P53-DEPENDENT IMPAIRMENT OF T-CELL PROLIFERATION IN FADD DOMINANT-NEGATIVE TRANSGENIC MICE

Members of the tumour necrosis factor (TNF) receptor family exert plei otropic 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 transduct ion of the apoptotic signal by recruiting other death-domain-containin g adaptor molecules like the Fas-associated protein FADD/MORT1 or the TNF receptor-associated protein TRADD [2-4]. FADD links the receptor s ignal to the activation of the caspase family of cysteine proteases [5 ,6]. Functional inactivation of individual receptor family members oft en fails to exhibit a distinctive phenotype, probably because of redun dancy [7-9]. To circumvent this problem, we used a dominant-negative m utant of FADD (FADD-DN) which should block all TNF receptor family mem bers that use FADD as an adaptor. We established transgenic mice expre ssing FADD-DN under the influence of the lck promoter and investigated the consequences of its expression in T cells. As expected, FADD-DN t hymocytes were protected from death induced by cogs (Fas/Apo1), wherea s apoptosis induced by ultraviolet (UV) irradiation, anti-CD3 antibody treatment or dexamethasone was unaffected, as was spontaneous cell de ath. Surprisingly, however, we also observed profound inhibition of th ymocyte proliferation in vivo and of activation-induced proliferation of thymocytes and mature T cells in vitro. This inhibition of prolifer ation was not due to increased cell death and appeared to be p53 depen dent. (C) Current Biology Ltd ISSN 0960-9822.