Effects of a dominant interfering mutant of FADD on signal transduction in activated T cells.
The cytoplasmic adaptor protein FADD is an essential component of the death-inducing signaling complexes (DISCs) that assemble when TNF receptor family members, such as Fas, are ligated. FADD inititates the proteolytic cascade that leads to apoptosis by binding to and promoting the autocatalytic activation of caspase-8 [1-4]. Surprisingly, FADD (but not caspase-8) is also required for T cells to proliferate upon their stimulation with mitogens [5-9]. Using transgenic mice expressing a dominant-negative mutant of FADD (FADD-DN), we show that functional FADD is required for T cells to proliferate in response to antigens in vivo as well as to mitogens in culture. The costimulation of wild-type and FADD-DN T cells with mitogens revealed that FADD-DN T cells have a cell-autonomous defect in intracellular signaling. In contrast to another study [6], p53 deficiency did not rescue mitogen-induced proliferation of FADD-DN T cells, and neither did enforced expression of the apoptosis inhibitor Bcl-2. Like wild-type T cells, FADD-DN T cells stimulated with mitogens mobilized intracellular calcium and activated members of the NF-kappaB transcription factor family as well as p38 mitogen-activated protein kinase (MAPK) and p44/42 MAPK. Therefore, FADD must act downstream of or in parallel to these signaling pathways.
The Walter and Eliza Hall Institute, Post Office Royal Melbourne Hospital, 3050, Victoria, Australia.
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D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D053200:Fas-Associated Death Domain Protein; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium