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)

The mechanisms for neurodegeneration in amyotrophic lateral sclerosis (ALS) are not understood. We found that motor neuron degeneration in ALS structurally resembles apoptosis. The progression of neuronal death is divisible into 3 sequential stages: chromatolysis, somatodendritic attrition, and apoptosis. In ALS spinal cord anterior horn and motor cortex, DNA fragmentation is detectable in situ and in gels and is internucleosomal, occurring in the presence of DNA fragmentation factor-45/40 activation and increased caspase-3 activity. By immunoblotting, changes occur in the subcellular distribution of cell death proteins that would promote apoptosis. In selectively vulnerable CNS regions in ALS compared with controls, the proapoptotic proteins Bax and Bak are elevated in the mitochondrial-enriched membrane compartment, but are reduced or unchanged in the cytosol. In contrast, the antiapoptotic protein Bcl-2 is decreased in the mitochondrial-enriched membrane compartment of vulnerable regions in ALS, but is increased in the cytosol, whereas Bcl-xL levels are unchanged in both subcellular compartments. Coimmunoprecipitation experiments showed that Bax-Bax interactions are greater in the mitochondrial-enriched membrane compartment of ALS motor cortex compared with controls, whereas Bax-Bcl-2 interactions are lower in the membrane compartment of ALS motor cortex compared with controls. We conclude that a PCD mechanism, involving cytosol-to-membrane and membrane-to-cytosol redistribution of cell death proteins and caspase-3 activation, participates in the pathogenesis of ALS.
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PMID:Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. 1033 34

Cerebellar Purkinje neurons (PNs) are selectively vulnerable to AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepriopionic acid)-induced delayed neurotoxicity known as dark cell degeneration (DCD) that is expressed as cytoplasmic and nuclear condensation, neuron shrinkage, and failure of physiology. The present study was initiated to determine whether AMPA-receptor-induced DCD in PNs is associated with Bax translocation to the mitochondria, cytochrome C release from the mitochondria, changes in mitochondrial potential, and activation of representative initiator and executor caspases that include caspase-9, caspase-3, and caspase-7. AMPA consistently and rapidly hyperpolarized mitochondria as reflected by an increase in MitoTracker Red CMS Ros fluorescence. Increases in Bax immunoreactivity were quantitatively and temporally variable and Bax failed to localize to mitochondria. Additionally, we observed a marked increase in immunoreactivity of cytochrome C although its release from mitochondria was not apparent. Mitochondrial membrane hyperpolarization and increases in cytochrome C immunoreactivity preceded caspase activation. Immunohistochemical analyses revealed the active form of caspases-3 and -9 were markedly and significantly increased in PNs following 30 microM AMPA, and caspase-9 activation preceded caspase-3. Increases in active caspase-7 immunoreactivity were less frequently encountered in PNs. Thus DCD shares some characteristics of apoptotic programmed cell death, but lacks typical mitochondrial pathophysiology associated with classic apoptosis. These findings suggest that AMPA-induced DCD is a form of active PCD that lies on a spectrum between classical apoptosis and passive necrosis.
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PMID:AMPA-induced dark cell degeneration of cerebellar Purkinje neurons involves activation of caspases and apparent mitochondrial dysfunction. 1464 40

Insulin-like growth factor-I (IGF-I) was found to promote proliferation, cell survival, and inhibition of apoptosis. But in some instances, IGF-I was found to mildly induce apoptosis, i. e. Fas-mediated apoptosis in human MG63 osteosarcoma cells. In the present study, we intended to further investigate IGF-I dependent pathways leading either to proliferation and cell survival or to cell death. MG63 osteosarcoma cells were treated with serum free medium alone or in combination with IGF-I, a neutralizing antibody against the human IGF-I receptor (alphaIR-3) or non-immune control IgG (1) for two to six days. We investigated cell survival (cell count), proliferation (CD71-FACS), apoptosis (Annexin-V-FACS, Caspase-3 activity, PCD) and anti-apoptosis (112-Ser Bad phosphorylation), and regulation of IGF-I receptor surface expression (IGF-I receptor-FACS). We found that IGF-I treatment (48 h) stimulated cell growth and proliferation, but also mildly induced apoptosis. IGF-I activated specific apoptotic pathways (Caspase-3 activation, Annexin-V binding and DNA degradation), as well as anti-apoptotic signals (Bad phosphorylation at serine 112). alphaIR-3 blocked cell proliferation, strongly induced apoptosis, and inhibited Bad-phosphorylation. Thus, IGF-I treatment overall resulted in increased tumour cell mass, despite a detectable stimulation of apoptosis; in other words proliferation exceeded cell death. If IGF-I was first added on day 0, 2, or 4 of serum free culture, we found decreasing IGF-I specific effects on proliferation and apoptosis. In parallel, we found a down-regulation of IGF-I receptors (FACS) by serum withdrawal, which was partly reversed if IGF-I was added. Therefore receptor number might have an impact on IGF-I function in MG63 cells. In conclusion, co-activation of apoptosis and proliferation by IGF-I might result in higher cell turnover in MG63 osteosarcoma cells. Furthermore, in sarcomas or carcinomas showing clinical association to IGF-I levels and malignancy, IGF-I dependent apoptosis and proliferation could be a significant mechanism of malignant tumour growth.
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PMID:Insulin-like growth factor I (IGF-I) stimulates proliferation but also increases caspase-3 activity, Annexin-V binding, and DNA-fragmentation in human MG63 osteosarcoma cells: co-activation of pro- and anti-apoptotic pathways by IGF-I. 1471 Mar 59

During the physiological process of PCD, the cell initiates a sequence of events culminating in the disintegration of the cell into small, membrane-bound apoptotic bodies. The intrinsic part of the PCD program arises from the mitochondria when it releases cytochrome c from the mitochondrial intermembrane space into the cytosol, forming the caspase-activating complex or apoptosome. The family of caspases is involved in the execution of genetically controlled PCD. Caspase-3 is expressed in normal and neoplastically transformed human cells and, like other caspases, is synthesized as an inactive, 32kDa proenzyme. Caspase-6 cleaves nuclear mitotic apparatus protein (NuMA) and mediates the shrinkage and fragmentation of cell nuclei. Caspase-8 is an initiation caspase that activates the caspase cascade during apoptosis, while caspase-9 is the initiator caspase in the caspase cascade in apoptotic normal and neoplastically transformed cells. During our immunocytochemical study, a sensitive, four-step, alkaline phosphatase conjugated antigen detection technique was employed. The results did in fact demonstrate the presence of high apoptotic activity within the cellular microenvironment of high-grade astrocytomas and glioblastomas. The observations identified cytoplasmic expression of caspase-3 and caspase-6 in more than 50 per cent of tumor cells, caspase-8 and caspase-9 in more than 10 per cent of tumor cells in high-grade anaplastic ASTR and glioblastoma. The immunocytochemical expression pattern in about 10 per cent of the tumor cells for caspase-3 and caspase-6 and about 1 to 5 per cent of the tumor cells for caspase-8 and caspase-9 demonstrated a translocation tendency from the cytoplasm to the cell nuclei in the apoptotic cells. This phenomenon may play an important role in these tumors' maintenance of immune privilege and evasion of immune attacks. We suggest that caspase-3, -6, -8 and -9 immunocytochemistry could have prognostic and immunotherapeutic significance in the treatment of these highly malignant glial tumors.
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PMID:Immunocytochemical detection of members of the caspase cascade of apoptosis in high-grade astrocytomas. 1552 99

We report that the effect of Tau-Cl on the cell fate strongly depends on the cellular context. In leukemic Jurkat cells Tau-Cl (> 200 microM) triggers mitochondrial, p53-independent apoptosis and amplifies PCD induced by anti-Fas treatment. In contrast, Tau-Cl affects RA FLS in a dose-dependent manner. At the noncytotoxic (200-400 microM) concentrations it induces: (i) p53-dependent growth arrest (Kontny et al., 2005), and (ii) Bax translocation and caspase 9 activity. Although the last events are characteristic for apoptotic state, there is not execution of RA FLS apoptosis, probably due to simultaneous inhibition of caspase 3 activity and prevention of PARP degradation. The last two events suggest an excessive ATP deprivation in Tau-Cl-treated RA FLS. At sufficiently high concentrations (> or = 500 microM) Tau-Cl causes therefore necrosis of these cells. Altogether our results suggest that Tau-Cl is able to eliminate the cells with both functional (RA FLS) and mutated (Jurkat) p53 tumor suppressor. This observation is clinically relevant because Tau-Cl is used in many animal inflammatory models and its sodium salt (used in this study) has been introduced to human therapy (Gottardi and Nagl, 2002; Teuchner et al., 2005).
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PMID:Cytotoxicity of taurine metabolites depends on the cell type. 1715 99

This study tested the hypothesis that the remodeling of the cardiac outflow tract (OFT) may represent a developmental window of vulnerability to reactive oxygen species (ROS). Chick embryos were exposed in ovo or ex ovo to increasing concentrations of the stable oxidant hydrogen peroxide (H2O2). As assessed by trypan blue staining, H2O2 induced cell injury in the stage 25-30 OFT at concentrations as low as 1 nM. Higher concentrations were required to induce cell injury in the ventricular and atrial myocardium. Using DCFDA as an indicator of oxidant stress, H2O2 also induced a greater fluorescent signal in the OFT myocardium. H2O2 at these low concentrations also induced Caspase activity, indicative of activation of the pathway of PCD. Interestingly, the induction of Caspase-3 activity was predominately in the OFT cushion mesenchymal cells. Thus, the developing OFT is particularly sensitive to ROS-mediated injury, suggesting that ROS could play a role in the development of congenital defects of the cardiac OFT.
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PMID:The developing embryonic cardiac outflow tract is highly sensitive to oxidant stress. 1799 43

NRPs (N-rich proteins) were identified as targets of a novel adaptive pathway that integrates endoplasmic reticulum (ER) and osmotic stress signals based on coordinate regulation and synergistic up-regulation by tunicamycin and polyethylene glycol treatments. This integrated pathway diverges from the molecular chaperone-inducing branch of the unfolded protein response (UPR) in several ways. While UPR-specific targets were inversely regulated by ER and osmotic stresses, NRPs required both signals for full activation. Furthermore, BiP (binding protein) overexpression in soybean prevented activation of the UPR by ER stress inducers, but did not affect activation of NRPs. We also found that this integrated pathway transduces a PCD signal generated by ER and osmotic stresses that result in the appearance of markers associated with leaf senescence. Overexpression of NRPs in soybean protoplasts induced caspase-3-like activity and promoted extensive DNA fragmentation. Furthermore, transient expression of NRPs in planta caused leaf yellowing, chlorophyll loss, malondialdehyde production, ethylene evolution, and induction of the senescence marker gene CP1. This phenotype was alleviated by the cytokinin zeatin, a potent senescence inhibitor. Collectively, these results indicate that ER stress induces leaf senescence through activation of plant-specific NRPs via a novel branch of the ER stress response.
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PMID:A new branch of endoplasmic reticulum stress signaling and the osmotic signal converge on plant-specific asparagine-rich proteins to promote cell death. 1849 Apr 46

Development of effective agents for treatment of hormone-refractory prostate cancer (HRPC) has become a national medical priority. D-Allose is a monosaccharide (C-3 epimer of glucose) distributed rarely in nature; because of its scarcity and cost, the biological effect has hardly been studied. In the present study, we demonstrated the inhibitory action of D-allose on proliferation of human HRPC cell lines, DU145 and PC-3 in a dose- and time-dependent manner, while human normal prostate epithelial (NPE) cell line, PrEC showed no remarkable effect. In vitro treatment of D-allose resulted in the alteration of Bcl-2/Bax ratio in favor of apoptosis (programmed cell death, PCD) in both the HRPC cell lines, which was associated with the lowering of mitochondrial transmembrane potential (Deltapsi(m)) and the release of cytochrome C (cyt C), the cleavage of caspase 3 and poly (ADP-ribose) polymerase (PARP), and the elevation of calcium concentration in cytosol ([Ca(2+)](c)). D-Allose also induced G1 phase arrest of the cell cycle in DU145 cell line. This study for the first time suggested the antiproliferative effect of D-allose through induction of PCD in HRPC cell lines, which could be due to the modulation of mitochondria mediated intrinsic apoptotic pathway.
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PMID:Rare sugar D-allose induces programmed cell death in hormone refractory prostate cancer cells. 1862 5

The casepase is considered to regulate the process of programmed cell death in the development of organisms. In this study, caspase 3-like protease was detected by immunohistochemistry and immunoelectron microscopy during the development of sieve element and tracheary element of stem in Cucurbita moschata Duch. Antibody with brown color (under light microscopy) and gold particles (under transmission electron microscopy) for detecting caspase 3-like protease was mainly displayed in inner phloem, external phloem and xylem in the region close to procambium. From the results it was considered that caspase 3-like protease did exist in vascular elements and played different roles during the development of sieve and tracheary elements, and different types of programmed cell death might be carried out. The caspase 3-like protease mainly participated in making cytoplasmic streaming cease and in degrading P-protein bodies; however, it rarely participated in the function for signal transferring in the developmental sieve element. However, it might induce calcium accumulation for rupturing the tonoplast in the signal of PCD in the developmental tracheary element.
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PMID:Location of caspase 3-like protease in the development of sieve element and tracheary element of stem in Cucurbita moschata. 1909 68

Two-photon excitation (TPE) fluorescence lifetime imaging microscopy (FLIM) and emission spectral imaging (ESI) are powerful tools for fluorescence resonance energy transfer (FRET) measurement. In this study, we use these two techniques to analyze caspase-3 activation inside single living cells during anticancer drug-induced human lung adenocarcinoma (ASTC-a-1) cell death. TPE-ESI of SCAT3, a caspase-3 indicator based on FRET, was performed inside single living cell stably expressing SCAT3. The TPE-ESI measurement was performed using 780 nm excitation which was considered to selectively excite the donor ECFP of SCAT3 by measuring the emission ratio of 526 to 476 nm. The emission peak at 526 nm disappeared and that of 476 nm increased after STS or bufalin treatment, but taxol treatment did not induce a significant change for the SCAT3 emission spectra, indicating that caspase-3 was activated during STS- or bufalin-induced cell apoptosis, but was not involved in taxol-induced PCD. Fluorescence lifetime of ECFP inside living cells was acquired using FLIM. The lifetime of ECFP was the same as that of the control group after taxol treatment, but increased from 1.83 +/- 0.02 to 2.05 +/- 0.03 and 1.90 +/- 0.03 ns, respectively after STS and bufalin treatment, which agree with the results obtained using TPE-ESI. Taken together, TPE-FLIM and ESI analysis were proved to be valuable approaches for monitoring caspase-3 activation inside single living cells.
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PMID:FLIM and emission spectral analysis of caspase-3 activation inside single living cell during anticancer drug-induced cell death. 1913 66


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