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)

Mutations in the gene ced-3, which encodes a protease similar to interleukin-1beta converting enzyme and related proteins termed caspases, prevent programmed cell death in the nematode Caenorhabditis elegans. We used site-directed mutagenesis to demonstrate that both the presumptive active-site cysteine of the CED-3 protease and the aspartate residues at sites of processing of the CED-3 proprotein are required for programmed cell death in vivo. We characterized the phenotypes caused by and the molecular lesions of 52 ced-3 alleles. These alleles can be ordered in a graded phenotypic series. Of the 30 amino acid sites altered by ced-3 missense mutations, 29 are conserved with at least one other caspase, suggesting that these residues define sites important for the functions of all caspases. Animals homozygous for the ced-3(n2452) allele, which is deleted for the region of the ced-3 gene that encodes the protease domain, seemed to be incompletely blocked in programmed cell death, suggesting that some programmed cell death can occur independently of CED-3 protease activity.
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PMID:Mutational analysis of the Caenorhabditis elegans cell-death gene ced-3. 1058 Dec 74

Macrophages differentiated from circulating peripheral blood monocytes are essential for host immune responses and have been implicated in the pathogenesis of rheumatoid arthritis and atherosclerosis. In contrast to monocytes, macrophages are resistant to Fas-induced cell death by an unknown mechanism. FLICE (Fas-associated death domain-like interleukin 1beta-converting enzyme)-inhibitory protein (Flip), a naturally occurring caspase-inhibitory protein that lacks the critical cysteine domain necessary for catalytic activity, is a negative regulator of Fas-induced apoptosis. Here, we show that monocyte differentiation into macrophages was associated with upregulation of Flip and a decrease in Fas-mediated apoptosis. Overexpression of Flip protected monocytes from Fas-mediated apoptosis, whereas acute Flip inhibition in macrophages induced apoptosis. Addition of an antagonistic Fas ligand antibody to Flip antisense-treated macrophages rescued cultures from apoptosis, demonstrating that endogenous Flip blocked Fas-induced cell death. Thus, the expression of Flip in macrophages conferred resistance to Fas-mediated apoptosis, which may contribute to the development of inflammatory disease.
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PMID:FLICE-inhibitory protein expression during macrophage differentiation confers resistance to fas-mediated apoptosis. 1058 58

Apoptosis induced by T cell receptor (TCR) triggering in T lymphocytes involves activation of cysteine proteases of the caspase family through their proteolytic processing. Caspase-3 cleavage was also reported during T cell stimulation in the absence of apoptosis, although the physiological relevance of this response remains unclear. We show here that the caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD) blocks proliferation, major histocompatibility complex class II expression, and blastic transformation during stimulation of peripheral blood lymphocytes. Moreover, T cell activation triggers the selective processing and activation of downstream caspases (caspase-3, -6, and -7), but not caspase-1, -2, or -4, as demonstrated even in intact cells using a cell-permeable fluorescent substrate. Caspase-3 processing occurs in different T cell subsets (CD4(+), CD8(+), CD45RA(+), and CD45RO(+)), and in activated B lymphocytes. The pathway leading to caspase activation involves death receptors and caspase-8, which is also processed after TCR triggering, but not caspase-9, which remains as a proenzyme. Most importantly, caspase activity results in a selective substrate specificity, since poly(ADP-ribose) polymerase (PARP), lamin B, and Wee1 kinase, but not DNA fragmentation factor (DFF45) or replication factor C (RFC140), are processed. Caspase and substrate processing occur in nonapoptotic lymphocytes. Thus, caspase activation is an early and physiological response in viable, stimulated lymphocytes, and appears to be involved in early steps of lymphocyte activation.
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PMID:Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. 1060 47

Caspases are a group of cysteine proteases critical for apoptosis of eukaryotic cells. Deletion of genes that encode murine caspases suggests that caspases are involved not only in apoptosis but also in cytokine maturation and cell growth and differentiation. Among them, caspase-1 and caspase-11 are primarily involved in the processing of pro-inflammatory cytokines. Caspase-3 and caspase-9 are essential for apoptosis during brain development. Caspase-8 is required for the development of heart muscle, cell proliferation in the hematopoietic lineage and death-receptor-mediated apoptosis. These studies suggest that caspases function in cell signaling events including apoptosis, cell growth and differentiation.
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PMID:Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies. 1067 65

Caspases, a family of cysteine proteases, have been recognized as the central executors of programmed cell death. Nonetheless, the information on the caspase family has been limited to mammals, Drosophila, and nematodes. To examine the structure and characterization of the Xenopus caspase family, we have cloned the cDNAs encoding caspase-2 and -6-10 in addition to caspase-1 and -3, which we characterized previously (Yaoita, Y., and Nakajima, K. (1997) J. Biol. Chem. 272, 5122-5127). First, the existence of these caspases in frog suggests that the caspase cascades clarified in mammals are conserved at least from Amphibia. Interestingly, Xenopus caspase-1, -8, and -10 (especially caspase-8) showed a lower degree of identity to human equivalents than the other caspases. Second, mRNAs of many caspases increased during the climax of metamorphosis in regressing organs, tail, and intestine, where programmed cell death occurs, but not in apoptotic tail-derived cultured cells (XLT-15-11) treated with thyroid hormone, showing that new RNA synthesis of caspases is dispensable to programmed cell death. Third, comparison of human and Xenopus caspase sequences implies that some proposed regulations of human caspases are not conserved in frog.
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PMID:Structure, expression, and function of the Xenopus laevis caspase family. 1074 39

Apoptosis, or programmed cell death, plays a central role in the development and homeostasis of an organism. The breakdown of cellular proteins in apoptosis is mediated by caspases, which comprise a highly conserved family of cysteine proteases with specificity for aspartic acid residues at the P1 positions of their substrates. Multiple lines of evidence show that caspase-9 is critical for an apoptosis pathway mediated via the mitochondria. In this study, the three-dimensional structure of the catalytic domain of caspase-9 and its interaction with the inhibitor acetyl-Asp-Val-Ala-Asp fluoromethyl ketone (Ac-DVAD-fmk) have been predicted by a segment matching modeling procedure. As expected, the predicted caspase-9 structure shows both a high similarity in the overall folding topology and remarkable differences in the surface loop regions as compared to other caspase family members such as caspase-1, -3 and -8, for which crystal structures have been determined. This kind of comparative analysis reflects the convergence-divergence duality among the caspases. Moreover, some subtle differences have been observed between caspase-9 and caspase-3 in the subsite contacts with the covalently linked inhibitor Ac-DVAD-fmk. Based on the X-ray structural analysis of caspase-8, a main chain carbonyl oxygen appears to be involved in a catalytic triad with the active site Cys and His residues. The corresponding carbonyl oxygen in caspase-9, together with other expected features of the catalytic apparatus, appears in our model. The predicted structure of caspase-9 can serve as a reference for subsite analysis relative to rational design of highly selective caspase inhibitors for therapeutic application.
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PMID:Prediction of the tertiary structure of a caspase-9/inhibitor complex. 1074 77

The list of interleukins is growing at a steady rate. Although, it is over 8 years since the initial description of interferon gamma inducing factor (IGIF, now called IL-18), this novel cytokine is still not well characterised. However, the data were sufficient to support the testing of IL-18 in experimental tumour therapy. IL-18 is produced mainly by macrophages. Similarly to IL-1beta, IL-18 does not possess a signal sequence allowing direct secretion through the plasma membrane. Although, the exact mechanism of IL-18 secretion is not confirmed, it seems that, like IL-1beta, IGIF is processed by the cysteine proteases belonging to caspase family, especially by ICE (interleukin 1beta converting enzyme). Among the target cells responding to IL-18 are T lymphocytes and NK cells, which, under the influence of IL-18, produce substantial amounts of IFN-gamma. In this respect IL-18 seems to be even stronger than IL-12. Similarly to IL-12, IL-18 stimulates cytotoxicity of T and NK cells. Moreover, it enhances FasL-mediated cytotoxicity of CD4+ T and NK cells. A potential role of IL-18 in tumour immunotherapy is discussed in this article with special emphasis on the similarities with IL-12 and the potential mechanisms of its antitumour activity in preclinical models in mice.
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PMID:Interleukin 18--interferon gamma inducing factor--a novel player in tumour immunotherapy? 1080 13

The dietary isothiocyanates and cancer chemopreventive agents phenethyl isothiocyanate and allyl isothiocyanate and their cysteine conjugates inhibited the growth and induced apoptosis of human leukaemia HL60 (p53-) and human myeloblastic leukaemia-1 cells (p53+) in vitro. The median growth inhibitory concentration (GC(50)) values were in the range 1.49-3.22 microM in cultures with 10% serum. Isothiocyanates and cysteine conjugates had increased potency against HL60 cells in serum-free medium, with GC(50) values of 0.8-0. 9 microM. The potency of the compounds decreased with increased serum content of the medium, but that of the cysteine conjugates decreased more markedly. Growth inhibition and toxicity was characterised by either a rapid interaction of the isothiocyanate with the cells in the first hour of culture or exposure to isothiocyanate liberated from the cysteine conjugate in the initial 3 hr of culture, inhibition of macromolecule synthesis, and a commitment to apoptosis which developed in the initial 24 hr. Activities of caspase-3 and caspase-8 were increased during isothiocyanate-induced apoptosis, but caspase-1 activity was not. The general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone and the specific caspase-8 inhibitor N-benzyloxycarbonyl-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoromethylketone inhibited apoptosis, but specific caspase-1 and caspase-3 inhibitors did not. The antiproliferative activities were limited by hydrolysis of the isothiocyanate. This suggests that caspase-8 has a critical role, and caspase-3 a supporting role, in isothiocyanate-induced apoptosis in which p53 is not an obligatory participant. Isothiocyanate-induced apoptosis may suppress the growth of preclinical tumours and contribute to the well-established decreased cancer incidence associated with a vegetable-rich diet.
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PMID:Studies on the mechanism of the inhibition of human leukaemia cell growth by dietary isothiocyanates and their cysteine adducts in vitro. 1082 67

Caspases are cysteine proteases which have important roles in the activation of cytokines and in apoptosis. The ICE subfamily of caspases comprise peptides closely related to caspase-1, or interleukin-1beta (IL-1beta) converting enzyme (ICE), which promotes maturation of interleukin IL-1beta and interleukin-18 (IL-18) by proteolytic cleavage of precursor forms to generate biologically active peptides. Other members of this subfamily include caspase-4, -5, -13 and isoforms of these proteins. We report the cloning and sequencing of two feline and canine ICE-related cDNAs amplified by RT-PCR. The predicted proteins are 410 and 404 amino acids in length respectively and are most closely related to caspase-1 sequences across the N-terminal 115 amino acids and to human caspase-13 across the C-terminal sequence.
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PMID:Cloning and sequencing of feline and canine ice-related cDNAs encoding hybrid caspase-1/caspase-13-like propeptides. 1082 95

Butylated hydroxyanisole (BHA), a commonly used food preservative, is reported to have anticarcinogenic properties in some animal models. However, the use of BHA as a chemopreventive agent against cancer in human has been challenged by the observation that BHA may exert toxic effect in some tissues of animals. Therefore, it is of great significance to understand the mechanism of BHA-induced toxicity. Here, we report that BHA induces apoptosis in freshly isolated rat hepatocytes. Treatment of hepatocytes with BHA also induced loss of mitochondrial transmembrane potential (Deltapsi(m)), cytochrome c, and activation of caspase-3, -8, and -9 but not caspase-1. Pretreatment with cyclosporin A, an agent that stabilizes mitochondrial permeability transition pore, inhibited BHA-induced loss of Deltapsi(m), cytochrome c release, caspase activation, and apoptosis. Interestingly, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone failed to prevent these mitochondrial events, although it blocked caspase activation and apoptosis. Furthermore, BHA-induced apoptosis appeared to be independent of formation of reactive intermediates, as evidenced by the lack of effects of antioxidants N-acetyl-L-cysteine and ascorbic acid. Indeed, direct incubation of BHA with isolated mitochondria triggered cytochrome c release. Thus, these results indicate that the cytotoxicity of BHA is due to the induction of apoptosis that is mediated by the direct release of cytochrome c and the subsequent activation of caspases.
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PMID:Molecular mechanisms of butylated hydroxylanisole-induced toxicity: induction of apoptosis through direct release of cytochrome c. 1090 12


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