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Cell Rep DOI:10.1016/j.celrep.2013.01.031

IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex.

Publication TypeJournal Article
Year of Publication2013
AuthorsZhou, AY, Shen, RR, Kim, E, Lock, YJ, Xu, M, Chen, ZJ, Hahn, WC
JournalCell Rep
Volume3
Issue3
Pages724-33
Date Published2013 Mar 28
ISSN2211-1247
KeywordsAmino Acid Sequence, Animals, Cell Line, Tumor, Cell Transformation, Neoplastic, I-kappa B Kinase, Inhibitor of Apoptosis Proteins, Interleukin-1beta, Lysine, Mice, Molecular Sequence Data, Neoplasms, Experimental, NF-kappa B, TNF Receptor-Associated Factor 2, Tumor Necrosis Factor-alpha, Ubiquitin-Protein Ligases, Ubiquitination
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S2211-1247(13)00055-7
DOI10.1016/j.celrep.2013.01.031
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23453969?dopt=Abstract

Alternate JournalCell Rep
PubMed ID23453969
PubMed Central IDPMC4135466
Grant ListR01 CA130988 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States