IKKε-Mediated Tumorigenesis Requires K63-Linked Polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 Ubiquitin Ligase Complex

Alicia Y. Zhou; Rhine R. Shen; Eejung Kim; Ying J. Lock; Ming Xu; Zhijian J. Chen; William C. Hahn

doi:10.1016/j.celrep.2013.01.031

IKKε-Mediated Tumorigenesis Requires K63-Linked Polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 Ubiquitin Ligase Complex

Alicia Y. Zhou, Rhine R. Shen, Eejung Kim, Ying J. Lock, Ming Xu, Zhijian J. Chen, William C. Hahn

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

49 Scopus citations

Abstract

IκB kinase ε (IKKε, IKBKE) is a key regulator of innate immunity and a breast cancer oncogene, amplified in ~30% of breast cancers, that promotes malignant transformation through NF-κB activation. Here, we show that IKKε is modified and regulated by K63-linked polyubiquitination at lysine 30 and lysine 401. Tumor necrosis factor alpha and interleukin-1β stimulation induces IKKε K63-linked polyubiquitination over baseline levels in both macrophages and breast cancer cell lines, and this modification is essential for IKKε kinase activity, IKKε-mediated NF-κB activation, and IKKε-induced malignant transformation. Disruption of K63-linked ubiquitination of IKKε does not affect its overall structure but impairs the recruitment of canonical NF-κB proteins. A cIAP1/cIAP2/TRAF2 E3 ligase complex binds to and ubiquitinates IKKε. Altogether, these observations demonstrate that K63-linked polyubiquitination regulates IKKε activity in both inflammatory and oncogenic contexts and suggests an alternative approach to targeting this breast cancer oncogene

Original language	English (US)
Pages (from-to)	724-733
Number of pages	10
Journal	Cell Reports
Volume	3
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2013.01.031
State	Published - 2013

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2013.01.031

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title = "IKKε-Mediated Tumorigenesis Requires K63-Linked Polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 Ubiquitin Ligase Complex",

abstract = "IκB kinase ε (IKKε, IKBKE) is a key regulator of innate immunity and a breast cancer oncogene, amplified in ~30% of breast cancers, that promotes malignant transformation through NF-κB activation. Here, we show that IKKε is modified and regulated by K63-linked polyubiquitination at lysine 30 and lysine 401. Tumor necrosis factor alpha and interleukin-1β stimulation induces IKKε K63-linked polyubiquitination over baseline levels in both macrophages and breast cancer cell lines, and this modification is essential for IKKε kinase activity, IKKε-mediated NF-κB activation, and IKKε-induced malignant transformation. Disruption of K63-linked ubiquitination of IKKε does not affect its overall structure but impairs the recruitment of canonical NF-κB proteins. A cIAP1/cIAP2/TRAF2 E3 ligase complex binds to and ubiquitinates IKKε. Altogether, these observations demonstrate that K63-linked polyubiquitination regulates IKKε activity in both inflammatory and oncogenic contexts and suggests an alternative approach to targeting this breast cancer oncogene",

author = "Zhou, {Alicia Y.} and Shen, {Rhine R.} and Eejung Kim and Lock, {Ying J.} and Ming Xu and Chen, {Zhijian J.} and Hahn, {William C.}",

note = "Funding Information: We thank J. Wade Harper and members of the Hahn and Cichowski labs for thoughtful discussion, reagents, and technical assistance. W.C.H. is a consultant for Novartis Pharmaceuticals. This work was supported in part by National Institutes of Health/National Cancer Institute grant R01 CA130988 (W.C.H.) and Department of Defense Breast Cancer Research Program Predoctoral Traineeship Award W81XWH-08-1-0763 (A.Y.Z.). ",

year = "2013",

doi = "10.1016/j.celrep.2013.01.031",

language = "English (US)",

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AU - Zhou, Alicia Y.

AU - Shen, Rhine R.

AU - Kim, Eejung

AU - Lock, Ying J.

AU - Xu, Ming

AU - Chen, Zhijian J.

AU - Hahn, William C.

N1 - Funding Information: We thank J. Wade Harper and members of the Hahn and Cichowski labs for thoughtful discussion, reagents, and technical assistance. W.C.H. is a consultant for Novartis Pharmaceuticals. This work was supported in part by National Institutes of Health/National Cancer Institute grant R01 CA130988 (W.C.H.) and Department of Defense Breast Cancer Research Program Predoctoral Traineeship Award W81XWH-08-1-0763 (A.Y.Z.).

PY - 2013

Y1 - 2013

N2 - IκB kinase ε (IKKε, IKBKE) is a key regulator of innate immunity and a breast cancer oncogene, amplified in ~30% of breast cancers, that promotes malignant transformation through NF-κB activation. Here, we show that IKKε is modified and regulated by K63-linked polyubiquitination at lysine 30 and lysine 401. Tumor necrosis factor alpha and interleukin-1β stimulation induces IKKε K63-linked polyubiquitination over baseline levels in both macrophages and breast cancer cell lines, and this modification is essential for IKKε kinase activity, IKKε-mediated NF-κB activation, and IKKε-induced malignant transformation. Disruption of K63-linked ubiquitination of IKKε does not affect its overall structure but impairs the recruitment of canonical NF-κB proteins. A cIAP1/cIAP2/TRAF2 E3 ligase complex binds to and ubiquitinates IKKε. Altogether, these observations demonstrate that K63-linked polyubiquitination regulates IKKε activity in both inflammatory and oncogenic contexts and suggests an alternative approach to targeting this breast cancer oncogene

AB - IκB kinase ε (IKKε, IKBKE) is a key regulator of innate immunity and a breast cancer oncogene, amplified in ~30% of breast cancers, that promotes malignant transformation through NF-κB activation. Here, we show that IKKε is modified and regulated by K63-linked polyubiquitination at lysine 30 and lysine 401. Tumor necrosis factor alpha and interleukin-1β stimulation induces IKKε K63-linked polyubiquitination over baseline levels in both macrophages and breast cancer cell lines, and this modification is essential for IKKε kinase activity, IKKε-mediated NF-κB activation, and IKKε-induced malignant transformation. Disruption of K63-linked ubiquitination of IKKε does not affect its overall structure but impairs the recruitment of canonical NF-κB proteins. A cIAP1/cIAP2/TRAF2 E3 ligase complex binds to and ubiquitinates IKKε. Altogether, these observations demonstrate that K63-linked polyubiquitination regulates IKKε activity in both inflammatory and oncogenic contexts and suggests an alternative approach to targeting this breast cancer oncogene

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IKKε-Mediated Tumorigenesis Requires K63-Linked Polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 Ubiquitin Ligase Complex

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