title: p53-dependent impairment of T-cell proliferation in FADD dominant-negative transgenic mice.
abstract: Members of the tumour necrosis factor (TNF) receptor family exert pleiotropic effects and can trigger both apoptosis and proliferation [1]. In their cytoplasmic region, some of these receptors share a conserved sequence motif - the 'death domain' - which is required for transduction of the apoptotic signal by recruiting other death-domain-containing adaptor molecules like the Fas-associated protein FADD/MORT1 or the TNF receptor-associated protein TRADD [2-4]. FADD links the receptor signal to the activation of the caspase family of cysteine proteases [5,6]. Functional inactivation of individual receptor family members often fails to exhibit a distinctive phenotype, probably because of redundancy [7-9]. 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. We established transgenic mice expressing FADD-DN under the influence of the lck promoter and investigated the consequences of its expression in T cells. As expected, FADD-DN thymocytes were protected from death induced by CD95 (Fas/Apo1), whereas apoptosis induced by ultraviolet (UV) irradiation, anti-CD3 antibody treatment or dexamethasone was unaffected, as was spontaneous cell death. Surprisingly, however, we also observed profound inhibition of thymocyte proliferation in vivo and of activation-induced proliferation of thymocytes and mature T cells in vitro. This inhibition of proliferation was not due to increased cell death and appeared to be p53 dependent.
authors.affiliation: Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK.
authors.forename: M
authors.initials: M
authors.lastname: Zörnig
authors.forename: A O
authors.initials: AO
authors.lastname: Hueber
authors.forename: G
authors.initials: G
authors.lastname: Evan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002455:Cell Division; D002478:Cells, Cultured; D053200:Fas-Associated Death Domain Protein; D005799:Genes, Dominant; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008934:Mitogens / Q000494:pharmacology; D009154:Mutation; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D019014:fas Receptor / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D008934:Mitogens; D018124:Receptors, Tumor Necrosis Factor; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor