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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Initiation of apopotosis requires the conversion of procaspases to mature caspases. Here we show that oligomerization of pro-caspases is sufficient to induce proteolytic generation of mature caspase subunits and activation of their cell death activity. Deletion of the protein interaction motif DED from pro-caspase-8 greatly suppresses its apoptotic activity. Cell death activity can be restored by oligomerization of pro-caspase-8 protease domains by two heterologous inducible oligomerization systems. Induced oligomerization also activates the apoptotic activity of pro-caspase-1 but not pro-caspase-3. In vitro, oligomerization leads to pro-caspase processing to from the mature caspase subunits; this processing requires the intrinsic caspase activity of zymogens and proceeds via a novel order of cleavage events.
Mol Cell 1998 Jan
PMID:Autoproteolytic activation of pro-caspases by oligomerization. 965 28

We examined whether apoptosis is involved in hypoxic cell death using primary cultures of rat cortical neurons and whether the cell death is associated with changes in Bcl-2 and Bax expressions and activities of caspases. Hypoxic insult accelerates apoptosis, as shown by apoptotic nuclei and by chromatin degradation of internucleosomal fragments. This apoptotic process is accompanied by a rapid and sustained down-regulation of Bcl-2, whereas levels of Bax are unchanged. Furthermore, hypoxic insult activates sequentially caspase-1-like and caspase-3-like proteases, following down-regulation of Bcl-2 expression. Peptide inhibitors of either caspase-1 or caspase-3 protect against neuronal death, although they do not prevent hypoxia-induced down-regulation of Bcl-2. Furthermore, treatment of cortical neurons with either insulin-like growth factor-1 (IGF-1) or basic fibroblast growth factor (bFGF), growth factors which are implicated to prevent neuronal loss in ischemic brain, partly prevented neuronal death accompanied by inhibition of alterations in Bcl-2 protein levels and caspase-3-like activities. These results suggest that hypoxia induces neuronal death by down-regulation of Bcl-2 protein levels followed by sequential activation of the caspases, and the protection from neuronal cell death of these growth factors under hypoxic conditions derives at least partly from their capability to prevent down-regulation of the anti-apoptotic protein levels.
Brain Res Mol Brain Res 1998 Jul 15
PMID:Roles of Bcl-2 and caspases in hypoxia-induced neuronal cell death: a possible neuroprotective mechanism of peptide growth factors. 968 76

The interleukin-1 (IL-1) family comprises IL-1 alpha and IL-1 beta and an endogenous IL-1 receptor antagonist (IL-1ra). IL-1 has diverse actions in the brain and has been implicated in both acute and chronic neurodegeneration. However, neither IL-1 alpha nor IL-1 beta are neurotoxic per se in vivo, so other IL-1 related ligands may be important in neurodegeneration. The cytokine interleukin-18 (also called interferon gamma inducing factor, IGIF) was first isolated from the liver of mice during toxic shock. It was later proposed as a member of the IL-1 family, based on protein sequence homology with IL-1 beta and IL-1ra, and has tentatively been called IL-1 gamma. We cloned IL-18 from adult rat brain and demonstrated, by RT-PCR, that it is expressed constitutively in cerebellum, hippocampus, hypothalamus, cortex and striatum. Rat brain IL-18 shows close homology to mouse and human IL-18, and to the recently published sequence from the rat adrenal gland. Mouse pro-IL-18 and pro-IL-1 beta are processed by caspase-1. We demonstrate that caspase-1 also cleaves rat IL-18 in vitro and that the caspase inhibitor, zVAD-DCB inhibits this cleavage.
Mol Psychiatry 1998 Jul
PMID:Cloning of rat brain interleukin-18 cDNA. 970 48

We have presently determined the effect of inhibition of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) on the occurrence of apoptosis in insulin-producing cells. The ADP-ribosylation activities of intact cells were decreased by incubation of RINm5F cells for 16 h with the PARP inhibitors nicotinamide (NA) (20-50 mM) or 3-aminobenzamide (3-ABA) (10 mM). Exposure to 20-50 mM NA or 10 mM 3-ABA both resulted in massive apoptosis in RINm5F cells. A 24 h exposure to 50 mM nicotinamide induced apoptosis in fetal but not adult rat islet cells. In addition, exposure of RINm5F cells to 50 mM NA for 12-24 h induced the appearance of the 85 kDa proteolytic PARP fragment, indicating activation of the ICE-like protease caspase-3. Incubation with 20-50 mM NA did not induce any consistent effects upon transcription factor NF-kappaB activity, demonstrating that this pathway is not involved in induction of apoptosis by NA. It is concluded that in insulin-producing cells with a high mitotic rate, inhibition of ADP-ribosylation--and consequently of auto-modification and release of PARP bound to DNA strand breaks--leads to activation of programmed cell death.
Mol Cell Endocrinol 1998 Apr 30
PMID:Nicotinamide-induced apoptosis in insulin producing cells is associated with cleavage of poly(ADP-ribose) polymerase. 970 78

The requirement for caspases (ICE-like proteases) were investigated in mediating apoptosis of WEHI7.2 mouse lymphoma cells in response to two death inducers with different mechanisms of action, the glucocorticoid hormone dexamethasone (DX) and the calcium-ATPase inhibitor thapsigargin (TG). Apoptosis induction by these agents followed different kinetics, and was closely correlated with in vivo activation of caspase-3 (CPP32/Yama/Apopain) and cleavage of the caspase target protein poly(ADP-ribose) polymerase (PARP). Caspase activation and PARP cleavage were inhibited by Bcl-2 overexpression. Cell extracts from DX- and TG-treated cells cleaved the in vitro synthesized baculovirus p35 ICE-like protease target, producing 25 and 10 kDa fragments. p35 cleavage was inhibited by mutating the active site aspartic acid to alanine, and by a panel of protease inhibitors that inhibit caspase-3-like proteases, including iodoacetamide, N-ethylmaleimide, and Ac-DEVD-cho. Treatment of cells in vivo with two cell permeant peptide fluoromethylketone inhibitors of caspase activity, Z-VAD-fmk and Z-DEVD-fmk, inhibited DX- and TG-induced apoptotic nuclear changes and maintained plasma membrane integrity, whereas the cathepsin inhibitor, Z-FA-fmk, and two calpain inhibitors failed to inhibit apoptosis. An unexpected observation was that due to the delayed time course of DX-induced apoptosis, optimal preservation of plasma membrane integrity was achieved by adding caspase inhibitors beginning 8 h after DX addition. In summary, the findings indicate that two diverse apoptosis-inducing signals converge into a common Bcl-2-regulated pathway that leads to caspase activation and apoptosis.
Mol Cell Endocrinol 1998 Apr 30
PMID:Apoptosis induction by the glucocorticoid hormone dexamethasone and the calcium-ATPase inhibitor thapsigargin involves Bc1-2 regulated caspase activation. 970 90

In apoptosis induced by Reaper in Drosophila, as well as in a number of other systems, it has been suggested that the increased synthesis of ceramide might be a consequence of the activation of the caspase/ICE (Interleukin-1beta converting enzyme) protease pathway involved in cell death, implying that ceramide generation might often be the result rather than the cause of apoptosis. WEHI 231 B cells have previously been shown to undergo apoptosis following exposure to exogenous ceramide and to produce increased amounts of ceramide in response to anti-IgM crosslinking. We show here that in WEHI 231 cells a peptide inhibitor of caspase activity blocks cell death in response to both anti-IgM and exogenous ceramide. However, the induction of ceramide synthesis by WEHI 231 cells in response to anti-IgM crosslinking is not blocked by this peptide. These results indicate that antigen receptor induced ceramide generation in WEHI 231 cells does not require caspase activation, and support the view that ceramide generation in immature B cells may be the cause rather than the consequence of activation of the caspase dependent death pathway.
Mol Immunol 1998 Mar
PMID:Inhibition of caspase activity prevents anti-IgM induced apoptosis but not ceramide generation in WEHI 231 B cells. 973 35

Genetic studies of the nematode Caenorhabditis elegans (C. elegans) have identified several important components of the cell death pathway, most notably CED-3, CED-4, and CED-9. CED-4 directly interacts with the Bcl-2 homologue CED-9 (or the mammalian Bcl-2 family member Bcl-xL) and the caspase CED-3 (or the mammalian caspases ICE and FLICE). This trimolecular complex of CED-4, CED-3, and CED-9 is functional in that CED-9 inhibits CED-4 from activating CED-3 and thereby inhibits apoptosis in heterologous systems. The E1B 19,000-molecular weight protein (E1B 19K) is a potent apoptosis inhibitor and the adenovirus homologue of Bcl-2-related apoptosis inhibitors. Since E1B 19K and Bcl-xL have functional similarity, we determined if E1B 19K interacts with CED-4 and regulates CED-4-dependent caspase activation. Binding analysis indicated that E1B 19K interacts with CED-4 in a Saccharomyces cerevisiae two-hybrid assay, in vitro, and in mammalian cell lysates. The subcellular localization pattern of CED-4 was dramatically changed by E1B 19K, supporting the theory of a functional interaction between CED-4 and E1B 19K. Whereas expression of CED-4 alone could not induce cell death, coexpression of CED-4 and FLICE augmented cell death induction by FLICE, which was blocked by expression of E1B 19K. Even though E1B 19K did not prevent FLICE-induced apoptosis, it did inhibit CED-4-dependent, FLICE-mediated apoptosis, which suggested that CED-4 was required for E1B 19K to block FLICE activation. Thus, E1B 19K functions through interacting with CED-4, and presumably a mammalian homologue of CED-4, to inhibit caspase activation and apoptosis.
Mol Cell Biol 1998 Oct
PMID:E1B 19,000-molecular-weight protein interacts with and inhibits CED-4-dependent, FLICE-mediated apoptosis. 974 22

Mice exposed to 100% O2 die after 3 or 4 d with diffuse alveolar damage and alveolar edema. Extensive cell death is evident by electron microscopy in the alveolar septa, affecting both endothelial and epithelial cells. The damaged cells show features of both apoptosis (condensation and margination of chromatin) and necrosis (disruption of the plasma membrane). The electrophoretic pattern of lung DNA indicates both internucleosomal fragmentation, characteristic of apoptosis, and overall degradation, characteristic of necrosis. Hyperoxia induces a marked increase in RNA or protein levels of p53, bax, bcl-x, and Fas, which are known to be expressed in certain types of apoptosis. However, we did not detect an increased activity of proteases belonging to the apoptosis "executioner" machinery, such as CPP32 (caspase 3), ICE (caspase 1), or cathepsin D. Furthermore, administration of an ICE-like protease inhibitor did not significantly enhance the resistance to oxygen. Additionally, neither p53-deficient mice nor lpr mice (Fas null) manifested an increased resistance to hyperoxia-induced lung damage. These results show that both necrosis and apoptosis contribute to cell death during hyperoxia. Multiple apoptotic pathways seem to be involved in this, and an antiapoptotic strategy does not attenuate alveolar damage.
Am J Respir Cell Mol Biol 1998 Oct
PMID:Oxygen toxicity in mouse lung: pathways to cell death. 976 53

Merbarone (5-[N-phenyl carboxamido]-2-thiobarbituric acid) is an anticancer drug that inhibits the catalytic activity of DNA topoisomerase II (topo II) without damaging DNA or stabilizing DNA-topo II cleavable complexes. Although the cytotoxicity of the complex-stabilizing DNA-topo II inhibitors such as VP-16 (etoposide) has been partially elucidated, the cytotoxicity of merbarone is poorly understood. Here, we report that merbarone induces programmed cell death or apoptosis in human leukemic CEM cells, characterized by internucleosomal DNA cleavage and nuclear condensation. Treatment of CEM cells with apoptosis-inducing concentrations of merbarone caused activation of c-Jun NH2-terminal kinase/stress-activated protein kinase, c-jun gene induction, activation of caspase-3/CPP32-like protease but not caspase-1, and the proteolytic cleavage of poly(ADP-ribose) polymerase. Treatment of CEM cells with a potent inhibitor of caspases, Z-Asp-2. 6-dichlorobenzoyloxymethyl-ketone, inhibited merbarone-induced caspase-3/CPP32-like activity and apoptosis in a dose-dependent manner. These results indicate that the catalytic inhibition of topo II by merbarone leads to apoptotic cell death through a caspase-3-like protease-dependent mechanism. These results further suggest that c-Jun and c-Jun NH2-terminal kinase/stress-activated protein kinase signaling may be involved in the cytotoxicity of merbarone.
Mol Pharmacol 1999 Mar
PMID:Merbarone, a catalytic inhibitor of DNA topoisomerase II, induces apoptosis in CEM cells through activation of ICE/CED-3-like protease. 1005 40

Interleukin 18 (IL-18 or interferon-gamma inducing factor) is a recently discovered pro-inflammatory cytokine and powerful stimulator of the cell-mediated immune response. IL-18 is produced by several sources including monocytes/macrophages, keratinocytes and the zona reticularis and zona fasciculata of the adrenal cortex. IL-18 occurs in brain but its cellular source in the CNS has never been investigated. The presence of IL-18 and its response to stimulation in the brain was tested with primary cultures of microglia, astrocytes and hippocampal neurons. IL-18 mRNA was present in astrocytes and microglia, but not in neurons. The endotoxin lipopolysaccharide (LPS) did not affect IL-18 in astrocytes, but LPS robustly increased IL-18 mRNA in microglia. IL-18 protein was constitutively expressed in astrocytes and induced in microglia by LPS. The levels of interleukin-1beta converting enzyme (ICE), an activating enzyme, and caspase 3 (CPP32), an inactivating enzyme, were assessed to investigate the presence of the appropriate processing enzymes in the cultured cells. ICE was present at constitutive levels in microglia and astrocytes suggesting that these cell types may produce and secrete matured IL-18. Active forms of CPP32 were not detectable in either cell type indicating the absence of a degradative pathway of IL-18. The present results demonstrate that microglia and astrocytes are sources of brain IL-18 and add a new member to the family of cytokines produced in the brain.
Brain Res Mol Brain Res 1999 Apr 06
PMID:Cultures of astrocytes and microglia express interleukin 18. 1010 Dec 31


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