UNIPROT:P42574 - FACTA Search

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

We report here the structure-functional characterization of a novel intronless gene, BRCC2, located on human chromosome 11q24.1. BRCC2 open reading frame (327 bp) codes for an approximately 12-kDa protein (108 amino acids (aa)) localized predominantly in the cytosol and to a lesser extent in the mitochondria. Ectopic expression of BRCC2 cDNA also was found in both the cytosol and mitochondria. Exogenous expression of BRCC2 caused apoptotic cell death in three different cell lines as evidenced by enhanced chromatin condensation, DNA fragmentation, or an enhanced number of cells in the sub-G(1) phase. In human prostate cancer cells (PC-3), BRCC2-induced DNA fragmentation was blocked efficiently by coexpression of the anti-apoptotic molecule, Bcl-X(L). Transient transfection of BRCC2 cDNA into PC-3 cells in the presence of a broad-range caspase inhibitor, Z-VAD-fmk (100 microM, 24 h), abrogated DNA fragmentation. Consistently, BRCC2 expression correlated with the activation of caspase-3 and caspase-9. An N-terminal deletion mutant of BRCC2 (10.2 kDa, Delta1-16 aa) lacking a BH3-like domain (5-12 aa, LPIEGQEI) or BRCC2 containing a mutant BH3-like domain (leucine 5-->glutamate) failed to induce apoptosis, whereas a C-terminal deletion mutant (6.8 kDa, Delta62-108 aa) retained the apoptotic activity comparable to the full-length BRCC2. Finally, the treatment of HeLa cells with doxorubicin or hydrogen peroxide (H(2)O(2)) led to an increase in the mitochondrial (heavy membrane) level of endogenous BRCC2 (doxorubicin (100 ng/ml), 5 h, approximately 2-fold; H(2)O(2) (200 microM), 2 h, approximately 2-fold). These findings demonstrate that BRCC2 functions as a proapoptotic molecule and suggest that BRCC2 induces a caspase-dependent mitochondrial pathway of cell death.
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PMID:BRCC2, a novel BH3-like domain-containing protein, induces apoptosis in a caspase-dependent manner. 1506 58

Oxygen-glucose deprivation (OGD) induced neuron-specific cell death in organotypic hippocampal slice cultures. Neuronal death was first evident in the CA1 region 24 h after the injury as assessed by propidium iodide (PI) labeling, and continued to extend to the CA3/4 region up to 72 h. At 6 days post-OGD, PI labeling was weak and diffuse with no clear demarcation of pyknotic nuclei. To characterize biochemical changes produced by OGD, cellular efflux of three key amino acid neurotransmitters was evaluated. OGD elicited large increases in the release of GABA and aspartate (55- and 4.5-fold increase over basal, respectively), while there were no detectable changes in extracellular glutamate levels. In order to ascertain the existence of the synaptic pool of glutamate, sister cultures were treated with sodium azide. This evoked a strong increase in glutamate release, suggesting the intactness of the glutamate system. Further studies revealed a time-dependent activation of caspase 3 following OGD, shown by immunoblot analysis as well as by confocal laser scanning microscopy. While we did not observe the activation of caspases 1, 2, or 8 in our model, the activation of caspase 9 was evident, peaking at 12 h post-OGD. Despite no apparent increase in glutamate release by ischemic slices, treatment with a N-methyl-D-aspartate (NMDA) antagonist or an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist significantly reduced neuronal death. Furthermore, a pan-caspase inhibitor (zVAD-fmk), but not the caspase 3 inhibitor (DEVD-fmk), provided partial neuroprotection. Inhibition of a Ca(2+)-dependent cysteine protease, calpain, by MDL28170 also elicited partial neuroprotective effects.
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PMID:Spatiotemporal evidence of apoptosis-mediated ischemic injury in organotypic hippocampal slice cultures. 1508 29

N-methyl-d-aspartate (NMDA) subtype of glutamate receptors plays an important role during brain development and receptor activation has been shown to promote neuronal survival. The mechanisms by which NMDA increases neuronal survival are not fully understood. Here, we show that treatment with low concentrations of NMDA upregulates the neuroprotective molecule, X-chromosome-linked inhibitor of apoptosis protein (XIAP) in cultured hippocampal neurons at the post-transcriptional level. In contrast, NMDA treatment decreased mRNA and protein levels of caspase-3 in these neurons. The activation of the caspase-3 was also inhibited by NMDA, and the neurons were more resistant towards death caused by high concentrations of glutamate and staurosporine. Data on cytochrome c release in hippocampal neurons showed that NMDA pretreatment inhibits the mitochondrial pathway of cell death. The results demonstrate that the activation of NMDA receptors induces an anti-apoptotic program in hippocampal neurons that involves mitochondria and alterations of the levels of caspase-3 and XIAP. These findings are of importance for understanding the function of NMDA receptors in the control of neuronal survival during development and in other conditions.
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PMID:Differential regulation of X-chromosome-linked inhibitor of apoptosis protein (XIAP) and caspase-3 by NMDA in developing hippocampal neurons; involvement of the mitochondrial pathway in NMDA-mediated neuronal survival. 1509 30

Although excitotoxic and oxidative stress play important roles in spinal neuron death, the exact mechanisms are not fully understood. We examined cell damage of primary culture of 11 day-old rat spinal cord by addition of glutamate, nitric oxice (NO) or peroxynitrite (PN) with detection of caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) or 72 kDa heat shock protein (HSP72). With addition of glutamate, NOC18 (a slow NO releaser) or PN, immunoreactivity for caspase-3 became stronger in the cytoplasm of large motor neurons in the ventral horn at 6 to 24 hr. TUNEL positive nuclei were found in spinal large motor neurons from 24 h and the positive cell proportion greatly increased at 48 h in contrast to the vehicle. On the other hand, the immunoreactivity of HSP72 in the ventral horn was already positive at 0 h, and gradually decreased in the course of time with glutamate, NOC18 or PN than vehicle treatment. In the dorsal horn, the proportion of caspase-3 positive small neurons greatly increased at 6 to 48 h after addition of glutamate. The present results suggest that both excitotoxic and oxidative stress play important roles in the apoptotic pathway in cultured spinal neurons.
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PMID:Expressions of caspase-3, Tunel, and Hsp72 immunoreactivities in cultured spinal cord neurons of rat after exposure to glutamate, nitric oxide, or peroxynitrite. 1511 Dec 53

Glutamate toxicity causes neuronal death in neurodegenerative diseases; hence, there is a need for therapeutic agents rendering functional neuroprotection. We tested the effects of 17beta-estradiol (estrogen) in rat primary cortical neurons after glutamate exposure. Wright staining and ApopTag assays indicated that 0.5 microM glutamate for 24 hr caused apoptosis. Glutamate-induced apoptosis correlated with upregulation of calpain, a proapoptotic shift in the Bax:Bcl-2 ratio, and increased activation of caspase-3. Pretreatment with 10 nM estrogen prevented apoptosis, attenuated calpain upregulation, shifted the Bax:Bcl-2 ratio toward survival, and decreased caspase-3 activation. Single-cell voltage-clamp techniques were used to record whole-cell currents associated with Na+ channels, N-methyl-D-aspartate receptor channels, and kainate receptor channels. No significant differences were recorded in membrane capacitance at -70 mV in neurons treated with estrogen or estrogen plus glutamate, relative to controls. Notably, no changes in capacitance indicated that neurons treated with estrogen and glutamate did not experience apoptosis-associated cell shrinkage. No membrane potential could be recorded in the neurons treated with glutamate due to apoptosis. All recorded currents were similar in amplitude and activation/inactivation kinetics in control neurons and neurons treated with estrogen plus glutamate. Estrogen thus preserved both neuronal viability and function in this in vitro glutamate toxicity model.
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PMID:17beta-estradiol attenuates glutamate-induced apoptosis and preserves electrophysiologic function in primary cortical neurons. 1513 27

Electrical stimulation (ES) is used after cardiac arrest (CA) for diagnostic and therapeutic purposes. The effects of ES on brain damage induced by hypoxic-ischemic brain injury (HI) has not been investigated. Stimulation of afferent pathways by ES may increase neural injury by releasing excitatory neurotransmitters (glutamate) and thereby exacerbating excitotoxicity. To test this hypothesis, ES was applied to the median nerve (2 h) of adult male Wistar rats after 5 min of asphyxic CA and cardiopulmonary resuscitation. Control animals received no ES. Assessment of neuronal damage in five regions of interest was performed in survivors (ESn=15, Control n=10, Sham n=3) after 48 h using H&E, Cresyl-Violet, and TUNEL stains, and Caspase-3 and activated ERK 1/2 immunohistochemistry. Ratios of injured to normal cells were calculated. Most injury was found in hippocampus and cerebellum. ES animals showed significantly lower injury ratios in bilateral hippocampus as compared with controls (F=20.8, p<0.00001). TUNEL staining, caspase-3 and activated ERK 1/2 showed no differences between groups. It is concluded that ES during the acute phase of HI does not amplify neuronal damage at 48 h, but may have a protective effect that requires further investigation.
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PMID:Effects of somatosensory electrical stimulation on neuronal injury after global hypoxia-ischemia. 1514 5

Insulin-like growth factor I (IGF-I) is currently in clinical trials for treatment of amyotrophic lateral sclerosis (ALS), but little is known about how it promotes the survival of motor neurons. In the current study, we examined IGF-I-mediated neuroprotection in an in vitro model of ALS utilizing enriched cultures of embryonic rat spinal cord motor neurons. IGF-I binds to the IGF-I receptor (IGF-IR) in motor neurons and activates MAPK and the downstream effector of phosphatidylinositol 3-kinase (PI-3K) signaling, Akt. IGF-I:IGF-IR signaling involves phosphorylation of IRS-1 and Shc, but not IRS-2. Glutamate, which is elevated in the cerebrospinal fluid of ALS patients, induced DNA fragmentation and caspase-3 cleavage in the spinal cord motor neurons. These effects of glutamate were blocked by co-treatment with IGF-I. However, a delay of IGF-I treatment for as little as 30 min eliminated its neuroprotective effect. Finally, alone, neither the MAPK pathway inhibitor PD98059 nor the PI-3K inhibitor LY294002 blocked the neuroprotective effect of IGF-I, but both inhibitors together were effective in this regard. These results suggest that the dose and timing of IGF-I administration are critical for producing a neuroprotective effect, and also suggest that both the MAPK and PI-3K/Akt pathways can promote the survival of motor neurons. We discuss our results in terms of novel strategies for ALS therapy.
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PMID:IGF-I prevents glutamate-induced motor neuron programmed cell death. 1519 97

Glutamate can induce neuronal cell death by activating ionotropic glutamate receptors (iGluRs) as well as metabotropic glutamate receptors (mGluRs). In the present study, we investigated whether glutamate induces apoptosis of cultured anterior pituitary cells from female rats. Glutamate (1 mm) significantly reduced the metabolic activity of viable cells and increased the percentage of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells and caspase-3 activity in anterior pituitary cells. The inhibitory effect of glutamate on the viability of anterior pituitary cells was not observed in the presence of [2S]-alpha-ethylglutamic acid (0.75 mm), a specific group II mGluR antagonist. Also, (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG-I; 0.75 mm), a specific group II mGluR agonist, reduced viability and increased the percentage of TUNEL-positive anterior pituitary cells. Group I and III mGluRs and iGluRs agonists failed to modify the metabolic activity of anterior pituitary cells. Glutamate and LCCG-I increased the percentage of TUNEL-positive lactotropes and somatotropes. The subunit mGluR2/3, belonging to group II mGluR, was localized in these cell types. Glutamate increased nitric oxide (NO) synthase (NOS) activity and inducible NOS expression in anterior pituitary cells. N-methyl-l-arginine (NMMA, 0.5 mm), a NOS inhibitor, potentiated the apoptotic effect of glutamate in anterior pituitary cells, indicating that NO may restrain glutamate-induced apoptosis. Incubation of anterior pituitary cells with a cAMP analog (N6, 2'-o-dibutyryladenosine 3', 5'-cyclic monophosphate; 1 mm) attenuated the apoptosis induced by glutamate. Glutamate and LCCG-I decreased prolactin release from anterior pituitary cells. N6, 2'-o-dibutyryladenosine 3', 5'-cyclic monophosphate reversed the inhibitory effect of glutamate on prolactin release, but NMMA failed to modify it. Our data show that glutamate induces apoptosis of lactotropes and somatotropes through group II mGluR activation, probably by decreasing cAMP synthesis.
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PMID:Glutamate induces apoptosis in anterior pituitary cells through group II metabotropic glutamate receptor activation. 1520 12

The serine/threonine kinase, glycogen synthase kinase 3beta (GSK3beta), is abundant in CNS and is neuron specific. GSK3beta plays a pivotal role in the regulation of numerous cellular functions. GSK3beta phosphorylates and thereby regulates many metabolic, signaling, and structural proteins which can influence cell survival. Increased GSK3beta correlates with increased cell death, whereas reduced GSK3beta expression correlates with increased cell survival. We report that the GSK3beta inhibitor Chir025 is neuroprotective in vitro and in vivo. First, Chir025 reduced cultured hippocampal neuron death following glutamate exposure by 15-20% versus vehicle-treated controls. Second, Chir025 significantly reduced cultured cortical neuron death following oxygen-glucose deprivation (OGD) by approximately 50%. Third, Chir025 reduced infarct size following focal cerebral ischemia by nearly 20%. There were no significant differences in the number of TUNEL-positive neurons or in caspase-3 and -9 activities between Chir025- and vehicle-treated rats, although Chir025 elevated cytosolic Bcl-2 expression. These data show that Chir025-mediated inhibition of GSK3beta is neuroprotective and that the mechanism is probably not anti-apoptotic.
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PMID:Glycogen synthase kinase 3beta inhibitor Chir025 reduces neuronal death resulting from oxygen-glucose deprivation, glutamate excitotoxicity, and cerebral ischemia. 1524 37

The purpose of this study was to determine the efficacy and putative mechanisms of action of tetracycline and minocycline in inhibiting retinal cell apoptosis after glutamate-induced excitotoxicity and trophic factor deprivation in a retinal cell line (E1A-NR.3) and in primary mixed retinal cell cultures. In addition, a differentiated PC-12 cell line was used to determine whether minocycline was neuroprotective after trophic withdrawal in a pure neuronal cell line devoid of glia. Results from this study demonstrated that minocycline, but not tetracycline, is protective in in vitro models of excitotoxicity-induced retinal cell apoptosis. Moreover, the protective effects provided by minocycline in retinal cells seemed independent of actions on N-methyl-D-aspartate receptors (NMDARs) and glutamate receptor-mediated Ca(2+) influx. Doses of the NMDAR antagonist MK-801 (dizocilpine) and minocycline that alone provided no significant neuroprotection resulted in enhanced retinal cell survival when applied concurrently, suggestive of distinct signaling pathways, and minocycline was without effect on glutamate-induced Ca(2+) influx, as assessed by calcium imaging. Minocycline was also neuroprotective after trophic factor withdrawal, producing a decrease in apoptosis and caspase-3 activation in both retinal cells and the PC-12 neuronal-like cell line. These results support a role for minocycline as a retinal neuroprotectant and demonstrate that the antiapoptotic actions of minocycline in retinal cells do not arise from the blockage of NMDARs or glutamate receptor-mediated Ca(2+) influx but do involve inhibition of caspase-3 activation. In addition, the survival-promoting actions of minocycline may arise via actions on both neuronal and non-neuronal cell targets.
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PMID:An investigation of the neuroprotective effects of tetracycline derivatives in experimental models of retinal cell death. 1530 47

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