IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis

Eugene Varfolomeev; John W Blankenship; Sarah M Wayson; Anna V Fedorova; Nobuhiko Kayagaki; Parie Garg; Kerry Zobel; Jasmin N Dynek; Linda O Elliott; Heidi J A Wallweber; Johan Flygare; Wayne J Fairbrother; Kurt Deshayes; V Dixit

doi:10.1016/j.cell.2007.10.030

IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis

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

Genentech, Inc

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	669
Journal	Cell
Volume	131
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2007.10.030
Publication status	Published - 2007
Externally published	Yes

Subject classification (UKÄ)

Hematology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2007.10.030

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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., Fairbrother, W. J., Deshayes, K., & Dixit, V. (2007). IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell, 131(4), 669. https://doi.org/10.1016/j.cell.2007.10.030

@article{4893f09ce827459bac414529d6b6fa9d,

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.",

author = "Eugene Varfolomeev and Blankenship, {John W} and Wayson, {Sarah M} and Fedorova, {Anna V} and Nobuhiko Kayagaki and Parie Garg and Kerry Zobel and Dynek, {Jasmin N} and Elliott, {Linda O} and Wallweber, {Heidi J A} and Johan Flygare and Fairbrother, {Wayne J} and Kurt Deshayes and V Dixit",

year = "2007",

doi = "10.1016/j.cell.2007.10.030",

language = "English",

volume = "131",

pages = "669",

journal = "Cell",

issn = "1097-4172",

publisher = "Cell Press",

number = "4",

}

Varfolomeev, E, Blankenship, JW, Wayson, SM, Fedorova, AV, Kayagaki, N, Garg, P, Zobel, K, Dynek, JN, Elliott, LO, Wallweber, HJA, Flygare, J, Fairbrother, WJ, Deshayes, K & Dixit, V 2007, 'IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis', Cell, vol. 131, no. 4, pp. 669. https://doi.org/10.1016/j.cell.2007.10.030

TY - JOUR

T1 - IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis

AU - Varfolomeev, Eugene

AU - Blankenship, John W

AU - Wayson, Sarah M

AU - Fedorova, Anna V

AU - Kayagaki, Nobuhiko

AU - Garg, Parie

AU - Zobel, Kerry

AU - Dynek, Jasmin N

AU - Elliott, Linda O

AU - Wallweber, Heidi J A

AU - Flygare, Johan

AU - Fairbrother, Wayne J

AU - Deshayes, Kurt

AU - Dixit, V

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

U2 - 10.1016/j.cell.2007.10.030

DO - 10.1016/j.cell.2007.10.030

M3 - Article

SN - 1097-4172

VL - 131

SP - 669

JO - Cell

JF - Cell

IS - 4

ER -

IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis

Abstract

Subject classification (UKÄ)

UN SDGs

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