IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.
Cell
; 131(4): 669-81, 2007 Nov 16.
Article
em En
| MEDLINE
| ID: mdl-18022362
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
NF-kappa B
/
Fator de Necrose Tumoral alfa
/
Apoptose
/
Poliubiquitina
/
Proteínas Inibidoras de Apoptose
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Estados Unidos