Activation of a pro-apoptotic amplification loop through inhibition of NF-κB-dependent survival signals by caspase-mediated inactivation of RIP

Death domain containing members of the tumor necrosis factor receptor (TNFR) superfamily can induce apoptosis or cell activation. However, the mechanisms by which these opposing programs are selected remain unclear. Frequently, NF-kappa B activation conveys protection against cell death. We show that the serine/threonine kinase RIP that is required for TNF-induced NF-kappa B activation is processed by caspased into a dominant-negative (DN) fragment during death receptor-induced apoptosis, thereby leading to a blockade of NF-kappa B-mediated anti-apoptotic signals. Our results suggest that cleavage of RIP is part of an amplification loop which is triggered by Fas and most likely by other death receptors. (C) 2000 Federation of European Biochemical Societies.