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

Varfolomeev, Eugene; Blankenship, John W; Wayson, Sarah M; Fedorova, Anna V; Kayagaki, Nobuhiko; Garg, Parie; Zobel, Kerry; Dynek, Jasmin N; Elliott, Linda O and Wallweber, Heidi J A, et al. (2007) In Cell 131(4). p.669-669
Abstract
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... (More)
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. (Less)
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Contribution to journal
publication status
published
subject
in
Cell
volume
131
issue
4
pages
669 - 669
publisher
Cell Press
external identifiers
  • pmid:18022362
  • scopus:36048999753
ISSN
1097-4172
DOI
10.1016/j.cell.2007.10.030
language
English
LU publication?
no
id
4893f09c-e827-459b-ac41-4529d6b6fa9d (old id 1143647)
date added to LUP
2008-07-29 12:25:12
date last changed
2017-11-12 03:23:32
@article{4893f09c-e827-459b-ac41-4529d6b6fa9d,
  abstract     = {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.},
  author       = {Varfolomeev, Eugene and Blankenship, John W and Wayson, Sarah M and Fedorova, Anna V and Kayagaki, Nobuhiko and Garg, Parie and Zobel, Kerry and Dynek, Jasmin N and Elliott, Linda O and Wallweber, Heidi J A and Flygare, Johan and Fairbrother, Wayne J and Deshayes, Kurt and Dixit, V},
  issn         = {1097-4172},
  language     = {eng},
  number       = {4},
  pages        = {669--669},
  publisher    = {Cell Press},
  series       = {Cell},
  title        = {IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis},
  url          = {http://dx.doi.org/10.1016/j.cell.2007.10.030},
  volume       = {131},
  year         = {2007},
}