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IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis

Författare

  • Eugene Varfolomeev
  • John W Blankenship
  • Sarah M Wayson
  • Anna V Fedorova
  • Nobuhiko Kayagaki
  • Parie Garg
  • Kerry Zobel
  • Jasmin N Dynek
  • Linda O Elliott
  • Heidi J A Wallweber
  • Johan Flygare
  • Wayne J Fairbrother
  • Kurt Deshayes
  • V Dixit

Summary, in English

Inhibitor of apoptosis (IAP) proteins are antiapoptotic regulators that block cell death in response to diverse stimuli. They are expressed at elevated levels in human malignancies and are attractive targets for the development of novel cancer therapeutics. Herein, we demonstrate that small-molecule IAP antagonists bind to select baculovirus IAP repeat (BIR) domains resulting in dramatic induction of auto-ubiquitination activity and rapid proteasomal degradation of c-IAPs. The IAP antagonists also induce cell death that is dependent on TNF signaling and de novo protein biosynthesis. Additionally, the c-IAP proteins were found to function as regulators of NF-kappaB signaling. Through their ubiquitin E3 ligase activities c-IAP1 and c-IAP2 promote proteasomal degradation of NIK, the central ser/thr kinase in the noncanonical NF-kappaB pathway.

Publiceringsår

2007

Språk

Engelska

Sidor

669-669

Publikation/Tidskrift/Serie

Cell

Volym

131

Issue

4

Dokumenttyp

Artikel i tidskrift

Förlag

Cell Press

Ämne

  • Hematology

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1097-4172