morphology of U-251MG cells. The death of cRGDfV-treated (20 microg/ml) glioma cells was blocked by pretreatment (10 microM) of cells with DEVD-FMK and LEHD-FMK, inhibitors of caspase-3 and caspase-9, respectively. Moreover, when glioma cells grown as spheroids were treated with cRGDfV (50 microg/ml), spheroid formation was markedly reduced. Further, treatment of intracranial U-87MG tumors in scid mice with cyclic peptide significantly (p < 0.001) prolonged their survival. These results indicated (i) that cRGDfV induced apoptosis of human glioma cells by binding alpha(v)beta3 integrin expressed on their cell surfaces and (ii) that cRGDfV may be an effective and non-toxic direct anti-tumor therapy for alpha(v)beta3-expressing GBMs.
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PMID:Human malignant glioma therapy using anti-alpha(v)beta3 integrin agents. 1089 66

Doxorubicin induces caspase-3 activation and apoptosis in Jurkat cells but inhibition of this enzyme did not prevent cell death, suggesting that another caspase(s) is critically implicated. Western blot analysis of cell extracts indicated that caspases 2, 3, 4, 6, 7, 8, 9, and 10 were activated by doxorubicin. Cotreatment of cells with the caspase inhibitors Ac-DEVD-CHO, Z-VDVAD-fmk, Z-IETD-fmk, and Z-LEHD-fmk alone or in combination, or overexpression of CrmA, prevented many morphological features of apoptosis but not loss of mitochondrial membrane potential (delta(psi)m), phospatidilserine exposure, and cell death. Western blot analysis of cells treated with doxorubicin in the presence of inhibitors allowed elucidation of the sequential order of caspase activation. Z-IETD-fmk or Z-LEHD-fmk, which inhibit caspase-9 activity, blocked the activation of all caspases studied, lamin B degradation, and the development of apoptotic morphology, but not cell death. All morphological and biochemical features of apoptosis, as well as cell death, were prevented by cotreatment of cells with the general caspase inhibitor Z-VAD-fmk or by overexpression of Bcl-2. Doxorubicin cytotoxicity was also blocked by the protein synthesis inhibitor cycloheximide. Delayed addition of Z-VAD-fmk after doxorubicin treatment, but prior to the appearance of cells displaying a low delta(psi)m, prevented cell death. These results, taken together, suggest that the key mediator of doxorubicin-induced apoptosis in Jurkat cells may be an inducible, Z-VAD-sensitive caspase (caspase-X), which would cause delta(psi)m loss, release of apoptogenic factors from mitochondria, and cell death.
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PMID:Doxorubicin treatment activates a Z-VAD-sensitive caspase, which causes deltapsim loss, caspase-9 activity, and apoptosis in Jurkat cells. 1091 4

In this study, we show that caspases 2, 3, 6, and 7 were activated during peroxynitrite-induced apoptosis in human leukemia HL-60 cells and that processing of these caspases was accompanied by cleavage of poly(ADP-ribose) polymerase and lamin B. Treatment of cells with DEVD-fluoromethyl ketone (FMK), a selective inhibitor for caspase 3-like proteases, resulted in a marked diminution of apoptotic cells. VAVAD-FMK, an inhibitor of caspase 2, partially inhibited the apoptotic response to peroxynitrite. However, selective inactivation of caspase 6 by VEID-FMK did not affect apoptosis rates. These data suggest that caspase 3-like proteases and caspase 2, but not caspase 6, are required for peroxynitrite-induced apoptosis in this cell type. Moreover, we demonstrate that peroxynitrite treatment stimulated activation of caspases 8 and 9, two initial caspases in the apoptotic signaling pathway, and preincubation of cells with their inhibitor, IETD-FMK, inhibited activation of caspase 3-like proteases and caspase 2 at the concentration that prevents the apoptosis. These observations, together, suggest that caspase 8 and/or caspase 9 mediates activation of caspase 3-like proteases and caspase 2 during the apoptosis induced by peroxynitrite in HL-60 cells.
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PMID:Peroxynitrite-induced apoptosis involves activation of multiple caspases in HL-60 cells. 1091

The endocannabinoid anandamide (AEA) is shown to induce apoptotic bodies formation and DNA fragmentation, hallmarks of programmed cell death, in human neuroblastoma CHP100 and lymphoma U937 cells. RNA and protein synthesis inhibitors like actinomycin D and cycloheximide reduced to one-fifth the number of apoptotic bodies induced by AEA, whereas the AEA transporter inhibitor AM404 or the AEA hydrolase inhibitor ATFMK significantly increased the number of dying cells. Furthermore, specific antagonists of cannabinoid or vanilloid receptors potentiated or inhibited cell death induced by AEA, respectively. Other endocannabinoids such as 2-arachidonoylglycerol, linoleoylethanolamide, oleoylethanolamide, and palmitoylethanolamide did not promote cell death under the same experimental conditions. The formation of apoptotic bodies induced by AEA was paralleled by increases in intracellular calcium (3-fold over the controls), mitochondrial uncoupling (6-fold), and cytochrome c release (3-fold). The intracellular calcium chelator EGTA-AM reduced the number of apoptotic bodies to 40% of the controls, and electrotransferred anti-cytochrome c monoclonal antibodies fully prevented apoptosis induced by AEA. Moreover, 5-lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid and MK886, cyclooxygenase inhibitor indomethacin, caspase-3 and caspase-9 inhibitors Z-DEVD-FMK and Z-LEHD-FMK, but not nitric oxide synthase inhibitor Nomega-nitro-l-arginine methyl ester, significantly reduced the cell death-inducing effect of AEA. The data presented indicate a protective role of cannabinoid receptors against apoptosis induced by AEA via vanilloid receptors.
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PMID:Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. 1091 56


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