title: IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis.
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.
authors.affiliation: Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Varfolomeev
authors.forename: John W
authors.initials: JW
authors.lastname: Blankenship
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Wayson
authors.forename: Anna V
authors.initials: AV
authors.lastname: Fedorova
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kayagaki
authors.forename: Parie
authors.initials: P
authors.lastname: Garg
authors.forename: Kerry
authors.initials: K
authors.lastname: Zobel
authors.forename: Jasmin N
authors.initials: JN
authors.lastname: Dynek
authors.forename: Linda O
authors.initials: LO
authors.lastname: Elliott
authors.forename: Heidi J A
authors.initials: HJ
authors.lastname: Wallweber
authors.forename: John A
authors.initials: JA
authors.lastname: Flygare
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: Kurt
authors.initials: K
authors.lastname: Deshayes
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
authors.forename: Domagoj
authors.initials: D
authors.lastname: Vucic
mesh_terms: 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
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex