Disease relevance of Fadd

• Here we demonstrate that expression of either CrmA, the cowpox virus serpin, or an inhibitor of the adapter protein FADD/MORT1 blocks Fas-mediated apoptosis but has no effect on BCR ligation-induced apoptosis of the B cell line WEHI-231 [1].
• Mice with a deletion in the FADD gene did not survive beyond day 11.5 of embryogenesis; these mice showed signs of cardiac failure and abdominal hemorrhage [2].
• Dominant negative MORT1/FADD rescues mice from CD95 and TNF-induced liver failure [3].
• These data suggest a primary role for FADD/caspase-8 signaling that is necessary and sufficient for apoptosis of CMs subjected to hypoxia/SD [4].
• METHODS: A FADD deletion mutant lacking the death effector domain was introduced into mice by transduction with an adenovirus vector, and the effect of this FADD dominant negative mutant was examined in several liver injury models [5].

High impact information on Fadd

• FADD (also known as Mort-1) is a signal transducer downstream of cell death receptor CD95 (also called Fas) [2].
• FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis [2].
• Chimeric embryos showing a high contribution of FADD null mutant cells to the heart reproduce the phenotype of FADD-deficient mutants [2].
• We show here that FADD has a domain implicated in cell proliferation [6].
• Mutant FADD T cells are defective in cell cycle progression, suggesting that regulation of phosphorylation at serine 191 is essential for growth/proliferation [6].

Chemical compound and disease context of Fadd

• In contrast to Pc 4 photosensitization, TNF did not induce either apoptosis or ceramide accumulation in FADD k/o cells [7].

Biological context of Fadd

• Thus, mouse Mort/FADD is an essential downstream component that mediates Fas-induced apoptosis [8].
• In FADD-/- embryonic fibroblasts reconstituted by transfection with a FADD cDNA expression construct, the TNF responsiveness of A-SMase was restored [9].
• 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 [10].
• FADD is a key adaptor modulating several signaling pathways such as apoptosis induced by Fas (CD95) and tumor necrosis factor receptor 1, and cell proliferation induced by mitogens [11].
• Further mutagenesis was targeted at charged residues in the FADD death domain, presumably mediating electrostatic interactions with Fas [11].

Anatomical context of Fadd

• Loss of FADD protein expression results in a biased Fas-signaling pathway and correlates with the development of tumoral status in thyroid follicular cells [12].
• Ionizing radiation and chemotherapeutic drugs induce apoptosis in lymphocytes in the absence of Fas or FADD/MORT1 signaling. Implications for cancer therapy [13].
• To investigate the role of MORT1/FADD in hepatocyte apoptosis, we generated transgenic mice expressing liver-specific dominant negative mutant [3].
• Furthermore, 661W cells are highly sensitive to the FADD protein, which may suggest a number of novel therapeutic approaches to halt photoreceptor cell apoptosis [14].
• The switch in astrocyte sensitivity was accompanied by up-regulation of caspase-8 and CD95 as well as the capacity to recruit Fas-associated death domain (FADD) to the activated death receptor complex [15].

Associations of Fadd with chemical compounds

• In conclusion, our experiments provide evidence that MORT1/FADD is indispensable for Fas and TNF-mediated hepatic injury [3].
• In one exception, replacing arginine 117 with an uncharged residue disrupted target binding and apoptosis signaling, but restoring the positive charge at position 117 failed to reconstitute the FADD function [11].
• Western blot analysis also showed that alpha-tocotrienol did not induce FasL or FADD translocation from the cytosolic to membrane fraction in these cells [16].
• In contrast, both GCDC and TCDC treatment resulted in Fas aggregation and recruitment of a dominant-negative FADD green fluorescent protein (GFP) and C360S procaspase 8-GFP to the plasma membrane [17].
• In this study we report the interesting and unexpected result that actinomycin D increased the expression of FADD protein, and we demonstrate that other cellular stresses like ultraviolet irradiation or heat shock could also increase FADD levels in hepatocytes [18].

Physical interactions of Fadd

• Whereas mutations in Fas disrupt its binding to FADD and cause autoimmune lymphoproliferative (lpr) syndromes, a FADD deficiency blocks embryonic development in mice [11].

Regulatory relationships of Fadd

• Requirement of FADD for tumor necrosis factor-induced activation of acid sphingomyelinase [9].
• FADD inititates the proteolytic cascade that leads to apoptosis by binding to and promoting the autocatalytic activation of caspase-8 [1-4] [19].
• To circumvent this problem, we used a dominant-negative mutant of FADD (FADD-DN) which should block all TNF receptor family members that use FADD as an adaptor [20].
• CONCLUSION: TNF-alpha induces hepatocyte apoptosis by up regulation expression of FADD protein [21].

Other interactions of Fadd

• 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 [22].
• In addition, interleukin-1-induced activation of A-SMase in FADD-deficient cells was unaltered [9].
• In an in-depth study of the Fas/FasL-signaling pathway in thyroid tumor development, we have demonstrated that tumor cells specifically downregulate the multideath receptor adapter Fas-associated death domain (FADD) [12].
• In particular, the TNF-R55-associated protein FADD seems to be responsible for recruitment and subsequent activation of caspase 8 [9].
• Fas-associated death domain (FADD) and caspase-8 are key signal transducers for death receptor-induced apoptosis, whereas cellular FLICE-inhibitory protein (cFLIP) antagonizes this process [23].

Analytical, diagnostic and therapeutic context of Fadd

• In primary embryonic fibroblasts from FADD-deficient mice the activation of A-SMase by TNF-R55 ligation was almost completely impaired [9].
• Immunoprecipitates of fas antigen from membrane preparations made from control or castrated rat prostates were analyzed for coprecipitation of FADD and RIP proteins to assess the activation state of the fas antigen before and after castration [24].
• Purified peripheral FADD-deficient T cells failed to undergo extensive homeostatic expansion after adoptive transfer into lymphocyte-deficient hosts, and responded poorly to proliferation induced by ex vivo TCR stimulation [25].
• PyLT-Ag co-precipitated following immunoprecipitation of caspase-8 or FADD, both components of the DISC [26].
• The expression of protein and mRNA of FADD were detected by immunohistochemistry and PT-PCR [21].

References