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)

Fas ligand is a potent inducer of apoptosis in human glioma cells by the Fas/Fas ligand pathway. With comparable efficiency, metalloprotease inhibitors including puromycin and bestatin induce apoptosis in glioma cells. To evaluate the involvement of potential components involved in Fas ligand- and metalloprotease inhibitor-induced apoptosis, we investigated the effect of anti human Fas antibody, soluble Fas ligand and puromycin on cultures of human malignant glioma cell lines (LN-18, LN-229, T98G). Stimulation with Fas ligand lead to apoptotic cell death within 16 h. Costimulation with the translational inhibitor cycloheximide and the transcription blocker actinomycin D did not reduce Fas ligand toxicity. In contrast, apoptosis induced by puromycin was blocked by cycloheximide and decreased by subtoxic doses of actinomycin D in all three gliomas. Whereas inhibition of caspase activity with the general inhibitor zVAD-fmk resulted in a complete block of Fas ligand-induced cell death, puromycin-mediated apoptosis was found to be unaffected by zVAD-fmk as well as by more specific inhibitors for caspase-1 (Interleukin-1 beta converting enzyme) and caspase-3 (CPP32/Yama). Other prominent components involved in many apoptotic pathways as bcl-2 and reactive oxygen intermediates were also examined. Bcl-2 which protects glioma cells from Fas ligand-induced cell death, was shown to have only a small protective effect on puromycin-induced apoptosis. The tested radical scavengers did not reduce Fas- or puromycin-mediated killing of human glioma cells.
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PMID:Differential activity of bcl-2 and ICE enzyme family protease inhibitors on Fas and puromycin-induced apoptosis of glioma cells. 940 14

Platelets are physiologically anucleated cells, derived from megakaryocytes, that undergo vesiculation and transformation into small particles when they are stimulated in vitro by ionomycin and other agents. Electron microscopy images suggest a similarity to apoptosis in cells with nuclei, which ends with cell disintegration and formation of apoptotic bodies. By PCR, we have demonstrated mRNA expression of bcl-2, bax, and p53 in highly purified non-stimulated platelets. A side-scatter shift and a decrease in the Bcl-2/Bax protein ratio were observed by flow cytometry analysis after stimulation with ionomycin. The ionomycin-induced modifications were inhibited by the calpain I inhibitor calpeptin and, less effectively, by VAD-cmk, a broad-spectrum caspase inhibitor. However, caspase 3-like activity was very low, with only a twofold increase after ionomycin stimulation, as measured by the cleavage of the fluorogenic peptide substrate DEVD-AMC. Our data indicate that platelets may constitute a natural model for the analysis of cytoplasmic events in apoptosis.
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PMID:Alterations in Bcl-2/Bax protein levels in platelets form part of an ionomycin-induced process that resembles apoptosis. 943 28

We have demonstrated that ginsenoside Rh2 (G-Rh2), a ginseng saponin with a dammarane skeleton, induces apoptosis of human hepatoma SK-HEP-1 cells as evidenced by analyses of DNA fragmentation, flow cytometry and changes in cell morphology. Ac-YVAD-CMK or Ac-DEVD-CHO effectively prevented G-Rh2-induced DNA fragmentation, indicating the involvement of caspase-like proteases in the process of apoptosis. In addition, G-Rh2 induced the processing of caspase-3 to an active form, p17. In stable Bcl-2 transfectants, G-Rh2 also induced DNA fragmentation, while staurosporine-induced DNA fragmentation was totally blocked. As it did in wild-type cells, G-Rh2 induced the proteolytic activation of caspase-3 protease and subsequent cleavage of PARP in the bcl-2 transfectants. In summary, G-Rh2 contains an apoptotic inducing activity in SK-HEP-1 cells which functions via Bcl-2-insensitive activation of caspase-3, followed by proteolytic cleavage of PARP.
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PMID:Activation of caspase-3 protease via a Bcl-2-insensitive pathway during the process of ginsenoside Rh2-induced apoptosis. 945 77

Prevention of hypoxic cell death is a key to successful liver transplantation. We developed a new method for preventing liver hypoxic cell death by introducing an anti-cell death gene directly into rat livers. When the human bcl-2 gene (hbcl-2) was directly transfected into rat livers together with non-histone chromosomal protein high mobility group 1 (HMG1) by the hemagglutinating virus of Japan (Sendai virus; HVJ)-liposome method, human Bcl-2 protein (hBcl-2) was efficiently expressed. Electron microscopy and fluorescence microscopy revealed that hepatocytes expressing exogenous hBcl-2 were almost completely protected the hypoxic cell necrosis. The expression of the hBcl-2 also inhibited activation of caspase-3 (-like) proteases and liver dysfunction. Thus, we conclude that transfection of the hbcl-2 gene through HVJ-liposome method is useful to prevent liver cell necrosis induced by hypoxia. This finding could lead to new strategies to avoid the hypoxic cell death, the major problem in liver transplantation.
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PMID:Prevention of hypoxic liver cell necrosis by in vivo human bcl-2 gene transfection. 947 7

Apoptosis is induced in cells via distinct pathways, which may differ according to various stimuli and different cell types. One apoptotic stimulus is the activation of receptors such as the p55 tumor necrosis factor (TNF) receptor. These receptors transduce their apoptotic signals via a cytoplasmic region termed the death domain. Here we investigated the apoptotic pathway induced by overexpression of the intracellular domain of p55 TNF receptor (p55-IC) in a neuronal model system consisting of PC12 cells. Using the tetracycline-regulated transactivator system, which allows controlled gene expression, we show that overexpression of p55-IC induces apoptosis in both naive and neuronal PC12 cells. The apoptosis-inducing effect of p55-IC is blocked by the expression of bcl-2, suggesting that p55-IC induces apoptosis in PC12 cells via a pathway controlled by bcl-2. The need for caspases in the p55-IC-induced cell death effect in naive and neuronal PC12 cells was studied by examining the effects of broad-spectrum and specific inhibitors of caspases as well as expression of antisense caspase-2 RNA. The broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone blocked p55-IC-induced cell death in both naive and neuronal cells, suggesting that caspases are needed for this process in both cell types. Caspase-1-like proteases are most probably not involved in the process since neither expression of crmA nor treatment with the caspase-1-specific peptide inhibitor Ac-Try-Val-Ala-Asp-aldehyde had any protective effect. Interestingly, expression of antisense caspase-2 RNA blocked the p55-IC-induced cell death in naive but not in neuronal PC12 cells, whereas the caspase-3-like specific inhibitor Ac-Asp-Glu-Val-Asp-aldehyde partially inhibited this death in neuronal but not in naive cells. These results suggest that the apoptosis-inducing effect of p55-IC requires different caspases in naive and neuronal PC12 cells.
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PMID:The intracellular domain of p55 tumor necrosis factor receptor induces apoptosis which requires different caspases in naive and neuronal PC12 cells. 958 83

CD95 ligand (CD95L)-induced apoptosis is a novel immunotherapeutic approach to malignant glioma. Here, we report that interferon-alpha (IFN-alpha) sensitizes LN-229 and T98G human malignant glioma cells to CD95L-induced apoptosis. In contrast to the effects of IFN-gamma and TNF-alpha which sensitize glioma cells to CD95 antibody-induced apoptosis in part by enhancing CD95 expression, IFN-alpha has no effect on CD95 expression at the cell surface of LN-229 and T98G cells. To confirm that changes in CD95 expression are not required for the effects of IFN-alpha, we show that IFN-alpha enhances CD95L-induced apoptosis even in CD95-transfected LN-308 glioma cells. These LN-308 cells have little endogenous CD95 expression but express high levels of CD95 from a stably integrated CD95 expression plasmid. The sensitizing effects of IFN-alpha appear to be independent of cell cycle effects of IFN-alpha and are unaffected by ectopic expression of the bcl-2 proto-oncogene. IFN-alpha enhances CD95L-induced activation of caspase-3, a critical mediator of CD95L-induced cell death. IFN-alpha also increases the cytotoxic effects of BCNU, teniposide and cytarabine in both cell lines, and of vincristine in LN-229 cells. Doxorubicin and 5-fluorouracil toxicity are unaffected by IFN-alpha. IFN-alpha may be a useful adjunct to novel strategies of immunochemotherapy for malignant gliomas that target CD95-mediated apoptosis.
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PMID:Interferon-alpha enhances CD95L-induced apoptosis of human malignant glioma cells. 967 Aug 53

Caspases are aspartate-specific cysteine proteases that play a pivotal role in drug-induced cell death. We designed RT-PCR assays to analyse the expression of CASP-3, CASP-4, CASP-6 and the long and short isoforms of CASP-2 genes in human cells. These genes heterogeneously coexpress in leukemic cell lines and bone marrow samples from patients with de novo acute myelogenous leukemia at diagnosis. Treatment of U937 and HL60 leukemic cells and HT29 colon carcinoma cells with the topoisomerase II inhibitor etoposide upregulates CASP-2 and CASP-3 genes in these cells before inducing their apoptosis. This effect of etoposide is not observed in K562 cells and bcl-2-transfected U937 cells which are less sensitive to drug-induced apoptosis. Nuclear run-on experiments demonstrate that etoposide increases CASP gene transcription in U937 cells, an effect that is prevented by Bcl-2 overexpression. Upregulation of CASP genes is associated with an enhanced synthesis of related procaspases that precedes the appearance of apoptosis markers including caspase-3 activation, poly(ADP-ribose) polymerase cleavage and internucleosomal DNA fragmentation. These results suggest that the ability of tumor cells to upregulate CASP-2 and CASP-3 genes in response to cytotoxic drugs could be predictive of their sensitivity to drug-induced apoptosis.
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PMID:Upregulation of CASP genes in human tumor cells undergoing etoposide-induced apoptosis. 967 9

Burkitt's lymphoma cells that vary in their phenotypic characteristics show significantly different degrees of susceptibility to radiation-induced apoptosis. Propensity to undergo apoptosis is reflected in the degradation of substrates such as DNA-dependent protein kinase but the status of bcl-2, c-myc and p53 has been uninformative. In this study, we have focused on 2 Epstein-Barr virus (EBV)-associated Burkitt's cell lines, one (WW2) susceptible and the other (BL29) resistant to etoposide-induced apoptosis. Differences in expression of BHRF1, an EBV gene that is homologous to the Bcl-2 proto-oncogene and known to inhibit apoptosis, or changes in apoptosis inhibitory proteins (IAPs), did not appear to account for the difference in susceptibility in the 2 cell lines. Cytoplasmic extracts from etoposide-treated WW2 cells caused apoptotic changes in nuclei isolated from either BL29 or WW2 cells, whereas extracts from BL29 cells failed to do so. In addition, extracts from etoposide-treated WW2 cells degraded the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), an important indicator of apoptosis, but this protein was resistant to degradation by BL29 extracts. It appears likely that caspase 3 (CPP32) is involved in this degradation since it was activated only in the apoptosis susceptible cells and the pattern of cleavage of DNA-PKcs was similar to that reported previously with recombinant caspase 3. As observed previously, addition of caspase 3 to nuclei failed to induce morphological changes indicative of apoptosis, but addition of caspase 3 to nuclei in the presence of extract from the resistant cells led to apoptotic changes. We conclude that resistance to apoptosis in BL29 cells is due to a failure of etoposide to activate upstream effectors of caspase activity.
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PMID:Resistance to etoposide-induced apoptosis in a Burkitt's lymphoma cell line. 968 10

The bcl-2 protein plays an essential role in preventing cell death. Its activity is regulated through association with bcl-2 homologous and nonhomologous proteins and also by serine phosphorylation. We now report that bcl-2 can be proteolytically cleaved towards its N-terminus by a cysteine proteinase present in RL-7 lymphoma cell lysates, yielding a major product of apparent MW 20 kDa, different from the products of bcl-2 cleavage by HIV protease. Moreover, bcl-2 proteins mutated for Asp residues at positions 31 and 34 were efficiently cleaved by RL-7 cell lysates, indicating that this proteolytic activity is distinct from the caspase-3 that cleaves bcl-2 at Asp 34. This bcl-2 cleaving activity is inhibited by E-64 and is therefore distinct from the proteinases of the ICE/Ced-3 family (caspases), whereas reciprocally, ICE (caspase-1) is unable to cleave bcl-2. It is optimally active at pH 5, a feature distinguishing it from calpain, another non-ICE cysteine proteinase which has been associated with apoptosis. This novel bcl-2 cleaving protease, although constitutively present in RL-7 cells and resting peripheral blood lymphocytes (PBL) was upregulated following induction of apoptosis in RL-7 cells or mitogen activation in PBL. The N-terminus of bcl-2 which contains the BH4 domain that binds the kinase Raf-1 and the phosphatase calcineurin is essential for anti-apoptotic activity. Its cleavage might provide a novel post-translational mechanism for regulating bcl-2 function and could amplify ongoing programmed cell death.
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PMID:N-terminus cleavage of bcl-2 by a novel cellular non-ICE cysteine proteinase. 973 98

Bcl-xL, a member of the bcl-2 family of proteins is required for the survival of neurons early in development. To study the mechanism of action of Bcl-xL in a neuronal context, we generated rat PC12 cells overexpressing Bcl-xL and examined their susceptibility to apoptotic stimuli that induce apoptosis through different pathways involving trophic-factor deprivation, staurosporine, tumor necrosis factor alpha or cisplatin. Overexpression of Bcl-xL in both naive and neuronal PC12 cells inhibited apoptosis induced by the different pathways. However, the extent of this protective effect varied, suggesting that the contribution of the Bcl-xL-controlled step to apoptosis differs in the different pathways. Our findings also showed that TNF alpha-induced activation of caspase-3 is inhibited by overexpression of Bcl-xL, suggesting that Bcl-xL acts upstream of caspase activation.
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PMID:Bcl-xL inhibits different apoptotic pathways in rat PC12 cells. 975 99


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