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)

It is well established that apoptosis is accompanied by activation of procaspases and by mitochondrial changes, such as decrease in mitochondrial transmembrane potential (DeltaPsim) and release of cytochrome c. We analyzed the causal relationship between activated caspases and these mitochondrial phenomena. Purified recombinant caspase-1, -11, -3, -6, -7, and -8 were incubated with mitochondria in the presence or absence of additional cellular components, after which DeltaPsim was determined. At lower caspase concentrations, only caspase-8 was able to activate a cytosolic factor, termed caspase-activated factor (CAF), which resulted in decrease in DeltaPsim and release of cytochrome c. Both CAF-mediated activities could not be blocked by protease inhibitors, including oligopeptide caspase inhibitors. CAF-induced cytochrome c release, but not decrease of DeltaPsim, was blocked in mitochondria from cells overexpressing Bcl-2. CAF is apparently involved in decrease of DeltaPsim and release of cytochrome c, whereas Bcl-2 only prevents the latter. Hence, CAF may form the link between death domain receptor-dependent activation of procaspase-8 and the mitochondrial events studied.
J Exp Med 1998 Dec 07
PMID:A caspase-activated factor (CAF) induces mitochondrial membrane depolarization and cytochrome c release by a nonproteolytic mechanism. 984 33

We analyzed changes of growth and apoptotic cell death in human hair follicles. In anagen hair follicles, terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate-biotin nick labeling-positive cells were observed in the keratogenous zone of the upper bulb matrix, the inner root sheath, and the companion layer of the outer root sheath. DNA ladder formation was also detected in anagen hair follicles. In catagen hair follicles, the lower bulb matrix cells around the dermal papilla and the outer layer cells of the outer root sheath became strongly positive, showing that apoptosis in catagen hair is distinct from that in anagen hair. We also confirmed the mRNA expression of four caspases (caspase-1, caspase-3, caspase-4, and caspase-7) in anagen hair follicles by reverse transcriptase-polymerase chain reaction and in situ hybridization. When human anagen hair follicles were cultured in the presence of transforming growth factor-beta or tumor necrosis factor-alpha in the serum-free medium, transforming growth factor-beta but not tumor necrosis factor-alpha induced catagen-like morphologic changes, which were indistinguishable from normal catagen hair follicles. Tumor necrosis factor-alpha, however, strongly inhibited the elongation of the hair shaft in a dose-dependent manner, accompanied by abnormal morphology and increased cell death in the bulb matrix cells. Our results suggest that apoptosis in hair follicles involves two different types. One is related to the terminal differentiation of follicular epithelial cells in anagen hair. The other occurs as a major driving force to eliminate the distinct portion of epithelial components in catagen hair. Furthermore, this study strongly indicates that the transforming growth factor-beta pathway is involved in the induction of catagen phase in human hair cycle.
J Invest Dermatol 1998 Dec
PMID:Analysis of apoptotic cell death in human hair follicles in vivo and in vitro. 985 1

Bax (a death-promoting member of the bcl-2 gene family), the tumor suppressor gene product p53, and the ICE/ced-3-related proteases (caspases) have all been implicated in programmed cell death in a wide variety of cell types. However, their roles in radiation-induced neuronal cell death are poorly understood. In order to further elucidate the molecular mechanisms underlying radiation-induced neuronal cell death, we have examined the ability of ionizing radiation to induce cell death in primary cultured hippocampal neurons obtained from wild-type, p53-deficient and Bax-deficient newborn mice. Survival in neuronal cultures derived from wild-type mice decreased in a dose-dependent manner 24 hr after a single 10 Gy to 30 Gy dose of ionizing radiation. In contrast, neuronal survival in irradiated cultures derived from p53-deficient or Bax-deficient mice was equivalent to that observed in control, nonirradiated cultures. Western blot analyses indicated that neuronal p53 protein levels increased after irradiation in wild-type cells. However, Bax protein levels did not change, indicating that other mechanisms exist for regulating Bax activity. Adenovirus-mediated overexpression of p53 also caused neuronal cell death without increasing Bax protein levels. Irradiation resulted in a significant induction in caspase activity, as measured by increased cleavage of fluorogenic caspase substrates. However, specific inhibitors of caspase activity (zVAD-fmk, zDEVD-fmk and BAF) failed to protect postnatal hippocampal neurons from radiation-induced cell death. Staurosporine (a potent inducer of apoptosis in many cell types) effectively induced neuronal cell death in wild-type, p53-deficient and Bax-deficient hippocampal neurons, indicating that all were competent to undergo programmed cell death. These results demonstrate that both p53 and Bax are necessary for radiation-induced cell death in postnatal cultured hippocampal neurons. The fact that cell death occurred despite caspase inhibition suggests that radiation-induced neuronal cell death may occur in a caspase-independent manner.
J Neurosci Res 1998 Dec 15
PMID:Evidence for involvement of Bax and p53, but not caspases, in radiation-induced cell death of cultured postnatal hippocampal neurons. 985 57

The mechanism by which mutations in the superoxide dismutase (SOD1) gene cause motor neuron degeneration in familial amyotrophic lateral sclerosis (ALS) is unknown. Recent reports that neuronal death in SOD1-familial ALS is apoptotic have not documented activation of cell death genes. We present evidence that the enzyme caspase-1 is activated in neurons expressing mutant SOD1 protein. Proteolytic processing characteristic of caspase-1 activation is seen both in spinal cords of transgenic ALS mice and neurally differentiated neuroblastoma (line N2a) cells with SOD1 mutations. This activation of caspase-1 is enhanced by oxidative challenge (xanthine/xanthine oxidase), which triggers cleavage and secretion of the interleukin 1beta converting enzyme substrate, pro-interleukin 1beta, and induces apoptosis. This N2a culture system should be an instructive in vitro model for further investigation of the proapoptotic properties of mutant SOD1.
Proc Natl Acad Sci U S A 1998 Dec 22
PMID:Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. 986 Oct 44

Peroxynitrite, a cytotoxic oxidant formed in the reaction of superoxide and nitric oxide is known to cause programmed cell death. However, the mechanisms of peroxynitrite-induced apoptosis are poorly defined. The present study was designed to characterize the molecular mechanisms by which peroxynitrite induces apoptosis in HL-60 cells, with special emphasis on the role of caspases. Peroxynitrite induced the activation of apopain/caspase-3, but not ICE/caspase-1 as measured by the cleavage of fluorogenic peptides. Considering the short half-life of peroxynitrite and the kinetics of caspase-3 activation (starting 3-4 h after peroxynitrite treatment), the enzyme is not likely to become activated directly by the oxidant. Caspase-3 activation proved to be essential for DNA fragmentation, because pretreatment of the cells with the specific tetrapeptide inhibitor DEVD-fmk completely blocked peroxynitrite-induced DNA fragmentation. Peroxynitrite-induced cytotoxicity was also significantly altered by the inhibition of caspase-3, whereas phosphatidylserine exposure was unaffected by DEVD-fmk treatment. Because many of the effects of peroxynitrite are mediated by poly(ADP-ribose) synthetase (PARS) activation, we have also investigated the effect of PARS-inhibition on peroxynitrite-induced apoptosis. We have found that PARS-inhibition modulates peroxynitrite-induced apoptotic DNA fragmentation in the HL-60 cells. The effect of the PARS inhibitors, 3-aminobenzamide and 5-iodo-6-amino-1,2-benzopyrone were dependent on the concentration of peroxynitrite used. While PARS-inhibition resulted in increased DNA-fragmentation at low doses (15 microM) of peroxynitrite, a decreased DNA-fragmentation was found at high doses (60 microM) of peroxynitrite. PARS inhibition negatively affected viability as determined by flow cytometry. These data demonstrate the crucial role of caspase-3 in mediating apoptotic DNA fragmentation in HL-60 cells exposed to peroxynitrite.
Free Radic Biol Med 1998 Dec
PMID:Crucial role of apopain in the peroxynitrite-induced apoptotic DNA fragmentation. 987 May 61

The activation of caspases appears to play a key role in programmed cell death. An increasing number of substrates have been identified that are cleaved by caspases. In a previous study, we have reported that human cPLA2 is proteolytically inactivated during apoptosis through cleavage by a caspase-3-like activity. Here, we show that in cotransfection experiments the previously identified cleavage site at Asp522 can be used by a wide variety of caspases belonging to different subfamilies. The formation of additional fragments implied differences in cleavage site usage between the closely related caspases-3 and -7. A different cleavage pattern of cPLA2 was observed with caspase-1. Mutational analysis identified the caspase-1 cleavage site at Asp459 within the sequence YQSD/N. Most interestingly, we found that even caspase-8, an upstream component of the proposed caspase cascade, cleaves cPLA2 in vitro. The presence of multiple cleavage sites warrants proteolysis and inactivation of the proinflammatory cPLA2 during apoptosis.
Biochem Biophys Res Commun 1998 Dec 09
PMID:Cleavage of human cytosolic phospholipase A2 by caspase-1 (ICE) and caspase-8 (FLICE). 987 25

We have evaluated the combination of ifosfamide, carboplatin and etoposide (ICE regimen) along with mesna in 26 previously untreated patients with non small cell lung cancer (NSCLC). Thirteen stage III B and 13 stage IV patients received intermediate doses of ifosfamide (1000 mg/m2), carboplatin (120 mg/m2) and etoposide (120 mg/m2) given intravenously on day 1 to 3 every 4 weeks. Except for one patient who experienced grade 3 transient thrombocytopenia no major events of hematological or systemic toxicity were observed. Response rate (27%, 95% C.I., 10 to 44%), median duration of response (9 months, range 6-15), and survival (9.5 months, range 2-44+) were comparable to those achieved with conventional cisplatin-containing regimens. Our ICE combination, as compared to standard or high dose schedules appears effective, safe, well tolerated, and devoid of severe hematological toxicity.
J Chemother 1998 Dec
PMID:Phase II study with ifosfamide, carboplatin, etoposide (ICE regimen) at intermediate dosage for advanced non small cell lung cancer (NSCLC). 987 59

The combination of ifosfamide, carboplatin and etoposide (modified ICE), was evaluated for its toxicity and activity in relapsed or refractory aggressive non-Hodgkin's lymphoma. Twenty patients, 14-69 years of age, with relapsed (19 cases) or refractory (one case) aggressive non-Hodgkin's lymphoma were treated with modified ICE therapy, consisting of ifosfamide 6 g/m2 (1.2 g/m2 day 1-5), carboplatin 400 mg/m2 (day 1) and etoposide 500 mg/m2 (100 mg/m2 day 1-5). The regimen was repeated at approximately 28-day intervals. All patients had undergone a doxorubicin-containing regimen before modified ICE therapy. Median total dose of previously received doxorubicin was 406 mg/m2 (range: 200-825 mg/m2). The median interval from diagnosis to modified ICE therapy was 9.4 months (range: 3.6-121 months). Two patients achieved CR and five achieved PR out of 16 patients with measurable lesions (response rate 43.8%; 95% confidence interval 19.0-68.6%). Median overall survival was 227 days (range: 41-552 days) from the start of modified ICE therapy. Myelosuppression was the most serious toxicity, namely 16 patients (80%) and 11 patients (55%) showed grade 4 neutropenia and grade 4 thrombocytopenia after the first course, respectively. Modified ICE therapy might be an active regimen with acceptable toxicity as a salvage chemotherapy in aggressive non-Hodgkin's lymphoma.
Int J Hematol 1998 Dec
PMID:Toxicity and efficacy of ifosfamide, carboplatin and etoposide (modified ICE) as a salvage chemotherapy in Japanese patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. 988 42

Apoptosis is well accepted as a type of cell death occurring in the development of mammalian muscles, but the death of adult myofibres in neuromuscular disorders and exercise-induced muscle damage is usually explained in terms of muscle necrosis. The current view that apoptosis precedes necrosis in death of dystrophin-deficient muscle fibres of mdx mouse has been well substantiated. Moreover, apoptotic myonuclei have been reported to increase in mdx mice 2 days after spontaneous exercise. To investigate the contribution of apoptosis to exercise-induced damage of normal muscle fibre a time-course analysis has been performed in adult C57BL/6 mice. Groups of five mice were sacrificed immediately after the end of the exercise, and after a rest period of 6 or 96 h. The amount of apoptosis in leg muscles was assessed by electron microscopy, by the terminal deoxynucleotidyl transferase assay and by electrophoretic detection of fragmented DNA; the expression of Bcl-2, Bax, Fas, ICE, p53 and ubiquitin was examined by immunohistochemistry and Western blot. Absent in muscles of normal 'sedentary' mice, apoptotic myonuclei peak in muscles of normal mice after a night of spontaneous wheel-running (4% +/- 3.5, immediately and 2.5% +/- 1.8 after 6 h rest, P < 0.05 vs non-runner mice); they then decrease but are present 4 days later (0.8% +/- 1.5). Satellite cells are also involved in the apoptotic process. Myofibre content of Bcl-2 decreases whereas Bax, Fas, ICE and ubiquitin modify their pattern of expression in correlation with the changes in apoptotic myonuclei. Apoptosis of endothelial cells is present after the night of wheel-running and with a twofold increase 4 days later (1.5 +/- 2.3 and 4.8 +/- 4.4 P < 0.05, respectively). Satellite cells are also involved in the apoptotic process. Thus, spontaneous running in unaccustomed mice increases the number of apoptotic nuclei in adult muscle fibres and in endothelial cells. It remains to be established whether muscle apoptosis is restricted to the repair mechanisms, as often suggested in many pathologic processes, or it is also part of pathogenesis of muscle damage. Regardless of whether these results are extended to human dystrophies, the clinical implications in terms of secondary pathogenetic mechanisms and muscle training are obvious.
Neuropathol Appl Neurobiol 1998 Dec
PMID:Apoptosis of myofibres and satellite cells: exercise-induced damage in skeletal muscle of the mouse. 988 62

The multifunctional cytokine interleukin-1 (IL-1) is a key mediator in the cytokine network. The IL-1 family consists of two zymogen isoforms of IL-1 (IL-1alpha and IL-1beta), the IL-1 receptor antagonists, two receptors and receptor-associated proteins. Identification of the enzyme responsible for cleavage and activation of the IL-1beta precursor, the IL-1beta converting enzyme (ICE; caspase 1), unexpectedly linked the IL-1 family to the apoptosis machinery, since ICE is the founding molecule of the caspase family, which is important for regulation of apoptosis. Although it has been suggested that cytokines are involved in pathogenesis of cardiovascular diseases only few informations exist regarding the endogenous production and function of IL-1 and the associated enzyme(s) of the caspase family in the cardiovascular system. Here, we summarize informations regarding the IL-1 and the caspase family in the cardiovascular system.
Eur Cytokine Netw 1998 Dec
PMID:The interleukin-1 and interleukin-1 converting enzyme families in the cardiovascular system. 988 13


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