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: EC:3.4.22.36 (caspase-1)
6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Shigella, the etiological agent of bacillary dysentery, rapidly kills human monocyte-derived macrophages in vitro. Wild-type Shigella flexneri, but not a nonvirulent derivative, induced human macrophage apoptosis as determined by morphology and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL). Shigella-mediated macrophage cell death was blocked by the peptide inhibitors of caspases, acetyl-Tyr-Val-Ala-Asp-aldehyde (acetyl-YVAD-CHO) and acetyl-Tyr-Val-Ala-Asp-chloromethylketone (acetyl-YVAD-CMK). Protection from apoptosis by YVAD was observed in monocytes matured in the presence or absence of colony-stimulating factors (CSF) like macrophage-CSF or granulocyte-macrophage-CSF. Furthermore, lipopolysaccharide (LPS) or gamma interferon (IFN-gamma) rendered human macrophages partially resistant to Shigella cytotoxicity. Macrophages stimulated with either LPS or IFN-gamma were also protected by YVAD from Shigella-induced cell death. During Shigella infections of human macrophages, interleukin-1beta (IL-1beta) was cleaved to the mature form. IL-1beta maturation was severely retarded by YVAD, indicating that IL-1beta-converting enzyme (ICE; caspase 1) is activated in Shigella-induced apoptosis. The finding that Shigella induces apoptosis in human macrophages by activating ICE supports the hypothesis that the acute inflammation characteristic of shigellosis is initially triggered by apoptotic macrophages which release mature IL-1beta during programmed cell death.
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PMID:The interleukin 1beta-converting enzyme, caspase 1, is activated during Shigella flexneri-induced apoptosis in human monocyte-derived macrophages. 939 11

Interleukin-1 beta (IL-1 beta) is a pleiotropic proinflammatory cytokine. Mechanisms leading to its secretion include not only release of newly synthesized protein, but also cleavage of a preformed immature precursor protein into an active secretory form by the intracellular protease caspase-1 (formerly termed IL-1-converting enzyme [ICE]). Caspase-1 belongs to a rapidly growing family of cysteine proteases with substrate specificity for aspartate involved in cellular apoptosis. We have used an assay determining the caspase-1 activity based on cleavage of a fluorogenic peptide substrate to elucidate its role in lipopolysaccharide (LPS)-induced secretion of IL-1 beta. We show that LPS induces moderate caspase-1 activity in the monocytic cell line THP-1, in freshly isolated peripheral blood monocytes, and in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent fashion. Caspase-1 activation by LPS was associated with cleavage of the IL-1 beta precursor protein that was followed by release of the mature IL-1 beta protein in monocytic cells. In contrast, subsequent release of IL-1 beta by HUVECs was not significant. LPS-induced caspase-1 activation appeared not to result from modulation of caspase-1 transcript accumulation and inhibition of caspase-1 activity was accomplished by two specific inhibitors, YVAD-CHO and YVAD-CMK, capable of alleviating the release of mature IL-1 beta. Taken together, these results show that LPS moderately activates caspase-1 and that caspase-1 activation contributes to LPS induction of IL-1 beta secretion.
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PMID:Lipopolysaccharide activates caspase-1 (interleukin-1-converting enzyme) in cultured monocytic and endothelial cells. 942 12

Using an organotypic slice culture system of neonatal rat cerebellum, we examined developmental stage-specific mechanisms of cell death of granule neurons. This culture system allows a serial process of granule neuron development including their proliferation during the early culture period and the proceeding migration from the external granular layer to the internal granular layer in the presence of a supraphysiological concentration (5 micrograms/ml) of insulin. Insulin deprivation induced apoptosis of granule neurons in external granular layer but not in internal granular layer. A truncated analogue of insulin-like growth factor-I (des (1-3) insulin-like growth factor-I) prevented this apoptosis at a concentration of 65-650 ng/ml. Some apoptotic granule neurons expressed proliferating cell nuclear antigen but not TAG-1, a marker protein of the postmitotic and premigratory granule neurons. Thus, this apoptosis occurred at a specific stage in granule neuron development: at the stage before TAG-1 expression and at least partly at the proliferative state. Ac-YVAD-CHO, an inhibitor of interleukin-1 beta converting enzyme (caspase-1)-like proteases, had a protective effect on this apoptosis. Interleukin-1 beta converting enzyme (caspase-1)-like protease activity increased under the apoptosis-induced condition. High concentration of K+, which is known to prevent granule neuron apoptosis in dissociated cultures, had a partial protective effect on this apoptosis. These findings suggest that (i) cerebellar granule neurons fall into apoptosis at the specific developmental stage unless stimulated by insulin-like growth factor-I (analogue), (ii) this apoptosis is mediated through an interleukin-1 beta converting enzyme-like protease, and (iii) this apoptosis consists of K(+)-sensitive and K(+)-insensitive components.
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PMID:Insulin-like growth factor-I analogue prevents apoptosis mediated through an interleukin-1 beta converting enzyme (caspase-1)-like protease of cerebellar external granular layer neurons: developmental stage-specific mechanisms of neuronal cell death. 952 65

Infection of erythroid-lineage cells by human parvovirus B19 is characterized by a gradual cytocidal effect. Accumulating evidence now implicates the nonstructural (NS1) protein of the virus in cytotoxicity, but the mechanism underlying the NS1-induced cell death is not known. Using a stringent regulatory system, we demonstrate that NS1 cytotoxicity is closely related to apoptosis, as evidenced by cell morphology, genomic DNA fragmentation, and cell cycle analysis with the human erythroleukemia cell line K562 and the erythropoietin-dependent megakaryocytic cell line UT-7/Epo. Apoptosis was significantly inhibited by an interleukin-1beta (IL-1beta)-converting enzyme (ICE)/CED-3 family protease inhibitor, Ac-DEVD-CHO (CPP32; caspase 3), whereas a similar inhibitor of ICE (caspase 1), Ac-YVAD-CHO, had no effect. Furthermore, stable expression of the human Bcl-2 proto-oncogene resulted in near-total protection from cell death in response to NS1 induction. Mutations engineered into the nucleoside triphosphate-binding domain of NS1 significantly rescued cells from NS1-induced apoptosis without having any effect on NS1-induced activation of the IL-6 gene expression which is mediated by NF-kappaB. Furthermore, using pentoxifylline, an inhibitor of NF-kappaB activation, we demonstrate that the NF-kappaB-mediated IL-6 activation by NS1 is uncoupled from the apoptotic pathway. This functional dissection indicates a complexity underlying the biochemical function of human parvovirus NS1 in transcriptional activation and induction of apoptosis. Our findings indicate that NS1 of parvovirus B19 induces cell death by apoptosis in at least erythroid-lineage cells by a pathway that involves caspase 3, whose activation may be a key event during NS1-induced cell death.
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PMID:Human parvovirus B19 nonstructural (NS1) protein induces apoptosis in erythroid lineage cells. 952 24

Interleukin-1beta-converting enzyme is a member of a family of human cysteine proteases with specificity for aspartic acid, which have been named caspases. Within this family of enzymes, transcript X (TX) and transcript Y (TY) (caspases 4 and 5, respectively) are very similar to ICE (caspase 1) and form the ICE subfamily. Given the high degree of conservation in the sequences of these proteases (more than 50% amino acid identity in the mature enzymes), it was of interest to examine whether they shared similar substrate specificities. The three enzymes, ICE, TX and TY, were therefore expressed in baculovirus-infected insect cells, as 30-kDa proteins lacking the propeptide. Automaturation into p20 and p10 subunits occurred within the cells. Active ICE, TX and TY were collected in the cell culture supernatants. In addition, their production induced the activation of an endogenous 32-kDa putative cysteine protease (CPP32) like caspase. T7-tagged ICE, TX and TY were purified by immunoaffinity and tested for their catalytic efficiency on YVAD-containing synthetic substrates and on the ICE natural substrate, pro-interleukin-1beta. TX cleaved the same synthetic substrates as ICE (Km of 90 microM and k(cat) of 0.4 s(-1) for Suc-YVAD-NH-Mec, where Suc represents succinyl and NH-Mec represents amino-4-methylcoumarin) and could cleave pro-interleukin-1beta into the same peptides as ICE but less efficiently. On the other hand, TY showed very little efficacy on the different ICE substrates (Km of 860 microM for Suc-YVAD-NH-Mec). These results show that the ICE/TX/TY subfamily has functional heterogeneity and that ICE remains the preferred enzyme for pro-interleukin-1beta cleavage.
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PMID:Enzymatic activity of two caspases related to interleukin-1beta-converting enzyme. 957 63

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

IL-1 beta-converting enzyme (ICE), also known as caspase-1, subserves two dichotomous biologic roles. It processes newly synthesized pro-IL-1 beta to yield the active cytokine and, as the human homologue of the Caenorhabditis elegans gene product, ced-3, it also induces cellular apoptosis through the cleavage of key intracellular structural and regulatory proteins and through the catalytic activation of other caspase family members. We show here that two different proinflammatory stimuli, LPS and granulocyte-macrophage-CSF, up-regulate the expression of both ICE and IL-1 beta in human polymorphonuclear neutrophils, and that the ICE-dependent cleavage of pro-IL-1 beta results in delayed expression of the constitutive cell death program. The apoptotic delay can be blocked by inhibiting tyrosine kinases or NF-kappa B activation and by inhibiting protein synthesis. Since an antisense oligonucleotide for IL-1 beta, a blocking Ab to IL-1 beta, and preincubation with the IL-1R antagonist all prevent the delay in apoptosis, we conclude that IL-1 beta acts in an autocrine manner to inhibit granulocyte programmed cell death. We conclude that caspase-1 (ICE) subserves both pro- and antiapoptotic roles; the latter role is evident during inflammation as an inhibition of spontaneous neutrophil apoptosis through the processing of IL-1 beta. The ICE-dependent activation of IL-1 beta may represent a common autocrine pathway for the divergent stimuli that inhibit the constitutive expression of neutrophil programmed cell death during inflammation.
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PMID:The IL-1 beta-converting enzyme (caspase-1) inhibits apoptosis of inflammatory neutrophils through activation of IL-1 beta. 967 Sep 75

Apoptosis is a morphologically distinct form of programmed cellular death that plays a central role during embryogenesis, tissue homeostasis, and to remove not necessary or potentially dangerous cells. Moreover, disregulation of genes mediating or modulating apoptosis contributes to the pathogenesis of a number of human diseases, including cancer, autoimmune diseases, neurodegenerative disorders, viral infections and acquired immunodeficiency syndrome. A number of genes and molecules promoting or protective against cell death is at present-day known and an important information about the external and internal signals involved in stimulation and suppression of apoptosis is also emerging. In the intracellular pathway of the death deregulation of [Ca2+](i) plays a pivotal role. Increased ionized intracellular calcium stimulates both the activation of enzymes (protein kinases, endonucleases, proteases and phospholipases) and plasma membrane K+ channels. This calcium-mediated activation leads to morphostructural changes, such as cell shrinkage, cytoplasmatic blebbing, nuclear chromatin condensation and DNA degradation into oligonucleosomal fragments. At least some genes of the cell death pathway have been conserved throughout animal evolution; ced-3 e ced-9 that regulate the initiation of cellular suicide in the nematode Caenorhabditis elegans are homologous to genes that in mammalian cells are thought to play a similar role (interleukin-1 beta converting enzyme [ICE] family, Bcl-2). It is possible to suppose that these regulators could constitute a target for treatment of disorders related with disregulation of apoptosis.
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PMID:[Genes, molecules, and mechanisms regulating programmed cell death]. 973 54

Biologic activity of IL-1 beta requires processing of the inactive precursor, a function generally ascribed to IL-1 beta-converting enzyme (caspase-1). However, alternative mechanisms of IL-1 beta activation have been postulated in local inflammatory reactions. Expression of IL-1 beta and matrix metalloproteinases (MMPs) frequently occurs simultaneously at sites of inflammation. We describe here that stromelysin-1 (MMP-3), as well as the gelatinases A (MMP-2) and B (MMP-9), processes recombinant human IL-1 beta precursor (pIL-1 beta) into biologically active forms. Detection of both pIL-1 beta processing and biologic IL-1 beta activity demonstrated different processing capacities of the respective MMPs. Conversion of pIL-1 beta by stromelysin-1 required coincubation for at least 1 h, and biologic activity faded after 8 h to 24 h. Gelatinase A was less effective in processing pIL-1 beta, requiring at least 24 h of coincubation. In contrast, gelatinase B processed pIL-1 beta within minutes, resulting in immunoreactive products as well as biologic activity stable for 72 h. In addition, prolonged incubation of mature IL-1 beta with stromelysin-1, and to a lesser extent also with gelatinases, but not with interstitial collagenase, resulted in the degradation of mature IL-1 beta. None of the MMPs processed the second isoform of IL-1, IL-1 alpha. The present study indicates a biphasic regulation of IL-1 beta activity by MMPs: a caspase-1-independent pathway of IL-1 beta activation and inhibition of IL-1 beta activity by degrading the mature cytokine. The balance of the respective MMPs and pIL-1 beta might regulate the long term appearance of IL-1 beta activity at sites of acute or chronic inflammation.
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PMID:Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. 975 50

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.
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PMID:Oxygen toxicity in mouse lung: pathways to cell death. 976 53


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