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

Autor:	Zhou AY; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA., Shen RR, Kim E, Lock YJ, Xu M, Chen ZJ, Hahn WC
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2013 Mar 28; Vol. 3 (3), pp. 724-33. Date of Electronic Publication: 2013 Feb 28.
DOI:	10.1016/j.celrep.2013.01.031
Abstrakt:	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. (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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