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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BackgroundResult
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Targeting Inhibitor of Apoptosis Proteins Protects from Bleomycin-Induced Lung Fibrosis
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BV6, an IAP Antagonist, Activates Apoptosis and Enhances Radiosensitization of Non-small Cell Lung Carcinoma In Vitro
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NF-κB inducing kinase (NIK) modulates melanoma tumorigenesis by regulating expression of pro-survival factors through the β-catenin pathway
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“Other studies have also reported that cell death can be induced by TNFα in the presence of NF-κB activation when other survival signals such as those of cIAPs are disrupted in cancer cells (Petersen et al., 2007; Varfolomeev et al., 2007; Vince et al., 2007).”
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“Previous studies have demonstrated that treatment with SMAC-memetic compounds with high potency in degrading cIAP1/2 proteins, such as BV6 and compound A, could stabilize NIK and activate alternative NF- B signaling, thereby upregulating TNFα (Varfolomeev et al., 2007; Vince et al., 2007).”
Influential
Minnelide: A Novel Therapeutic That Promotes Apoptosis in Non-Small Cell Lung Carcinoma In Vivo
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NIK Stabilization in Osteoclasts Results in Osteoporosis and Enhanced Inflammatory Osteolysis
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Background
Radiosensitization of Head and Neck Squamous Cell Carcinoma by a SMAC-Mimetic Compound, SM-164, Requires Activation of Caspases
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Background
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Background
hnRNP A1 regulates UV-induced NF-κB signalling through destabilization of cIAP1 mRNA
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BIRC2 Expression Impairs Anti-Cancer Immunity and Immunotherapy Efficacy
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Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator
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BackgroundMethod
Design of Potent pan-IAP and Lys-Covalent XIAP Selective Inhibitors Using a Thermodynamics Driven Approach
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BackgroundMethodInfluential
Carboxyl Terminus of HSC70-interacting Protein (CHIP) Down-regulates NF-κB-inducing Kinase (NIK) and Suppresses NIK-induced Liver Injury
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“cIAP1 and cIAP2 have been described as two important ubiquitin E3 ligases for NIK (13, 14).”
Background

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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