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)

Treatment with NGF causes long-term cultures of oligodendrocytes to die via a yet undefined mechanism mediated by the p75 neurotrophin receptor. The p75 receptor belongs to the TNF receptor superfamily of molecules, which includes Fas and p55 TNF receptors. The Fas and TNF receptors use adaptor molecules to recruit and activate caspase-8 to the receptor. Using a combination of immunohistochemical and Western blotting assays, we have examined caspase activity during NGF-induced apoptosis. Interestingly, although caspase-1 [interleukin-1beta-converting enzyme (ICE)], caspase-2, caspase-3, and caspase-8 were expressed in oligodendrocytes, only caspase-1, -2, and -3 were activated after NGF treatment, whereas caspase-8 was not. These data suggest that the mechanism of apoptosis by NGF through the p75 receptor is different from TNF and Fas-mediated killing. gamma Radiation of oligodendrocytes also activated a similar subset of caspases as NGF, indicating that NGF-induced oligodendrocyte apoptosis uses a similar cell death execution mechanism as injury models. This consolidates a potential role of the p75 neurotrophin receptor during stress and inflammatory conditions.
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PMID:Oligodendrocyte apoptosis mediated by caspase activation. 1019 21

Tumor necrosis factor (TNF)alpha is considered to play a key pathogenetic role in inflammatory bowel diseases. In this study we analyzed the mechanisms by which TNFalpha induces intestinal epithelial cell apoptosis. TNFalpha alone, and more potently in combination with IFNgamma, induced a high degree of IEC-6 cell apoptosis. This effect was more than 100-fold stronger if both of the TNF-R were stimulated, compared to stimulation of the p55-TNF-R alone, indicating an important apoptosis enhancing effect of the p75-TNF-R. TNFalpha-induced apoptosis required activation of ICE caspases and was completely abolished by its inhibitor, zVAD-fmk. Specific inhibition of caspase-3 with zDEVD-fmk did not alter the effect of TNFalpha. Western blot analyses confirmed that caspase-3 was not activated in response to TNFalpha. In the presence of complete inhibition of the caspase cascade with zVAD-fmk (>/=50 microM), TNFalpha induced cell necrosis rather than apoptosis. Our data reveal that TNFalpha can trigger enterocyte cell death via apoptosis or necrosis, depending upon the activation or blockade of specific caspases.
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PMID:TNFalpha-induced IEC-6 cell apoptosis requires activation of ICE caspases whereas complete inhibition of the caspase cascade leads to necrotic cell death. 1038 60

Several models of tumor necrosis factor (TNF)/TNF-receptor 1 (TNF-R1)-dependent liver injury in mice were investigated with respect to caspase-3-like protease activation representing a pivotal mechanism of apoptotic cell death. Injection of TNF or T-cell-activating agents (i.e., agonistic anti-CD3 antibody or staphylococcal enterotoxin B [SEB]) into galactosamine (GalN)-sensitized mice caused TNF/TNF-R1-dependent liver injury. Intravenous concanavalin A (Con A) alone induced TNF-mediated hepatotoxicity dependent on both TNF-R1 and TNF-R2. Hepatic caspase-3-like proteases were activated in GalN/TNF, GalN/anti-CD3, or GalN/SEB-treated mice, but not in Con A-treated mice. Consistently, the broad-spectrum caspase inhibitor, benzoyloxycarbonyl-val-ala-asp-fluoromethylketone (zVADfmk), prevented TNF-mediated hepatotoxicity in all GalN-dependent models, but failed to protect against Con A. Under transcriptional arrest, however, Con A induced TNF-R1-dependent, but not TNF-R2-dependent, activation of caspase-3-like proteases, and zVADfmk prevented animals from Con A-mediated liver injury under this condition. Histological analysis revealed distinct differences between Con A- and GalN/Con A-induced liver injury regarding apoptotic morphology of hepatocytes. We conclude that impaired transcription induces a switch of Con A hepatotoxicity toward a caspase-3-like protease-dependent pathway. The observation that the functional state of the transcriptional machinery decides whether TNF-driven hepatocyte apoptosis involves activation of caspase-3-like proteases or alternative signaling pathways in vivo might be of relevance for the immunopathology of the liver.
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PMID:Concanavalin A hepatotoxicity in mice: tumor necrosis factor-mediated organ failure independent of caspase-3-like protease activation. 1053 46

Neuronal survival during the developmental period of naturally occurring cell death is mediated through a successful competition for limiting concentrations of neurotrophic factors, and the deprived neurons will die. New results show that induced death through the p75 neurotrophin receptor (p75(NTR)), a member of the p55TNF/Fas family of cell death receptors, may also influence survival during development. We find that eliminating p75(NTR) or neurotrophin 4 (NT4) in mice leads to a marked attenuation of apoptosis during the programmed cell death period of the trigeminal ganglion neurons, suggesting that NT4 can induce the death of these neurons through the p75(NTR). These in vivo findings were reproduced in primary cell cultures, where NT4 was found to induce death in a p75(NTR)-dependent pathway. Analysis of p75 deficient and wild-type cells revealed two separate cell death pathways, a p75(NTR)- and caspase-3-independent pathway activated by trophic factor deprivation, and a p75(NTR)- and caspase-3-dependent pathway initiated by NT4. Crossing in the NT4 null alleles in brain-derived neurotrophic factor (BDNF) null mutant mice led to a rescue of a large proportion of BDNF-dependent neurons from excessive cell death, indicating that trophic factor deprivation is not sufficient for the death of many neurons and that additional death inducing signals might be required. Our results suggest that NT4 competitively signals survival and death of sensory neurons through trkB and p75(NTR), respectively.
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PMID:Attenuation of a caspase-3 dependent cell death in NT4- and p75-deficient embryonic sensory neurons. 1099 52

Estrogen receptors are extensively colocalized with neurotrophins and their receptors in the rodent forebrain. We have shown previously that estrogen increases mRNA and protein expression of the nerve growth factor (NGF)-specific tyrosine kinase receptor, trkA, while decreasing expression of the universal neurotrophin receptor p75. In view of the pro-survival roles described for trks and the context-dependent stimulation of survival and cell death pathways activated by p75, differential regulation of these receptors by estrogen is likely to alter neurotrophin-dependent cell signaling. This hypothesis was tested in vivo, using the rodent olfactory bulb as a model. We found that NGF activated the extracellular signal-regulated protein kinase (ERK) equally in estrogen replaced and hormone-deprived animals. However in the case of c-jun-kinase (JNK), a related MAP kinase, pretreatment with estrogen altered NGF activation of a specific isoform of this protein. Specifically, NGF stimulation did not alter JNK1 or JNK2 activation in the estrogen-deprived condition, but significantly increased JNK2 activation in estrogen-replaced animals. Increased JNK2 phosphorylation in the NGF-injected, estrogen- replaced animals was paralleled by decreased activity of caspase-3, an enzyme required for apoptosis. In view of the disparate roles assigned to JNK, this latter finding suggests that estrogen pretreatment may preferentially direct neurotrophin-dependent JNK activation toward regeneration and plasticity rather than cell death.
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PMID:NGF stimulation increases JNK2 phosphorylation and reduces caspase-3 activity in the olfactory bulb of estrogen-replaced animals. 1135 87

Nerve growth factor (NGF) binds to the TrkA tyrosine kinase and the p75 neurotrophin receptors. Depending upon which receptor is activated, NGF can induce differentiation or apoptosis. C6-2B glioma cells express the p75 receptor, but NGF decreases their growth only when TrkA is introduced (C6trk). It is unclear, however, whether TrkA reduces C6-2B cell growth by apoptosis or differentiation. To examine which mechanisms account for the anti-proliferative effect of NGF in these cells, we first analyzed whether NGF causes apoptosis by flow cytometry, two-site immunoassay and in situ TUNEL. None of these methods indicated that C6trk undergo apoptosis. Additional apoptotic markers, such as Bcl-2, Bax, Bad, p53, caspase 3, and NF-kappaB were also used. C6trk cells exhibited lower levels of Bcl-2 compared with the parental C6 mock cells, but no changes in the levels of other apoptotic proteins. Moreover, NGF increased AP-1 binding activity in C6trk cells, suggesting that NGF may induce differentiation. We then examined whether TrkA changes the glioma phenotype. In C6trk cells, but not in C6mock cells, NGF enhanced the levels of neuron-specific enolase as well as the levels of A2B5 and 2', 3'-cyclic nucleotide 3'-phosphodiesterase, markers for oligodendrocytes, without affecting the expression of other neuronal markers. Our data suggest that the antiproliferative properties of TrkA may rely on its ability to induce differentiation of C6 cells from undifferentiated glioma to oligodendrocytes.
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PMID:TrkA induces differentiation but not apoptosis in C6-2B glioma cells. 1139 88

After injury, the striatum displays several morphologic responses that may play a role in both regenerative and degenerative events. One such response is the de novo expression of the low-affinity p75 neurotrophin receptor (p75(NTR)), a gene that plays critical roles in central nervous system (CNS) cell death pathways. The present series of experiments sought to elucidate the cellular origins of this p75(NTR) response, to define the conditions under which p75(NTR) is expressed after striatal injury, and how this receptor expression is associated with neuronal plasticity. After chemical lesions, by using either the excitotoxin quinolinic acid (QA) or the complex II mitochondria inhibitor 3-nitropropionic acid (3-NP), we compared the expression of the p75(NTR) receptor within the rat striatum at different survival times. Intrastriatal administration of QA between 7 days and 21 days postlesion induced p75(NTR) expression in astrocytes that was preferentially distributed throughout the lesion core. P75(NTR) immunoreactivity within astrocytes was seen at high (100-220 nmol) but not low (50 nmol) QA doses. Seven and 21 days after 3-NP lesions, p75(NTR) expression was present in astrocytes at all doses tested (100-1,000 nmol). However, in contrast to QA, these cells were located primarily around the periphery of the lesion and not within the lesion core. At the light microscopic level p75(NTR) immunoreactive elements resembled vasculature: but did not colocalize with the pan endothelium cell marker RecA-1. In contrast, p75(NTR)-containing astrocytes colocalized with nestin, vimentin, and 5-bromo-2-deoxyuridine, indicating that these cells are newly born astrocytes. Additionally, striatal cholinergic neurons were distributed around the lesion core expressed p75(NTR) 3-5 days after lesion in both QA and 3-NP lesions. These cells did not coexpress the pro-apoptotic degradation enzyme caspase-3. Taken together, these data indicate that striatal lesions created by means of excitotoxic or metabolic mechanisms trigger the expression of p75(NTR) in structures related to progenitor cells. The expression of the p75(NTR) receptor after these chemical lesions support the concept that this receptor plays a role in the initiation of endogenous cellular events associated with CNS injury.
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PMID:Excitotoxic and metabolic damage to the rodent striatum: role of the P75 neurotrophin receptor and glial progenitors. 1189 44

Neurotrophins support neuronal survival and differentiation via Trk receptors, yet can also induce cell death via the p75 receptor. In these studies, we investigated signaling mechanisms governing p75-mediated death of hippocampal neurons, specifically the role of caspases. Although p75 is structurally a member of the Fas/TNFR1 receptor family, caspase-8 was not required for p75-mediated death, unlike other members of this receptor family. In contrast, p75-mediated neuronal death was associated with mitochondrial loss of cytochrome c and required Apaf-1 and caspase-9, -6, and -3. In particular, caspase-6 plays a central role in mediating neurotrophin-induced death, illuminating a novel role for this caspase. Inhibition of DIABLO/Smac, which blocks inhibitor of apoptosis proteins, protected cells from death, whereas simultaneous inhibition of both DIABLO/Smac and MIAP3 allowed trophin-induced death to proceed. In vivo, pilocarpine-induced seizures, previously shown to up-regulate p75 expression and increase neurotrophin production, caused activation of caspase-6 and -3 and cleavage of poly(ADP-ribose) polymerase in p75-expressing hippocampal neurons. In p75(-/-) mice, no activated caspase-3 was detected, and there was a marked reduction in the number of dying neurons after pilocarpine treatment compared with wild type mice. Neurotrophin-induced p75-mediated death is likely to play an important role in mediating neuronal loss consequent to brain injury.
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PMID:Mechanisms of p75-mediated death of hippocampal neurons. Role of caspases. 1209 34

To understand the functional interactions between the TrkA and p75 nerve growth factor (NGF) receptors, we stably transfected LAN5 neuroblastoma cells with an expression vector for ET-R, a chimeric receptor with the extracellular domain of the epidermal growth factor receptor (EGFR), and the TrkA transmembrane and intracellular domains. EGF activated the ET-R kinase and induced partial differentiation. NGF, which can bind to endogenous p75, did not induce differentiation but enhanced the EGF-induced response, leading to differentiation of almost all cells. A mutated NGF, 3T-NGF, that binds to TrkA but not to p75 did not synergize with EGF. Enhancement of EGF-induced differentiation required at least nanomolar concentrations of NGF, consistent with the low-affinity p75 binding site. EGF may induce a limited number of neuronal cells because it also enhanced apoptosis. Both NGF and a caspase inhibitor reduced apoptosis and, thereby, enhanced differentiation. NGF seems to enhance survival through the phosphatidylinositol-3 kinase (PI3K) pathway. Consistent with this hypothesis, Akt, a downstream effector of the PI3K pathway, was hyperphosphorylated in the presence of EGF+NGF. These results demonstrate that TrkA kinase initiates differentiation, and p75 enhances differentiation by rescuing differentiating cells from apoptosis via the PI3K pathway. Even though both EGF and NGF are required for differentiation of LAN5/ET-R cells, only NGF is required for survival of the differentiated cells. In the absence of NGF, the cells die by an apoptotic mechanism, involving caspase-3. An anti-p75 antibody blocked the survival effect of NGF. Brain-derived neurotrophic factor also enhanced cell survival, indicating that in differentiated cells, NGF acts through the p75 receptor to prevent apoptosis.
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PMID:Novel functional interactions between Trk kinase and p75 neurotrophin receptor in neuroblastoma cells. 1250 79

Amyotrophic lateral sclerosis is a lethal neurodegenerative disorder involving motoneuron loss in the cortex, brainstem and spinal cord, resulting in progressive paralysis. Aberrant neurotrophin signalling via the low affinity neurotrophin receptor p75 has been suggested to be involved in the motoneuron death by the activation of apoptotic pathways. In order to investigate the involvement of neurotrophin receptor p75 in the amyotrophic lateral sclerosis related motoneuron degeneration process, we have studied the expression of this receptor in the spinal cord of transgenic mice carrying a mutated human Cu, Zn superoxide dismutase gene. Mutations in the superoxide dismutase gene are one of the genetic causes for familiar amyotrophic lateras sclerosis and human superoxide dismutase-1 transgenic mice develop symptoms and pathology similar to those in human amyotrophic lateras sclerosis. Our study shows that in these mice, spinal motoneurons, which normally do not contain the neurotrophin receptor p75 receptor, express this receptor during the progress of the disease. Expression of the neurotrophin receptor p75 receptor coincides with the expression of activating transcription factor 3, a member of the activating transcription factor/cyclic AMP family of stress transcription factors. Only a minority of these spinal motoneurons actually showed co-expression of neurotrophin receptor p75 with caspase-3 activity, suggesting that expression of the neurotrophin receptor p75 receptor is not directly related to the execution phase of the apoptosis process.
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PMID:Expression of the low affinity neurotrophin receptor p75 in spinal motoneurons in a transgenic mouse model for amyotrophic lateral sclerosis. 1257 11


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