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)

Fas ligand is a potent inducer of apoptosis in human glioma cells by the Fas/Fas ligand pathway. With comparable efficiency, metalloprotease inhibitors including puromycin and bestatin induce apoptosis in glioma cells. To evaluate the involvement of potential components involved in Fas ligand- and metalloprotease inhibitor-induced apoptosis, we investigated the effect of anti human Fas antibody, soluble Fas ligand and puromycin on cultures of human malignant glioma cell lines (LN-18, LN-229, T98G). Stimulation with Fas ligand lead to apoptotic cell death within 16 h. Costimulation with the translational inhibitor cycloheximide and the transcription blocker actinomycin D did not reduce Fas ligand toxicity. In contrast, apoptosis induced by puromycin was blocked by cycloheximide and decreased by subtoxic doses of actinomycin D in all three gliomas. Whereas inhibition of caspase activity with the general inhibitor zVAD-fmk resulted in a complete block of Fas ligand-induced cell death, puromycin-mediated apoptosis was found to be unaffected by zVAD-fmk as well as by more specific inhibitors for caspase-1 (Interleukin-1 beta converting enzyme) and caspase-3 (CPP32/Yama). Other prominent components involved in many apoptotic pathways as bcl-2 and reactive oxygen intermediates were also examined. Bcl-2 which protects glioma cells from Fas ligand-induced cell death, was shown to have only a small protective effect on puromycin-induced apoptosis. The tested radical scavengers did not reduce Fas- or puromycin-mediated killing of human glioma cells.
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PMID:Differential activity of bcl-2 and ICE enzyme family protease inhibitors on Fas and puromycin-induced apoptosis of glioma cells. 940 14

Apoptosis has been described as one of the mechanisms of muscle fiber loss in infantile spinal muscular atrophy. In order to investigate if muscle fiber-apoptosis plays a role in other denervating disorders as well, we studied DNA-fragmentation, a hallmark of apoptosis, by the TUNEL-method and, moreover, the expression patterns of apoptosis-related proteins in 2 patients suffering from ALS and in 6 patients with polyneuropathy. We identified DNA-cleavage in muscle fibers of all these patients. Furthermore, we found strong expression of bax and ICE promoting apoptosis in muscle fibers. However, also strong expression of the anti-apoptotic factor bcl-2 was found. Our findings indicate that defective innervation may prompt muscle fibers to activate an intrinsic "suicide" programme which is promoted by the proapoptotic factors bax and ICE, which seems to induce formation of apoptotic bodies by cleavage of actin. Nevertheless, there are also anti-apoptotic strategies in muscle fibers manifested by expression of the bax-antagonist bcl-2 which is able to neutralize high bax levels.
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PMID:DNA-fragmentation and apoptosis-related proteins of muscle cells in motor neuron disorders. 944 76

In order to characterize cell death mechanisms involved in Alzheimer disease (AD), we quantitated the expression of ced-3 and ced-9 homologs in AD frontal cortex. Positive (ICE, ICErel-II, ICErel-III, Ich-1L, CPP32, mch2, mch3, bcl-xS, bax and bak) and negative (bcl-2, bcl-xL, MCL1 and Ich-1S) regulators of apoptosis were successively examined using a semi-quantitative technique of reverse transcription-polymerase chain reaction (RT-PCR). Total RNA was extracted from postmortem frontal cortex of AD patients (n = 7) and controls (n = 7) matched for age and autolysis time. Baseline levels of message were detected for 3 ced-3 (CPP32, Ich-1 and ICE) and 4 ced-9 homologs (bcl-x, MCL1, bcl-2 and bax) in the frontal cortex. There was an overexpression of the ICEalpha cDNA in AD patients as compared with age-matched controls (P = 0.03). Our results indicate that several ced-3 and ced-9 homologs are expressed in the adult human brain, and suggest that neuronal cell death in AD might involve an aberrant expression of ICEalpha.
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PMID:Expression of ced-3 and ced-9 homologs in Alzheimer's disease cerebral cortex. 957 87

Apoptosis is induced in cells via distinct pathways, which may differ according to various stimuli and different cell types. One apoptotic stimulus is the activation of receptors such as the p55 tumor necrosis factor (TNF) receptor. These receptors transduce their apoptotic signals via a cytoplasmic region termed the death domain. Here we investigated the apoptotic pathway induced by overexpression of the intracellular domain of p55 TNF receptor (p55-IC) in a neuronal model system consisting of PC12 cells. Using the tetracycline-regulated transactivator system, which allows controlled gene expression, we show that overexpression of p55-IC induces apoptosis in both naive and neuronal PC12 cells. The apoptosis-inducing effect of p55-IC is blocked by the expression of bcl-2, suggesting that p55-IC induces apoptosis in PC12 cells via a pathway controlled by bcl-2. The need for caspases in the p55-IC-induced cell death effect in naive and neuronal PC12 cells was studied by examining the effects of broad-spectrum and specific inhibitors of caspases as well as expression of antisense caspase-2 RNA. The broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone blocked p55-IC-induced cell death in both naive and neuronal cells, suggesting that caspases are needed for this process in both cell types. Caspase-1-like proteases are most probably not involved in the process since neither expression of crmA nor treatment with the caspase-1-specific peptide inhibitor Ac-Try-Val-Ala-Asp-aldehyde had any protective effect. Interestingly, expression of antisense caspase-2 RNA blocked the p55-IC-induced cell death in naive but not in neuronal PC12 cells, whereas the caspase-3-like specific inhibitor Ac-Asp-Glu-Val-Asp-aldehyde partially inhibited this death in neuronal but not in naive cells. These results suggest that the apoptosis-inducing effect of p55-IC requires different caspases in naive and neuronal PC12 cells.
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PMID:The intracellular domain of p55 tumor necrosis factor receptor induces apoptosis which requires different caspases in naive and neuronal PC12 cells. 958 83

The c-erbA protooncogene encodes the thyroid hormone (3,5,3'-triiodothyronine; T3) receptor alpha1 (TR alpha1). c-erbA/TR alpha1 is expressed in many cell types including glial cells, particularly in the immature state. We show here by morphological and biochemical criteria that c-erbA induces apoptosis of glial B3.1 cells in serum-deprived conditions. This effect is mostly T3 independent. Growth factors such as platelet-derived growth factor, basic fibroblast growth factor, or transforming growth factor-alpha prevent B3.1 + TR alpha1 cell death. Protein kinase C (PKC) activators also prevent the apoptosis phenomenon, an effect that was blocked by the PKC-specific inhibitor GF109203X. Expression of an exogenous bcl-2 gene led also to B3.1 + TR alpha1 cell survival. Neither a series of inhibitors including GF109203X nor T3 inhibits bcl-2 action, indicating that bcl-2 blocks a downstream step in the death-promoting process. B3.1 + TR alpha1 cell apoptosis is not blocked by caspase-1 or poly-ADP-ribosyltransferase inhibitors, suggesting that the activation of these classic pathways is not involved in the apoptotic mechanism. In addition, direct interaction with specific neuronal cells but not incubation with their conditioned medium inhibits also apoptosis of B3.1 + TR alpha1 cells. Our results show that c-erbA promotes an apoptotic process in glial B3.1 cells that is suppressible by PKC activation and bcl-2, probably by distinct mechanisms.
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PMID:The c-erbA alpha protooncogene induces apoptosis in glial cells via a protein kinase C- and bcl-2-suppressible mechanism. 960 96

Previous studies have shown that caspases (proteases related to interleukin-1beta converting enzyme) are needed for the death of trophic factor-deprived PC12 cells. However, the protease involved in this process has not been identified. The results presented here strongly suggest that caspase-2 (Nedd2/Ich-1) plays a major role in the death of serum-deprived PC12 cells. We show that in PC12 cells overexpression of caspase-2 induces cell death, serum deprivation induces processing (i.e., activation) of the 48-kDa pro-caspase-2, and stable expression of caspase-2 antisense RNA inhibits apoptosis induced by serum deprivation. In addition, overexpression of bcl-2, which prevents this death process, also inhibits the processing of pro-caspase-2, suggesting that bcl-2 acts upstream of pro-caspase-2 activation.
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PMID:Need for caspase-2 in apoptosis of growth-factor-deprived PC12 cells. 963 5

The extracellular microenvironment of tumors differs from that of most normal tissues. Many tumors have relatively acidic extracellular pH, although the intracellular pH of tumor cells remains normal due to the efficient maintenance of a large proton gradient across the membrane. This difference between tumors and normal tissues might be exploited therapeutically by disruption of the mechanisms that regulate intracellular pH, so that tumor cells are killed by intracellular acid-induced injury. To investigate the mechanisms by which intracellular acidification leads to cell death, we have studied the roles of the antiapoptotic gene bcl-2 and its proapoptotic binding partner bax, the stress-activated protein kinases (SAPK/JNK), and the caspase proteases in mediating acid-induced cell death. Whereas the expression of bcl-2 in human bladder cancer MGH-U1 cells had no effect on acid-induced death, overexpression of bax enhanced cell death, consistent with its proapoptotic function. Inhibition of SAPK, through the expression of a dominant negative mutant of its activator, SEK1, protected cells from acid-induced cell death. Caspase activation, as measured by poly(ADP-ribose) polymerase cleavage, was absent after lethal intracellular acidification. Consistent with this observation, inhibition of interleukin 1beta-converting enzyme proteases by the peptide z-Val-Ala-Asp(OMe)-CH2F did not protect against acid-induced cell killing. We conclude that acid-induced cell death depends on bax and on SAPK signaling pathways, but not on the caspase proteases. Therapeutic manipulation of bax and SAPK may enhance acid-induced tumor cell killing.
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PMID:Death of tumor cells after intracellular acidification is dependent on stress-activated protein kinases (SAPK/JNK) pathway activation and cannot be inhibited by Bcl-2 expression or interleukin 1beta-converting enzyme inhibition. 966 94

CuZn superoxide dismutase (CuZn SOD) is one of several antioxidant enzymes that defend the cell against damage by oxygen free radicals. Mutations of the SOD1 gene encoding CuZn SOD are found in patients with familial amyotrophic lateral sclerosis (FALS), a progressive and fatal paralytic disease that is caused by the death of motor neurons in cortex, brainstem and spinal cord. The disease can be reproduced in transgenic mice by expression of mutant human CuZn SOD. Recent studies both in vitro and in vivo suggest that the effect of mutation is to enhance the generation of oxygen radicals by the mutant enzyme. Thus, mutation converts a protective, antioxidant enzyme into a destructive, prooxidant form that catalyses free radical damage to which motor neurons are selectively vulnerable. Recent studies of neuroprotective agents in the FALS model show that inhibition of oxidative mechanisms (copper chelation therapy, dietary antioxidants, and coexpression of bcl-2) delays disease onset but does not extend disease duration. In contrast, inhibition of glutamatergic or apoptotic mechanisms (riluzole, gabapentin, and coexpression of glutamatergic or apoptotic mechanisms (riluzole, gabapentin, and coexpression of an inhibitor of caspase-1) has no effect on disease onset but extends survival by increasing the duration of symptomatic disease. Thus, neuroprotective agents differentially target the processes underlying disease initiation and propagation.
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PMID:Mutant CuZn superoxide dismutase in motor neuron disease. 972 38

The bcl-2 protein plays an essential role in preventing cell death. Its activity is regulated through association with bcl-2 homologous and nonhomologous proteins and also by serine phosphorylation. We now report that bcl-2 can be proteolytically cleaved towards its N-terminus by a cysteine proteinase present in RL-7 lymphoma cell lysates, yielding a major product of apparent MW 20 kDa, different from the products of bcl-2 cleavage by HIV protease. Moreover, bcl-2 proteins mutated for Asp residues at positions 31 and 34 were efficiently cleaved by RL-7 cell lysates, indicating that this proteolytic activity is distinct from the caspase-3 that cleaves bcl-2 at Asp 34. This bcl-2 cleaving activity is inhibited by E-64 and is therefore distinct from the proteinases of the ICE/Ced-3 family (caspases), whereas reciprocally, ICE (caspase-1) is unable to cleave bcl-2. It is optimally active at pH 5, a feature distinguishing it from calpain, another non-ICE cysteine proteinase which has been associated with apoptosis. This novel bcl-2 cleaving protease, although constitutively present in RL-7 cells and resting peripheral blood lymphocytes (PBL) was upregulated following induction of apoptosis in RL-7 cells or mitogen activation in PBL. The N-terminus of bcl-2 which contains the BH4 domain that binds the kinase Raf-1 and the phosphatase calcineurin is essential for anti-apoptotic activity. Its cleavage might provide a novel post-translational mechanism for regulating bcl-2 function and could amplify ongoing programmed cell death.
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PMID:N-terminus cleavage of bcl-2 by a novel cellular non-ICE cysteine proteinase. 973 98

The extracellular microenvironment of tumors differs from most normal tissues. Many tumors have relatively acidic extracellular pH (pHe), although the intracellular pH (pHi) of tumor cells remains normal due to efficient maintenance of a large proton gradient across the membrane. This difference between tumors and normal tissues might be exploited therapeutically by disruption of the mechanisms which regulate pHi, so that tumor cells are killed by intracellular acid-induced injury. To investigate the mechanisms by which intracellular acidification leads to cell death, we have studied the roles of the anti-apoptotic gene bcl-2 and its pro-apoptotic binding partner bax, the Stress Activated Protein Kinases (SAPK/JNK), and the caspase proteases in mediating acid-induced cell death. While expression of bcl-2 in human bladder cancer MGH-U1 cells had no effect on acid-induced death, overexpression of bax enhanced cell death, consistent with its pro-apoptotic function. Inhibition of SAPK, through expression of a dominant negative mutant of its activator, SEK1 protected cells from acid-induced cell death. Caspase activation, as measured by poly (ADP-ribose) polymerase cleavage, was absent after lethal intracellular acidification. Consistent with this observation, inhibition of ICE proteases by the peptide z-VAD.fmk did not protect against acid-induced cell killing. We conclude that acid-induced cell death depends on bax and on SAPK signaling pathways but not on the caspase proteases. Therapeutic manipulation of bax and SAPK may enhance acid-induced tumor cell killing.
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PMID:Inhibition of apoptotic signaling pathways in cancer cells as a mechanism of chemotherapy resistance. 977 Jan 20


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