Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Normal epithelial cells undergo apoptosis if integrinmediated matrix contacts are lost, in a process termed 'anoikis'. Anoikis prevents shed epithelial cells from colonizing elsewhere, and is thus essential for maintaining appropriate tissue organisation. Aberrant oncogenes or tumor suppressor genes can cause resistance to anoikis, thereby contributing substantially to malignancy. Apoptosis is mediated by a well-ordered signaling cascade, which involves activation of intracellular proteases known as caspases. However, the mechanism by which the caspase cascade is initiated following cell-matrix detachment is unknown. We have hypothesized that death receptor activation might be involved in anoikis. To test this hypothesis, we developed a transient assay for anoikis and used it to assay the effects of proteins that block the function of domains found within death receptors known as death domains. In this assay, silencer of death domains (SODD) and dominant-negative FAS-associated death domain protein (FADD) efficiently inhibited anoikis in Madin-Darby canine kidney (MDCK) cells. The protective activity of SODD required its BAG domain, which interacts with the heat shock proteins hsp70 and hsc70, and inhibits the chaperone activity of the latter. Both caspase 8, which physically associates with death receptors, and cleavage of the caspase-8 substrate BID, were activated by cell-matrix detachment. These findings indicate a role for death receptors or proteins with related death domains in triggering anoikis.
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PMID:Evidence for a function of death-receptor-related, death-domain-containing proteins in anoikis. 1050 12

The bovine viral diarrhea virus (BVDV) strains exist as two biotypes, cytopathic (cp) and noncytopathic (ncp), according to their effects on tissue culture cells. It has been previously reported that cell death associated to cp BVDV in vitro is mediated by apoptosis. Here, experiments were conducted to determine the involvement of the NS3 protein in the induction of apoptosis. The NS3- and NS3Delta50 (deleted from the NH2-terminal 50 amino acids)-cDNA encoding sequences of BVDV NADL cp reference strain were cloned into adenoviral vectors (AdV) from which the BVDV gene of interest could be expressed from a tetracycline-responsive promoter. A549tTA cells infected in vitro with NS3 or NS3Delta50-expressing AdV showed cytopathic changes characterized by cell rounding and detachment, and nucleus chromatin condensation. DNA fragmentation assays, cytochrome c release, and activation of cellular caspases performed on these infected cells clearly correlated with the observed cytopathic changes with apoptosis. The BVDV NS3Delta50-induced apoptotic process was inhibited by caspase-8- and -9-specific peptide inhibitors (Z-IETD-FMK and Z-LEHD-FMK). Furthermore, apoptosis was inhibited in cells expressing the R1 subunit of herpes simplex virus type 2 ribonucleotide reductase (HSV2-R1) or hsp70, two proteins which are known to inhibit apoptosis associated with caspase-8 activation and cytochrome c release-dependent caspase-9 activation, respectively. Given that HSV2-R1, a specific inhibitor of the caspase-8 activation pathway, efficiently suppressed apoptosis and also prevented caspase-9 activation, the overall results indicate that the BVDV NS3/NS3Delta50 induces apoptosis initiated by caspase-8 activation and subsequent cytochrome c release-dependent caspase-9 activation.
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PMID:The bovine viral diarrhea virus (BVDV) NS3 protein, when expressed alone in mammalian cells, induces apoptosis which correlates with caspase-8 and caspase-9 activation. 1572 Sep 74

We have previously showed that equine arteritis virus (EAV), an arterivirus, induces apoptosis in vitro. To determine the caspase activation pathways involved in EAV-induced apoptosis, target cells were treated with peptide inhibitors of apoptosis Z-VAD-FMK (pan-caspase inhibitor), Z-IETD-FMK (caspase-8-specific inhibitor) or Z-LEHD-FMK (caspase-9-specific inhibitor) 4 h prior to infection with the EAV T1329 Canadian isolate. Significant inhibition of apoptosis was obtained with all peptide inhibitors used. Furthermore, apoptosis was inhibited in cells expressing the R1 subunit of herpes simplex virus type 2 ribonucleotide reductase (HSV2-R1) or hsp70, two proteins which are known to inhibit apoptosis associated with caspase-8 activation and cytochrome c release-dependent caspase-9 activation, respectively. Given the activation of Bid and the translocation of cytochrome c within the cytoplasm, the overall results indicate that EAV induces apoptosis initiated by caspase-8 activation and subsequent mitochondria-dependent caspase-9 activation.
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PMID:The equine arteritis virus induces apoptosis via caspase-8 and mitochondria-dependent caspase-9 activation. 1758 60

Diatoms are ubiquitous and abundant primary producers that have been traditionally considered as a beneficial food source for grazers and for the transfer of carbon through marine food webs. However, many diatom species produce polyunsaturated aldehydes that disrupt development in the offspring of grazers that feed on these unicellular algae. Here we provide evidence that production of the physiological messenger nitric oxide increases after treatment with the polyunsaturated aldehyde decadienal in embryos of the sea urchin Paracentrotus lividus. At high decadienal concentrations, nitric oxide mediates initial apoptotic events leading to loss of mitochondrial functionality through the generation of peroxynitrite. At low decadienal concentrations, nitric oxide contributes to the activation of hsp70 gene expression thereby protecting embryos against the toxic effects of this aldehyde. When nitric oxide levels were lowered by inhibiting nitric oxide synthase activity, the expression of hsp70 in swimming blastula decreased and the proportion of abnormal plutei increased. However, in later pluteus stages nitric oxide was no longer able to exert this protective function: hsp70 and nitric oxide synthase expression decreased with a consequent increase in the expression of caspase-8. Our findings that nitric oxide production increases rapidly in response to a toxic exogenous stimulus opens new perspectives on the possible role of this gas as an important messenger to environmental stress in sea urchins and for understanding the cellular mechanisms underlying toxicity during diatom blooms.
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PMID:Nitric oxide mediates the stress response induced by diatom aldehydes in the sea urchin Paracentrotus lividus. 2202 85