Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell-adhesion and spread are important for cell survival. Although extensive studies have suggested several potential mechanisms of action, it is not yet clear how important cell-morphological change per se contributes to the cell-surviving signal. We employed a non-integrin-mediated cell-adhesion system to explore this question. BHK-Japanese encephalitis virus (JEV) cells (BHK21 cells that are persistently infected with JEV) express a large amount of JEV-envelope protein (JEV E) on their surfaces, and can attach and form pseudopodia on the anti-JEV E antibody-coated substrates. However, cells that adhered on the antibody substrate underwent a caspase-3-mediated apoptosis together with a down-regulation of mitogen-activated protein kinase activity within 20 h after adhesion, which indicates that viral-protein-mediated cell-adhesion and cell-spread are not sufficient for supporting cell survival. This provides a different perspective for the study of the relationships between the cell-morphological change and the cell-survival signal.
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PMID:Cell-adhesion and morphological changes are not sufficient to support anchorage-dependent cell growth via non-integrin-mediated attachment. 1266 69

Flaviviruses such as dengue virus (DEN) and Japanese encephalitis virus (JEV) are medically important in humans. The lipid kinase, phosphatidylinositol 3-kinase (PI3K) and its downstream target Akt have been implicated in the regulation of diverse cellular functions such as proliferation, and apoptosis. Since JEV and DEN appear to trigger apoptosis in cultured cells at a rather late stage of infection, we evaluated the possible roles of the PI3K/Akt signaling pathway in flavivirus-infected cells. We found that Akt phosphorylation was noticeable in the JEV- and DEN serotype 2 (DEN-2)-infected neuronal N18 cells in an early, transient, PI3K- and lipid raft-dependent manner. Blocking of PI3K activation by its specific inhibitor LY294002 or wortmannin greatly enhanced virus-induced cytopathic effects (CPEs), even at an early stage of infection, but had no effect on virus production. This severe CPE was characterized as apoptotic cell death as evidenced by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) staining and cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Mechanically, the initiator and effector caspases involved are mainly caspase-9 and caspase-6, since only a pan-caspase inhibitor and the inhibitors preferentially target caspase-9 and -6, but not the ones antagonizing caspase-8, -3, or -7 alleviated the levels of PARP cleavage after virus infection and PI3K blockage. Furthermore, Bcl-2 appears to be a crucial mediator downstream of PI3K/Akt signaling, since overexpression of Bcl-2 reduced virus-induced apoptosis even when PI3K activation was repressed. Collectively, our results suggest an anti-apoptotic role for the PI3K/Akt pathway triggered by JEV and DEN-2 to protect infected cells from early apoptotic cell death.
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PMID:Flavivirus activates phosphatidylinositol 3-kinase signaling to block caspase-dependent apoptotic cell death at the early stage of virus infection. 1595 83

Thrombocytopenia is frequently associated with dengue virus infection in humans. Although antiplatelet immunopathogenic processes have been implicated in the origin of dengue-associated thrombocytopenia, the effect of dengue viruses on megakaryocyte differentiation remains incompletely understood. In this study, we examined the effect of human dengue 2 virus isolates on the in vitro growth and differentiation of thrombopoietin-induced megakaryopoiesis of cord blood CD34+ cells. Dengue 2 viruses, but not Japanese encephalitis virus, showed a dose-dependent inhibition of CFU-Mk. Viral antigens could be detected by an immunohistochemical technique in 3-5% of the early megakaryocytic progenitors by the 5th postexposure day in liquid cultures with cell loss, increased annexin V binding and active caspase-3 expression. In summary, dengue 2 viruses can inhibit in vitro megakaryopoiesis, as well as infect and induce apoptotic cell death in a subpopulation of early megakaryocytic progenitors. These events might contribute towards the origin of thrombocytopenia in dengue disease.
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PMID:Dengue 2 virus inhibits in vitro megakaryocytic colony formation and induces apoptosis in thrombopoietin-inducible megakaryocytic differentiation from cord blood CD34+ cells. 1837 Oct 71

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, replicates primarily at the endoplasmic reticulum and thereby triggers apoptosis of infected cells. This study investigated the hierarchical activation of the caspase network induced by JEV infection. It was found that JEV activated the initiators caspase-8 and -9, as well as effector caspase-3, in infected baby hamster kidney and mouse neuroblastoma (N18) cells. In neuronal N18 cells, JEV infection triggered cytochrome c release from mitochondria, which in turn activated caspase-9 and -3. Treatment of JEV-infected N18 cells with cyclosporin A or ruthenium red, which attenuate mitochondrial injuries, blocked activation of caspase-9 or -3, typifying that, in neuronal cells, this apoptosis involves the mitochondrial pathway. Alternatively, in caspase-3-deficient MCF-7 cells, JEV persisted and readily triggered a typical apoptotic response, including cytochrome c release and full activation of caspase-9 and -8 along with caspase-6, indicating that JEV did not require caspase-3 to manifest caspase-8 activation and apoptosis. Interestingly, a Fas-associated death-domain-containing protein (FADD) dominant-negative mutant, which interfered with transmission of the extracellular death signals into cells through the Fas/tumour necrosis factor (TNF) receptor, failed to block JEV-induced apoptosis and caspase-8 activation, implying that receptor oligomerization of the Fas/TNF pathway might not participate in JEV-induced apoptosis. Taken together, these results illustrate that JEV infection triggers caspase cascades involving the initiators caspase-8 and -9, probably through FADD-independent but mitochondrion-dependent pathways.
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PMID:Japanese encephalitis virus infection activates caspase-8 and -9 in a FADD-independent and mitochondrion-dependent manner. 1863 64

Rana catesbeiana ribonuclease (RC-RNase) is a cytotoxic and antitumor RNase isolated from the oocyte yolk granules of the bullfrog R. catesbeiana. Our previous studies have shown that RC-RNase possesses antitumor activity by activating proapoptotic caspases. Here, we demonstrate that RC-RNase also possesses antiviral activity. By using cell viability and caspase activation assays, we show that RC-RNase largely enhances apoptosis of Japanese encephalitis virus (JEV)-infected BHK-21 cells by activating caspase-3, caspase-8, and caspase-9. In addition, immunoblotting experiments revealed that JEV infection enhances the internalization of RC-RNase by cells. In sum, these results indicate that RC-RNase provides a beneficial effect on JEV-infected cells by enhancing apoptosis.
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PMID:Rana catesbeiana ribonuclease inhibits Japanese encephalitis virus (JEV) replication and enhances apoptosis of JEV-infected BHK-21 cells. 2124 41

Japanese encephalitis virus (JEV), the most frequent and the single most important cause of encephalitis worldwide, has spread throughout most of Asia. For the development of appropriate and effective therapy, there is an immediate requirement to understand the role of host factors in JEV-induced neuropathogenesis. In the present study, we investigated the role of mitogen-activated protein kinases (MAPKs) in JEV infection of mouse neuroblastoma (N2A) cells. The MAPK pathway was studied at the transcriptional level to access the gene expression profile at different time points after JEV infection. The effector MAPK genes were also analyzed for protein expression and activation. Gene expression analysis showed a significant regulation of extracellular signal-regulated kinases (ERK)1, ERK2 and c-Jun N-terminal kinase (JNK)3 genes along with their downstream transcription factors such as Mef2c, c-Jun and Sfn. Experiments with the JNK inhibitor, SP600125, and the ERK inhibitor, PD98059, showed the involvement of JNK in JEV-induced caspase-3 activation and apoptosis, but ERK1/2 had no effect. Overall, our results show the transcriptional regulation of the MAPK pathway and the essential role of JNK in JEV-induced apoptosis in neuroblastoma cells. These findings provide a new insight into the role of the mitogen- and stress-activated kinases in JEV pathogenesis and opens up new avenues of therapeutics.
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PMID:Transcriptional regulation and activation of the mitogen-activated protein kinase pathway after Japanese encephalitis virus infection in neuroblastoma cells. 2132 Jan 73

Japanese encephalitis virus (JEV) infection induces uncontrolled neuronal apoptosis, leading to irreversible brain damage. However, the mechanism of JEV-induced neuronal apoptosis has not been clearly elucidated. This study aimed to investigate both virus replication and neuronal cell apoptosis during JEV infection in human neuroblastoma SH-SY5Y cells. As a result, the kinetic productions of new viral progeny were time- and dose-dependent. The stimulation of SH-SY5Y cell apoptosis was dependent on the multiplicity of infections (MOIs) and infection periods, particularly during the late period of infection. Interestingly, we observed that of full-length Bax (p21 Bax) level started to decrease, which corresponded to the increased level of its cleaved form (p18 Bax). The formation of p18 Bax resulting in cytochrome c release into the cytosol appeared to correlate with JEV-induced apoptotic cell death together with the activation of caspase-3/7 activity, especially during the late stage of a robust viral infection. Therefore, our results suggest another possible mechanism of JEV-induced apoptotic cell death via the induction of the proteolysis of endogenous p21 Bax to generate p18 Bax. This finding could be a new avenue to facilitate novel drug discovery for the further development of therapeutic treatments that could relieve neuronal damage from JEV infection.
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PMID:Elevation of Cleaved p18 Bax Levels Associated with the Kinetics of Neuronal Cell Death during Japanese Encephalitis Virus Infection. 3165 98