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)

In liver, apoptosis is a physiological process involved in the clearance of injured cells and in homeostatic control [1]. However, in patients with viral fulminant hepatitis or with nonacute liver diseases [2], dramatic liver failure or secondary cirrhosis results from the death of hepatocytes, which express the cell-surface receptor Fas, by apoptosis. To date, treatment of fulminant hepatitis relies mainly on orthotopic liver transplantation, which is limited by immunological complications and graft availability. Unravelling the molecular mechanisms that underlie acute liver failure could allow the design of an appropriate therapy. Ligand-bound Fas and tumour necrosis factor alpha (TNF-alpha) induce hepatic apoptosis in mice [3-6]. In various cell types, Fas- or TNF-alpha-induced apoptosis is blocked by viral proteins (such as p35 and CrmA) as well as by a decoy peptide (YVADcmk) [7-11], suggesting that these mechanisms of apoptosis involve ICE (interleukin-1 beta converting enzyme)-like proteases. Here, we report that, in vivo, pre-treatment of mice with YVADcmk protects them from the lethal effect of anti-Fas antibody and from liver failure induced by injection of TNF-alpha. Remarkably, YVADcmk administration is also highly effective in rescuing mice that have been pretreated with anti-Fas antibody from rapid death, despite extensive hepatic apoptosis. This dramatic curative effect could be of clinical benefit for the treatment of viral and inflammatory liver diseases.
Curr Biol 1996 Sep 01
PMID:ICE inhibitor YVADcmk is a potent therapeutic agent against in vivo liver apoptosis. 880 75

The retroviral oncoprotein v-Rel is a member of the Rel/ NF-kappa B family of transcription factors. We have previously characterized two v-Rel mutants (v-G37E and v-R273H) that are temperature-sensitive (ts) for transformation and immortalization of chicken spleen cells in vitro. We have now constructed vectors for the co-expression of wild-type or ts mutant v-Rel proteins and the anti-apoptosis proteins Bcl-2 or CrmA. The formation of v-Rel-transformed colonies is enhanced in the presence of overexpressed Bcl-2. Moreover, co-expression of Bcl-2 suppresses apoptosis that is induced when ts v-Rel-transformed cells are shifted to the non-permissive temperature. However, co-expression of Bcl-2 in these cells does not affect ts functions of v-Rel, such as DNA binding and stabilization of I kappa B-alpha. In contrast, co-expression of CrmA does not suppress apoptosis, but does block an amino-terminal proteolysis of I kappa B-alpha that occurs in ts v-G37E-transformed cells shifted to the nonpermissive temperature, indicating that an ICE-like protease activity is not involved in apoptosis in these cells but is involved in proteolysis of I kappa B-alpha. In addition, CrmA can block cycloheximide-induced amino-terminal processing of I kappa B-alpha in spleen cells transformed by wild-type v-Rel. In summary, these results suggest that v-Rel immortalizes chicken spleen cells through a pathway that involves the Bcl-2 family of proteins, and suggest that one pathway of proteolysis of I kappa B-alpha involves an ICE-like protease.
Oncogene 1996 Sep 05
PMID:Bcl-2 and CrmA have different effects on transformation, apoptosis and the stability of I kappa B-alpha in chicken spleen cells transformed by temperature-sensitive v-Rel oncoproteins. 880 78

Los Angeles College of Chiropractic (LACC) has developed a variety of methods to monitor the effectiveness of its competency based/problem-centered curriculum. The College introduced two Integrative Competency Examination courses (ICE I and ICE II) to assess the chiropractic program's effectiveness and students' competency levels. The ICE courses are pass/fail examinations that use a multistation, objective structured clinical examination (OSCE) format that involves standardized patients along with cognitive assessment of basic science information as methods of evaluation. ICE I requires students to perform psychomotor skills and interpret clinical data; ICE II requires students to perform at a higher level. They are directed to select, perform and interpret clinical data appropriately and correlate this data with relevant basic science information. Through these two levels of evaluation, the educational program, the individual courses and the competency level of each student are assessed. This paper describes the format, content and evaluation tools used in the ICE courses as well as the potential benefits of the courses.
J Manipulative Physiol Ther 1996 Sep
PMID:Description of integrated competency examination: tools to assess the chiropractic curriculum effectiveness and students' competency levels. 889 27

Anti-CEA F(ab')2 monoclonal antibody fragments [F6 MAb F(ab')2] were conjugated to two bifunctional semi-rigid chelating agents derived from trans-1,2-diaminocyclohexane tetraacetic acid (CDTA), the monolithium salt of N-[methyl(2-isothiocyanatoethyl)carbamide] trans-1,2-diaminocyclohexane-N,N',N'-triacetic acid (SCN), and 4 isothiocyanato-trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (4-ICE) and labelled with 111In to obtain IIIIn-labelled-F6 MAb F(ab')2 conjugates (111In-F6-SCN and 111In-F6-4-ICE respectively). Biodistribution in mice and clinical studies were undertaken to assess the potential of these two ligands in the detection of colorectal adenocarcinoma recurrences and metastases in humans. Toxicity studies were carried out on guinea pigs and Swiss mice injected with a dose proportionally 100 times greater than that used in human studies. Clinical studies were performed in patients with clinically and/or biologically suspected adenocarcinoma recurrences. No immunoconjugate-induced toxicity was found. The biodistribution studies in mice gave better visualization of tumour sites with 111In-F6-SCN and 111In-F6-4-ICE than with 111In-F6-DTPA. Ten patients were included in the clinical protocol. 111In-F6-SCN and 111In-F6-4-ICE effectively visualized adenocarcinoma recurrences. However, in this small series, 111In-F6-4-ICE performed somewhat better than 111In-F6-SCN. The present study has demonstrated the potential of new bifunctional semi-rigid chelating agents coupled to antibody and labelled with 111In to localize recurrences (especially in liver) in humans using a one-step targeting method.
Nucl Med Commun 1996 Sep
PMID:Pre-clinical and clinical studies of two new bifunctional chelating agents for immunoscintigraphy with 111In-anti-CEA monoclonal antibody. 889 5

During the past several years, it has become increasingly apparent that interleukin-1 (IL-1), particularly IL-1 beta plays an important role in brain injury during ischemia. Studies from various laboratories have shown that IL-1 beta mRNA and IL-1 beta protein are synthesized early in ischemia and that the injection of IL-1 beta into ischemic brain enhances edema formation. The most direct evidence that IL-1 beta contributes to ischemic injury, however, is the demonstration that infarct volume in focal ischemia is reduced following intraventricular injection of an endogenous interleukin-1 receptor antagonist (IL-1ra), or after IL-1ra is overexpressed in brain using an adenoviral vector to transfer IL-1ra cDNA to brain cells. Ischemic injury is also reduced in mice that fail to produce IL-1 beta because of an abnormal interleukin-1 beta converting enzyme gene (ICE knockout mice). At the present time, it is nuclear how IL-1 beta causes brain injury, but several possible mechanisms include 1) stimulation of an inflammatory response through the activation of glia or the induction of other cytokines and/or endothelial adhesion molecules and 2) release of free radicals through stimulation of arachidonic acid metabolism and/or nitric oxide synthase activity.
Keio J Med 1996 Sep
PMID:Interleukin-1 in cerebral ischemia. 889 66

Ten children with newly diagnosed medulloblastoma/primitive neuroectodermal tumor of the posterior fossa were treated with total surgical resection, radiation therapy, and ICE chemotherapy regimen with ifosfamide (900 mg/m2, days 1-5), cisplatin (20 mg/m2, days 1-5), and etoposide (60 mg/m2, days 1-5) every 4 weeks for eight cycles. Four children under 2 years old were at first treated with eight cycles of ICE chemotherapy, and then irradiated. The ICE regimen was well tolerated by all children, with no irreversible adverse effects. However, dose reductions during the eight cycles were inevitable mainly due to myelosuppression. Complete remissions were achieved in eight of 10 patients at 1 month after completion of the treatment. One child showed recurrence 21 months after complete remission. The disease-free survival rate was 70% with a mean observation period of 24 months after surgery. The ICE regimen is a useful treatment modality for children with medulloblastoma. Further study is warranted to clarify long-term outcome in a number of patients.
Neurol Med Chir (Tokyo) 1996 Sep
PMID:Combined irradiation and chemotherapy using ifosfamide, cisplatin, and etoposide for children with medulloblastoma/posterior fossa primitive neuroectodermal tumor--results of a pilot study. 891 79

In a number of experimental systems, the early stage of the apoptotic process, i.e., the stage that precedes nuclear disintegration, is characterized by the breakdown of the inner mitochondrial transmembrane potential (delta psi m). This delta psi m disruption is mediated by the opening of permeability transition (PT) pores and appears to be critical for the apoptotic cascade, since it is directly regulated by Bcl-2 and since mitochondria induced to undergo PT in vitro become capable of inducing nuclear chromatinolysis in a cell-free system of apoptosis. Here, we addressed the question of which apoptotic events are secondary to mitochondrial PT. We tested the effect of a specific inhibitor of PT, bongkrekic acid (BA), a ligand of the mitochondrial adenine nucleotide translocator, on a prototypic model of apoptosis glucocorticoid-induced thymocyte death. In addition to abolishing the apoptotic delta psi m disruption, BA prevents a number of phenomena linked to apoptosis: depletion of nonoxidized glutathione, generation of reactive oxygen species, translocation of NF kappa B, exposure of phosphatidylserine residues on the outer plasma membrane, cytoplasmic vacuolization, chromatin condensation, and oligonucleosomal DNA fragmentation. BA is also an efficient inhibitor of p53-dependent thymocyte apoptosis induced by DNA damage. These data suggest that a number of apoptotic phenomena are secondary to PT. In addition, we present data indicating that apoptotic delta psi m disruption is secondary to transcriptional events. These data connect the PT control point to the p53- and ICE/ Ced 3-regulated control points of apoptosis and place PT upstream of nuclear and plasma membrane features of PCD.
J Exp Med 1996 Sep 01
PMID:Mitochondrial permeability transition is a central coordinating event of apoptosis. 906 32

Protein tyrosine kinases activate the STAT (signal transducer and activator of transcription) signaling pathway, which can play essential roles in cell differentiation, cell cycle control, and development. However, the potential role of the STAT signaling pathway in the induction of apoptosis remains unexplored. Here we show that gamma interferon (IFN-gamma) activated STAT1 and induced apoptosis in both A431 and HeLa cells, whereas epidermal growth factor (EGF) activated STAT proteins and induced apoptosis in A431 but not in HeLa cells. EGF receptor autophosphorylation and mitogen-activated protein kinase activation in response to EGF were similar in both cell lines. The breast cancer cell line MDA-MB-468 exhibited a similar response to A431 cells, i.e., STAT activation and apoptosis correlatively resulted from EGF or IFN-gamma treatment. In addition, in a mutant A431 cell line in which STAT activation was abolished, no apoptosis was induced by either EGF or IFN-gamma. We further demonstrated that both EGF and IFN-gamma induced caspase 1 (interleukin-1beta converting enzyme [ICE]) gene expression in a STAT-dependent manner. IFN-gamma was unable to induce ICE gene expression and apoptosis in either JAK1-deficient HeLa cells (E2A4) or STAT1-deficient cells (U3A). However, ICE gene expression and apoptosis were induced by IFN-gamma in U3A cells into which STAT1 had been reintroduced. Moreover, both EGF-induced apoptosis and IFN-gamma-induced apoptosis were effectively blocked by Z-Val-Ala-Asp-fluoromethylketone (ZVAD) in all the cells tested, and studies from ICE-deficient cells indicated that ICE gene expression was necessary for IFN-gamma-induced apoptosis. We conclude that activation of the STAT signaling pathway can induce apoptosis through the induction of ICE gene expression.
Mol Cell Biol 1997 Sep
PMID:Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. 927 10

The mdm2 oncogene encodes a 90-kDa protein that can bind to the p53 tumor suppressor protein and negatively regulate its functions in transcription, cell cycle arrest, and apoptosis. The mdm2 gene is frequently amplified in human sarcomas, which may be responsible for the malignant transformations. We present evidence that the mdm2 oncoprotein is cleaved by an interleukin 1beta-converting enzyme-like protease (caspase) during p53-mediated apoptosis. The protease that cleaves mdm2 has a specificity similar to that of CPP32 (caspase-3), and recombinant caspase-3 is able to cleave mdm2 in vitro. The protease cleavage site has been mapped to between residue 361 and 362 of human mdm2. The proteolytic cleavage removes the COOH-terminal RING finger domain of mdm2, resulting in the loss of RNA binding activity. The p53 binding and inhibition functions of mdm2 are not affected by the cleavage. The cleavage site sequence of mdm2 is evolutionarily conserved, suggesting that regulation by caspase cleavage during apoptosis is an important feature of mdm2.
J Biol Chem 1997 Sep 05
PMID:Proteolytic cleavage of the mdm2 oncoprotein during apoptosis. 927 61

Anticancer agents have been shown to trigger apoptosis in chemosensitive tumors such as neuroblastomas. We previously identified activation of the CD95 system as one of the key mechanisms for doxorubicin-induced apoptosis in leukemic T cells. Here, we report that therapeutic concentrations of doxorubicin, cisplatinum, and VP-16 led to induction of CD95 receptor and CD95 ligand (CD95-L) that mediated cell death in chemosensitive neuroblastoma cells. Using F(ab')2 anti-CD95 antibody fragments to interfere with CD95-L-receptor interaction markedly reduced apoptosis induced by those drugs in vitro. Cyclosporin A inhibited induction of CD95 mRNA and CD95-L mRNA and blocked drug-mediated apoptosis. Drug-induced apoptosis involved activation of caspases (interleukin 1beta-converting enzyme/Ced-3-like proteases) and processing of the prototype caspase substrate PARP and was completely blocked by benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a peptide inhibitor of caspases. In addition, neuroblastoma cells that were resistant to CD95-triggered apoptosis also displayed cross-resistance to chemotherapeutic agents. These data provide new clues for understanding the molecular requirements for drug-induced apoptosis in chemosensitive neuroblastoma cells by demonstrating that cell death was mediated via the CD95-L-receptor system and may open new avenues for targeting drug resistance of neuroblastoma.
Cancer Res 1997 Sep 01
PMID:The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. 928 94


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