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)

Twenty-five patients with CML (chronic phase (CP): 15 patients; accelerated phase (AP): 10 patients) at a median of 40 months after diagnosis and ineligible for allogeneic BMT, received an intensive chemotherapy regimen consisting of idarubicin, intermediate-dose ara-C and etoposide (ICE protocol). All patients had previously received alpha-interferon and only two patients had had partial cytogenetic response. During recovery from chemotherapy-induced aplasia, blood progenitors cells (BPC) were harvested by leukapheresis. All metaphases were found to be Ph-negative in the collection of 12 of 25 (48%) patients (CP: 9 of 15 (60%), AP: 3 of 10 (30%)) and a decrease of < 50% Ph-positive metaphases was seen in an additional five (CP: 4 patients; AP: 1 patient). The percentage of complete Ph-disappearance was 66% in patients receiving this procedure within the first 2 years of diagnosis and 30% in those treated after the second year of diagnosis. So far, the Ph-negative collections have been used in 9 patients (CP: 8 patients; AP: 1 patient) as autograft after conditioning with total body irradiation/etoposide/CY. Seven of 9 patients engrafted and 5 are alive and well, Ph-negative at 2+, 3+, 6+, 10+ and 18+ months.
Bone Marrow Transplant 1993 Sep
PMID:Collection of 'normal' blood repopulating cells during early hemopoietic recovery after intensive conventional chemotherapy in chronic myelogenous leukemia. 769 24

In vitro brown adipose tissue (BAT) thermogenesis from cold-acclimated (CA) rats has been shown to exhibit the decreased responses to noradrenaline (NA) and glucagon (G), although an enhanced biochemical machinery for thermogenesis develops in the tissue. The present study was undertaken to clarify the inhibitory mechanism of in vitro thermogenic responses of BAT in CA rats. NA-treated rats were injected NA (40 micrograms/100g BW) twice a day for 2 or 4 weeks. The other rats were kept at 25 +/- 1 degree C (warm controls: WC), 5 +/- 1 degree C (CA), or 5 +/- 1 degree C/6h/day (intermittent cold exposure: ICE) for 5-6 weeks. The oxygen consumption, and glycerol as well as free fatty acids (FFA) release were measured on finely minced tissue blocks in Krebs-Ringer phosphate buffer at 37 degrees C. In vitro BAT thermogenic responses to NA and G in NA-treated rats did not differ from those in vehicle-injected controls. NA as well as G increased-oxygen consumption was greatest in WC, followed by ICE and CA. NA as well as G increased glycerol and FFA releases in WC and ICE, but the degree of increment was greater in WC than that in ICE, while NA or G did not increase glycerol and FFA releases in CA. FFA/glycerol ratio in WC was decreased by NA as well as G, but it was not changed in ICE, and increased in CA. Mitochondrial GDP binding as an index of BAT thermogenic capacity did not differ between CA and WC under resting state (CA rats were transferred in warm condition before 18h at the beginning of the experiment), but it was significantly greater in ICE. GDP binding was significantly greater in CA sacrificed at 5 degrees C compared with WC and CA resting. Acute cold exposure (5 degrees C/1h) enhanced GDP binding in WC, resting CA and ICE resting, but the degree of increment was greater in CA and ICE than in WC. These findings suggest that cold exposure inhibits BAT thermogenic responses according to the duration NA action during cold exposure, by means of suppressing fatty acid utilization and/or masking uncoupling protein.
Hokkaido Igaku Zasshi 1994 Sep
PMID:[Regulatory mechanism of non-shivering thermogenesis in cold acclimation--with special reference to in vitro thermogenic activity and lipolysis of brown adipose tissue]. 786 51

A squamous cell carcinoma cell line LK-17 was established from original surgical specimen of the lung. Doubling time of LK-17 in vitro is 43.2 hours, and chromosome analysis shows various abnormality and main modeat 62. LK-17 shows stable metastatic potential to the lung of nude mouse when injected i.v. LK-17 cells show platelet aggregating activity with number population dependent manner. LK-17 secretes direct factor X activating procoagulant which differs from those of tissue factor, cystein protease A and coagulant cancer antigen 1. These platelet aggregation potential and procoagulant activity may play a important roll in metastatic process.
Hum Cell 1993 Sep
PMID:[Establishment of a human lung squamous cell carcinoma cell line LK-17, and characterization of procoagulant, platelet aggregation and metastatic potential]. 829 20

Apoptosis is a regulated process of cell death by which cells actively participate in their own destruction. In multicellular organisms, the balance between cell proliferation and apoptosis provides homeostatic control, and a regulatory failure of either event can contribute to oncogenesis. The extracellular matrix (ECM) is known to play a regulatory role in cellular growth and differentiation, but only more recently has it been recognized as a regulator of apoptosis. In these processes the major transmitters of ECM-derived signals to the cell are members of the integrin family, although the mechanical process of cell spreading also plays a role. Both in vivo and in vitro the loss of adhesion to specific components of the ECM can lead to cell death, and such apoptosis can be induced experimentally by blocking integrin binding. Heterotypic and homotypic cell-cell adhesion can also protect from adhesion-dependent apoptosis and there is evidence to suggest that this too in integrin mediated. In addition, some integrin mediated signaling appears to promote apoptosis. The downstream mechanisms of integrin signaling causing cell death have not been greatly explored, but there is evidence from two different systems that the induction of ICE transcription and nuclear translocation of p53 are candidate processes. Alterations in integrin expression or signaling therefore are likely to contribute to tumor development by enabling escape from apoptosis. Also, the recognition of the importance of cell-cell adhesion in tumor cell survival offers the potential of developing improved drug regimes for the treatment of malignancy.
Cancer Metastasis Rev 1995 Sep
PMID:Involvement of integrins in cell survival. 854 68

Cytotoxic T lymphocytes (CTLs) are able to kill target cells bearing foreign antigen through two distinct mechanisms: granule- and Fas-mediated cytotoxicity. The exact events involved in the induction of target cell apoptosis remain elusive, but research indicates a role for members of the interleukin-1beta converting enzyme (ICE)/Ced-3 family of cysteine proteases. The exact nature of the protease(s) involved is yet to be determined. Here we use activity assays and peptide inhibitors of ICE/Ced-3 proteases to study their role in Fas-mediated killing. We find that while certain inhibitors block DNA fragmentation and chromium release, others do not. Most notably, potent inhibitors of CPP32 and ICE could not inhibit DNA fragmentation during all cases of Fas-mediated cytotoxicity although an "ICE" inhibitor could suppress 51Cr release. Additionally, we find that CPP32 is not cleaved in all target cells during Fas killing. Although ICE activity (as measured by a fluorogenic substrate) is present in cell lysates from anti-Fas-treated cells, we found no pro-IL-1beta-cleaving activity in these lysates. Taken together, our results suggest that an alternate pathway to DNA fragmentation exists, which does not involve CPP32 activity, and that CPP32 and ICE activities are not essential to Fas-mediated killing.
J Biol Chem 1996 Sep 06
PMID:An interleukin-1beta converting enzyme-like protease is a key component of Fas-mediated apoptosis. 870 62

Cytotoxic T lymphocytes (CTLs) are able to recognize and destroy target cells bearing foreign antigen using one of two distinct mechanisms: granule- or Fas-mediated cytotoxicity. The exact mechanisms involved in the induction of apoptotic cell death remain elusive; however, it seems likely that a family of cysteine proteases related to interleukin-1beta converting enzyme are involved. One family member, CPP32, has been identified as an intracellular substrate for granzyme B, a CTL-specific serine protease responsible for the early induction of target cell DNA fragmentation. Here we use cytolytic cells from granzyme B-deficient mice to confirm that cleavage and activation of CPP32 represents a nonredundant role for granzyme B and that this activation plays a role in the induction of DNA fragmentation in target cells, a signature event for apoptotic cell death. A peptide inhibitor of CPP32-like proteases confirmed the function of these enzymes in fragmentation. 51Cr release was not suppressed under these conditions, suggesting that granzyme B cleavage of CPP32 is primarily involved in the induction of DNA fragmentation and not membrane damage during CTL-induced apoptosis.
J Biol Chem 1996 Sep 06
PMID:Cleavage of CPP32 by granzyme B represents a critical role for granzyme B in the induction of target cell DNA fragmentation. 870 64

We report the preparation and characterization of interleukin-1beta converting enzyme (ICE) refolded from its p20 and p10 protein fragments. Refolded ICE heterodimer (p20p10) was catalytically active but unstable, and in size exclusion chromatography eluted at an apparent molecular mass of 30 kDa. The mechanisms of the observed instability were pH-dependent dissociation at low enzyme concentrations, and autolytic degradation of the p10 subunit at high concentrations. Binding and subsequent removal of a high affinity peptidic inhibitor increased the apparent molecular mass to 43 kDa (by size exclusion chromatography), and significantly increased its stability and specific activity. Chemical cross-linking and SDS-polyacrylamide gel electrophoresis analysis of the 43-kDa size exclusion chromatography conformer revealed a 60-kDa species, which was absent in the 30-kDa conformer, suggesting that inhibitor binding caused formation of a (p20p10)2 homodimer. The observation of a reversible equilibrium between ICE (p20p10) and (p20p10)2 suggests that analogous associations, possibly between ICE and ICE homologs, can occur in vivo, resulting in novel oligomeric protease species.
J Biol Chem 1996 Sep 06
PMID:Stability and oligomeric equilibria of refolded interleukin-1beta converting enzyme. 870 86

Vaccinia virus contains a gene, termed SPI-2 or B13R, that is closely related in its sequence to a potent inhibitor of apoptosis from cowpox virus (crmA). Infection by vaccinia virus protects HeLa cells against apoptosis that is induced by an immunoglobulin M antibody against the fas receptor or by tumor necrosis factor alpha. This effect is profoundly reduced when the SPI-2 gene is deleted. The SPI-2 gene, when transiently expressed in these cells, can also protect against apoptosis mediated by these agents. Given the similarity to crmA, it seems likely that SPI-2 functions in an analogous fashion, inhibiting the activity of ICE protease family members and blocking the onset of apoptosis.
J Virol 1996 Sep
PMID:Protection against apoptosis by the vaccinia virus SPI-2 (B13R) gene product. 870 86

The ICE/CED-3 family of proteases has been implicated in playing a fundamental role in programmed cell death. Bcl-2 protein represses a number of apoptotic death programs, but the biochemical mechanism of its action is not known. We investigated the activation of ICE/CED-3 proteases induced by three apoptotic stimuli (staurosporine, ceramide, and serum withdrawal) in the neuronal cell line GT1-7 and in cells overexpressing Bcl-2. Rapid activation of a 17 kDa subunit of an activated member of the ICE/CED-3 family is demonstrated by affinity-labeling GT1-7 extracts from apoptotic controls cells with a biotinylated ICE/CED-3 inhibitor. This activation corresponds to an increased ICE/CED-3-like protease activity in extracts measured by a fluorogenic substrate assay. In a cell-free system, these extracts induce apoptotic morphological changes in intact nuclei. All three activities are readily inhibited by treatment of control extracts with ICE/CED-3-like protease inhibitors. Overexpressed Bcl-2 inhibits the activation of the 17 kDa protein, the ICE/CED-3-like protease activity in the fluorogenic assay, and the induction of apoptotic morphological changes in HeLa nuclei in the cell-free system, similar to results obtained with ICE/CED-3 protease inhibitors. At the mRNA level, overexpression of Bcl-2 did not alter expression of five members of the ICE/CED-3 family: CPP32, ICE, Mch 2, Nedd 2, and TX. Overexpression of Bcl-2 prevented the apoptosis-induced processing of pro-Nedd 2 to the cleaved form. These data suggest that Bcl-2 participates upstream from the function of ICE/CED-3 proteases and may inhibit apoptosis by preventing the post-translational activation of ICE/CED-3 proteases.
J Neurosci 1996 Sep 15
PMID:Bcl-2 expression in neural cells blocks activation of ICE/CED-3 family proteases during apoptosis. 879 21

Recent work suggests that the proteolytic degradation of the nuclear lamins is a common event in apoptosis, although the nature of the proteases involved is still not clear. Our previous work showed that the degradation of lamin B1 in glucocorticoid-treated thymocytes occurs via a Ca2+-sensitive mechanism and that exogenous Ca2+ promotes lamin degradation in isolated thymocyte nuclei from untreated cells. Here we demonstrate that peptide-based inhibitors of the interleukin 1beta-converting enzyme family of cysteine proteases (Tyr-Val-Ala-Asp fluoromethyl ketone) and of the nuclear scaffold multicatalytic proteinase (Ala-Pro-Phe chloromethyl ketone) block the degradation of lamin B1 to a 21-kDa fragment in thymocytes treated with glucocorticoid, the Ca2+-mobilizing agent thapsigargin, or antibodies to the T cell receptor. However, among a panel of inhibitors specific for several different proteases implicated in apoptosis, only tosylphenylalanyl chloromethyl ketone and the nuclear scaffold protease inhibitor block lamin degradation, histone H1 cleavage, and DNA fragmentation in isolated thymocyte nuclei incubated with Ca2+. Overexpression of human BCL-2 in nuclei by stable transfection resulted in an inhibition of Ca2+-stimulated lamin degradation and DNA fragmentation, suggesting that endogenous nuclear BCL-2 regulates activation of the nuclear scaffold protease. The results demonstrate the existence of an alternative pathway of lamin degradation and DNA fragmentation mediated by a resident Ca2+-stimulated nuclear protease that is not directly dependent upon activation of the interleukin 1beta-converting enzyme family of cell death regulators.
J Biol Chem 1996 Sep 13
PMID:Calcium-dependent, interleukin 1-converting enzyme inhibitor-insensitive degradation of lamin B1 and DNA fragmentation in isolated thymocyte nuclei. 879 2


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