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)

Caspase-2 has been reported to play a role in the cell death observed under a number of different conditions; however, it is unclear whether caspase-2 plays a role in cell death triggered by endoplasmic reticulum (ER) stress. The purpose of this study was to determine whether caspase-2 is involved in SH-SY5Y neuroblastoma cell death caused by thapsigargin-induced ER stress. Thapsigargin treatment (1 microM, 16 hr) stimulated the proteolytic processing of caspases-2, -3, and -7, suggesting that these caspases are activated by ER stress. The role of these caspases in thapsigargin-induced cell death was examined by using cell-permeable caspase inhibitors. In the absence of pretreatment with caspase inhibitors, thapsigargin (0.1 microM, 20 hr) reduced the number of viable cells to 53.9% +/- 3.3% of starting-time control. Pretreatment for 90 min with either the pan-caspase inhibitor Z-VAD-FMK or the caspase-2-selective inhibitor Z-VDVAD-FMK inhibited thapsigargin-stimulated cell death, resulting in the number of viable cells being 115.6% +/- 5.3% (P < 0.001) and 69.3% +/- 2.9% (P < 0.01), respectively, of starting-time control. Neither the caspase-3- and -7-selective inhibitor Z-DEVD-FMK nor the caspase-9-selective inhibitor Z-LEHD-FMK significantly affected thapsigargin-stimulated cell death. An anticaspase-12-reactive protein was also identified in SH-SY5Y cells, but thapsigargin had no effect on proteolysis of this protein. These data demonstrate that caspases-2, -3, and -7 are involved in ER stress-mediated death of SH-SY5Y cells.
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PMID:Caspases-2, -3, and -7 are involved in thapsigargin-induced apoptosis of SH-SY5Y neuroblastoma cells. 1582 94

Caspase-12 is activated when the cells are exposed to excess levels of various stimuli, which cause endoplasmic reticulum (ER) stress. Protein kinase C (PKC) plays an important role in many signaling pathways in cells, and the activation of PKC has multiple actions in the signaling function of the ER. This study examined whether or not phorbol 12, 13-dibutyrate (PDBu)-induced PKC activation modulates caspase-12 cleavage and it's processing, using a wild type caspase-12 overexpressing neuronal cell line, known as Cas-12 cells. The thapsigargin treatment induced caspase-12 fragmentation in the Cas-12 cells. This was inhibited by PKC, which had previously been stimulated by PDBu. The PDBu treatment attenuated the ER stress-induced translocation of caspase-12 from the ER to the cytoplasm. The caspase-3 specific inhibitor blocked caspase-12 fragmentation, and purified caspase-12 was cleaved by the active caspase-3 in vitro, suggesting that caspase-12 might be a substrate for caspase-3. In addition, the PDBu treatment influenced the decrease of active caspase-3 fragment. These results suggest that an ER stress induces the activation of caspase-12 via caspase-3, and that PKC regulates both caspase-12 and caspase-3 activations in Cas-12 cells.
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PMID:ER stress-induced caspase-12 activation is inhibited by PKC in neuronal cells. 1584 1

The mechanism of how fluoride causes fluorosis remains unknown. Exposure to fluoride can inhibit protein synthesis, and this may also occur by agents that cause endoplasmic reticulum (ER) stress. When translated proteins fail to fold properly or become misfolded, ER stress response genes are induced that together comprise the unfolded protein response. Because ameloblasts are responsible for dental enamel formation, we used an ameloblast-derived cell line (LS8) to characterize specific responses to fluoride treatment. LS8 cells were growth-inhibited by as little as 1.9-3.8 ppm fluoride, whereas higher doses induced ER stress and caspase-mediated DNA fragmentation. Growth arrest and DNA damage-inducible proteins (GADD153/CHOP, GADD45alpha), binding protein (BiP/glucose-responsive protein 78 (GRP78), the non-secreted form of carbonic anhydrase VI (CA-VI), and active X-box-binding protein-1 (Xbp-1) were all induced significantly after exposure to 38 ppm fluoride. Unexpectedly, DNA fragmentation increased when GADD153 expression was inhibited by short interfering RNA treatment but remained unaffected by transient GADD153 overexpression. Analysis of control and GADD153(-/-) embryonic fibroblasts demonstrated that caspase-3 mediated the increased DNA fragmentation observed in the GADD153 null cells. We also demonstrate that mouse incisor ameloblasts are sensitive to the toxic effects of high dose fluoride in drinking water. Activated Ire1 initiates an ER stress response pathway, and mouse ameloblasts were shown to express activated Ire1. Ire1 levels appeared induced by fluoride treatment, indicating that ER stress may play a role in dental fluorosis. Low dose fluoride, such as that present in fluoridated drinking water, did not induce ER stress.
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PMID:Fluoride induces endoplasmic reticulum stress in ameloblasts responsible for dental enamel formation. 1584 62

Hepatitis C virus (HCV) core, known to be involved in liver carcinogenesis, is processed in the endoplasmic reticulum (ER). We thus investigated the impact of three HCV core isolates on ER stress, ER calcium signalling and apoptosis. We show that HCV core constructs trigger hyperexpression of Grp78/BiP, Grp 94, calreticulin and sarco/endoplasmic reticulum calcium ATPase, inducing ER stress. By using the ER-targeted aequorin calcium probe, we found that ER calcium depletion follows ER stress in core-expressing cells. HCV core induces apoptosis through overexpression of the CHOP/GADD153 proapoptotic factor, Bax translocation to mitochondria, mitochondrial membrane depolarization, cytochrome c release, caspase-3 and PARP cleavage. Furthermore, reversion of HCV core-induced ER calcium depletion (by transfection of SERCA2) completely abolished mitochondrial membrane depolarization, suggesting that both ER stress (through CHOP overexpression) and calcium signalling play a major role in the HCV core-mediated control of apoptosis. ER stress and apoptosis were also found in a proportion of HCV-full-length replicon-expressing cells and in the liver of HCV core transgenic mice. In conclusion, our data demonstrate that HCV core deregulates the control of apoptosis by inducing ER stress and ER calcium depletion providing new elements to understand the mechanisms involved in HCV-related liver chronic diseases.
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PMID:Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion. 1589 96

The most conspicuous feature in idiopathic parkinsonism is the degeneration of pigmented neurons in the substantia nigra. A major problem for the study of the significance of neuromelanin for the development of parkinsonism is that common experimental animals lack neuromelanin in substantia nigra. The aim of this study was to develop an in vitro model that could be used to study the role of neuromelanin in chemically induced toxicity in dopaminergic cells. Cultured neuron-like PC12 cells were exposed to synthetic dopamine melanin (0-1.0 mg/ml) for 48 h, resulting in uptake of dopamine melanin particles into the cells. The intracellular distribution of dopamine melanin granules was similar to that found in neuromelanin-containing neurons. Dopamine melanin, up to 0.5 mg/ml, had negligible effects on ultrastructure, induction of the endoplasmic reticulum-stress protein glucose regulating protein 78, activation of caspase-3 and cell viability. The decreased cell viability in response to the cytotoxic peptide amyloid-beta25-35 was similar in melanin-loaded cells and in control cells without melanin. The results of the studies suggest that melanin-loaded PC12 cells can serve as an in vitro model for studies on the role of neuromelanin for the toxicity of chemicals, in particular neurotoxicants with melanin affinity, in pigmented neurons.
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PMID:Dopamine melanin-loaded PC12 cells: a model for studies on pigmented neurons. 1602 23

Tunicamycin, an inhibitor of the glycosylation of newly biosynthesized proteins, induces endoplasmic reticulum (ER) stress and subsequent apoptosis, and caspase family proteases are activated during the process of ER stress-mediated apoptosis. In the present study, we showed that thapsigargin (Th), an inhibitor of the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase (SERCA), also induced ER stress-mediated apoptosis, and nerve growth factor (NGF) prevented the apoptosis in PC12 cells. We also found that LY 294002, an inhibitor of phosphatidylinositol 3-kinase (PI 3-K), reduced the survival of cells treated with NGF for 24h in the presence of Th. We discovered that the activities of caspase-3, -9 and -12 were increased time-dependently after the treatment with Th, and NGF suppressed the Th-triggered activation of caspase-3, -9 and -12. LY 294002 diminished the effect of NGF on the inactivation of all these caspases. These results indicate that the NGF-induced PI 3-K signaling pathway prevents Th-triggered ER stress-specific apoptosis via inhibition of caspase-mediated apoptotic signal.
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PMID:NGF-induced phosphatidylinositol 3-kinase signaling pathway prevents thapsigargin-triggered ER stress-mediated apoptosis in PC12 cells. 1609 15

C/EBP-homologous protein (CHOP)/gadd153 (or CHOP) is a transcription factor induced by endoplasmic reticulum (ER) stress. Forcible overexpression of CHOP causes apoptosis in keratinocytes in culture. Here, we asked whether CHOP might be increased in the skin after UVB (280-320 nm) exposure, thus implicating CHOP in sunburn cell (SBC) formation. SKH-1 hairless mice were exposed to a ultraviolet (UV) source (80 mJ per cm2; approximately 74% UVB, approximately 16% UVA), and skin biopsies examined by immunohistology and immunoprecipitation. Compared with non-irradiated epidermis, CHOP expression was significantly increased at 30 min, and reached maximal levels by 24 h. Similar increases in CHOP following UVB exposure were observed in human buttock skin. The time course of CHOP expression preceded SBC formation and another marker of apoptosis, caspase-3 cleavage. Intracellular CHOP accumulated mainly in cytoplasmic and perinuclear locations, with little remaining in the nucleus. To examine mechanisms, cultured keratinocytes were irradiated in vitro and examined by western blotting. Under conditions that eliminated ER stress because of cell handling, CHOP did not accumulate (and was in fact decreased) in the cells. Thus, induction of CHOP in keratinocytes requires factors present only in the native skin. Overall, the data suggest that CHOP participates in adaptive responses of the epidermis following UVB/UVA exposure in vivo.
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PMID:Ultraviolet light (UVB and UVA) induces the damage-responsive transcription factor CHOP/gadd153 in murine and human epidermis: evidence for a mechanism specific to intact skin. 1609 44

The endoplasmic reticulum (ER) is the principal organelle for the biosynthesis of proteins, steroids and many lipids, and is highly sensitive to alterations in its environment. Perturbation of Ca(2+) homeostasis, elevated secretory protein synthesis, deprivation of glucose or other sugars, altered glycosylation and/or the accumulation of misfolded proteins may all result in ER stress, and prolonged ER stress triggers cell death. Studies from multiple laboratories have identified the roles of several ER stress-induced cell-death modulators and effectors through the use of biochemical, pharmacological and genetic tools. In the present work, we describe the role of p23, a small chaperone protein, in preventing ER stress-induced cell death. p23 is a highly conserved chaperone protein that modulates HSP90 activity and is also a component of the steroid receptors. p23 is cleaved during ER stress-induced cell death; this cleavage, which occurs close to the carboxy-terminus, requires caspase-3 and/or caspase-7, but not caspase-8. Blockage of the caspase cleavage site of p23 was associated with decreased cell death induced by ER stress. Immunodepletion of p23 or inhibition of p23 expression by siRNA resulted in enhancement of ER stress-induced cell death. While p23 co-immunoprecipitated with the BH3-only protein PUMA (p53-upregulated modulator of apoptosis) in untreated cells, prolonged ER stress disrupted this interaction. The results define a protective role for p23, and provide further support for a model in which ER stress is coupled to the mitochondrial intrinsic apoptotic pathway through the activities of BH3 family proteins.
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PMID:Coupling endoplasmic reticulum stress to the cell-death program: a novel HSP90-independent role for the small chaperone protein p23. 1619 41

Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis is probably the main form of beta-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and Fas. We review herein the similarities and differences between the mechanisms of beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. IL-1beta and/or TNF-alpha plus IFN-gamma induce beta-cell apoptosis via the activation of beta-cell gene networks under the control of the transcription factors NF-kappaB and STAT-1. NF-kappaB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation of mitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial death signals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-cell dysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dual effects, triggering initially "glucose hypersensitization" and later apoptosis, via different mechanisms. High glucose, however, does not induce or activate IL-1beta, NF-kappaB, or inducible nitric oxide synthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cell apoptosis via ER stress, which is NF-kappaB and NO independent. Thus, cytokines and nutrients trigger beta-cell death by fundamentally different mechanisms, namely an NF-kappaB-dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-kappaB-independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type 1 and type 2 diabetes.
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PMID:Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. 1630 47

myo-Inositol 1,4,5-trisphosphate receptor (IP3R) degradation occurs in response to carbachol (Cch) stimulation of CHO-K1 cells. The response was mediated by endogenous muscarinic receptors and was blocked by atropine or proteasomal inhibitors. We have used these cells to identify the sites of ubiquitination on IP3Rs and study the role of Ca2+ and substrate recognition properties of the degradation system using exogenously expressed IP3R constructs. Employing caspase-3 for IP3R cleavage, we show that Cch promotes polyubiquitination in the N-terminal domain and monoubiquitination in the C-terminal domain. The addition of extracellular Ca2+ to Ca2+-depleted Chinese hamster ovary (CHO) cells initiates IP3R degradation provided Cch is present. This effect is inhibited by thapsigargin. The data suggest that both a sustained elevation of IP3 and a minimal content of Ca2+ in the endoplasmic reticulum lumen is required to initiate IP3R degradation. Transient transfection of IP3R constructs into CHO cells indicated the selective degradation of only the SI+ splice variant of the type I IP3R. This was also the splice form present endogenously in these cells. A pore-defective, nonfunctional SI+ IP3R mutant (D2550A) was also degraded in Cch-stimulated cells. The Cch-mediated response in CHO cells provides a convenient model system to further analyze the Ca2+ dependence and structural requirements of the IP3R proteasomal degradation pathway.
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PMID:Mechanism of proteasomal degradation of inositol trisphosphate receptors in CHO-K1 cells. 1631 91


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