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)

Therapeutic brain irradiation can cause progressive decline in cognitive function, particularly in children, but the reason for this effect is unclear. The study explored whether age-related differences in apoptotic sensitivity might contribute to the increased vulnerability of the young brain to radiation. Postnatal day 1 (P1) to P30 mice were treated with 0-16 Gy whole-body X-irradiation. Apoptotic cells were identified and quantified up to 48 h later using the TdT-UTP nick end-labelling method (TUNEL) and immunohistochemistry for activated caspase-3. The number of neuron-specific nuclear protein (NeuN)-positive and -negative cells were also counted to measure neuronal and non-neuronal cell loss. Significantly greater TUNEL labelling occurred in the cortex of irradiated P1 animals relative to the other age groups, but there was no difference among the P7, P14 and P30 groups. Irradiation decreased the %NeuN-positive cells in the mice irradiated on P1, whereas in P14 animals, irradiation led to an increase in the %NeuN-positive cells. These data demonstrate that neocortical neurons of very young mice are more susceptible to radiation-induced apoptosis. However, this sensitivity decreases rapidly after birth. By P14, acute cell loss due to radiation occurs primarily in non-neuronal populations.
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PMID:Sensitivity to radiation-induced apoptosis and neuron loss declines rapidly in the postnatal mouse neocortex. 1626 58

Apoptosis is a genetically determined cell suicidal program that plays critical roles in many physiological and pathological processes. In this study, we report the cloning and characterization of a novel human gene, nuclear apoptosis-inducing factor 1 (NAIF1), overexpression of which induces apoptosis in cells. Human NAIF1 is located on chromosome 9q34.11 and encodes 327 amino acids with a homeodomain-like region and two nuclear localization signals at its N-terminal region. NAIF1 is conserved across diverse species, including human, mouse, crab-eating macaque, dog, chicken and frog, and shares no obvious homology to any known genes or proteins. Northern blot analysis revealed wide expression of NAIF1 mRNA throughout human tissues. NAIF1 was predominantly localized in the nucleus. Overexpression of NAIF1 inhibited cell growth and induced apoptosis. Furthermore, NAIF1 transfection caused both decreases in mitochondrial membrane potential and caspase-3 activation. In summary, NAIF1 is a nuclear protein that induces apoptosis when overexpressed.
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PMID:Overexpression of the novel human gene, nuclear apoptosis-inducing factor 1, induces apoptosis. 1637 48

Noxa is a pro-apoptotic BH3-only member of the Bcl-2 family of proteins that is up-regulated at a transcriptional level by the nuclear protein p53 in response to cellular stresses such as DNA damage or growth factor deprivation. Noxa is able to interact with anti-apoptotic members of the Bcl-2 family and causes release of cytochrome c into the cytosol, leading to the activation of caspases and induction of apoptosis. Here we demonstrate that MG132, a proteasomal inhibitor, rapidly induces Noxa mRNA and protein in two human cell lines, T/C28a and Saos2. The induction of Noxa is associated with a significant reduction in the number of metabolically active cells over the first 24 h of exposure to MG132 and progressive activation of caspase-3, a hallmark of caspase-dependent apoptosis. Partial rescue of the phenotype is observed when cells are transfected with Noxa siRNA prior to treatment with MG132, indicating functional significance of the induction of Noxa. p53 has previously been shown to be non-functional in the T/C28a cell line and is absent by Western blotting in Saos2 cells, suggesting that the induction of Noxa is through a p53 independent mechanism. Western blotting and confocal microscopy showed that total beta-catenin protein is increased in both cell lines at the time of Noxa induction, with the bulk of the beta-catenin present in the nucleus. Transfection with the Tcf reporter vector pTOPFLASH confirms that treatment with MG132 leads to early increased transcriptional activity of beta-catenin in both T/C28a and Saos2 cells. However, although over-expression of transcriptionally active beta-catenin in T/C28a cells also induced apoptosis through a p53-independent mechanism, the levels of Noxa protein were unchanged, suggesting that beta-catenin mediated signaling and Noxa may play independent roles in MG132 induced apoptosis. In summary, our results demonstrate that MG132 induces the pro-apoptotic protein Noxa via a p53-independent mechanism that leads to caspase-dependent apoptosis. This is the first report showing that treatment with MG132 induces Noxa. This study also provides further evidence for a link between beta-catenin mediated signaling and the induction of apoptosis.
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PMID:MG132 induced apoptosis is associated with p53-independent induction of pro-apoptotic Noxa and transcriptional activity of beta-catenin. 1667 57

Evidence suggests that neurotrophins are essential for the survival and phenotypic maintenance of cholinergic basal forebrain (BF) neurons. We evaluated the pattern of programmed cell death in the BF of the rat during development and after ablations of the cerebral cortex, a major target area and source of neurotrophins for BF neurons. We identified dying cells using the TUNEL (terminal deoxynucleotidyl-transferase-mediated dUTP-biotin nick end labelling) method and confirmed their apoptotic morphology with electron microscopy. Moreover, we demonstrated the expression of the apoptotic marker active caspase-3 in cells with features of apoptosis. TUNEL(+) cells were present in the developing BF during the first two postnatal weeks. Their frequency peaked at postnatal day (P)1 and at P5. TUNEL used in conjunction with immunofluorescence for neuronal nuclear protein (NeuN) showed that, at both peak stages, the majority of apoptotic cells were neurons. Extensive lesions of the cerebral cortex at different ages (P0, P7 and P14) did not induce significant changes in the frequency of apoptotic BF neurons. However, they resulted in alterations in the morphological phenotype of choline acetyltransferase (ChAT)-immunoreactive neurons in the BF, and a reduction in their number which was inversely proportional to the age at which the lesions were performed. We suggest that: (i) apoptosis is temporally coordinated with the morphological and neurochemical differentiation of BF neurons and the establishment of connections with their target areas; and (ii) cortical ablations do not affect the survival of BF neurons, but they influence the phenotype of cholinergic BF neurons.
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PMID:Apoptosis in the rat basal forebrain during development and following lesions of connections. 1690 59

The chick optic tectum displays an alternating pattern of cellular and plexiform layers and at embryonic day (ED) 12 there are mainly four cellular layers: transient cell compartment 3 (TCC3), compartment "h-i-j"(C"h-i-j"), stratum griseum centrale (SGC) and subventricular zone (SvZ). In the present work we characterized the programmed cell death (PCD) of these layers and their vulnerability to acute hypoxia at ED12, and also identified the main cellular type involved in hypoxic cell death. The colocalization of three independent markers of cell degeneration: pyknotic nuclei by Hoechst staining, fragmented DNA by TdT-mediated dUTP nick-end labeling (TUNEL), and presence of active caspase-3 by immunofluorescence, was analyzed in embryos that developed in normoxic conditions (control embryos) and embryos that were subjected to hypoxia (8% O(2)/92% N(2)) for 60 min (hypoxic embryos), followed by 0-12 h of normoxic recovery. In control embryos cell death rate within each layer was constant through time, but there were significant differences (P<0.01) in cell death rates among the different layers. In contrast, in hypoxic embryos, a significant increase (P<0.01) in cell death rate was observed in layers TCC3, C"h-i-j" and SGC. This change was evident only at 6 h post-hypoxia, and at later time points cell death rate was similar to control values. Each of these layers had a different vulnerability to the hypoxic event while the SvZ layer was not affected. In addition, the significant colocalization between the neuron specific nuclear protein (NeuN) and TUNEL signal showed that hypoxia affected primarily neurons. In conclusion, our findings demonstrate that in the chick optic tectum at ED12, PCD is layer dependent and that acute hypoxia causes a transient increase in neuronal death in a delayed fashion, which is also layer dependent. The morphological features of the neuronal death process at the light microscope level resembled apoptosis.
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PMID:Acute hypoxia and programmed cell death in developing CNS: Differential vulnerability of chick optic tectum layers. 1690 33

We provide a comprehensive analysis on c-Jun N-terminal kinase (JNK) actions leading to death or differentiation in postnatal hippocampal and cortical neurons. Stimulation with glutamate or 6-hydroxy-dopamine caused activation of caspase-3 and apoptotic neuronal death which were both attenuated by JNK-inhibition. In cortical neurons, stress-induced nuclear JNK distribution was rather complex. We observed a decrease of activated and total JNK in the nucleus after stimulation, but an increase of the phosphorylated transcription factor c-Jun. Isoform-analysis revealed a nuclear translocation of JNK2, while nuclear protein levels of JNK1 decreased. This activation pattern differed from neurite formation. In hippocampal and cortical neurons, JNK activity continuously increased during neuritogenesis, whereas levels of phosphorylated c-Jun gradually declined. Despite these similarities, JNK inhibition by SP600125 only affected neurite outgrowth in hippocampal cells. Furthermore, experiments in JNK-deficient mice demonstrated that all JNK isoforms contributed to neuritogenesis. Summarizing, JNKs are involved in both neuritogenesis and death of primary neurons with differentially regulated nuclear translocation of specific isoforms after degenerative stress, while neuritogenesis is supported by all JNK isoforms.
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PMID:c-Jun N-terminal kinases trigger both degeneration and neurite outgrowth in primary hippocampal and cortical neurons. 1797 77

Methylprednisolone (MP) is used to treat a variety of neurological disorders involving white matter injury, including multiple sclerosis, acute disseminated encephalomyelitis, and spinal cord injury (SCI). Although its mechanism of action has been attributed to anti-inflammatory or antioxidant properties, we examined the possibility that MP may have direct neuroprotective activities. Neurons and oligodendrocytes treated with AMPA or staurosporine died within 24 h after treatment. MP attenuated oligodendrocyte death in a dose-dependent manner; however, neurons were not rescued by the same doses of MP. This protective effect was reversed by the glucocorticoid receptor (GR) antagonist (11, 17)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one (RU486) and small interfering RNA directed against GR, suggesting a receptor-dependent mechanism. MP reversed AMPA-induced decreases in the expression of anti-apoptotic Bcl-x(L), caspase-3 activation, and DNA laddering, suggesting anti-apoptotic activity in oligodendrocytes. To examine whether MP demonstrated this selective protection in vivo, neuronal and oligodendrocyte survival was assessed in rats subjected to spinal cord injury (SCI); groups of rats were treated with or without MP in the presence or absence of RU486. Eight days after SCI, MP significantly increased oligodendrocytes (CC-1-immunoreactive cells) after SCI, but neuronal (neuronal-specific nuclear protein-immunoreactive cells) number remained unchanged; RU486 reversed this protective effect. MP also inhibited SCI-induced decreases in Bcl-x(L) and caspase-3 activation. Consistent with these findings, the volume of demyelination, assessed by Luxol fast blue staining, was attenuated by MP and reversed by RU486. These results suggest that MP selectively inhibits oligodendrocyte but not neuronal cell death via a receptor-mediated action and may be a mechanism for its limited protective effect after SCI.
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PMID:Methylprednisolone protects oligodendrocytes but not neurons after spinal cord injury. 1835 17

Clinical evidence suggests that factors other than cerebral vasospasm, such as delayed neuronal and astrocytic cell death, may play a role in the poor prognosis of patients with subarachnoid hemorrhage (SAH). Here we examined this using immunohistochemistry and confocal microscopy in 3 different brain areas in a dog model of SAH. Using antibodies against neuronal marker neuronal nuclear protein (NeuN) and astrocyte marker glial fibrillary acidic protein (GFAP) in conjunction with apoptosis marker (cleaved caspase-3), we quantified neurons and astrocytes to monitor the degree of apoptosis in both groups. Experimental SAH group showed 44 +/- 1% caspase-3 positive neurons in comparison to the 2.0 +/- 0.1% in the control group (P < 0.001, 6 animals each group). For astrocytes, a total 25 +/- 1% were caspase-3 positive in day 7 SAH group, as compared to 0.40 +/- 0.01% for controls (P < 0.001). Regional analysis revealed that neuronal caspase-3 immunoreactivity in all 3 regions were significantly higher (P < 0.001) in SAH animals than that in the control animals. However, the analysis of total area, size and signal co-localization of GFAP with caspase-3 indicated that astrocytic reactivity and proliferation are seen primarily in the hippocampal area, with the least changes detectable in the brainstem. We conclude that in the dog model, there was a significant increase of neuronal and astrocytic cleaved caspase-3, possibly reflecting apoptosis, following SAH induction. These changes coupled with neurological deterioration seen in patients may present a possible reason for the poor outcome in SAH patients.
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PMID:Neuronal and astrocytic apoptosis after subarachnoid hemorrhage: a possible cause for poor prognosis. 1878 13

Immunohistochemistry for neuron-specific nuclear protein (NeuN), caspase-3, calcitonin gene-related peptide (CGRP), and calcium-binding proteins was performed on the trigeminal ganglion (TG) in wild type and Brn-3a knockout mice at embryonic days 12.5-16.5 (E12.5-E16.5). In Brn-3a knockout mice, the number of NeuN-immunoreactive (ir) neuron profiles increased at E14.5 (40.0% increase) and decreased at E16.5 (28.3% reduction) compared to wild type mice. Caspase-3-ir neuron profiles were abundant in the TG of wild type mice at E12.5-E16.5. However, the loss of Brn-3a decreased the number of caspase-3-ir neuron profiles at E12.5 (69.7% reduction) and E14.5 (51.7% reduction). At E16.5, the distribution of caspase-3-ir neuron profiles was barely affected by the deficiency. CGRP-ir neuron profiles were observed in the TG of wild type mice but not knockout mice at E12.5. At E14.5 and E16.5, CGRP-ir neuron profiles were abundant in both wild type and knockout mice. Calbindin D-28 k (CB)-ir neuron profiles decreased in the TG of mutant mice at E12.5 compared to wild type mice (56.4% reduction). At E14.5, however, Brn-3a deficiency transiently increased CB-ir neuron profiles (169.4% increase as compared to wild type mice). Calretinin (CR)-ir neuron profiles could not be detected in the TG of wild type mice at E12.5-16.5. However, numerous CR-ir neuron profiles transiently appeared in the knockout mouse at E14.5. Parvalbumin (PV)-ir neurons appeared in wild type and knockout mice at E14.5. At this stage, the number of large (>50 mum(2)) PV-ir neuron profiles in knockout mice was fewer than that in wild type mice. The number and cell size of PV-ir neuron profiles were barely affected by the deficiency at E16.5. The present study indicates that the loss of Brn-3a causes increase of TG neurons at E14.5 and decrease of TG neurons at E16.5. It is also suggested that Brn-3a deficiency affects the number and cell size of CGRP- and calcium-binding protein-containing neurons at E12.5 and E14.5. Caspase-3-dependent cell death of CB- and CR-ir neurons may be suppressed by the deficiency at E14.5.
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PMID:Brn-3a deficiency transiently increases expression of calbindin D-28 k and calretinin in the trigeminal ganglion during embryonic development. 1928 86

Structurally diverse small molecules, including 5-(2-benzofuryl)-4-phenyl-1,2,4-triazole-3-thiol (BETT), have been identified via high-throughput screening as activators of caspase-3 in HeLa cell extracts. However, little is known about their mechanism of action. In this study, we investigate how BETT regulates prothymosin alpha (ProT), a nuclear protein previously shown to play essential roles in apoptosis. We first showed that Apaf-1 is the direct target protein of BETT. We further demonstrated that BETT relieved ProT-mediated inhibition of apoptosome formation by blocking the interaction between Apaf-1 and ProT. Using two-dimensional (1)H-(15)N heteronuclear single-quantum correlation (HSQC) experiments, we were also able to examine the interaction between Apaf-1 and (15)N-labeled ProT alpha. Furthermore, we were able to reconstitute the entire caspase-3 activation pathway using purified ProT, Apaf-1, procaspase-9, procaspase-3, Hsp70, cytochrome c, PHAPI, CAS, and regulatory compounds to mimic stress-induced apoptosis in vitro. Together, these studies would lead to novel and specific methods for the prevention, diagnosis, and treatment of human cancer.
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PMID:Novel small molecules relieve prothymosin alpha-mediated inhibition of apoptosome formation by blocking its interaction with Apaf-1. 2012 Oct 50


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