Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The plasma membrane Ca(2+) pump (PMCA) is an essential element in the complex of mechanisms that maintain low intracellular Ca(2+) concentration in the living cell. This pump is tightly regulated by calmodulin through binding to a high affinity calmodulin-binding domain at the C terminus that also serves as an autoinhibitor of the enzyme. Inspection of the C terminus of hPMCA4b, the most widely distributed form of PMCA, revealed a caspase-3 consensus sequence ((1077)DEID(1080)) just a few residues upstream of the calmodulin-binding domain. We demonstrate here that, in the early phase of apoptosis, hPMCA4b is cleaved at aspartic acid Asp(1080) in hPMCA4b-transfected COS-7 cells or in HeLa cells that naturally express this protein. This cleavage of hPMCA4b produces a single 120-kDa fragment that is fully active in the absence of calmodulin, because the whole inhibitory region downstream of the (1077)DEID(1080) sequence is removed. Our experiments show that caspase-3 or a caspase-3-like protease is responsible for the formation of the constitutively active 120-kDa PMCA4b fragment: 1) Pretreatment of the cells with the caspase-3 inhibitor Z-DEVD-FMK (benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone) was able to block the production of the 120-kDa fragment. 2) In vitro treatment of hPMCA4b with recombinant caspase-3 also generated a 120-kDa cleavage product, consistent with that seen in cells undergoing apoptosis. 3) Mutants in which the caspase-3 consensus sequence was altered ((1077)AEID(1080), (1077)DEIA(1080), and (1077)AEIA(1080) mutants) were resistant to proteolysis. Based on these data, we conclude that hPMCA4b is a newly identified, natural caspase-3 substrate. We suggest that a constitutively active form of this protein, responding much faster to an increase in Ca(2+) concentration than the autoinhibited form, may have an important role in regulating intracellular Ca(2+) concentration in the apoptotic cell.
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PMID:Plasma membrane Ca2+ATPase isoform 4b is cleaved and activated by caspase-3 during the early phase of apoptosis. 1175 8

Apoptotic death is known to be an active process requiring the activation of several apoptotic proteins. Depending on the tissue studied and the stimulus used, these processes are distinct. In this work, we studied if there is a putative implication of the p53 and the caspase-3 proteins in kainic acid (KA) and N-methyl-D-aspartic acid (NMDA)-induced apoptosis in organotypic cultures and if there is any relationship between their respective expressions. We found that KA and NMDA both induce apoptosis but only KA-induced apoptosis is p53- and caspase-3-dependent. This demonstrates that KA and NMDA induce apoptosis following different intracellular pathways.
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PMID:Implication of p53 and caspase-3 in kainic acid but not in N-methyl-D-aspartic acid-induced apoptosis in organotypic hippocampal mouse cultures. 1209 86

We recently reported that the T-cell receptor (TCR)-zeta chain is cleaved by caspase-3 and -7 in apoptotic T lymphocytes or in a cell-free system. We report here that the zeta chain is also a direct substrate for granzyme B (GrB) proteolytic activity. Loss in expression of TCR-zeta was observed in Jurkat T leukemic cells treated by a combination of GrB and a replication-deficient adenovirus. Although the apoptosis initiated in these cells by GrB was significantly reduced by the pancaspase inhibitor Z-VAD-FMK, TCR-zeta degradation was not prevented. These findings suggest that the GrB-mediated degradation of TCR-zeta chain can proceed despite the efficient inhibition of caspase activity. An in vitro translated TCR-zeta product was efficiently cleaved by GrB, which suggests that the TCR-zeta protein is a direct substrate for GrB. As assessed by site-directed mutagenesis, the activity of GrB was directed toward aspartic acid residues that were different from those of recombinant caspase-3. Whereas caspase-3 cleavage products appear to accumulate, the GrB-generated products seem to undergo further degradation, which suggests the presence of multiple GrB-specific cleavage sites within the TCR-zeta protein. These findings suggest that the TCR-zeta protein in target T lymphocytes serves as a substrate for the proteolytic activities that are featured by the two major mechanisms of cytotoxicity: death receptor pathways mediated by caspases and granule exocytosis mediated by direct GrB activity or GrB-activated caspases. TCR-zeta protein degradation may be of significance in cytotoxic mechanisms directed against T cells infected with viruses, such as HIV-1, in which the TCR-zeta protein is used for viral pathogenesis.
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PMID:Granzyme B-mediated degradation of T-cell receptor zeta chain. 1220 35

Disintegrins, the snake venom-derived arginine-glycine-aspartic acid-containing peptides, have been demonstrated to inhibit angiogenesis through induction of endothelial cell apoptosis. However, it is not clear how a disintegrin causes endothelial apoptosis. In this study, we elucidated the action mechanism of disintegrin in causing endothelial apoptosis by using rhodostomin as a tool. We showed that cell detachment was observed at the early stage of rhodostomin treatment. It was initiated through the blockade by integrin alphanubeta3 and was accelerated by a mechanical stretch from neighboring cells. Both rhodostomin and poly(HEME) induced a higher percentage of cells at G2-M phase, the cleavage of beta-catenin and poly(ADP-ribose) polymerase during apoptosis, indicating that cell detachment is a prerequisite for rhodostomin-induced apoptosis. Moreover, pp125(FAK) phosphorylation and actin cytoskeleton were affected upon rhodostomin treatment. The activation of caspase-3 but not that of caspase-9 was detected after rhodostomin treatment. In addition, general caspase inhibitors inhibited the cleavage of beta-catenin and poly(ADP-ribose) polymerase, and DNA fragmentation, whereas they did not prevent cell shape change or detachment. According to these results, we concluded that disintegrin-induced endothelial apoptosis is a complex process, not merely caused by a blockade of endothelial integrin alphanubeta3 but also by an accompanied shape change and mechanical stretches among cells.
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PMID:Disintegrin causes proteolysis of beta-catenin and apoptosis of endothelial cells. Involvement of cell-cell and cell-ECM interactions in regulating cell viability. 1272

Transforming growth factor-alpha (TGF-alpha), a ligand of the epidermal growth factor receptor, reduces the infarct size after focal cerebral ischemia in rat, but the molecular basis underlying the protection is unknown. Excitotoxicity and global inhibition of translation are acknowledged to contribute significantly to the ischemic damage. Here we studied whether TGF-alpha can rescue neurons from excitotoxicity in vitro and how it affects calcium homeostasis, protein synthesis, and the associated Akt and extracellular signal-regulated kinase 1/2 (Erk1/2) intracellular signaling pathways in mixed neuron-glia cortical cultures. We found that 100 ng/ml TGF-alpha attenuated neuronal cell death induced by a 30-min exposure to 35 microM N-methyl-D-aspartic acid (NMDA) (as it reduced lactate dehydrogenase release, propidium iodide staining, and caspase-3 activation) and decreased the elevation of intracellular Ca2+ elicited by NMDA. TGF-alpha induced a prompt and sustained phosphorylation of Erk1/2 and prevented the loss of Akt-P induced by NMDA 3 h after exposure. The protective effect of TGF-alpha was completely prevented by PD 98059, an inhibitor of the Erk1/2 pathway. Studies of incorporation of [3H]leucine into proteins showed that NMDA decreased the rate of protein synthesis, and TGF-alpha attenuated this effect. TGF-alpha stimulated the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) but did not affect eIF2 alpha, two proteins involved in translation regulation. PD 98059 abrogated the TGF-alpha effect on eIF4E. Our data demonstrate that TGF-alpha exerts a neuroprotective action against NMDA toxicity, in which Erk1/2 activation plays a key role, and suggest that the underlying mechanisms involve recovery of translation inhibition, mediated at least in part by eIF4E phosphorylation.
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PMID:Transforming growth factor-alpha attenuates N-methyl-D-aspartic acid toxicity in cortical cultures by preventing protein synthesis inhibition through an Erk1/2-dependent mechanism. 1277 Nov 52

Caspase-3 is a cysteinyl protease that mediates apoptotic cell death. Its inhibition may have an important impact in the treatment of several degenerative diseases. Since P(1) aspartic acid is a required element of recognition for this enzyme, a library of capped aspartyl aldehydes was synthesized using solid-phase chemistry. The 5-bromonicotinamide derivative of the aspartic acid aldehyde was identified to be an inhibitor of caspase-3. Substitution at the 5-position of the pyridine ring and conversion of the aldehyde to ketones led to a series of potent inhibitors of caspase-3.
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PMID:Nicotinyl aspartyl ketones as inhibitors of caspase-3. 1279 21

The c-Jun N-terminal kinases (JNKs) are a subfamily of the mitogen-activated protein kinases (MAPKs). The JNKs are encoded by three separate genes (jnk1, jnk2, and jnk3), which are spliced alternatively to create 10 JNK isoforms that are either p46 or p54 in size. In this study, we found that the p52 form of JNK emerged in human leukemia MOLT-4 or U937 cells following X-irradiation or heat treatment. The accumulation of p52 coincided with the reduction of p54 JNK. On the other hand, the amounts of p46 JNK did not change by X-irradiation. Induction of the p52 form of JNK also paralleled the appearance of the active form of caspase-3 and was suppressed by a caspase-specific inhibitor, Ac-DEVD-CHO, but not by Ac-YVAD-CHO. In vitro cleavage assays indicated that recombinant human JNK1beta2 and JNK2beta2 were cleaved by caspase-3, and that the mutation of aspartic acid at position 413 of JNK1beta2 or 410 of JNK2beta2 to alanine abolished the cleavage. Altogether, our results demonstrated that p54 JNKs, at least JNK1beta2 and JNK2beta2, were new selective targets of caspases in JNK splicing variants, and suggested that the p52 form could serve as a marker of apoptosis.
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PMID:Caspase-mediated cleavage of JNK during stress-induced apoptosis. 1282 Nov 18

Apoptosis and necrosis are two distinct forms of cell death that can occur in response to different agents and stress conditions. In order to verify if the oxidative stress induced by dietary selenium and vitamin E deficiencies can lead muscle cells to apoptosis, one-day-old chicks were reared using diets differing in their vitamin E (0 or 10 IU/kg) and selenium (0 or 0.15 ppm) supplementation. Chick skeletal muscle tissue was obtained from 28-day-old animals and used to verify apoptosis occurrence based on caspase activity detection and DNA fragmentation. Antioxidant deficiency significantly increased caspase-like activity assessed by the hydrolysis of fluorogenic peptide substrates (Abz-peptidyl-EDDnp) at lambda exc = 320 nm and lambda em = 420 nm. Proteolytic activation was not accompanied by typical internucleosomal DNA fragmentation detected by field inversion gel electrophoresis. Although the general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone (Z-VAD-fmk) (0 to 80 muM) did not block caspase-like activity when preincubated for 30 min with muscle homogenates, the hydrolyzed substrates presented the same cleavage profile in HPLC (at the aspartic acid residue) when incubated with the purified recombinant enzyme caspase-3. These data indicate that oxidative stress causes caspase-like activation in muscle cells and suggest that cell death associated with exudative diathesis (dietary deficiency of selenium and vitamin E) can follow the apoptotic pathway.
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PMID:Antioxidant dietary deficiency induces caspase activation in chick skeletal muscle cells. 1288 58

During rat estrous cycle, the endometrium proliferates in response to sex steroids and specific endometrial epithelial cells undergo apoptosis in absence of embryonic factors. The central executioner of apoptosis is a family of aspartic acid-specific cysteine proteases known as caspases. Smac/DIABLO is released from the mitochondria during apoptosis and its stimulation promotes caspases activation by neutralizing members of the inhibitor of apoptosis proteins (IAPs) family, such as X-linked inhibitor of apoptosis protein (XIAP). The aim of this study was to investigate the involvement of Smac/DIABLO and XIAP in the control of caspases activation in endometrium of cycling rats. Polyoestrus female rats were sacrificed at each stage of estrous cycle (diestrus, proestrus, estrus, and metestrus). Endometrial protein extracts were collected to perform Western Blot analysis. Alternatively, uterine horns were sectioned for immunohistochemistry (IHC). We and others showed previously the presence of apoptosis at estrus in rat uterine epithelium. In the present study, cleaved caspase-3, -6, and -7 fragments were detected at estrus. IHC confirmed that caspase-3 was present only in luminal and glandular epithelium at estrus. XIAP was highly expressed at estrus in both epithelial and stromal cells. In contrast, expression of Smac/DIABLO was elevated at diestrus, proestrus and metestrus but was minimal at estrus. Treatment of ovariectomized rats with 17beta-estradiol induced XIAP expression and inhibited Smac/DIABLO protein expression in the endometrium. Cleaved caspase-3, -6, and -7 fragments increased in endometrial protein extracts following 17beta-estradiol treatment. Expression of NF-kappaB and IkappaB proteins, and IkappaB phosphorylation status were detected in the endometrium but were not influenced by the estrous cycle. These findings suggest that Smac/DIABLO and XIAP are regulated differently and may play important roles in the regulation of endometrial cell fate. Moreover, this study confirms a key role for executioner caspases in the control of apoptotic processes at estrus in the rat uterus.
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PMID:Opposite regulation of XIAP and Smac/DIABLO in the rat endometrium in response to 17beta-estradiol at estrus. 1296 50

A growing body of evidence indicates that estrogens affect apoptotic processes in neuronal cells. However, their effects seem to depend on type of neuronal tissue, stage of development and apoptosis inducing factors. In the present study we compared effects of estrone (100 and 500 nM) on N-methyl-D-aspartic acid (NMDA) (1 mM)- and staurosporine (1 microM)-induced caspase-3-like activity and lactate dehydrogenase (LDH)-release in primary cultures of rat hippocampal and neocortical neurons. Fluorometric and colorimetric determination of enzyme activity was performed 6 h, 14 h, and 24 h after exposure to apoptotic agents. In the hippocampal cell cultures on 7 days in vitro (DIV), a time-dependent NMDA-induced activation of caspase-3-like proteases was accompanied by increased LDH-release. In neocortical cell cultures on 7 DIV NMDA did not affect caspase activity and decreased LDH-release. In neocortical cell cultures on 12 DIV NMDA inhibited spontaneous caspase activity, but was toxic to neurons after 24 h exposure suggesting that these cells underwent necrotic rather than apoptotic death. Estrone has attenuated both pro- and anti-apoptotic NMDA-induced changes in rat primary neuronal cultures acting independently of estrogen receptors, as detected with ICI 182, 780. In hippocampal neurons estrone antagonized not only the NMDA-induced caspase-3-like activity, but also NMDA-mediated LDH-release. However, in neocortical neurons estrone either attenuated NMDA-induced inhibition of caspase-3-like activity (12 DIV) or partly blocked NMDA-mediated decrease in LDH-release (7 DIV). In contrast to NMDA, staurosporine elevated caspase-3-like activity and LDH-release in a time-dependent manner in all used culture systems. Estrone inhibited pro-apoptotic effects of staurosporine in neocortical neurons, but only at later stage of development in vitro, which points to the protective role of estrogens during the brain tissue maturation. Since estrone triggered its effects via non-genomic mechanisms, it suggests that the other estradiol metabolites exhibiting low affinity to hormone receptors may be potent neuroprotective agents, which could retain the favorable and minimize the adverse side effects of estrogens.
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PMID:Effects of estrone on N-methyl-D-aspartic acid- and staurosporine-induced changes in caspase-3-like protease activity and lactate dehydrogenase-release: time- and tissue-dependent effects in neuronal primary cultures. 1469 58


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