INDUCTION OF CELL-DEATH BY MYRISTYLATED DEATH DOMAIN OF P55 TNF RECEPTOR IS NOT ABOLISHED BY IPR(CG)-LIKE POINT MUTATION IN DEATH DOMAIN

We transiently expressed the intracellular domains of p55 TNF receptor (TNFR1) as either a cytosolic- or a membrane-associated form and exam ined their effects on the endogenous receptor-mediated gene expression as well as on cell viability. We found that gene expression as measur ed by luciferase activity under NF-kappa B-controlling elements was bl ocked by all forms of the intracellular domain of TNFR1. The blockade of reporter gene expression was due to the cell death induced by the i ntracellular domain of TNFR1 per se. The killing mechanism of the intr acellular domain peptides appeared to be apoptotic. Interestingly, myr istylated form of the intracellular domain, consisting of mainly death domain showed the most potent cell-killing activity. Moreover, this m yristylated death domain could still induce cell death even if lpr(cg) -like point mutation (Leu351 to Ala), which has been reported to abrog ate TNF-induced cytotoxicity, was introduced. This result suggests tha t the myristylated death domain activates an additional death signalin g pathway which is not involved in TNF-induced cell death. (C) 1995 Wi ley-Liss, Inc.