Author/Authors :
Eugene Varfolomeev، نويسنده , , John W. Blankenship، نويسنده , , Sarah M. Wayson، نويسنده , , Anna V. Fedorova، نويسنده , , Nobuhiko Kayagaki، نويسنده , , Parie Garg، نويسنده , , Kerry Zobel، نويسنده , , Jasmin N. Dynek، نويسنده , , Linda O. Elliott، نويسنده , , Heidi J.A. Wallweber، نويسنده , , John A. Flygare، نويسنده , , Wayne J. Fairbrother and Melissa A. Starovasnik، نويسنده , , Kurt Deshayes، نويسنده , , Vishva M. Dixit، نويسنده , , Domagoj Vucic، نويسنده ,
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-κB 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-κB pathway.
