Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maedi-visna virus (MVV) causes encephalitis, pneumonia and arthritis in sheep. In vitro, MVV infection and replication lead to strong cytopathic effects characterized by syncytia formation and subsequent cellular lysis. It was demonstrated previously that MVV infection in vitro induces cell death of sheep choroid plexus cells (SCPC) by a mechanism that can be associated with apoptotic cell death. Here, the relative implication of several caspases during acute infection with MVV is investigated by employing diverse in vitro and in situ strategies. It was demonstrated using specific pairs of caspase substrates and inhibitors that, during in vitro infection of SCPC by MVV, the two major pathways of caspase activation (i.e. intrinsic and extrinsic pathways) were stimulated: significant caspase-9 and -8 activities, as well as caspase-3 activity, were detected. To study the role of caspases during MVV infection in vitro, specific, cell-permeable, caspase inhibitors were used. First, these results showed that both z-DEVD-FMK (a potent inhibitor of caspase-3-like activities) and z-VAD-FMK (a broad spectrum caspase inhibitor) inhibit caspase-9, -8 and -3 activities. Second, both irreversible caspase inhibitors, z-DEVD-FMK and z-VAD-FMK, delayed MVV-induced cellular lysis as well as virus growth. Third, during SCPC in vitro infection by MVV, cells were positively stained with FITC-VAD-FMK, a probe that specifically stains cells containing active caspases. In conclusion, these data suggest that MVV infection in vitro induces SCPC cell death by a mechanism that is strongly dependent on active caspases.
J Gen Virol 2002 Dec
PMID:Implication of caspases during maedi-visna virus-induced apoptosis. 1246 93

The mechanism of West Nile (WN) virus-induced cell death is determined by the initial infectious dose. In Vero cells infected with WN virus at an m.o.i. of 10 or greater, morphological changes characteristic of necrosis were observed as early as 8 h post-infection (p.i.). Pathological changes included extensive cell swelling and loss of plasma membrane integrity, as revealed by optical and electron microscopy. High extracellular lactate dehydrogenase (LDH) activity was observed together with leakage of the high mobility group 1 (HMGB1) protein into the extracellular space. When cells undergo necrosis, they release the HMGB1 protein, a pro-inflammatory mediator cytokine. At high infectious doses, loss of cell plasma membrane integrity was due to the profuse budding of WN progeny virus particles during maturation. When this profuse budding process was disrupted using cytochalasin B, LDH activity was reduced dramatically. In contrast, WN virus-induced cell killing occurred predominantly by apoptosis when cells were infected with an m.o.i. of </=1; the process of apoptosis observed was much later after infection (32 h p.i.). Fragmentation of DNA, chromatin condensation and formation of apoptotic bodies were all observed. This WN virus-induced apoptosis pathway was initiated by the release of cytochrome c from the mitochondria and was accompanied by the formation of apoptosomes. In turn, this led to the activation of caspase-9 and -3, and to the cleavage of the poly(ADP-ribose) polymerase.
J Gen Virol 2003 Dec
PMID:The mechanism of cell death during West Nile virus infection is dependent on initial infectious dose. 1464 11

HeLa and 16HBE14o(-) bronchial epithelium cells infected with human rhinovirus serotype 14 (HRV14) were found to exhibit typical apoptotic morphological alterations, such as cell contraction and nuclear condensation. These events coincided with high-molecular-weight DNA fragmentation, activation of caspase-9 and caspase-3 and poly(ADP-ribose) polymerase cleavage. Caspase activation was preceded by cytochrome c translocation from the mitochondria to the cytoplasm, indicating that apoptosis caused by HRV14 infection was triggered predominantly via the mitochondrial pathway. Apoptosis did not affect HRV14 replication per se, but it facilitated the release of newly formed virus from cells. As apoptosis was fully induced at the time of maximal accumulation of progeny HRV14, it is postulated that apoptosis contributed to the destabilization of the cell and facilitated viral progeny release.
J Gen Virol 2005 May
PMID:Apoptotic events induced by human rhinovirus infection. 1583 50

The present in vitro study demonstrates the effect of androgen on thymocyte apoptosis leading to thymic atrophy in the wall lizard, Hemidactylus flaviviridis. Thymocytes collected from castrated lizards were incubated with varying concentrations of dihydrotestosterone (DHT) to observe its effect on proliferation and apoptosis. DHT treatment reduced the tritiated thymidine incorporation in thymocytes, suggesting that androgen directly inhibits thymocyte proliferation. It also caused apoptosis of thymocytes effectively at 10(-7)M. However, the increased apoptotic action of DHT was indirectly mediated through thymic epithelial cell-rich stromal cell components (TEC). This observation was reaffirmed by in vitro incubation of thymocytes with DHT-pretreated TEC-conditioned medium. However, the DHT-induced TEC-secreted apoptotic factors could induce thymocyte DNA fragmentation only when DHT was added to the conditioned medium. It implies that DHT priming of thymocytes is required for the apoptotic effect of DHT-induced TEC-secreted factor. DHT-induced thymocyte apoptosis was found to be caspase-dependent since it activated the initiator (caspase-9) and effector caspases (caspases-3 and -7) as well as cleaved the enzyme substrate poly(ADP-ribose) polymerase (PARP). Further, the apoptotic effect of DHT was routed through its classical receptors, as non-steroidal antiandrogen flutamide blocked the DHT-induced thymocyte apoptosis. The inhibition of apoptosis by transcription/translation inhibitors further substantiates the genomic pathway of DHT action. It can be concluded that DHT, in addition to inhibiting thymocyte proliferation directly, accelerates caspase-dependent apoptotic process in thymocytes indirectly through TEC via a genomic pathway. Nevertheless, the priming of thymocytes with DHT is required for the apoptotic effect of TEC-secreted factor.
Gen Comp Endocrinol 2005 Oct
PMID:Mechanism of androgen-induced thymic atrophy in the wall lizard, Hemidactylus flaviviridis: an in vitro study. 1600 99

Feline calicivirus (FCV) belongs to the family Caliciviridae and is an important pathogen of the upper respiratory tract of cats. Recent studies have shown that cells infected with FCV undergo apoptosis, as evidenced by caspase activation, chromatin condensation and cleavage of poly(ADP-ribose) polymerase. Here, the upstream events were investigated in order to define the molecular mechanism of apoptosis in FCV-infected cells. It was shown that FCV induced translocation of phosphatidylserine to the cell outer membrane and release of cytochrome c from mitochondria at about 6-8 h post-infection. These events were preceded by the loss of mitochondrial membrane potential and Bax translocation from the cytosol to mitochondria between 4 and 6 h after infection. Release of cytochrome c from mitochondria triggered the activation of caspase-9 and the subsequent activation of the executioner caspase, caspase-3. These results suggest that the mitochondrial pathway of apoptosis is triggered during FCV infection.
J Gen Virol 2006 Feb
PMID:The mitochondrial pathway of apoptosis is triggered during feline calicivirus infection. 1643 22

The paramyxovirus Simian virus 5 (SV5) is largely non-cytopathic in human epithelial and fibroblast cells. WF-PIV has been described previously as a naturally occurring SV5 variant that encodes P and V proteins differing from the wild-type (WT) SV5 proteins in eight and five amino acid positions, respectively. In this study, it is shown that WF-PIV is like WT SV5 by being largely non-cytopathic in A549 lung epithelial cells. However, substitution of the WF-PIV P/V gene into the background of WT SV5 resulted in a hybrid virus (P/V-WF) that induced apoptotic cell death not seen with either of the parental viruses. The kinetics of HeLa cell killing and induction of apoptosis by the P/V-WF chimera differed from those of the previously described P/V-CPI- chimera by being slower and less extensive. HeLa cell killing by the P/V-WF chimera was effectively reduced by inhibitors of caspase-9, but not of caspase-8. These results demonstrate that an exchange of P/V genes from two non-cytopathic SV5 variants can produce apoptosis-inducing chimeras, and that the role of the SV5 P/V gene products in limiting apoptosis can be dependent on expression in the context of a native viral genome.
J Gen Virol 2006 Dec
PMID:Exchange of P/V genes between two non-cytopathic simian virus 5 variants results in a recombinant virus that kills cells through death pathways that are sensitive to caspase inhibitors. 1709 80

Growth hormone (GH) is found in the developing eye, where it is synthesized by retinal ganglion cells (RGCs). In this location, GH variants appear to have an autocrine or paracrine anti-apoptotic neuroprotective role, and may contribute to the regulation of the developmental waves of apoptosis that characterize RGC differentiation. Here, we investigate the intracellular signaling pathways that are activated by GH as a neuroprotective agent in cultured chick embryo RGCs. We show that GH treatment reduces the cleavage of caspase-9, and that an inhibitor of caspase-9 cleavage can abrogate the pro-apoptotic effect of GH immunoneutralization. These findings complement previous results implicating caspase-3 in GH action on these cells. We had also previously shown that Akt pathways are involved in the neuroprotection of RGCs by GH. We now extend those findings to show that these pathways involve the activation of cytosolic tyrosine kinases (Trks) and extracellular-signal-related kinases (ERKs). Therefore, although the GH receptor, unlike other neurotrophin receptors, is not itself a receptor tyrosine kinase (receptor Trk), occupation of the receptor by GH involves downstream intracellular Trk pathways. Finally, we show that the Akt and Trk pathways converge on the activation of cAMP response element binding protein (CREB) which is able to initiate transcription of pro- or anti-apoptotic genes. These results indicate that the action of GH in the neuroprotection of embryonic RGCs involves pathways that are common to other neurotrophins, and that GH can be considered to be an authentic growth and differentiation factor in the development of the embryonic retina.
Gen Comp Endocrinol 2008 May 01
PMID:Growth hormone-mediated survival of embryonic retinal ganglion cells: signaling mechanisms. 1835 75

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.
J Gen Virol 2008 Aug
PMID:Japanese encephalitis virus infection activates caspase-8 and -9 in a FADD-independent and mitochondrion-dependent manner. 1863 64

The molecular mechanisms governing severe acute respiratory syndrome coronavirus-induced pathology are not fully understood. Virus infection and some individual viral proteins, including the 3a protein, induce apoptosis. However, the cellular targets leading to 3a protein-mediated apoptosis have not been fully characterized. This study showed that the 3a protein modulates the mitochondrial death pathway in two possible ways. Activation of caspase-8 through extrinsic signal(s) caused Bid activation. In the intrinsic pathway, there was activation of caspase-9 and cytochrome c release from the mitochondria. This was the result of increased Bax oligomerization and higher levels of p53 in 3a protein-expressing cells, which depended on the activation of p38 MAP kinase (MAPK) in these cells. For p38 activation and apoptosis induction, the 3a cytoplasmic domain was sufficient. In direct Annexin V staining assays, the 3a protein-expressing cells showed increased apoptosis that was attenuated with the p38 MAPK inhibitor SB203580. A block in nuclear translocation of the STAT3 transcription factor in cells expressing the 3a protein was also observed. These results have been used to present a model of 3a-mediated apoptosis.
J Gen Virol 2008 Aug
PMID:Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation. 1863 68

Punta Toro virus (PTV; genus Phlebovirus, family Bunyaviridae) causes apoptosis of hepatocytes in vivo in experimentally infected hamsters and in vitro in cultured HepG2 cells. Screening for expression of apoptosis-related genes has shown alterations in the genes for tumour necrosis factor-alpha (TNF-alpha) and the TNF receptor family. This study examined the roles of the TNF receptor-related extrinsic pathway and the Bcl-2 family-associated mitochondrial pathway in PTV-induced cell death. The effects of caspase inhibitors (caspIs) and TNF on cellular viability, virus replication, and morphological and biochemical changes in apoptosis were examined in HepG2 cells at different time points after infection with PTV (Adames strain). The results showed that caspIs dampened the virus-induced reduction in cellular viability, partially suppressed and delayed viral titres and antigen expression, and partially decreased the expression of apoptotic genes, caspase activities and DNA fragmentation. TNF treatment further decreased cellular viability after PTV infection and increased the level of apoptosis, whilst caspIs partially inhibited these effects. These findings indicate that TNF, caspase-8 and caspase-9 contribute to PTV-induced hepatocytic apoptosis and that additional mediators are probably also involved in this process. These mediators from different pathways correlated with one another and may be interlinked.
J Gen Virol 2008 Sep
PMID:Characterization of cell-death pathways in Punta Toro virus-induced hepatocyte injury. 1875 27


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