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IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis
Open accessAbstract
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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“This switch between target substrate ubiquitylation and autoubiquitylation following changes in binding partner might be a general feature of RING E3 ligases, since ligand binding to IAP (a member of the RING E3 inhibitor of apoptosis proteins) stimulates IAP auto-destruction [43].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [43]
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“TNF-a and RIPK1 Since Smac mimetic induces apoptosis in certain tumor lines as a result of autocrine TNF-a (Petersen et al., 2007; Vince et al., 2007; Varfolomeev et al., 2007), we checked whether autocrine TNF-a is required for the observed necrosis in HT-29 cells.”
Background
Metadata
- 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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2007-11
- Volume
- 131
- Issue
- 4
- Pages
- 669-681
- ISSN
- 0092-8674 (ISSN-L)
- 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
- 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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