IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex.
Cell Rep
; 3(3): 724-33, 2013 Mar 28.
Article
em En
| MEDLINE
| ID: mdl-23453969
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-1ß 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transformação Celular Neoplásica
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Ubiquitina-Proteína Ligases
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Fator 2 Associado a Receptor de TNF
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Quinase I-kappa B
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Proteínas Inibidoras de Apoptose
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Ubiquitinação
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article