p53-dependent impairment of T-cell proliferation in FADD dominant-negative transgenic mice

• Published in: Current biology 1998-04, Vol.8 (8), p.467-470
• Main Authors: Zörnig, Martin, Hueber, Anne-Odile, Evan, Gerard
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Carrier Proteins - genetics; Carrier Proteins - immunology; Cell Division; Cells, Cultured; fas Receptor - pharmacology; Fas-Associated Death Domain Protein; Genes, Dominant; Lymphocyte Activation; Mice; Mice, Transgenic; Mitogens - pharmacology; Mutation; Receptors, Tumor Necrosis Factor - immunology; T-Lymphocytes - cytology; Thymus Gland - immunology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/S0960-9822(98)70182-4

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.