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)

Tumorigenic leporipoxviruses encode catalytically inactive homologs of cellular Cu-Zn superoxide dismutase (SOD1). The function of the orthologous myxoma virus M131R and Shope fibroma virus S131R gene products is uncertain, but they inhibit SOD1 activity by a process linked to binding its copper chaperone. Using a superoxide-sensitive dye (hydroethidine), we observed that virus infection increased intracellular superoxide levels in an M/S131R-dependent manner. To see whether this effect promotes infection, we deleted the Shope fibroma virus S131R gene and compared the clinical manifestations of wild-type and mutant virus infections in rabbits. S131RDelta virus produced significantly smaller fibroxanthosarcoma-like growths in vivo and, at a point where these growths were already receding, wild-type infections still showed extensive leukocyte infiltration, necrosis, and fibromatous cell proliferation. Coincidentally, whereas Jurkat cells are protected from mitochondria- and Fas-mediated apoptosis by wild-type myxoma virus in vitro, M131RDelta virus could not block Fas-initiated apoptosis as judged by DNA laddering, terminal deoxynucleotidyltransferase-mediated dUTP-fluorescein nick end labeling, and caspase 3 cleavage assays. These data suggest that tumorigenic poxviruses can modulate intracellular redox status to their advantage to stimulate infected cell growth and inhibit programmed cell death.
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PMID:Tumorigenic poxviruses up-regulate intracellular superoxide to inhibit apoptosis and promote cell proliferation. 1582 94

Porcine circovirus type 2 (PCV2) is the causative agent of postweaning multisystemic wasting syndrome in pigs. In this study, transcription and translation of a novel viral gene (termed ORF3 here) was detected during productive infection of PCV2 in PK15 cells. The results of infection with ORF3-deficient PCV2 by site-directed mutagenesis indicated that the protein is not essential for viral replication. To investigate the underlying mechanism of cell death caused by replication of PCV2, apoptosis characterized by chromosomal condensation and fragmentation, formation of apoptotic bodies, and significant increase in hypodiploids were detected in infected cells. We further demonstrated that PCV2-induced apoptosis required the activation of caspase-8 but not caspase-9. The activation of caspase-8 results in the activation of caspase-3 as shown by an increase in the cleavage of the caspase substrate in the infected cells. To determine whether ORF3 protein could trigger apoptosis, ORF3 as well as ORF1 and ORF2 genes were transiently expressed in PK15 and Cos-7 cells for apoptotic activity assay. Transfection of cells with the ORF3 alone induced apoptosis using a pathway similar to that described in the context of viral infection. This is further confirmed by a significant decrease in apoptotic activity of infected cells in the absence of the ORF3 expression, suggesting that the protein plays a major role in the induction of virus-induced apoptosis. Altogether, these results indicate that ORF3 is a novel PCV2 protein that is not essential for viral replication in cultured cells but is involved in PCV2-induced apoptosis by activating caspase-8 and caspase-3 pathways.
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PMID:Characterization of a previously unidentified viral protein in porcine circovirus type 2-infected cells and its role in virus-induced apoptosis. 1595 72

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

Multinucleated epithelial giant cells (MEG) simulating viral cytopathic effect and/or dysplasia have been reported in the esophagus in association with inflammation, but the occurrence of similar cells in the colon has not been documented. Twenty-three colon specimens (22 biopsies and 1 partial colectomy) featuring MEG from 21 patients were evaluated for a variety of histologic features and correlated with clinical, endoscopic, and follow-up data. Patients included 9 males and 12 females (mean age, 64.9 years; range, 45-86 years). Eleven cases were obtained from 10 asymptomatic patients undergoing surveillance biopsies. Presenting symptoms in the remaining patients were dyspepsia, anemia, abdominal pain, and hematochezia. Over half (13 of 23) of the specimens were from descending and rectosigmoid colon, and almost all were visualized as polyps on endoscopy. Microscopically, all but 1 of the cases featured multiple MEG (range, 6 to >50 cells per biopsy) in the base and mid crypt zones of inflamed polyps with serrated architecture. Immunohistochemical stains for CMV, HSV, adenovirus, EBV, and polyoma virus were negative and no viral particles were identified on ultrastructural examination. Nuclear staining for hMLH1 and hMSH2, markers of microsatellite instability, was similar in distribution to adjacent serrated crypts, but reduced staining intensity was noted in occasional multinucleated cells. Expression of Ki-67 and cleaved caspase 3 was consistent with a quiescent or low proliferative state. Clinical follow-up was available for 9 patients (mean duration, 22.7 months). One patient died of heart failure; all others were well at last follow-up. Bizarre MEG may occasionally be seen within the crypts of inflamed polyps with serrated architecture, raising concern for dysplasia or viral infection. Immunohistochemical and ultrastructural studies fail to establish a viral etiology, and follow-up does not indicate clinically aggressive disease. These changes appear to represent a nonspecific, possibly degenerative response to inflammation and injury, and should be distinguished from dysplasia.
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PMID:Multinucleated epithelial giant cells in colorectal polyps: a potential mimic of viropathic and/or dysplastic changes. 1595 56

Type I IFN (IFN-I or IFN-alphabeta) plays an important role in the innate immune response against viral infection. Here we report that a potent inducer of IFN-alphabeta, polyinosinic-polycytidylic acid [poly(I:C)], led to the depletion of T cells in young, but not aged mice, and that this depletion was limited to central memory, but not effector memory, T cells. Although early activation of T cells in vivo by poly(I:C), as demonstrated by CD69, was not impaired with aging, the expression of active caspase-3 was higher in young compared with aged mice. This depletion of T cells and induction of active caspase-3 in young mice and of CD69 in both young and aged mice by poly(I:C) were blocked by anti-IFN-alphabeta Ab. Although poly(I:C) stimulated lower circulating levels of IFN-alphabeta in aged mice, administration of IFN-alphabeta after poly(I:C) did not induce depletion of T cells in aged mice. These results indicate that IFN-alphabeta plays a critical role in the depletion of T cells of young mice, and further suggest that the lower level of functional IFN-alphabeta and decreased induction of active caspase-3 in T cells of aged mice after poly(I:C) may be responsible for the increased resistance of T cells of aged mice to depletion.
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PMID:Depletion of T cells by type I interferon: differences between young and aged mice. 1603 24

The baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) can successfully infect Spodoptera frugiperda SF9 cells, but in contrast, in Spodoptera littoralis SL2 cells it induces apoptosis aborting the infection. To understand better the mechanism of induction and execution of apoptosis in SL2 cells, we identified and characterized the first Spodoptera littoralis caspase, Sl-caspase-1. Sl-caspase-1 is an effector caspase that cleaves DEVD but not IETD and LEHD substrates, and the caspase-3 inhibitor DQMD-CHO inhibited this activity. It was involved in two apoptotic pathways induced by UV irradiation and virus infection. Moreover processing of Sl-caspase-1 was a determinant factor for baculovirus induction of apoptosis in SL2 cells. Since very little is known on the regulation of expression of Lepidopteran caspases, we studied Sl-caspase-1 expression after exposure to apoptosis stimuli. We found that triggering apoptosis in SL2 cells increased the steady-state level of Sl-caspase-1 without changing the level of sl-caspase-1 mRNA, suggesting that Sl-caspase-1 was post-transcriptionally up regulated. This regulation might occur as an early event in transduction of the apoptotic signal.
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PMID:Spodoptera littoralis caspase-1, a Lepidopteran effector caspase inducible by apoptotic signaling. 1613 69

It is well-documented that alcohol drinking together with hepatitis viral infection accelerates liver injury; however the underlying mechanisms remain unknown. In this paper, we demonstrated that primary hepatocytes from transgenic mice overexpressing hepatitis B virus X protein (HBX) were more susceptible to ethanol- and TNF-alpha-induced apoptotic killing. Compared to normal control mouse hepatocytes, ethanol and/or TNF-alpha treatment led to a significant increase in reactive oxygen species, mitochondrial permeability transition, cytochrome C release, caspase-3 activity, and poly (ADP-ribose) polymerase degradation in hepatocytes from HBX transgenic mice. Blocking caspase-3 activity antagonized ethanol- and TNF-alpha-induced apoptosis in primary hepatocytes from HBX transgenic mice. Taken together, our findings suggest that HBX sensitizes primary mouse hepatocytes to ethanol- and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism, which may partly explain the synergistic effects of alcohol consumption and hepatitis B virus infection on liver injury.
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PMID:Hepatitis B virus X protein sensitizes primary mouse hepatocytes to ethanol- and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism. 1621 10

Many viruses have evolved strategies to counteract cellular immune responses, including apoptosis. Vaccinia virus, a member of the poxvirus family, encodes an antiapoptotic protein, F1L. F1L localizes to mitochondria and inhibits apoptosis by preventing the release of cytochrome c by an undetermined mechanism (S. T. Wasilenko, T. L. Stewart, A. F. Meyers, and M. Barry, Proc. Natl. Acad. Sci. USA 100:14345-14350, 2003; T. L. Stewart, S. T. Wasilenko, and M. Barry, J. Virol. 79:1084-1098, 2005). Here, we show that in the absence of an apoptotic stimulus, F1L associates with Bak, a proapoptotic member of the Bcl-2 family that plays a pivotal role in the release of cytochrome c. Cells infected with vaccinia virus were resistant to Bak oligomerization and the initial N-terminal exposure of Bak following the induction of apoptosis with staurosporine. A mutant vaccinia virus missing F1L was no longer able to inhibit apoptosis or Bak activation. In addition, the expression of F1L was essential to inhibit tBid-induced cytochrome c release in both wild-type murine embryonic fibroblasts (MEFs) and Bax-deficient MEFs, indicating that F1L could inhibit apoptosis in the presence and absence of Bax. tBid-induced Bak oligomerization and N-terminal exposure of Bak in Bax-deficient MEFs were inhibited during virus infection, as assessed by cross-linking and limited trypsin proteolysis. Infection with the F1L deletion virus no longer provided protection from tBid-induced Bak activation and apoptosis. Additionally, infection of Jurkat cells with the F1L deletion virus resulted in cellular apoptosis, as measured by loss of the inner mitochondrial membrane potential, caspase 3 activation, and cytochrome c release, indicating that the presence of F1L was pivotal for inhibiting vaccinia virus-induced apoptosis. Our data indicate that F1L expression during infection inhibits apoptosis and interferes with the activation of Bak.
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PMID:The vaccinia virus F1L protein interacts with the proapoptotic protein Bak and inhibits Bak activation. 1625 38

Infectious bursal disease virus (IBDV), the causative agent of a highly contagious disease in chickens, carries a small nonstructural protein (NS). This protein has been implicated to play a role in the induction of apoptosis. In this study, we investigate the kinetics of viral replication during a single round of viral replication and examine the mechanism of IBDV-induced apoptosis. Our results show that it is caspase dependent and activates caspases 3 and 9. Nuclear factor kappa B (NF-kappaB) is also activated and is required for IBDV-induced apoptosis. The NF-kappaB inhibitor MG132 completely inhibited IBDV-induced DNA fragmentation, caspase 3 activation, and NF-kappaB activation. To study the function of the NS protein in this context, we generated the recombinant rGLS virus and an NS knockout mutant, rGLSNSdelta virus, using reverse genetics. Comparisons of the replication kinetics and markers for virally induced apoptosis indicated that the NS knockout mutant virus induces earlier and increased DNA fragmentation, caspase activity, and NF-kappaB activation. These results suggest that the NS protein has an antiapoptotic function at the early stage of virus infection.
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PMID:Nonstructural protein of infectious bursal disease virus inhibits apoptosis at the early stage of virus infection. 1653 4

Patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have progressive liver disease that frequently leads to cirrhosis and death. We previously showed that hepatocytes exposed to HCV and HIV envelope proteins undergo apoptosis via an innocent-bystander mechanism as a result of the cell surface binding of these proteins, independent of direct viral infection. Here, we have defined the mechanism of this hepatocytic apoptosis. We observed enhanced signal transducer and activator of transcription factor 1 (STAT1) activation and phosphorylation after costimulation with HCV-E2 and HIV-gp120. Moreover, inhibitor studies indicated that Lyn kinase, p38 mitogen-activated protein kinase, and protein kinase C delta might be involved in STAT1 phosphorylation. To elucidate the downstream STAT1-mediated signaling, we overexpressed wild-type STAT1 alpha and the C-terminal domain-deleted mutant STAT1 beta . STAT1 alpha overexpression increased cell apoptosis and Fas ligand expression, compared with STAT1 beta overexpression. STAT1 alpha also enhanced the release of cytochrome c from the mitochondria and caspase-3 activity. These studies indicate that the HCV/HIV envelope proteins cooperatively induce hepatocytic apoptosis by activating a novel downstream STAT1 signaling pathway.
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PMID:Signal transducer and activator of transcription factor 1 mediates apoptosis induced by hepatitis C virus and HIV envelope proteins in hepatocytes. 1719 63


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