Cited by 1,218Cell death mechanisms and regulationNF-κB Signaling PathwaysUbiquitin and proteasome pathways

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IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis

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Varfolomeev, Eugene, Blankenship, John W., Wayson, Sarah M., Fedorova, Anna V., Kayagaki, Nobuhiko, Garg, Parie, Zobel, Kerry, Dynek, Jasmin N., Elliott, Linda O., Wallweber, Heidi J.A., Flygare, John A., Fairbrother, Wayne J., Deshayes, Kurt, Dixit, Vishva M., Vucic, Domagoj·2007·Cell

DOI 10.1016/j.cell.2007.10.030

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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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Background
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BackgroundInfluential
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Background
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Influential
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Background
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Background
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“An interesting speculation is whether IAPs constitutively inhibit complex 2 formation (in much the same way they target NIK kinase [13,14]) and that one of the functions of TNFSF DL signalling is to reassign them.”
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“Binding of TNFα, TRAIL or other death agonists to their receptors typically leads to cell death via FADD through the activation of caspase-8 and induction of apoptosis, or alternatively, activation of RIP kinase 1 (RIPK1), MLKL, and induction of necroptosis (5-10).”
Design of Small-Molecule Smac Mimetics as IAP Antagonists
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Authors: Varfolomeev, E., Blankenship, J. W., Wayson, S. M., Fedorova, A. V., Kayagaki, N., Garg, P., Zobel, K., Dynek, J. N., Elliott, L. O., Wallweber, H. J. A., Flygare, J. A., Fairbrother, W. J., Deshayes, K., Dixit, V. M., & Vucic, D.
Affiliations: Genentech (US)
Corresponding author: Dixit, Vishva M.
Vucic, Domagoj
ORCID: Varfolomeev, Eugene
Blankenship, John W.
Fedorova, Anna V.
Kayagaki, Nobuhiko
Zobel, Kerry
Fairbrother, Wayne J.
Dixit, Vishva M.
Vucic, Domagoj
Venue: Cell
Publisher: Elsevier BV
Published: 2007-11
Volume: 131
Issue: 4
Pages: 669-681
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2007.10.030
OpenAlex: W2064299413
Cited by: 1,218
References: 51
Citations by year: 2026: 28 · 2025: 24 · 2024: 39 · 2023: 45 · 2022: 41 · 2021: 60 · 2020: 59 · 2019: 54 · 2018: 69 · 2017: 64 · 2016: 78 · 2015: 80 · 2014: 100 · 2013: 78 · 2012: 71
FWCI: 33.22
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2085 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Lund University Publications (Lund University) (submittedVersion)
Funders: Genentech
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: inhibitor of apoptosis proteins, IAP antagonists, cIAP1, cIAP2, autoubiquitination, proteasomal degradation, NF-κB signaling, non-canonical NF-κB signaling, NIK, TNF signaling, apoptosis, cancer therapeutics
MeSH terms: Animals, Cell Line, Humans, Neoplasms, Tumor Necrosis Factor-alpha, Molecular Structure, Signal Transduction, NF-kappa B, Apoptosis, Protein Structure, Tertiary, Polyubiquitin, Proteasome Endopeptidase Complex, Inhibitor of Apoptosis Proteins, Mice, Ubiquitination

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IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis

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