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)

In this paper, we examine the hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxidation, is a key mediator of cell death resulting from beta-amyloid exposure. We revisit the effects of HNE on different neuronal cell types to determine which caspase or caspases are required for HNE-induced death, and to compare these results with the known caspase requirements in other death paradigms. We have previously shown that in a given neuronal cell type different death stimuli can evoke stimulus-specific apoptotic pathways. We now show that HNE treatment of neuronal cells induced dose-dependent death and caspase activity which were blocked by inhibition of caspases. Antisense down-regulation of caspases-3, -7 or -9 provided complete protection from HNE-induced death, as did down-regulation of the caspase regulators APAF-1 and DIABLO. Conversely, this work and our previous studies of three other death paradigms show that caspase-3 is not required for death induced by beta-amyloid, SOD1 down-regulation, or trophic factor deprivation. We also show that HNE accumulated in settings where death does not ensue. We conclude that HNE toxicity is mediated via a caspase-9-dependent pathway but that HNE accumulation need not induce cell death nor is it an obligate mediator of Abeta-induced cell death.
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PMID:Divergence of the apoptotic pathways induced by 4-hydroxynonenal and amyloid beta-protein. 1521 31

Tumorigenic leporipoxviruses encode catalytically inactive homologs of cellular Cu-Zn superoxide dismutase (SOD1). The function of the orthologous myxoma virus M131R and Shope fibroma virus S131R gene products is uncertain, but they inhibit SOD1 activity by a process linked to binding its copper chaperone. Using a superoxide-sensitive dye (hydroethidine), we observed that virus infection increased intracellular superoxide levels in an M/S131R-dependent manner. To see whether this effect promotes infection, we deleted the Shope fibroma virus S131R gene and compared the clinical manifestations of wild-type and mutant virus infections in rabbits. S131RDelta virus produced significantly smaller fibroxanthosarcoma-like growths in vivo and, at a point where these growths were already receding, wild-type infections still showed extensive leukocyte infiltration, necrosis, and fibromatous cell proliferation. Coincidentally, whereas Jurkat cells are protected from mitochondria- and Fas-mediated apoptosis by wild-type myxoma virus in vitro, M131RDelta virus could not block Fas-initiated apoptosis as judged by DNA laddering, terminal deoxynucleotidyltransferase-mediated dUTP-fluorescein nick end labeling, and caspase 3 cleavage assays. These data suggest that tumorigenic poxviruses can modulate intracellular redox status to their advantage to stimulate infected cell growth and inhibit programmed cell death.
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PMID:Tumorigenic poxviruses up-regulate intracellular superoxide to inhibit apoptosis and promote cell proliferation. 1582 94

The primary pathogenic mechanism of amyotrophic lateral sclerosis (ALS) remains largely unclear. We recently observed that motoneuron cell death mediated by G93A or A4V mutant SOD1, causing familial ALS, was related with decrease of survival signals, such as phosphatidylinositol 3-kinase (PI3-K) and Akt, which play a pivotal role in neuronal survival. Using a G93A or A4V mutant SOD1 transfected VSC4.1 motoneuron cells (G93A or A4V cells, respectively), we presently investigated whether PI3-K activator could reduce mutant SOD1-mediated motoneuron cell death. To investigate the effect of PI3-K activator on viability of G93A and A4V cells, these cells were treated with 10, 50 or 100ng/ml PI3-K activator for 24h and viability and intracellular signals, including Akt, glycogen synthase kinase-3 (GSK-3), heat shock transcription factor-1 (HSTF-1), cytosolic cytochrome c, caspase-3 and poly(ADP-ribose) polymerase (PARP), were compared with those without treatment (control). Compared with non-treated control G93A or A4V cells, the PI3-K activator treatment increased their viability by enhancing the survival signals, including pAkt, pGSK-3, and by inhibiting the death signals, including caspase-3 activation and PARP cleavage. These results suggest that PI3-K activator protects G93A or A4V cells from mutant SOD1-mediated motoneuron cell death by both activating survival signals and inactivating death signals.
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PMID:Phosphatidylinositol 3-kinase activator reduces motor neuronal cell death induced by G93A or A4V mutant SOD1 gene. 1599 7

To obtain insight into the morphological and molecular correlates of motoneuron degeneration in amyotrophic lateral sclerosis (ALS) mice that express G93A mutant superoxide dismutase (SOD)1 (G93A mice), we have mapped and characterized 'sick' motoneurons labelled by the 'stress transcription factors' ATF3 and phospho-c-Jun. Immunocytochemistry and in situ hybridization showed that a subset of motoneurons express ATF3 from a relatively early phase of disease before the onset of active caspase 3 expression and motoneuron loss. The highest number of ATF3-expressing motoneurons occurred at symptom onset. The onset of ATF3 expression correlated with the appearance of ubiquitinated neurites. Confocal double-labelling immunofluorescence showed that all ATF3-positive motoneurons were immunoreactive for phosphorylated c-Jun. Furthermore, the majority of ATF3 and phospho-c-Jun-positive motoneurons were also immunoreactive for CHOP (GADD153) and showed Golgi fragmentation. A subset of ATF3 and phosphorylated c-Jun-immunoreactive motoneurons showed an abnormal appearance characterized by a number of distinctive features, including an eccentric flattened nucleus, perikaryal accumulation of ubiquitin immunoreactivity, juxta-nuclear accumulation of the Golgi apparatus and the endoplasmic reticulum, and intense Hsp70 immunoreactivity. These abnormal cells were not immunoreactive for active caspase 3. We conclude that motoneurons in ALS-SOD1 mice prior to their death and disappearance experience a prolonged sick phase, characterized by the gradual accumulation of ubiquitinated material first in the neurites and subsequently the cell body.
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PMID:ATF3 expression precedes death of spinal motoneurons in amyotrophic lateral sclerosis-SOD1 transgenic mice and correlates with c-Jun phosphorylation, CHOP expression, somato-dendritic ubiquitination and Golgi fragmentation. 1626 28

EAAT2 is a high affinity, Na+-dependent glutamate transporter with predominant astroglial localization. It accounts for the clearance of the bulk of glutamate released at central nervous system synapses and therefore has a crucial role in shaping glutamatergic neurotransmission and limiting excitotoxicity. Caspase-3 activation and impairment in expression and activity of EAAT2 are two distinct molecular mechanisms occurring in human amyotrophic lateral sclerosis (ALS) and in the transgenic rodent model of the disease. Excitotoxicity caused by down-regulation of EAAT2 is thought to be a contributing factor to motor neuron death in ALS. In this study, we report the novel evidence that caspase-3 cleaves EAAT2 at a unique site located in the cytosolic C-terminal domain of the transporter, a finding that links excitotoxicity and activation of caspase-3 as converging mechanisms in the pathogenesis of ALS. Caspase-3 cleavage of EAAT2 leads to a drastic and selective inhibition of this transporter. Heterologous expression of mutant SOD1 proteins linked to the familial form of ALS leads to inhibition of EAAT2 through a mechanism that largely involves activation of caspase-3 and cleavage of the transporter. In addition, we found evidence in spinal cord homogenates of mutant SOD1 ALS mice of a truncated form of EAAT2, likely deriving from caspase-3-mediated proteolytic cleavage, which appeared concurrently to the loss of EAAT2 immunoreactivity and to increased expression of activated caspase-3. Taken together, our findings suggest that caspase-3 cleavage of EAAT2 is one mechanism responsible for the impairment of glutamate uptake in mutant SOD1-linked ALS.
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PMID:Caspase-3 cleaves and inactivates the glutamate transporter EAAT2. 1656 4

Recent investigations have indicated that the nucleocytoplasmic transport system is essential for maintaining cell viability and cellular functions and that its dysfunction could lead to certain disorders. To investigate the involvement of this system in the pathomechanisms of amyotrophic lateral sclerosis (ALS), we examined the immunohistochemical localization of proteins associated with nucleocytoplasmic transport in the lumbar spinal cord in a mutant SOD1 (G93A) transgenic mouse model of ALS. This model is widely used for ALS research, and the mutant mice are known to exhibit neuronal loss and Lewy body-like hyaline inclusions (LBHIs) in the anterior horns, similar to the pathology seen in familial ALS patients associated with an SOD1 mutation and in several other transgenic rodent models. Using antibodies against the importin beta family of proteins, the major carrier proteins of nucleocytoplasmic transport, and those against their adapter protein, importin alpha, we found that the immunoreactivities were decreased within the nuclei and increased within the cytoplasm of a subset of the surviving anterior horn cells of the transgenic mice. In addition, LBHIs were invariably reactive toward these antibodies. Furthermore, the immunoreactivities for histone H1 and beta-catenin, representative cargo proteins transported by importin beta-dependent and beta-independent nucleocytoplasmic transport pathways, respectively, showed distributions similar to those for importin beta family and importin alpha proteins. The altered distributions of these proteins were not associated with caspase-3 expression, suggesting that the findings are unlikely to be a manifestation of apoptotic processes. Chronological quantitative analysis of importin beta-immunostained sections from the transgenic mice revealed a statistically significant progressive decrease in the proportion of the anterior horn cells exhibiting a more intense reactivity for these proteins in the nucleus than in the cytoplasm. To the contrary, we found that the anterior horn cells with the immunoreactivity in their cytoplasm, being more pronounced than that in their nucleus, were significantly increased in number along with the disease progression. This is the first report investigating nucleocytoplasmic transport in the ALS model mouse, and our present results imply that its dysfunction could be involved in the pathomechanisms underlying ALS.
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PMID:Altered distributions of nucleocytoplasmic transport-related proteins in the spinal cord of a mouse model of amyotrophic lateral sclerosis. 1695 27

The purpose of this study is to evaluate neuroprotective effects of (-)-Epigallocatechin-3-gallate (EGCG) in a transgenic mouse model of Amyotrophic lateral sclerosis (ALS). SOD1-G93A transgenic mice and wild-type mice were randomly divided into EGCG-treated groups (10 mg/kg, p.o) and vehicle-treated control groups. Rotarod measurement was performed to assess the motor function of mice starting at the age of 70 days. Nissl staining to examine the number of motor neurons and CD11b immunohistochemical staining to evaluate activation of microglia in the lumbar spinal cords were conducted at the age of 120 days. In addition, for further observation of regulation of cell signaling pathways by EGCG, we used immunohistochemical analysis for nuclear factor kappa B (NF-kappaB) and cleaved caspase-3 as well as western blot analysis to determine the expression of nitric oxide synthase (iNOS) and NF-kappaB in the spinal cord. This study demonstrated that oral administration of EGCG beginning from a pre-symptomatic stage significantly delayed the onset of disease, and extended life span. Furthermore, EGCG-treated transgenic mice showed increased number of motor neurons, diminished microglial activation, reduced immunohistochemical reaction of NF-kappaB and cleaved caspase-3 as well as reduced protein level of iNOS and NF-kappaB in the spinal cords. In conclusion, this study provides further evidences that EGCG has multifunctional therapeutic effects in the mouse model of ALS.
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PMID:Neuroprotective effects of (-)-epigallocatechin-3-gallate in a transgenic mouse model of amyotrophic lateral sclerosis. 1702 48

There is increasing evidence showing dual functions of antioxidant enzymes in coping with reactive oxygen species (ROS) versus reactive nitrogen species (RNS). The objective of this study was to compare the impacts of knockout of Cu, Zn-superoxide dismutase (SOD1) and Se-dependent glutathione peroxidase-1 (GPX1) on cell death and related signaling mediated by acetaminophen (APAP), a RNS inducer in liver. Two groups of young adult knockout mice (SOD1(-/-) and GPX1(-/-)), along with their wild types (WT), were killed 5 hrs after an ip injection of saline or APAP (300 mg/kg body wt). While the WT mice showed more hepatic necrosis and DNA breakage than the GPX1(-/-) mice, the SOD1(-/-) mice had essentially no positive response compared with their saline-injected controls. The APAP treatment activated liver c-jun N-terminal kinase (JNK) in the WT and GPX1(-/-) mice, but not in the SOD1(-/-) mice. The APAP-induced changes in other cell death-related signal proteins such as p21, caspase-3, and poly(ADP-ribose) polymerase (PARP) also were obviated in the SOD1(-/-) mice. In conclusion, knockout of GPX1 did not potentiate APAP-induced cell death and related signaling, whereas the SOD1 null blocked APAP-induced hepatic JNK phosphorylation and cell death.
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PMID:Impact of Cu, Zn-superoxide dismutase and Se-dependent glutathione peroxidase-1 knockouts on acetaminophen-induced cell death and related signaling in murine liver. 1713 59

The mechanism of selective and age-dependent motor neuron degeneration in human amyotrophic lateral sclerosis (ALS) has not been defined and the role of glutathione (GSH) in association with motor neuron death remains largely unknown. A motor neuron-like cell culture system and a transgenic mouse model were used to study the effect of cellular GSH alteration on motor neuron cell death. Exposure of NSC34 motor neuron-like cells to ethacrynic acid (EA) or l-buthionine sulfoximine (BSO) dramatically reduced the cellular GSH levels, and was accompanied by increased production of reactive oxygen species (ROS) measured by the dichlorofluorescin (DCF) fluorescent oxidation assay. In addition, GSH depletion enhanced oxidative stress markers, AP-1 transcriptional activation, c-Jun, c-Fos and heme oxygenase-1 (HO-1) expression in NSC34 cells analyzed by a luciferase reporter, Western blotting and quantitative PCR assays respectively. Furthermore, depletion of GSH decreased mitochondrial function, facilitated apoptosis inducing factor (AIF) translocation, cytochrome c release, and caspase 3 activation, and consequently led to motor neuron-like cell apoptosis. In an ALS-like transgenic mouse model overexpressing mutant G93A-Cu, Zn-superoxide dismutase (SOD1) gene, we showed that the reduction of GSH in the spinal cord and motor neuron cells is correlated with AIF translocation, caspase 3 activation, and motor neuron degeneration during ALS-like disease onset and progression. Taken together, the in vitro and in vivo data presented in the current report demonstrated that decreased GSH promotes multiple apoptotic pathways contributing, at least partially, to motor neuron degeneration in ALS.
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PMID:Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo. 1715 Mar 7

In this work, we have investigated the effects of nutritional antioxidants as antidegenerative agents on glutamate-induced apoptosis in primary cultures of cerebellar granule neurons (CGNs). Glutamate-induced apoptosis is also associated with intracellular [Ca(2+)]i overload, generation of reactive oxygen species (ROS), depression of cell energy metabolism, cytochrome c release, and increase in caspase-3 activity. Pretreatment (3 h) with red wine extract (5 microg/mL) and ascorbic acid (30 microM) blocks glutamate-induced apoptosis in CGNs. In vivo experiments carried out on transgenic mice expressing the human mutated Cu, Zn superoxide dismutase (SOD1) G93A (mSOD1(G93A)) show that mice fed with lyophilized red wine have significantly increased survival as compared to control, untreated animals.
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PMID:Red wine extract prevents neuronal apoptosis in vitro and reduces mortality of transgenic mice. 1726 57


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