IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.
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.
Varfolomeev
Eugene
E
Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080, USA.
Blankenship
John W
JW
Wayson
Sarah M
SM
Fedorova
Anna V
AV
Kayagaki
Nobuhiko
N
Garg
Parie
P
Zobel
Kerry
K
Dynek
Jasmin N
JN
Elliott
Linda O
LO
Wallweber
Heidi J A
HJ
Flygare
John A
JA
Fairbrother
Wayne J
WJ
Deshayes
Kurt
K
Dixit
Vishva M
VM
Vucic
Domagoj
D
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D025821:Polyubiquitin / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D054875:Ubiquitination
D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex