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

---

Query: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Influenza virus infection induces apoptosis in cultured cells with an augmented expression of Fas (APO-1/CD95). Caspases, a family of cysteine proteases structurally related to interleukin-1-beta-converting enzyme (ICE), play crucial roles in apoptosis induced by various stimuli, including Fas. However, activation of the caspase-cascade seems to be different in various pathways of apoptotic stimuli. We therefore examined the involvement of caspases in influenza virus-induced apoptosis using caspase inhibitors. We found that z-VAD-fmk and z-IETD-fmk effectively inhibited virus-induced apoptosis, whereas Ac-DEVD-CHO and Ac-YVAD-CHO showed partial and little effect on virus-induced cell death, respectively. Consistently, caspase-3-like activity, but not caspase-1-like activity, was increased in the virus-infected cells. The transfection of plasmids encoding viral inhibitors of caspase (v-FLIP or crmA) into HeLa cells inhibited apoptosis by virus infection. The peptide inhibitors of caspases used in this study did not inhibit viral replication. We conclude that influenza virus infection activates some caspases, and that this activation may be downstream of viral replication.
...
PMID:Recruitment of apoptotic cysteine proteases (caspases) in influenza virus-induced cell death. 1033 94

A combination of the pro-inflammatory cytokines interleukin (IL)-1alpha, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha induces nitric oxide synthase mRNA expression and nitric oxide (NO) generation in the human colon carcinoma cell line HT-29. This can be inhibited by pretreatment with IL-13 via a phosphatidylinositol (PI) 3-kinase-dependent mechanism (Wright, K., Ward, S. G., Kolios, G., and Westwick, J. (1997) J. Biol. Chem. 272, 12626-12633). Since NO has been implicated in regulating mechanisms leading to cell death, while activation of PI 3-kinase-dependent signaling cascades are thought to be involved with promoting cell survival events, we have investigated the outcome of these cytokine treatments on apoptosis and cell survival of HT-29 cells. Initiation of apoptosis can be achieved by the combinations of IFN-gamma/TNF-alpha, IFN-gamma/CD95, IL-1alpha/IFN-gamma, and IL-1alpha/IFN-gamma/TNF-alpha to varying extents. Induction of apoptotic markers by HT-29 cells in response to cytokine treatment is not dependent on NO production. Pretreatment with IL-13 protects against IL-1alpha/IFN-gamma/TNF-alpha- and IFN-gamma/TNF-alpha- as well as IFN-gamma/CD95-induced (but not IL-1alpha/IFN-gamma-induced) cell death. In addition, IFN-gamma/TNF-alpha and IL-1alpha/IFN-gamma/TNF-alpha stimulate activation of caspase-8 and caspase-3, which IL-13 pretreatment was able to partially inhibit and delay. IL-13 also stimulates activation of the major PI 3-kinase effector, protein kinase B. The PI 3-kinase inhibitors wortmannin and LY294002 inhibit IL-13 stimulation of protein kinase B as well as the cell survival effects of IL-13. These data demonstrate that cytokine-induced apoptosis of HT-29 cells is NO-independent and that the activation of a PI 3-kinase-dependent signaling cascade by IL-13 is a key signal responsible for the inhibition of apoptosis.
...
PMID:Cytokine-induced apoptosis in epithelial HT-29 cells is independent of nitric oxide formation. Evidence for an interleukin-13-driven phosphatidylinositol 3-kinase-dependent survival mechanism. 1035 77

Dysregulation of CD95/Fas-mediated apoptosis has been implicated as a contributing factor in autoimmune disorders. Animal studies clearly have established a connection between mercury exposure and autoimmune disease in rodents, while case reports have suggested a link between accidental mercury contamination and autoimmune disease in humans. The mechanism(s) for these associations are poorly understood. Using the Jurkat cell model, we have found that low levels (</=10 microM) of inorganic mercury (i.e., HgCl2) attenuated anti-CD95-mediated growth arrest and markedly enhanced cell survival. Several biochemical assays for apoptosis, including DNA degradation, poly(ADP-ribose) polymerase degradation, and phosphatidylserine externalization, directly verified that HgCl2 attenuated anti-CD95-mediated apoptosis. In an attempt to further characterize the effect of mercury on CD95-mediated apoptosis, several signaling components of the CD95 death pathway were analyzed to determine whether HgCl2 could modulate them. HgCl2 did not modulate CD95 expression; however, it did block CD95-induced caspase-3 activation. HgCl2 was not able to attenuate TNF-alpha-mediated apoptosis in U-937 cells, or ceramide-C6-mediated apoptosis in Jurkat cells, suggesting that mercury acts upstream of, or does not involve, these signals. Thus, inorganic mercury specifically attenuates CD95-mediated apoptosis likely by targeting a signaling component that is upstream of caspase-3 activation and downstream of CD95.
...
PMID:Protection against CD95-mediated apoptosis by inorganic mercury in Jurkat T cells. 1035 62

The proteolytic caspase cascade plays a central role in the signaling and execution steps of apoptosis. This study investigated the activation of different caspases in apoptosis induced by MAL (a folding variant of human alpha-lactalbumin) isolated from human milk. Our results show that the caspase-3-like enzymes, and to a lesser extent the caspase-6-like enzymes, were activated in Jurkat and A549 cells exposed to MAL. Activated caspases subsequently cleaved several protein substrates, including PARP, lamin B, and alpha-fodrin. A broad-range caspase inhibitor, zVAD-fmk, blocked the caspase activation, the cleavage of proteins, and DNA fragmentation, indicating an important role for caspase activation in MAL-induced apoptosis. Since an antagonistic anti-CD95 receptor antibody, ZB4, did not influence the MAL-induced killing, we conclude that this process does not involve the CD95-mediated pathway. While MAL did not directly activate caspases in the cytosol, it colocalized with mitochondria and induced the release of cytochrome c. Thus, these results demonstrate that caspases are activated and involved in apoptosis induced by MAL and that direct interaction of MAL with mitochondria leads to the release of cytochrome c, suggesting that this release is an important step in the initiation and/or amplification of the caspase cascade in these cells.
...
PMID:Protease activation in apoptosis induced by MAL. 1036 25

Neutrophils undergo constitutive apoptosis when aged ex vivo. Recent studies have indicated roles for Fas/CD95 and the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase system in this process. We have investigated the role of protein kinase C (PKC) in neutrophil death. We show that there is proteolysis and activation of the novel isoform PKCdelta in aged neutrophils and that this process is accelerated by the addition of an agonistic Fas antibody. PKCdelta proteolysis occurs before the onset of any detectable features of apoptosis and pharmacologic inhibition of this enzyme inhibits neutrophil apoptosis. PKCdelta cleavage and activation is dependent on caspase-8/FADD-like interleukin-1beta converting enzyme (FLICE)-mediated processing of caspase-3/CPP32. Neutrophil survival is prolonged by the addition of broad spectrum (BD.fmk) or caspase-8 targeted (zIETD.fmk) peptide caspase inhibitors. Inhibition of PKCdelta does not prevent apoptosis triggered by factor withdrawal in immature hematopoietic cells, including normal human CD34(+) progenitors indicating that within a given lineage, the mechanisms of apoptosis may be differentiation-stage-specific. Ex vivo aging of neutrophils leads to the increasing production of reactive oxygen species and this is attenuated in cells treated with either caspase or PKCdelta inhibitors. Proteolytically activated PKCdelta acts as a molecular link between the Fas/CD95 receptor and the NADPH-oxidase system and plays a central role in regulating the process of neutrophil apoptosis.
...
PMID:Caspase-mediated proteolysis and activation of protein kinase Cdelta plays a central role in neutrophil apoptosis. 1038 25

Agonistic engagement of the cytokine receptor CD95 in mice leads to activation of hepatic caspases, followed by massive hepatocyte apoptosis, acute liver failure, and death. This mechanism of cell death is thought to be associated with several human liver disorders. Because hepatic glutathione represents the major defense against toxic liver injury, we investigated its role in CD95-mediated liver failure, which represents a model for hyperinflammatory organ destruction. As a tool for modulating the liver glutathione status of mice in vivo, we used the GSH transferase substrate, phorone, which rapidly depleted hepatic glutathione in a dose-dependent manner. When GSH was depleted, CD95-initiated hepatic caspase-3-like activity and DNA fragmentation were completely blocked, and animals were protected from liver injury dose-dependently as assessed by histological examination and determination of liver enzymes in plasma. Conversely, repletion of hepatic glutathione by treatment with the permeable glutathione monoethylester restored susceptibility of GSH-depleted mice toward CD95-mediated liver injury. In contrast, the antioxidants, GSH, N-acetyl cysteine, alpha-tocopherol, butyl-hydroxytoluene, and catalase failed to do so. Animals treated once with phorone survived for more than 3 months after an otherwise lethal injection of the activating anti-CD95 antibody. We investigated the thiol sensitivity of recombinant caspase-3 in vitro and observed that its activity was dependent on the presence of a reducing agent such as GSH, while GSSG attenuated proteolytic activity. Based on our finding that CD95-mediated hepatocyte apoptosis requires an intact intracellular glutathione status, we propose that the activation of apoptosis-executing caspases is controlled by reduced glutathione.
...
PMID:CD95-Mediated murine hepatic apoptosis requires an intact glutathione status. 1038 54

UVB-induced DNA damage is a crucial event in UVB-mediated apoptosis. On the other hand, UVB directly activates death receptors on the cell surface including CD95, implying that UVB-induced apoptosis can be initiated at the cell membrane through death receptor clustering. This study was performed to measure the relative contribution of nuclear and membrane effects in UVB-induced apoptosis of the human epithelial cell line HeLa. UVB-mediated DNA damage can be reduced by treating cells with liposomes containing the repair enzyme photolyase followed by exposure to photoreactivating light. Addition of photolyase followed by photoreactivation after UVB reduced the apoptosis rate significantly, whereas empty liposomes had no effect. Likewise, photoreactivating treatment did not affect apoptosis induced by the ligand of CD95, CD95L. UVB exposure at 4 degrees C, which prevents CD95 clustering, also reduced the apoptosis rate, but to a lesser extent. When cells were exposed to UVB at 4 degrees C and treated with photolyase plus photoreactivating light, UVB-induced apoptosis was almost completely prevented. Inhibition of caspase-3, a downstream protease in the CD95 signaling pathway, blocked both CD95L and UVB-induced apoptosis, whereas blockage of caspase-8, the most proximal caspase, inhibited CD95L-mediated apoptosis completely, but UVB-induced apoptosis only partially. Although according to these data nuclear effects seem to be slightly more effective in mediating UVB-induced apoptosis than membrane events, both are necessary for the complete apoptotic response. Thus, this study shows that nuclear and membrane effects are not mutually exclusive and that both components contribute independently to a complete response to UVB.
...
PMID:Nuclear and cell membrane effects contribute independently to the induction of apoptosis in human cells exposed to UVB radiation. 1039 32

NF-kappa B is involved in the transcriptional control of various genes that act as extrinsic and intrinsic survival factors for T cells. Our findings show that suppression of NF-kappa B activity with cell-permeable SN50 peptide, which masks the nuclear localization sequence of NF-kappa B1 dimers and prevents their nuclear localization, induces apoptosis in resting normal human PBL. Inhibition of NF-kappa B resulted in the externalization of phosphatidylserine, induction of DNA breaks, and morphological changes consistent with apoptosis. DNA fragmentation was efficiently blocked by the caspase inhibitor Z-VAD-fmk and partially blocked by Ac-DEVD-fmk, suggesting that SN50-mediated apoptosis is caspase-dependent. Interestingly, apoptosis induced by NF-kappa B suppression, in contrast to that induced by TPEN (N,N,N',N'-tetrakis [2-pyridylmethyl]ethylenediamine) or soluble Fas ligand (CD95), was observed in the absence of active death effector proteases caspase-1-like (IL-1 converting enzyme), caspase-3-like (CPP32/Yama/apopain), and caspase-6-like and without cleavage of caspase-3 substrates poly(ADP-ribose) polymerase and DNA fragmentation factor-45. These findings suggest either low level of activation is required or that different caspases are involved. Preactivation of T cells resulting in NF-kappa B nuclear translocation protected cells from SN50-induced apoptosis. Our findings demonstrate an essential role of NF-kappa B in survival of naive PBL.
...
PMID:Inhibition of NF-kappa B activity in human T lymphocytes induces caspase-dependent apoptosis without detectable activation of caspase-1 and -3. 1039 45

We have recently identified two different pathways of CD95-mediated apoptosis (Scaffidi, C., Fulda, S., Srinivasan, A., Feng, L., Friesen, C., Tomaselli, K. J., Debatin, K.-M., Krammer, P. H., and Peter, M. E. (1998) EMBO J. 17, 1675-1687). CD95-mediated apoptosis in type I cells is initiated by large amounts of active caspase-8 formed at the death-inducing signaling complex (DISC) followed by direct cleavage of caspase-3. In contrast, in type II cells very little DISC and small amounts of active caspase-8 sufficient to induce the apoptogenic activity of mitochondria are formed causing a profound activation of both caspase-8 and caspase-3. Only in type II cells can apoptosis be blocked by overexpressed Bcl-2 or Bcl-x(L). We now show that a number of apoptosis-inhibiting or -inducing stimuli only affect apoptosis in type II cells, indicating that they act on the mitochondrial branch of the CD95 pathway. These stimuli include the activation of protein kinase C, which inhibits CD95-mediated apoptosis resulting in a delayed cleavage of BID, and the induction of apoptosis by the ceramide analog C(2)-ceramide. In addition, we have identified the CD95 high expressing cell line Boe(R) as a CD95 apoptosis-resistant type II cell that can be sensitized by treatment with cycloheximide without affecting formation of the DISC. This also places the effects of cycloheximide in the mitochondrial branch of the type II CD95 pathway. In contrast, c-FLIP was found to block CD95-mediated apoptosis in both type I and type II cells, because it acts directly at the DISC of both types of cells.
...
PMID:Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. 1042 30

Transduction of cancer cells with herpes simplex virus thymidine kinase gene (HSVtk) followed by prodrug ganciclovir (GCV) treatment has been shown to induce apoptosis. In this study, four murine tumors including B16F10 melanoma, NG4TL4 sarcoma, H6 hepatoma and 1MEA 7R.1 hepatoma were found to vary in sensitivity to this gene therapy strategy in vitro but, at effective doses of GCV, the HSVtk-transduced cells of all four tumors showed similar kinetics of early rise in p53 protein levels, then cell cycle S-/G2-phase arrest and finally signs of apoptosis. Immunoblot analyses revealed that Fas (CD95/APO-1), Fas ligand (FasL) and two downstream mediators, RIP and caspase-3, (CPP32, YAMA, Apopain) were increased in GCV-treated HSVtk-transduced tumor cells the cell cycle arrest and before apoptosis. Increased expression of FasL could also be observed in vivo in HSVtk-transduced tumors induced to regress by GCV treatment. Enzyme measurements using specific substrate showed that the caspase-3 activation followed kinetically the FasL expression. More than half of the HSVtk/GCV-induced cell death could be abrogated by addition to the cell culture medium of a specific antisense oligonucleotide to block FasL synthesis, a recombinant Fas/Fc chimeric protein to compete with Fas receptor for FasL binding, or cell-permeable specific tetrapeptide inhibitors of caspase-3 or caspase-8.
...
PMID:Involvement of Fas (CD95/APO-1) and Fas ligand in apoptosis induced by ganciclovir treatment of tumor cells transduced with herpes simplex virus thymidine kinase. 1043 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---