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

Jin Woo Kim, Eui Ju Choi, Cheol O. Joe

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

The two opposite signaling pathways that stimulate NF-κB 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-κB activation. The uncleavable RIP(D324A) mutant was less apoptotic, but its ability to activate NF-κB activation was greater than the wild type counterpart. Ectopic expression of the pro-apoptotic C-terminal fragment of RIP inhibited TNF-induced NF-κB activation by suppressing the activity of I-κB kinaseβ (IKKβ) which phosphorylates 1-kB, an inhibitor of NF-κB, 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-κB activation, and thereby amplifies the activation of caspase-8 which initiates the downstream apoptotic events.

Original languageEnglish
Pages (from-to)4491-4499
Number of pages9
JournalOncogene
Volume19
Issue number39
Publication statusPublished - 2000 Sep 14

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Death Domain Receptor Signaling Adaptor Proteins
Receptor-Interacting Protein Serine-Threonine Kinases
Caspase 8
Tumor Necrosis Factor Receptors
Apoptosis
Ubiquitin
Proteins
Phosphotransferases

Keywords

  • Apoptosis
  • Caspase-8
  • I-κB kinase
  • NF-κB activation
  • RIP

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

Activation of death-inducing signaling complex (DISC) by pro-apoptotic C-terminal fragment of RIP. / Kim, Jin Woo; Choi, Eui Ju; Joe, Cheol O.

In: Oncogene, Vol. 19, No. 39, 14.09.2000, p. 4491-4499.

Research output: Contribution to journalArticle

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