scholarly journals Fas-associated Death Domain Protein (FADD) and Caspase-8 Mediate Up-regulation of c-Fos by Fas Ligand and Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) via a FLICE Inhibitory Protein (FLIP)-regulated Pathway

2001 ◽  
Vol 276 (35) ◽  
pp. 32585-32590 ◽  
Author(s):  
Daniela Siegmund ◽  
Davide Mauri ◽  
Nathalie Peters ◽  
Peter Juo ◽  
Margot Thome ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Fas Ligand ◽  
Caspase 8 ◽  
Death Domain ◽  
Inhibitory Protein ◽  
Domain Protein ◽  
Necrosis Factor

scholarly journals Hepatitis C Virus Core Protein Inhibits Tumor Necrosis Factor Alpha-Mediated Apoptosis by a Protective Effect Involving Cellular FLICE Inhibitory Protein

2006 ◽  
Vol 80 (9) ◽  
pp. 4372-4379 ◽  
Author(s):  
Kousuke Saito ◽  
Keith Meyer ◽  
Rebecca Warner ◽  
Arnab Basu ◽  
Ratna B. Ray ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Core Protein ◽  
Death Domain ◽  
Inhibitory Protein ◽  
Necrosis Factor Alpha ◽  
Hcv Core Protein ◽  
Tnf Α ◽  
Factor Alpha ◽  
Domain Protein ◽  
Necrosis Factor

ABSTRACT We have previously shown that hepatitis C virus (HCV) core protein modulates multiple cellular processes, including those that inhibit tumor necrosis factor alpha (TNF-α)-mediated apoptosis. In this study, we have investigated the signaling mechanism for inhibition of TNF-α-mediated apoptosis in human hepatoma (HepG2) cells expressing core protein alone or in context with other HCV proteins. Activation of caspase-3 and the cleavage of DNA repair enzyme poly(ADP-ribose) polymerase were inhibited upon TNF-α exposure in HCV core protein-expressing HepG2 cells. In vivo protein-protein interaction studies displayed an association between TNF receptor 1 (TNFR1) and TNFR1-associated death domain protein (TRADD), suggesting that the core protein does not perturb this interaction. A coimmunoprecipitation assay also suggested that HCV core protein does not interfere with the TRADD-Fas-associated death domain protein (FADD)-procaspase-8 interaction. Further studies indicated that HCV core protein expression inhibits caspase-8 activation by sustaining the expression of cellular FLICE (FADD-like interleukin-1β-converting enzyme)-like inhibitory protein (c-FLIP). Similar observations were also noted upon expression of core protein in context to other HCV proteins expressed from HCV full-length plasmid DNA or a replicon. A decrease in endogenous c-FLIP by specific small interfering RNA induced TNF-α-mediated apoptotic cell death and caspase-8 activation. Taken together, our results suggested that the TNF-α-induced apoptotic pathway is inhibited by a sustained c-FLIP expression associated with the expression of HCV core protein, which may play a role in HCV-mediated pathogenesis.

scholarly journals LIGHT, a Member of the Tumor Necrosis Factor Ligand Superfamily, Prevents Tumor Necrosis Factor-α-mediated Human Primary Hepatocyte Apoptosis, but Not Fas-mediated Apoptosis

2002 ◽  
Vol 277 (51) ◽  
pp. 50054-50061 ◽  
Author(s):  
Hideki Matsui ◽  
Yukiko Hikichi ◽  
Isamu Tsuji ◽  
Takao Yamada ◽  
Yasushi Shintani
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Time Course ◽  
Caspase 3 ◽  
Nuclear Factor Κb ◽  
Caspase 8 ◽  
Death Domain ◽  
Human Primary Hepatocytes ◽  
Induced Apoptosis ◽  
Necrosis Factor

LIGHT is a member of tumor necrosis factor (TNF) superfamily, and its receptors have been identified as lymphotoxin-β receptor (LTβR) and the herpesvirus entry mediator (HVEM)/ATAR/TR2, both of which lack the cytoplasmic sequence termed the “death domain.” The present study has demonstrated that LIGHT inhibits TNFα-mediated apoptosis of human primary hepatocytes sensitized by actinomycin D (ActD), but not Fas- or TRAIL-mediated apoptosis. Furthermore, LIGHT does not prevent some cell lines such as HepG2 or HeLa from undergoing ActD/TNFα-induced apoptosis. This protective effect requires LIGHT pretreatment at least 3 h prior to ActD sensitization. LIGHT stimulates nuclear factor-κB (NF-κB)-dependent transcriptional activity in human hepatocytes like TNFα. The time course of NF-κB activation after LIGHT administration is similar to that of the pretreatment required for the anti-apoptotic effect of LIGHT. LIGHT inhibits caspase-3 processing on the apoptotic protease cascade in TNFα-mediated apoptosis but not Fas-mediated apoptosis. In addition, increased caspase-3 and caspase-8 activities in ActD/TNFα-treated cells are effectively blocked by LIGHT pretreatment. However, LIGHT does not change the expression of TNFRp55, TNFRp75, and Fas. These results indicate that LIGHT may act as an anti-apoptotic agent against TNFα-mediated liver injury by blocking the activation of both caspase-3 and caspase-8.

scholarly journals CD40 Induces Apoptosis in Carcinoma Cells through Activation of Cytotoxic Ligands of the Tumor Necrosis Factor Superfamily

2000 ◽  
Vol 20 (15) ◽  
pp. 5503-5515 ◽  
Author(s):  
Aristides G. Eliopoulos ◽  
Clare Davies ◽  
Pauline G. Knox ◽  
Neil J. Gallagher ◽  
Simon C. Afford ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Fas Ligand ◽  
Carcinoma Cells ◽  
Death Domain ◽  
Cd40 Ligation ◽  
Soluble Cd40 Ligand ◽  
Trail Receptors ◽  
Necrosis Factor

ABSTRACT CD40, a tumor necrosis factor (TNF) receptor (TNFR) family member, conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death. The ability of CD40 to mediate apoptosis in carcinoma cells is intriguing given the fact that the CD40 cytoplasmic C terminus lacks a death domain homology with the cytotoxic members of the TNFR superfamily, such as Fas, TNFR1, and TNF-related apoptosis-inducing ligand (TRAIL) receptors. In this study, we have probed the mechanism by which CD40 transduces death signals. Using a trimeric recombinant soluble CD40 ligand to activate CD40, we have found that this phenomenon critically depends on the membrane proximal domain (amino acids 216 to 239) but not the TNFR-associated factor-interacting PXQXT motif in the CD40 cytoplasmic tail. CD40-mediated cytotoxicity is blocked by caspase inhibitors, such as zVAD-fmk and crmA, and involves activation of caspase 8 and caspase 3. Interestingly, CD40 ligation was found to induce functional Fas ligand, TRAIL (Apo-2L) and TNF in apoptosis-susceptible carcinoma cells and to up-regulate expression of Fas. These findings identify a novel proapoptotic mechanism which is induced by CD40 in carcinoma cells and depends on the endogenous production of cytotoxic cytokines and autocrine or paracrine induction of cell death.

scholarly journals Stat1 as a Component of Tumor Necrosis Factor Alpha Receptor 1-TRADD Signaling Complex To Inhibit NF-κB Activation

2000 ◽  
Vol 20 (13) ◽  
pp. 4505-4512 ◽  
Author(s):  
Yingjian Wang ◽  
Tong R. Wu ◽  
Shiying Cai ◽  
Thomas Welte ◽  
Y. Eugene Chin
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Death Domain ◽  
Necrosis Factor Alpha ◽  
Signaling Complex ◽  
Tnf Α ◽  
Factor Alpha ◽  
Domain Protein ◽  
Necrosis Factor

ABSTRACT Activated tumor necrosis factor alpha (TNF-α) receptor 1 (TNFR1) recruits TNFR1-associated death domain protein (TRADD), which in turn triggers two opposite signaling pathways leading to caspase activation for apoptosis induction and NF-κB activation for antiapoptosis gene upregulation. Here we show that Stat1 is involved in the TNFR1-TRADD signaling complex, as determined by employing a novel antibody array screening method. In HeLa cells, Stat1 was associated with TNFR1 and this association was increased with TNF-α treatment. TNFR1 signaling factors TRADD and Fas-associated death domain protein (FADD) were also found to interact with Stat1 in a TNF-α-dependent process. Our in vitro recombinant protein-protein interaction studies demonstrated that Stat1 could directly interact with TNFR1 and TRADD but not with FADD. Interaction between Stat1 and receptor-interacting protein (RIP) or TNFR-associated factor 2 (TRAF2) was not detected. Examination of Stat1-deficient cells showed an apparent increase in TNF-α-induced TRADD-RIP and TRADD-TRAF2 complex formation, while interaction between TRADD and FADD was unaffected. As a consequence, TNF-α-mediated I-κB degradation and NF-κB activation were markedly enhanced in Stat1-deficient cells, whereas overexpression of Stat1 in 293T cells blocked NF-κB activation by TNF-α. Thus, Stat1 acts as a TNFR1-signaling molecule to suppress NF-κB activation.

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