Jw. Kim et al., Activation of death-inducing signaling complex (DISC) by pro-apoptotic C-terminal fragment of RIP, ONCOGENE, 19(39), 2000, pp. 4491-4499
The two opposite signaling pathways that stimulate NF-kappa B activation an
d apoptosis are both mediated by tumor necrosis factor receptor 1 (TNFR1) a
nd its cytosolic associated proteins. In this study, we demonstrate that th
e proteolytic cleavage of receptor interacting protein (RIP) by caspase-8 d
uring TNF-induced apoptosis abrogates the stimulatory role of RIP on TNF-in
duced NF-kappa B activation. The uncleavable RIPD324A mutant was less apopt
otic, but its ability to activate NF-kappa B activation was greater than th
e wild type counterpart, Ectopic expression of the pro-apoptotic C-terminal
fragment of RIP inhibited TNF-induced NF-kappa B activation by suppressing
the activity of I-kappa B kinase beta (IKK beta) which phosphorylates I-ka
ppa B, an inhibitor of NF-kappa B, and triggers its ubiquitin-mediated degr
adation, The C-terminal fragment of RIP also enhanced the association betwe
en TNFR1 and death domain proteins including TNFR1 associated death domain
(TRADD) and Fas associated death domain (FADD), resulting in the activation
of caspase-8 and stimulation of apoptosis, The present study suggest that
the C-terminal fragment of RIP produced by caspase-8 activates death-induci
ng signaling complex (DISC), attenuates NF-kappa B activation, and thereby
amplifies the activation of caspase-8 which initiates the downstream apopto
tic events.