Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B-chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived B lymphocytes that express high levels of Bcl-2. We examined the involvement of CED-3/ICE-like proteases in the apoptosis of B-CLL cells. One of the substrates of these proteases is poly(ADP [adenosine 5'-diphosphate]-ribose) polymerase (PARP). The effect of different factors that induce the apoptosis of B-CLL cells on the proteolytic cleavage of PARP has been studied. Treatment of B-CLL cells with different concentrations of dexamethasone (1 to 1,000 micromol/L) induced in a dose-dependent manner the cleavage of PARP. Dexamethasone induced PARP cleavage after 12 hours of incubation, which was almost complete at 48 hours. PARP cleavage during apoptosis of B-CLL cells was studied in cells from eight patients and a correlation was found between cell viability and the degree of PARP cleavage. Incubation in vitro of B-CLL cells with fludarabine for 48 hours induced PARP cleavage in all the cases studied. Protein kinase C (PKC) activation with 100 nmol/L TPA (12-O-tetradecanoylphorbol 13-acetate) or incubation with interleukin-4 (10 ng/mL) prevented either dexamethasone- or fludarabine-induced proteolysis of PARP. Incubation of B-CLL cells with the CED-3/ICE-like protease inhibitor Z-VAD.fmk inhibited spontaneous and dexamethasone-induced PARP cleavage and DNA fragmentation in a dose-dependent manner. Furthermore, Z-VAD.fmk prevented the cytotoxic effect of dexamethasone. These results indicate that CED-3/ICE-like proteases play an important role in the apoptosis of B-CLL cells.
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PMID:Involvement of CED-3/ICE proteases in the apoptosis of B-chronic lymphocytic leukemia cells. 912 45

Peripheral macrophages infiltrating the central nervous system and resident microglia phagocytize myelin in cell-mediated demyelinating diseases, including experimental autoimmune encephalomyelitis and multiple sclerosis. A cascade of cytokines is believed to modulate the immunological sequence of events occurring in these conditions, and several of these mediate their effects through the protein kinase C pathway. Therefore, we compared the effects of phorbol myristate acetate (PMA), an activator of protein kinase C, on various functions of cultured macrophages and microglia. PMA at moderate concentrations induced apoptosis in macrophages, and this process appeared to be increased in the presence of myelin. In contrast, microglia were activated by PMA, and greatly increased their phagocytosis of myelin. Control macrophages released a considerable amount of proteolytic activity into the medium, as measured by the breakdown of myelin basic protein, and in the process of undergoing apoptosis from PMA-treatment, even higher amounts were released. The enzyme activity in control macrophage medium was inhibited mainly by PMSF and calpain inhibitors, while that from PMA-treated macrophages was inhibited by calpain inhibitors only. An ICE inhibitor was ineffective in inhibiting activity in medium from PMA-treated cells undergoing apoptosis. Medium from microglia contained very little proteolytic activity, and this was not increased by PMA. Cultured macrophages showed little evidence of oxygen free radical release as measured by the TBARS procedure, and PMA had no effect. Microglia, on the other hand, produced higher levels of reactive oxygen species, with a further increase of 18% by PMA. Thus major functions of these phagocytic cells appear to be modulated by the protein kinase C pathway, although the two cell types show very different responses to an activator of this signal.
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PMID:Effects of phorbol myristate acetate (PMA) on functions of macrophages and microglia in vitro. 948 57

Although phorbol 12-myristate 13-acetate (PMA) inhibits apoptosis and promotes the growth of some types of cells, it induces apoptosis in other cells. We evaluated the apoptotic effects of PMA on murine fibroblasts (L-929) that had been exposed to ultraviolet-B (UV-B) radiation at 312 nm, which promotes tumor cell growth. Exposure to PMA alone did not induce Fas, Fas-L, or apoptosis. Cells exposed to mild UV-B irradiation (80 J/m(2)) alone exhibited a slight expression of Fas and Fas-L 36 to 48 h after the exposure, and exhibited apoptosis as evidenced by DNA fragmentation 72 h after exposure. The addition of PMA (0.8 x 10(-5) to 3.2 x 10(-5) M) to the medium 24 h after the UV-B exposure markedly and dose-dependently enhanced these cell responses. Confluent untreated cells, cells cocultured with PMA, and cells cocultured with PMA for 24 h after the UV-B exposure consistently expressed mRNAs for wild-type p53, bcl-2, and ICE. Expression of c-myc mRNA was initially observed, but became undetectable in the cells cocultured for 24 h with a high concentration of PMA (3.2 x 10(-5) M) following UV-B exposure. Such cells subsequently exhibited the maximal apoptotic response. We conclude that mild exposure to UV-B altered murine fibroblast cells in such a way as to facilitate their death by apoptosis upon addition of PMA.
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PMID:Phorbol ester facilitates apoptosis in murine fibroblasts pretreated by mild ultraviolet radiation. 1042 27

Caspase-3 knockout mice exhibit thickening of the internal granule cell layer of the cerebellum. Concurrently, it has been shown that intracerebral injection of pituitary adenylate cyclase-activating polypeptide (PACAP) induces a transient increase of the thickness of the cerebellar cortex. In the present study, we have investigated the possible effect of PACAP on caspase activity in cultured cerebellar granule cells from 8-day-old rat. Incubation of granule neurons with PACAP for 24 h promoted cell survival and prevented DNA fragmentation. Exposure of cerebellar granule cells to the specific caspase-3 inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp fluoromethylketone (Z-DEVD-FMK) for 24 h markedly enhanced cell survival and inhibited apoptotic cell death. Time-course studies revealed that PACAP causes a prolonged inhibition of caspase-3 activity without affecting caspase-1. Administration of graded concentrations of PACAP for 3 h induced a dose-dependent inhibition of caspase-3 activity. Incubation of granule cells with both dibutyryl-cAMP (dbcAMP) and phorbol 12-myristate 13-acetate (PMA) mimicked the inhibitory effect of PACAP on caspase-3. Cotreatment of cultured neurons with the protein kinase A inhibitor H89 and the protein kinase C inhibitor chelerythrine abrogated the effect of PACAP on caspase-3 activity. In contrast, the ERK kinase inhibitor U0126 did not affect the action of PACAP on caspase-3 activity. These data demonstrate that PACAP prevents cerebellar granule neurons from apoptotic cell death through a protein kinase A- and protein kinase C-dependent inhibition of caspase-3 activity.
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PMID:The neuroprotective effect of pituitary adenylate cyclase-activating polypeptide on cerebellar granule cells is mediated through inhibition of the CED3-related cysteine protease caspase-3/CPP32. 1108 78

Patients with NHL and two or three factors of the International Prognostic Index (IPI) have a poor prognosis. We performed a prospective trial of intensive induction therapy followed with high-dose consolidation in such patients to determine the feasibility of this approach, as well as the response rate and survival. Untreated patients with aggressive lymphoma under the age of 60 with two or three adverse prognostic factors (disseminated stage, increased serum LDH, ECOG performance status >1) were prospectively included between June 1995 and April 1998 in a trial evaluating intensive induction chemotherapy with the ACE regimen (adriamycin day 1; cyclophosphamide days 1-2; etoposide days 1-3), with G-CSF support. Patients in complete remission after induction received one course of intensification with stem cell support (BEAM regimen), whereas patients in partial response received two intensifications (BEAM, then ICE regimens). Thirty-three patients (median age 38 years) were included. All patients presented WHO grade 4 leukopenia and 84% grade 3-4 thrombocytopenia during induction. There was one toxic death during induction. Twenty-nine patients proceeded to high-dose consolidation, including 12 patients who received a second high-dose treatment. The overall response rate was 88% (95% CI 76-99%), both after induction therapy and treatment completion. Thirty-nine percent of the patients had achieved complete remission after induction, and 73% after treatment completion. With a median follow-up after treatment onset of 29 months, the projected 3-year overall survival was 71% (95% CI 64-78%) and the event-free survival 58% (95% CI 50-66%). Event-free survival was significantly shorter in patients who did not achieve CR after induction therapy or after treatment completion. Early therapeutic intensification after intensive induction chemotherapy is feasible in patients with poor prognosis aggressive NHL and shows promising response and survival rates.
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PMID:A prospective study of intensive induction therapy with high-dose consolidation in patients with aggressive non-Hodgkin's lymphoma and two or three adverse prognostic factors. 1118 6

The human myeloid HL-60 cell line and its cell variant HL-525 were used to study signaling events leading to apoptosis induction by phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC) enzymes. Unlike parental cells, HL-525 cells are PKC-beta deficient and resistant to PMA-induced apoptosis. These cells regain susceptibility to apoptosis induction after transfection with a PKC-beta expression vector. By using this vector and specific neutralizing monoclonal antibodies (mAbs), it was established that PMA-induced apoptosis also called for an interaction between cell-surface alpha(5)beta(1)-integrin and its deposited ligand fibronectin (FN), which is downstream of PKC-beta activation. Experiments with mAbs, the PKC-beta vector, and exogenous FN revealed that the next step entailed an interaction between secreted tumor necrosis factor-alpha and its type I receptor. By using a sphingomyelinase inhibitor, it was concluded that the subsequent step involved ceramide production. Moreover, a permeable ceramide was effective in inducing apoptosis in both HL-60 and HL-525 cells, and this induction was caspase-1 and/or -4 dependent because an inhibitor of these caspases abrogated the induced apoptosis. Based on these and related differentiation studies, we conclude that the above signaling events, the early ones in particular, are shared with PMA-induced macrophage differentiation in the HL-60 cells. It is likely that once these cells acquire their macrophage phenotype and perform their tasks, they become superfluous and are eliminated from the body by a self-triggered apoptotic process that involves our proposed signaling scheme.
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PMID:Protein kinase C-beta, fibronectin, alpha(5)beta(1)-integrin, and tumor necrosis factor-alpha are required for phorbol diester-induced apoptosis in human myeloid leukemia cells. 1174 31

Proteinase inhibitor 9 (PI-9) inhibits caspase-1 (interleukin (IL)-1beta-converting enzyme) and granzyme B, thereby regulating production of the pro-inflammatory cytokine IL-1beta and susceptibility to granzyme B-induced apoptosis. We show that cellular PI-9 mRNA and protein are induced by IL-1beta, lipopolysaccharide, and 12-O-tetradecanoylphorbol-13-acetate. We identified functional imperfect nuclear factor-kappaB (NF-kappaB) sites at -135 and -88 and a consensus activator protein-1 (AP-1) site at -308 in the PI-9 promoter region. Using transient transfections in HepG2 cells to assay PI-9 promoter mutations, we find that mutational ablation of the AP-1 site or of either NF-kappaB site reduces IL-1beta-induced expression of PI-9 by approximately 60%. Mutational ablation of the two NF-kappaB sites and of the AP-1 site nearly abolishes both basal and IL-1beta-induced expression of PI-9. Nuclear extracts from IL-1beta-treated HepG2 cells exhibited strong, IL-1beta-inducible binding to the NF-kappaB sites and to the AP-1 site. Electrophoretic mobility shift assays show that after IL-1beta treatment c-Jun/c-Fos and JunD bind to the AP-1 site, whereas the p50/p65 heterodimer binds to the two NF-kappaB sites. Estrogens induce PI-9, but induction of PI-9 by estrogens and IL-1beta is not synergistic. In transiently transfected, estrogen receptor-positive HepG2ER7 cells, estrogens do not interfere with IL-1beta induction, whereas IL-1beta exhibits dose-dependent repression of estrogen-inducible PI-9 expression. Our surprising finding that the pro-inflammatory cytokine IL-1beta strongly induces PI-9 suggests a novel mechanism for regulating inflammation and apoptosis through a negative feedback loop controlling expression of the anti-inflammatory and anti-apoptotic protein, PI-9.
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PMID:Modulators of inflammation use nuclear factor-kappa B and activator protein-1 sites to induce the caspase-1 and granzyme B inhibitor, proteinase inhibitor 9. 1217 49

Oxidative stress has been shown to be associated with apoptosis (programmed cell death) in a number of cell systems. We earlier reported in vitro cultured Spodoptera frugiperda (Sf9) cells as a model system to study oxidative stress induced apoptosis (J Biosciences 24 (1999) 13) and the inhibition of UV-induced apoptosis by the baculovirus antiapoptotic p35 protein that acts as a sink to sequester reactive oxygen species (Proc Natl Acad Sci USA 96 (1999) 4838). We now show that UV-induced apoptosis in Sf9 cells, is preceded by the release of mitochondrial cytochrome c into the cytosol and consequent activation of Sf-caspase-1. The inhibitory effect of different antioxidants including scavengers of oxygen radicals such as butylated hydroxyanisole (BHA), alpha tocopherol acetate, benzoate and reduced-glutathione (GSH) on ultra violet B (UVB)-induced apoptosis in cultured Sf9 cells was assessed. Both, cytochrome c release as well as Sf-caspase-1 activation was inhibited by pre-treatment with antioxidants such as BHA and alpha tocopherol acetate, suggesting that these antioxidants inhibit apoptosis by acting quite upstream in the apoptosis cascade at the mitochondrial level, as well as downstream at the caspase level.
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PMID:Antioxidants prevent UV-induced apoptosis by inhibiting mitochondrial cytochrome c release and caspase activation in Spodoptera frugiperda (Sf9) cells. 1279 76

The meeting covered a diverse range of topics, from therapeutic design of inhibitors of human proteases involved in disease, to the discovery of novel protease targets in infectious organisms. Various techniques were described, including the bioinformatics-based scanning of genomes for novel enzymes that might be linked to disease or virulence. In addition, crystal structures of well-known proteases were presented. The key focus however, was on designing inhibitors of proteolytic enzymes and their use in controlling disease processes mediated by proteases. Inhibitors described ranged from naturally occurring novel peptides such as Ascaris pepsin inhibitor, to trials with finely tuned peptidomimetics inhibiting human peptidases (interleukin converting enzyme; ICE and angiotensin converting enzyme; ACE) and rhinovirus 3C protease (antirhinovirus therapeutics; Pfizer Inc). The meeting also included presentations on the development of new techniques for detecting and analyzing protease activities such as luminescent protease assays, in vivo imaging of protease activity, surface plasmon resonance and novel peptide library screening methods.
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PMID:Proteolytic Enzymes as Therapeutic Targets - Keystone Symposium. Targeting ICE and ACE. 3-8 February 2002, Keystone, CA, USA. 1556 30

This paper mainly aims to study the linear element influence on the estimation of vascular plant species diversity in five Mediterranean landscapes modeled as land cover patch mosaics. These landscapes have several core habitats and a different set of linear elements--habitat edges or ecotones, roads or railways, rivers, streams and hedgerows on farm land--whose plant composition were examined. Secondly, it aims to check plant diversity estimation in Mediterranean landscapes using parametric and non-parametric procedures, with two indices: Species richness and Shannon index. Land cover types and landscape linear elements were identified from aerial photographs. Their spatial information was processed using GIS techniques. Field plots were selected using a stratified sampling design according to relieve and tree density of each habitat type. A 50x20 m2 multi-scale sampling plot was designed for the core habitats and across the main landscape linear elements. Richness and diversity of plant species were estimated by comparing the observed field data to ICE (Incidence-based Coverage Estimator) and ACE (Abundance-based Coverage Estimator) non-parametric estimators. The species density, percentage of unique species, and alpha diversity per plot were significantly higher (p < 0.05) in linear elements than in core habitats. ICE estimate of number of species was 32% higher than of ACE estimate, which did not differ significantly from the observed values. Accumulated species richness in core habitats together with linear elements, were significantly higher than those recorded only in the core habitats in all the landscapes. Conversely, Shannon diversity index did not show significant differences.
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PMID:The influence of linear elements on plant species diversity of Mediterranean rural landscapes: assessment of different indices and statistical approaches. 1676 45


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