Disease relevance of Casp8

• Silencing of caspase-8 in murine hepatocellular carcinomas is mediated via methylation of an essential promoter element [1].
• In a murine model of acute ischemia, caspase-8 is relocated into the nucleus of apoptotic neurons, where it cleaves PARP-2, a member of the poly(ADP-ribose) polymerase family involved in DNA repair [2].
• Recently, we have shown that Sendai virus (SeV) infection triggers apoptotic cell death by activation of the effector caspase-3 and initiator caspase-8 [3].
• Lyssavirus matrix protein induces apoptosis by a TRAIL-dependent mechanism involving caspase-8 activation [4].
• Reduced myocarditis following Coxsackievirus infection in cellular FLICE inhibitory protein--long form-transgenic mice [5].

High impact information on Casp8

• BID's activity is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, resulting in a change of cellular localization [6].
• Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis [7].
• Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy [8].
• Bax was dispensable for apical death-receptor signaling events including caspase-8 activation, but crucial for mitochondrial changes and downstream caspase activation [9].
• Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency [10].

Chemical compound and disease context of Casp8

• Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease [11].
• Apoptosis by gemcitabine in non-small cell lung cancer cell line KNS62 is induced downstream of caspase 8 and is profoundly blocked by Bcl-xL over-expression [12].
• To restore apoptosis sensitivity in dexamethasone-treated carcinomas, caspase-8 and caspase-9 were transfected [13].
• We conclude that caspase 8 and caspase 3 activation, but not ceramide generation, are required for CD95 ligand-induced apoptosis of glioma cells and that bcl-2, crm-A and NDGA all act upstream of caspases to inhibit apoptosis [14].
• Here, using primary cultures of rat hepatocytes and in vivo thioacetamide-induced liver failure, we showed that Me(2)SO failed to prevent any cleavage of initiator caspase-8 and -9 but constantly inhibited procaspase-3 maturation and apoptosis execution, pointing to an efficient inhibition of cleaved initiator caspase activities [15].

Biological context of Casp8

• Mice have a single structural locus (named Eef1b2) spanning six exons, which is ubiquitously expressed and maps close to Casp8 on mouse chromosome 1, and a processed pseudogene [16].
• These results suggest that Casper has two distinct roles: to cooperate with FADD and caspase-8 during embryonic development and to mediate cytoprotection against death factor-induced apoptosis [17].
• This phenotype is reminiscent of that reported for FADD-/- and caspase-8-/- embryos [17].
• To support our data, we mimicked the methylation pattern of a tumor-derived caspase-8 promoter in vitro using CpG methylase and found a strong reduction of promoter activity [1].
• In this study, we investigated caspase-8 expression in hepatocellular carcinomas (HCCs) using recently described HCC mouse models (c-myc and IgEGF transgenes) [1].

Anatomical context of Casp8

• Rather, Casp8-deficient B cells failed to proliferate in response to dsRNA and LPS, ligands for TLR3 and TLR4, respectively, but responded normally to the TLR9 agonist CpG DNA [18].
• The Caspase 8 null embryos exhibited impaired heart muscle development and congested accumulation of erythrocytes [19].
• Cellular FLICE-inhibitory protein is required for T cell survival and cycling [20].
• During both apoptosis signalling and mitogenic activation, FADD and caspase-8 aggregated in multiprotein complexes and formed caps at the plasma membrane but they did not colocalise with lipid rafts [21].
• Mitochondria significantly amplified the caspase-8 initiated DEVD-specific cleavage activity [22].

Associations of Casp8 with chemical compounds

• The murine caspase-8 promoter was characterized by luciferase-reporter analysis and the analysis of promoter methylation was performed by bisulfite genomic sequencing [1].
• DEX-induced caspase-8 activation, like ceramide-induced caspase-8 activation, correlates with the formation of Fas-associated death domain protein (FADD)/caspase-8 complex [23].
• Our results suggest that, in addition to processing procaspase-3 and the BH3 protein Bid, active caspase-8 can cleave and activate procaspase-9 in response to TNF receptor crosslinking in murine cells [24].
• Knockout of caspase-8, a cysteine protease that participates in the signaling for cell death by receptors of the TNF/nerve growth factor family, is lethal to mice in utero [25].
• Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway [26].

Physical interactions of Casp8

• Axonal dynactin p150Glued transports caspase-8 to drive retrograde olfactory receptor neuron apoptosis [27].
• Fas ligand binding on oocytic fas may result in caspase 8 activation [28].
• In cultured podocytes, cross-linking of the Fas receptor to mimic ligand binding induced caspase 8 activity and apoptosis in both normal and HIVAN podocytes [29].
• Chromatin immunoprecipitation and luciferase reporter analyses showed that c-myc binds and represses the human FLIP promoter. c-myc expression enhanced TRAIL-induced caspase 8 cleavage and FLIP cleavage at the death-inducing signaling complex [30].

Enzymatic interactions of Casp8

• In addition, caspase-8 cleaves Bid, the truncated form of which has the capacity to translocate to the mitochondria and induce cytochrome c release [31].
• Immunoblot analysis revealed that the upstream caspases-8 and -9 are both activated in a time-dependent fashion, and caspase-8 is cleaved prior to caspase-9 [32].
• The NH(2)-terminal region of BID contains a caspase-8 (Casp-8) cleavage site and the cleaved form of BID translocates to mitochondrial membranes where it is a potent inducer of cytochrome c release [33].

Regulatory relationships of Casp8

• Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex [34].
• This effect was secondary to the failure of jnk2-/- mice to activate caspase-8 [26].
• TNF-alpha in vivo stimulates apoptosis in fibroblasts through caspase-8 activation and modulates the expression of pro-apoptotic genes [35].
• The presence of FLIP strongly interfered with FasL-induced activation of caspase-8 and caspase-3 preventing subsequent cell death [36].
• CONCLUSION: Fas may rely on both caspase-8 activation (extrinsic pathway) and mitochondria (intrinsic pathway) to activate caspase-3 [37].

Other interactions of Casp8

• We show that murine caspase-9 is efficiently processed by active caspase-8 at SEPD, the motif at which caspase-9 autoprocesses following its recruitment to the apoptosome [24].
• We generated novel monoclonal antibodies specific for mouse FADD and caspase-8 to investigate whether cellular responses, apoptosis or proliferation, might be explained by differences in post-translational modification and subcellular localisation of these proteins [21].
• Procaspase-2 was maturated by caspase-8 and -3, and to a lesser extent by caspase-7, while the active caspase-2 did not process any of the procaspases examined, except its own precursor [38].
• Fas recruits caspase 8, which initiates the death program through the subsequent activation of caspase 3 [39].
• We have, for the first time, identified a predominant role for the caspase-8/Bid pathway in signaling associated with hyperoxic lung injury and cell death in vivo and in vitro [40].

Analytical, diagnostic and therapeutic context of Casp8

• Direct targeting of caspase-8 with siRNA and antisense (AS) approaches abolished TNF-alpha-induced activation of NF-kappaB in NIH3T3, HeLa, and HEK293 cells as determined with luciferase reporter gene and cell fractionation assays [41].
• Caspase-8 and caspase-3 small interfering RNA decreases ischemia/reperfusion injury to the liver in mice [42].
• Molecular cloning and characterization of mouse caspase-8 [43].
• Expression of caspase-8 was detected in the various tissues of adult mouse and in embryos at 9.5 days and 17.5 days of development by Northern-blot analysis [43].
• Western blot analysis showed that gamma-tocotrienol treatment increased the levels of cleaved (active) caspase-8 and caspase-3 [44].

References