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Activation of death-inducing signaling complex (DISC) by pro-apoptotic C-terminal fragment of RIP.

Kim JW, Choi EJ, Joe CO


The two opposite signaling pathways that stimulate NF-kappaB activation and apoptosis are both mediated by tumor necrosis factor receptor 1 (TNFR1) and its cytosolic associated proteins. In this study, we demonstrate that the proteolytic cleavage of receptor interacting protein (RIP) by caspase-8 during TNF-induced apoptosis abrogates the stimulatory role of RIP on TNF-induced NF-kappaB activation. The uncleavable RIPD324A mutant was less apoptotic, but its ability to activate NF-kappaB activation was greater than the wild type counterpart. Ectopic expression of the pro-apoptotic C-terminal fragment of RIP inhibited TNF-induced NF-kappaB activation by suppressing the activity of I-kappaB kinasebeta (IKKbeta) which phosphorylates I-kB, an inhibitor of NF-kappaB, and triggers its ubiquitin-mediated degradation. The C-terminal fragment of RIP also enhanced the association between 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-inducing signaling complex (DISC), attenuates NF-kappaB activation, and thereby amplifies the activation of caspase-8 which initiates the downstream apoptotic events. Oncogene (2000) 19, 4491 - 4499.

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