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: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Caspases plays a key role in the execution phase of apoptosis. "Initiator" caspases, such as caspase-8, activate "effector" caspases, such as caspase-3 and -7, which subsequently cleave cellular substrates thereby precipitating the dramatic morphological changes of apoptosis. Following treatment of mice with an agonistic anti-Fas antibody to induce massive hepatocyte apoptosis, we now demonstrate a distinct subcellular localization of the effector caspases-3 and -7. Active caspase-3 is confined primarily to the cytosol, whereas active caspase-7 is associated almost exclusively with the mitochondrial and microsomal fractions. These data suggest that caspases-3 and -7 exert their primary functions in different cellular compartments and offer a possible explanation of the presence of caspase homologs with overlapping substrate specificities. Translocation and activation of caspase-7 to the endoplasmic reticulum correlates with the proteolytic cleavage of the endoplasmic reticular-specific substrate, sterol regulatory element-binding protein 1. Liver damage, induction of apoptosis, activation and translocation of caspase-7, and proteolysis of sterol regulatory element-binding protein 1 are all blocked by the caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD. fmk). Our data demonstrate for the first time the differential subcellular compartmentalization of specific effector caspases following the induction of apoptosis in vivo.
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PMID:Different subcellular distribution of caspase-3 and caspase-7 following Fas-induced apoptosis in mouse liver. 955 51

Thymocytes expressing self-reactive T-cell receptors (TCR) are eliminated in the thymus through a TCR-mediated signal. This cell death signal (negative selection) generates nuclear morphological change and DNA fragmentation in thymocytes. However, the pathway leading to DNA fragmentation of thymocytes following TCR engagement remains obscure. In this study, we investigated the localization and function of caspase-activated DNAse (CAD) and its inhibitor (ICAD) in thymocytes prior to or after in vivo TCR stimulation. We showed that CAD and ICAD are co-localized in microsome, nuclei and cytosol in unstimulated thymocytes. Following in vivo TCR engagement, ICAD located in cytosol and microsome was degraded and the resulting activated CAD induced chromosomal DNA fragmentation. CAD present in cytosol and microsome of unstimulated thymocytes was activated by recombinant caspase-3, and microsomal CAD was released to the cytosol. These results demonstrate that TCR engagement of thymocytes induces caspase-3-dependent activation of CAD localized in both cytosol and microsome, leading to DNA fragmentation in harmony.
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PMID:The regulation of DNAse activities in subcellular compartments of activated thymocytes. 1198 60

Regardless of the existence of ceramide-related molecules, such as sphingomyelin (SM), neutral sphingomyelinase (nSMase), and SM synthase, in the nucleus, the regulation of ceramide in the nucleus is poorly understood in stress-induced apoptosis. In Fas-induced Jurkat T-cell apoptosis, we found a time- and dose-dependent increase of ceramide content in the nuclear and microsomal fractions. Fas-induced increase of ceramide content in the nucleus also was detected by confocal microscopy using anticeramide antibody. Activation of nSMase and inhibition of SM synthase were evident in the nuclear fraction after Fas cross-linking, whereas nSMase was activated, but SM synthase was not affected, in the microsomal fraction. Pretreatment with D-609, a putative SM synthase inhibitor, enhanced Fas-induced increase of ceramide in the nucleus and induction of apoptosis along with increase of Fas-induced inhibition of nuclear SM synthase. Fas-induced activation of caspase-3 was detected in the nuclear fraction and in whole cell lysate. A caspase-3 inhibitor, acetyl-Asp-Glu-Val-Asp-chloromethyl ketone, blocked not only Fas-induced increases of apoptosis and ceramide content but also Fas-induced activation of nSMase and inhibition of SM synthase in the nuclear fraction. Taken together, it is suggested that the nucleus is a site for ceramide increase and caspase-3 activation in Fas-induced Jurkat T-cell apoptosis and that caspase-3-dependent regulation of the "SM cycle" consisting of nSMase and SM synthase plays a role in Fas-induced ceramide increase in the nucleus.
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PMID:Increase of nuclear ceramide through caspase-3-dependent regulation of the "sphingomyelin cycle" in Fas-induced apoptosis. 1487 31

It has been reported that two inducible prostaglandin synthetic enzymes, cylooxygenase-2 (COX-2) and microsomal PGE synthase, are over-expressed in non-small cell lung cancer (NSCLC). Using quantitative reverse transcription-polymerase chain reaction, we analyzed RNA levels of the key prostaglandin catabolic enzyme, NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH), in 19 pairs of NSCLC tumors and adjacent non-malignant tissue from the same patient. We found that 100% of tumor-tissue pairs showed at least a 2-fold decrease and 61% showed a 10-fold decrease. This suggests that the increased expression of COX-2 and PGE synthase in tumors may work in concert with the decreased expression of 15-PGDH to amplify an increase in tissue levels of proliferative PGE2. To further explore if 15-PGDH is related to tumorigenesis, athymic nude mice were injected with control A549 cells or cells transiently over-expressing wild-type or mutant 15-PGDH (Y151F). It was found that mice injected with control A549 cells or with cells expressing mutant enzyme produced tumors normally. However, mice injected with A549 cells expressing wild-type 15-PGDH had a significant decrease in tumor growth. Examining the effects of 15-PGDH expression on cellular changes in A549 cells, we found that over-expression of 15-PGDH induced apoptosis of A549 cells as evidenced by fragmentation of DNA, activation of pro-caspase 3, cleavage of poly(ADP-ribose) polymerase and decreased expression of Bcl-2. We also found that the expression of 15-PGDH was negatively related to that of pro-adhesive and invasive CD44. Furthermore, the expression of 15-PGDH was found to be stimulated by hyaluronidase. These results suggest that 15-PGDH may decrease the level of proliferative PGE2, induce apoptosis and function like a tumor suppressor.
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PMID:NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer. 1535 36

This study evaluated the biologic activity of epicatechin gallate (ECG), a polyphenol in tea, to carcinoma HSC-2 cells and normal HGF-2 fibroblasts cells from the human oral cavity. The relative cytotoxicity of ECG, as compared to five other polyphenols in tea, was evaluated. For the HSC-2 carcinoma cells, ECG, catechin gallate (CG), and epigallocatechin gallate (EGCG) grouped as highly toxic, epigallocatechin (EGC) as moderately toxic, and catechin (C) and epicatechin (EC) as least toxic. For the HGF-2 fibroblasts, ECG and CG grouped as highly toxic, EGCG as moderately toxic, and EGC, C, and EC as least toxic. The cytotoxic effects of the polyphenols were more pronounced to the carcinoma, than to the normal, cells. The addition of ECG to cell culture medium led to the generation of hydrogen peroxide (H2O2). However, ECG, as compared to EGCG, was a poor generator of H2O2 and, hence, the cytotoxicity of ECG was unaffected by the presence of the antioxidants, N-acetyl cysteine and glutathione, and catalase. The cytotoxicity of ECG was unaffected by a metabolic activating system, i.e., a hepatic microsomal S-9 mix. DNA fragmentation, caspase-3 activity, and nuclear staining, both with acridine orange and the TUNEL procedure, were used to assess ECG-induced apoptosis. ECG induced apoptosis in the carcinoma HSC-2 cells, but not in the normal HGF-2 fibroblasts. This research supports those studies suggesting that tea green is an effective chemopreventive agent of oral carcinoma.
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PMID:Differential in vitro cytotoxicity of (-)-epicatechin gallate (ECG) to cancer and normal cells from the human oral cavity. 1564 37

Apoptosis signaling pathways are implicated in the pathogenesis of temporal lobe epilepsy (TLE), but the role of endoplasmic reticulum (ER) stress and ER-localized apoptosis signaling components remains largely unexplored. Presently, we investigated ER stress and ER localization of proapoptotic Bcl-2 family members and initiator and effector caspases in resected hippocampus from patients with intractable TLE and compared findings with autopsy controls. Hippocampal immunoreactivity for KDEL (Lys-Asp-Glu-Leu), a motif in ER stress chaperones glucose-regulated proteins 78 and 94, and calnexin, was significantly higher in TLE hippocampus compared with controls. The ER-containing microsomal fraction in control brain contained Bid, Bim, and caspase 3, whereas Bad and caspases 6, 7, and 9 were very low or absent. In contrast, caspases 6, 7, and 9 were present within the microsomal fraction of TLE brain. Furthermore, cleaved caspases 7 and 9 were detected in TLE samples but not controls, and KDEL-expressing neurons coexpressed cleaved caspase 9. Potentially adaptive changes were also detected, including lowered Bim levels in this fraction, and binding of caspase 7 to the X-linked inhibitor of apoptosis protein. These data suggest seizures may induce ER stress and trigger proapoptotic signaling pathways in the ER that are counteracted by antiapoptotic signals in chronic human TLE.
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PMID:Endoplasmic reticulum stress and apoptosis signaling in human temporal lobe epilepsy. 1665 83

Apoptosis plays a key role in the maintenance of a constant cell number and a low incidence of cancer in the mucosa of the intestine. Although the small GTPase Rac1 has been established as an important regulator of migration of intestinal epithelial cells, whether Rac1 is also involved in apoptosis is unclear. The present study tested the hypothesis that Rac1 mediates TNF-alpha-induced apoptosis in IEC-6 cells. Rac1 is activated during TNF-alpha-induced apoptosis as judged by the level of GTP-Rac1, the level of microsomal membrane-associated Rac1, and lamellipodia formation. Although expression of constitutively active Rac1 does not increase apoptosis in the basal condition, inhibition of Rac1 either by NSC-23766 (Rac1 inhibitor) or expression of dominant negative Rac1 protects cells from TNF-alpha-induced apoptosis by inhibiting caspase-3, -8, and -9 activities. Inhibition of Rac1 before the administration of apoptotic stimuli significantly prevents TNF-alpha-induced activation of JNK1/2, the key proapoptotic regulator in IEC-6 cells. Inhibition of Rac1 does not modulate TNF-alpha-induced ERK1/2 and Akt activation. Inhibition of ERK1/2 and Akt activity by U-0126 and LY-294002, respectively, increased TNF-alpha-induced apoptosis. However, inhibition of Rac1 significantly decreased apoptosis in the presence of ERK1/2 and Akt inhibitors, similar to the effect observed with NSC-23766 alone in response to TNF-alpha. Thus, Rac1 inhibition protects cells independently of ERK1/2 and Akt activation during TNF-alpha-induced apoptosis. Although p38 MAPK is activated in response to TNF-alpha, inhibition of p38 MAPK did not decrease apoptosis. Rac1 inhibition did not alter p38 MAPK activity. Thus, these results indicate that Rac1 mediates apoptosis via JNK and plays a key role in proapoptotic pathways in intestinal epithelial cells.
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PMID:Rac1 mediates intestinal epithelial cell apoptosis via JNK. 1679 28

Chronic alcohol abuse, a major health problem, causes liver and pancreatic diseases and is known to impair hepatic alcohol dehydrogenase (ADH). Hepatic ADH-catalyzed oxidation of ethanol is a major pathway for the ethanol disposition in the body. Hepatic microsomal cytochrome P450 (CYP2E1), induced in chronic alcohol abuse, is also reported to oxidize ethanol. However, impaired hepatic ADH activity in a rat model is known to facilitate a nonoxidative metabolism resulting in formation of nonoxidative metabolites of ethanol such as fatty acid ethyl esters (FAEEs) via a nonoxidative pathway catalyzed by FAEE synthase. Therefore, the metabolic basis of ethanol-induced cytotoxicity was determined in HepG2 cells and recombinant HepG2 cells transfected with ADH (VA-13), CYP2E1 (E47) or ADH + CYP2E1 (VL-17A). Western blot analysis shows ADH deficiency in HepG2 and E47 cells, compared to ADH-overexpressed VA-13 and VL-17A cells. Attached HepG2 cells and the recombinant cells were incubated with ethanol, and nonoxidative metabolism of ethanol was determined by measuring the formation of FAEEs. Significantly higher levels of FAEEs were synthesized in HepG2 and E47 cells than in VA-13 and VL-17A cells at all concentrations of ethanol (100-800 mg%) incubated for 6 h (optimal time for the synthesis of FAEEs) in cell culture. These results suggest that ADH-catalyzed oxidative metabolism of ethanol is the major mechanism of its disposition, regardless of CYP2E1 overexpression. On the other hand, diminished ADH activity facilitates nonoxidative metabolism of ethanol to FAEEs as found in E47 cells, regardless of CYP2E1 overexpression. Therefore, CYP2E1-mediated oxidation of ethanol could be a minor mechanism of ethanol disposition. Further studies conducted only in HepG2 and VA-13 cells showed lower ethanol disposition and ATP concentration and higher accumulation of neutral lipids and cytotoxicity (apoptosis) in HepG2 cells than in VA-13 cells. The apoptosis observed in HepG2 vs. VA-13 cells incubated with ethanol appears to be mediated by release of mitochondrial cytochrome c via activation of caspase-9 and caspase-3. These results strongly support our hypothesis that diminished hepatic ADH activity facilitates nonoxidative metabolism of ethanol and the products of ethanol nonoxidative metabolism cause apoptosis in HepG2 cells via intrinsic pathway.
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PMID:Metabolic basis of ethanol-induced cytotoxicity in recombinant HepG2 cells: role of nonoxidative metabolism. 1680 43

Although augmented prostaglandin E(2) (PGE(2)) synthesis and accumulation have been demonstrated in the lesion sites of rodent transient focal ischemia models, the role of PGE(2) in neuronal survival has been controversial, showing both protective and toxic effects. Here we demonstrate the induction of microsomal PGE synthase 1 (mPGES-1), an inducible terminal enzyme for PGE(2) synthesis, in neurons, microglia, and endothelial cells in the cerebral cortex after transient focal ischemia. In mPGES-1 knockout (KO) mice, in which the postischemic PGE(2) production in the cortex was completely absent, the infarction, edema, apoptotic cell death, and caspase-3 activation in the cortex after ischemia were all reduced compared with those in wild-type (WT) mice. Furthermore, the behavioral neurological dysfunctions observed after ischemia in WT mice were significantly ameliorated in KO mice. The ameliorated symptoms observed in KO mice after ischemia were reversed to almost the same severity as WT mice by intracerebroventricular injection of PGE(2) into KO mice. Our observations suggest that mPGES-1 may be a critical determinant of postischemic neurological dysfunctions and a valuable therapeutic target for treatment of human stroke.
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PMID:Microsomal prostaglandin E synthase-1 is a critical factor of stroke-reperfusion injury. 1686 2

We have demonstrated a direct association between alpha5beta1 integrin and caspase 3, both pro- and mature enzyme, in various sub-cellular compartments of rat fibroblasts undergoing anoikis. Integrin associated caspase 3 showed high activity in the plasma membranes, whereas in the cytosol and microsomal fraction it showed little or no activity. Our results suggest a possible role for recycled un-ligated alpha5beta1 integrin molecules between cytosol and plasma membrane, in regulation of caspase-3 activity and induction of cell death in adhesion-deprived cells.
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PMID:Direct association between caspase 3 and alpha5beta1 integrin and its role during anoikis of rat fibroblasts. 1690 43


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