Disease relevance of CASP8

• However, approximately 20% of the neuroblastoma cell lines with methylated CASP8 alleles are also highly resistant to staurosporine (STS)- and radiation-induced cell death, presumably because cytochrome c is not released from mitochondria [1].
• We have previously reported that the key apoptosis related gene caspase 8 (CASP8) is frequently silenced in small cell lung cancer (SCLC) tumors and cell lines usually, but not always, by aberrant promoter methylation [2].
• Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant [3].
• We conclude that epigenetic TSG inactivation is a significant feature of medulloblastoma, and identify RASSF1A, HIC1 and CASP8 as potentially critical genes in its pathogenesis [4].
• The percentages of TRAIL pathway genes (CASP8, TFRSF10C, and TFRSF10D) methylated were 30, 9.5, and 36.4%, respectively, in ependymomas and 50, 50, and 16.7%, respectively, in choroid plexus papillomas [5].
• The most prominent distinction was the presence of previously undetected CASP8 hypermethylation in the GBM relapses (P = 0.031) [6].
• Transfection of wild type but not mutant caspase-8 into caspase-8-deficient Ewing's sarcoma cells restored sensitivity to TRAIL, indicating that up-regulation of caspase-8 is sufficient to restore TRAIL sensitivity [7].
• A significant decreased risk of bladder cancer was found for the CASP8 -652 6N ins/del (adjusted odds ratio, 0.72; 95% confidence interval, 0.53-0.99) and del/del (odds ratio, 0.37; 95% confidence interval, 0.18-0.77) genotypes [8].

Psychiatry related information on CASP8

• These radiologic findings are an optical illusion (Mach band, background contrast effect) [9].
• This hypothesis was addressed by assessing Mach IV psychometric scale performance in a group of 51 patients with schizophrenia and in 93 controls [10].
• Visual illusions in computed tomography: phenomena related to Mach effect [11].
• Machiavellianism: dimensionality of the Mach IV and its relation to self-monitoring in a Spanish sample [12].
• To estimate this association in a sample of Turkish people, 361 physicians were selected among the total number of 5,959 working in Ankara City Center. A self-administered questionnaire including the Mach IV scale and Job Satisfaction scale developed by Kasapoğlu was applied to the subjects [13].

High impact information on CASP8

• We have cloned a novel protein, MACH, that binds to MORT1 [14].
• Expression of MACH isoforms that contain an incomplete ICE/CED-3 region provides effective protection against the cytotoxicity induced by Fas/APO-1 or p55-R triggering [14].
• These findings suggest that MACH is the most upstream enzymatic component in the Fas/APO-1- and p55-R-induced cell death signaling cascades [14].
• Cellular expression of the proteolytic MACH isoforms results in cell death [14].
• Expression and methylation of CASP8 in neuroblastoma: identification of a promoter region [15].

Chemical compound and disease context of CASP8

• Sensitization to TRAIL-induced apoptosis and modulation of FLICE-inhibitory protein in B chronic lymphocytic leukemia by actinomycin D [16].
• Lactacystin activates FLICE (caspase 8) protease and induces apoptosis in Fas-resistant adult T-cell leukemia cell lines [17].
• Here, we show that treatment with the histone deacetylase (HDAC) inhibitor FR901228 renders Fas-resistant osteosarcoma cell lines sensitive to Fas-mediated apoptosis by downregulating expression of cellular FLIP (cellular FLICE-inhibitory protein), an inhibitor of Fas-mediated activation of caspase-8 [18].
• 15d-PGJ(2)-induced inhibition of NF-kappaB function is rapidly followed by down-regulation of NF-kappaB-dependent antiapoptotic proteins cIAPs 1/2, Bcl-X(L), and cellular FLICE-inhibitory protein, leading to caspase activation and induction of apoptosis in breast cancer cells resistant to treatment with paclitaxel and doxorubicin [19].
• Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH I Study [20].

Biological context of CASP8

• No association was detected between methylation of RASSF1A, CASP8 or MGMT in individual tumours [21].
• CASP8 gene expression was frequently lost (79%) at message and protein levels in SCLC but not in non-SCLC (NSCLC) [2].
• The putative tumor suppressor gene RASSF1A was methylated in all 13 cell lines, and TSP-1 and CASP8 were methylated in 11 of 13 cell lines [22].
• Recruitment of both caspases 10 and 8 (CASP10 and CASP8, respectively) to DISC and apoptosome leads to their activation by dimerization [3].
• Structure and chromosome localization of the human CASP8 gene [23].

Anatomical context of CASP8

• Importantly, normal lung fibroblasts are resistant to DR4-CD overexpression and show no evidence of PARP-, CASP8- or CASP3-cleavage despite similar levels of adenovirus-delivered DR4-CD protein as the cancer cells [24].
• From our results we conclude that methylation of the CASP8 5' UTR region may play a role in inactivation of CASP8 in neural crest tumors [25].
• However, the experiments presented suggest that resistance to CD95-mediated apoptosis in T cells can also be regulated at the level of recruitment of FLICE to the DISC [26].
• Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand-mediated apoptosis [27].
• This may indicate the presence of inhibitors within the cells, but resistance to apoptosis could not be correlated with expression of the caspase inhibitor FLICE-inhibitory protein. mRNA for another TRAIL receptor, osteoprotegerin, was expressed in 22 of the melanoma lines but not on melanocytes [28].

Associations of CASP8 with chemical compounds

• Death receptors of the Tumor Necrosis Factor (TNF) family form membrane-bound self-activating signaling complexes that initiate apoptosis through cleavage of proximal caspases including CASP8 and 10 [24].
• The retinoic acid analogue 4HPR, IFN-gamma, and the demethylating agent 5-aza-cytidine activate this promoter in NB cells that lack endogenous caspase-8, indicating that this element may regulate both constitutive and inducible CASP8 expression [29].
• Activation of FLICE is blocked by the peptide inhibitors zVAD-fmk, zDEVD-fmk and zIETD-fmk, but not by crmA or Ac-YVAD-CHO [30].
• We demonstrate that recombinant Mch5 is able to process/activate all known ICE/Ced-3-like cysteine proteases and is potently inhibited by CrmA [31].
• We thus studied aberrant methylation of the genes RASSF1A and CASP8 and its consequence on expression in cell lines and primary tumors using a combination of semiquantitative methylation specific PCR (MSP), bisulfite sequencing and RT-PCR [32].
• Instead, we find that integrin-mediated adhesion promotes caspase 8 phosphorylation on tyrosine 380 [33].

Physical interactions of CASP8

• In addition, MRIT simultaneously and independently interacts with BclXL and FLICE in mammalian cells [34].
• FLICE binds to the death effector domain of FADD and upon overexpression induces apoptosis that is blocked by the ICE family inhibitors, CrmA and z-VAD-fmk [35].
• In addition, analysis revealed that CED-4 can simultaneously interact with CED-3 and its mammalian counterparts interleukin-1beta-converting enzyme (ICE) and FLICE [36].
• Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis [37].

Regulatory relationships of CASP8

• Here, we show that E2F1 triggers apoptosis in various lung adenocarcinoma cell lines by a mechanism involving the specific downregulation of the cellular FLICE-inhibitory protein short, leading to caspase-8 activation at the death-inducing signaling complex [38].
• Interaction of the adenovirus 14.7-kDa protein with FLICE inhibits Fas ligand-induced apoptosis [39].
• Furthermore, we have observed that TCR-mediated neosynthesis of FLICE-like inhibitory protein mRNA is suppressed either by protein tyrosine kinase inhibitors or cyclosporin A [40].
• Fibroblast-like synoviocytes from rheumatoid arthritis patients express less FLICE-inhibitory protein than fibroblast-like synoviocytes from trauma patients: comment on the article by Schedel et al [41].
• These findings suggest a novel model for the regulation of caspase-8 during Mn(2+)-induced apoptosis based on the sequential activation of p38 MAPK, MSK1, caspase-8 and mitochondria, respectively [42].
• In the nucleus, DEDa interacts with TOPORS, a p53 and topoisomerase I binding protein, and possibly displaces p53 from TOPORS, allowing p53 to stimulate caspase-8 gene expression [43].
• Interaction between caspase 8 and p85alpha promotes Rab5 GTP loading, alters endosomal trafficking, and results in the accumulation of Rab5-positive endosomes at the edge of the cell [44].

Other interactions of CASP8

• Since the overall architecture and function of this molecule is similar to that of FLICE, it has been designated FLICE2 [45].
• In contrast, complete methylation of HIC1 and CASP8 in a subset of primary tumours (17/44 and 14/39) occurred against a consistent background of partial methylation in the normal cerebellum [4].
• Less frequent methylation was observed for CASP8, MGMT and TP73 (5-20%) [46].
• However, unlike FLICE, the C-terminal domain of MRIT lacks the caspase catalytic consensus sequence QAC(R/Q)G [34].
• Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases [31].

Analytical, diagnostic and therapeutic context of CASP8

• Western blots showed that FLICE/caspase-8 was upregulated and activated by 24 hours of incubation with IFNgamma [47].
• Western blots of ICE/caspase-1, which might be required for amplification of the initial FLICE activation signal, showed that pro-ICE expression significantly increased after treatment with IFNgamma for 24 hours and cleavage of pro-ICE also increased [47].
• Flow cytometry of fresh erythroblasts revealed a considerable expression of the caspases CPP32 and FLICE in both their constitutive proenzymatic forms and in cleaved subunits [48].
• Ceramide, in contrast to Fas ligation, did not induce activation of caspase-8/FLICE and neither SPP nor TPA were able to prevent this activation [49].
• Silicon phthalocyanine 4 photodynamic therapy also caused a significant activation of FLICE, as evident from the appearance of cleaved products of pro-caspase 8 [50].

References