Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant.
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Dysregulation of apoptosis plays a crucial role in carcinogenesis. As part of death receptor- and mitochondrion-mediated apoptosis, the homologues caspases 10 and 8 may act as low-penetrance breast cancer (BC) susceptibility genes. In death receptor-mediated apoptosis, engagement of death receptors by their ligands involves the assembly of the death-inducing signalling complex (DISC). In mitochondrion-mediated apoptosis, the release of cytochrome c into the cytosol results in apoptosome formation. Recruitment of both caspases 10 and 8 (CASP10 and CASP8, respectively) to DISC and apoptosome leads to their activation by dimerization. We investigated the influence of the coding CASP10 variant V410I (G1228A) by performing a case-control study - using 511 familial BC cases and 547 control subjects - on BC risk and revealed a significant association of V410I with a reduced risk (OR = 0.62, 95% CI = 0.43-0.88, P = 0.0076) related to the number of variant alleles (P(trend) = 0.0039). As CASP10 and CASP8 functionally co-operate during apoptosis, we analysed the mutual effect of both CASP10 V410I and CASP8 D302H, resulting in a significant association between the number of the variant alleles I410 and H302 and a highly decreased familial BC risk (OR = 0.35, P(trend) = 0.007), pointing to the interaction between the CASP10 and CASP8 polymorphisms in breast carcinogenesis. (+info)
c-Flip expression and function in fetal mouse gonocytes.
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Apoptosis is a key mechanism in spermatogenesis, and in testis, most gonocytes degenerate at fetal and postnatal ages to select a cell subset committed to become germ stem cells. The aim of the present study is to investigate mechanisms controlling the massive apoptosis of fetal gonocytes. We evaluated the expression and function of c-Flip, an apoptosis inhibitor known to interfere with the proapoptotic Fas-signaling pathway in a variety of cell types, but never investigated in fetal testis. Expression of c-Flip long isoform (c-FlipL) within fetal testis was localized in gonocytes at 16.5 and 18.5 days post coitum (dpc), both at the mRNA and protein level, while it was weakly expressed or undetectable at earlier stages. Moreover, Fas protein was found in fetal testes at 13.5, 16.5, and 18.5 dpc. Testes at 18.5 dpc, expressing high levels of c-FlipL, were resistant to Fas-induced apoptosis while they became highly sensitive when c-FlipL was inhibited by antisense c-Flip oligos. In addition, there was an inverse relation between gonocyte spontaneous apoptosis sensitivity and c-FlipL levels. Furthermore, caspase-10 activity was inversely related with c-FlipL expression, suggesting that caspase-10 might be a target of c-FlipL. These data represent the first evidence demonstrating c-Flip expression in fetal testes and its role in protecting gonocytes from Fas-dependent apoptosis. (+info)
Crystal structure of a viral FLIP: insights into FLIP-mediated inhibition of death receptor signaling.
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Death receptor signaling is initiated by the assembly of the death-inducing signaling complex, which culminates in the activation of the initiator caspase, either caspase-8 or caspase-10. A family of viral and cellular proteins, known as FLIP, plays an essential role in the regulation of death receptor signaling. Viral FLIP (v-FLIP) and short cellular FLIP (c-FLIPS) inhibit apoptosis by interfering with death receptor signaling. The structure and mechanisms of v-FLIP and c-FLIPS remain largely unknown. Here we report a high resolution crystal structure of MC159, a v-FLIP derived from the molluscum contagiosum virus, which is a member of the human poxvirus family. Unexpectedly, the two tandem death effector domains (DEDs) of MC159 rigidly associate with each other through a hydrophobic interface. Structure-based sequence analysis suggests that this interface is conserved in the tandem DEDs from other v-FLIP, c-FLIPS, and caspase-8 and -10. Strikingly, the overall packing arrangement between the two DEDs of MC159 resembles that between the caspase recruitment domains of Apaf-1 and caspase-9. In addition, each DED of MC159 contains a highly conserved binding motif on the surface, to which loss-of-function mutations in MC159 map. These observations, in conjunction with published evidence, reveal significant insights into the function of v-FLIP and suggest a mechanism by which v-FLIP and c-FLIPS inhibit death receptor signaling. (+info)
Crystal structure of MC159 reveals molecular mechanism of DISC assembly and FLIP inhibition.
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The death-inducing signaling complex (DISC) comprising Fas, Fas-associated death domain (FADD), and caspase-8/10 is assembled via homotypic associations between death domains (DDs) of Fas and FADD and between death effector domains (DEDs) of FADD and caspase-8/10. Caspase-8/10 and FLICE/caspase-8 inhibitory proteins (FLIPs) that inhibit caspase activation at the DISC level contain tandem DEDs. Here, we report the crystal structure of a viral FLIP, MC159, at 1.2 Angstroms resolution. It reveals a noncanonical fold of DED1, a dumbbell-shaped structure with rigidly associated DEDs and a different mode of interaction in the DD superfamily. Whereas the conserved hydrophobic patch of DED1 interacts with DED2, the corresponding region of DED2 mediates caspase-8 recruitment and contributes to DISC assembly. In contrast, MC159 cooperatively assembles with Fas and FADD via an extensive surface that encompasses the conserved charge triad. This interaction apparently competes with FADD self-association and disrupts higher-order oligomerization required for caspase activation in the DISC. (+info)
The TRAF3-binding site of human molluscipox virus FLIP molecule MC159 is critical for its capacity to inhibit Fas-induced apoptosis.
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Members of the viral Flice/caspase-8 inhibitory protein (v-FLIP) family prevent induction of apoptosis by death receptors through inhibition of the processing and activation of procaspase-8 and -10 at the level of the receptor-associated death-inducing signaling complex (DISC). Here, we have addressed the molecular function of the v-FLIP member MC159 of the human molluscum contagiosum virus. MC159 FLIP powerfully inhibited both caspase-dependent and caspase-independent cell death induced by Fas. The C-terminal region of MC159 bound TNF receptor-associated factor (TRAF)3, was necessary for optimal TRAF2 binding, and mediated the recruitment of both TRAFs into the Fas DISC. TRAF-binding-deficient mutants of MC159 showed impaired inhibition of FasL-induced caspase-8 processing and Fas internalization, and had reduced antiapoptotic activity. Our findings provide evidence that a MC159/TRAF2/TRAF3 complex regulates a new aspect of Fas signaling, and identify MC159 FLIP as a molecule that targets multiple features of Fas-induced cell death. (+info)
Caspase activity is downregulated in choriocarcinoma: a cDNA array differential expression study.
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BACKGROUND: Placental trophoblast can be considered to be pseudomalignant tissue and the pathogenesis of gestational trophoblastic diseases remains to be clarified. AIMS: To examine the role of caspases 8 and 10, identified by differential expression, on trophoblast tumorigenesis. METHODS: cDNA array hybridisation was used to compare gene expression profiles in choriocarcinoma cell lines (JAR, JEG, and BeWo) and normal first trimester human placentas, followed by confirmation with quantitative real time polymerase chain reaction and immunohistochemistry. Caspase 10 and its closely related family member caspase 8 were analysed. RESULTS: Downregulation of caspase 10 in choriocarcinoma was detected by both Atlastrade mark human cDNA expression array and Atlastrade mark human 1.2 array. Caspase 10 mRNA expression was significantly lower in hydatidiform mole (p = 0.035) and chorioarcinoma (p = 0.002) compared with normal placenta. The caspase 8 and 10 proteins were expressed predominantly in the cytotrophoblast and syncytiotrophoblast, respectively, with significantly lower expression in choriocarcinomas than other trophoblastic tissues (p < 0.05). Immunoreactivity for both caspase 8 and 10 correlated with the apoptotic index previously assessed by terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (p = 0.02 and p = 0.04, respectively) and M30 (p < 0.001 and p = 0.003, respectively) approaches. CONCLUSIONS: These results suggest that the downregulation of capases 8 and 10 might contribute to the pathogenesis of choriocarcinoma. (+info)
The broad spectrum of autoimmune lymphoproliferative disease: molecular bases, clinical features and long-term follow-up in 31 patients.
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Autoimmune lymphoproliferative disorders, including autoimmune lymphoproliferative syndrome (ALPS) and Dianzani autoimmune lymphoproliferative disease (DALD), are inherited defects of the Fas apoptotic pathway characterized by lymphoid accumulation and autoimmune manifestations. We report the molecular, clinical, immunologic features and the long-term progress of 31 patients. Four carried Fas gene mutations and one also displayed a caspase 10 polymorphism that probably contributed to the phenotype. Seven patients developed antibody deficiency and their clinical pictures overlapped those of subjects with common variable immunodeficiency (CVID). We postulate the existence of a disorder that involves the Fas pathway and displays the characteristics of both autoimmune lymphoproliferative disease and CVID. (+info)
Roles of caspase-8 and caspase-10 in innate immune responses to double-stranded RNA.
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Upon viral infection, host cells trigger antiviral immune responses by inducing type I IFN and inflammatory cytokines. dsRNA generated during viral replication is recognized by the cytoplasmic RNA helicases retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, which interact with an adaptor, IFN-beta promoter stimulator-1, to activate the transcription factors NF-kappaB and IFN regulatory factor 3. In this article we demonstrate that caspase-8 and caspase-10 are involved in these pathways. Both caspases were cleaved during dsRNA stimulation, and overexpression of a cleaved form of these caspases activated NF-kappaB. Knockdown of caspase-10 or caspase-8 in a human cell line resulted in the reduction of inflammatory cytokine production. Cells derived from caspase-8-deficient mice also showed reduced expression of inflammatory cytokines as well as NF-kappaB activation. Furthermore, the Fas-associated death domain protein interacted with these two caspases and IFN-beta promoter stimulator 1. These results indicate that caspase-8 and caspase-10 are essential components that mediate NF-kappaB-dependent inflammatory responses in antiviral signaling. (+info)