FADD, A NOVEL DEATH DOMAIN-CONTAINING PROTEIN, INTERACTS WITH THE DEATH DOMAIN OF FAS AND INITIATES APOPTOSIS

Using the cytoplasmic domain of Pas in the yeast two-hybrid system, we have identified a novel interacting protein, FADD, which binds Pas and Fas-FD5, a mutant of Fas possessing enhanced killing activity, but not the functionally inactive mutants Fas-LPR and Fas-FD8. FADD contains a death domain homologous to the death domains of Pas and TNFR-1. A point mutation in FADD, analogous to the lpr mutation of Fas, abolishes its ability to bind Pas, suggesting a death domain to death domain interaction. Overexpression of FADD in MCF7 and BJAB cells induces apoptosis, which, like Pas-induced apoptosis, is blocked by CrmA, a specific inhibitor of the interleukin-1 beta-converting enzyme; These findings suggest that FADD may play an important role in the proximal signal transduction of Fas.