Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2.
Nat Cell Biol
; 6(2): 146-53, 2004 Feb.
Article
em En
| MEDLINE
| ID: mdl-14743220
ABSTRACT
NF-kappa B/Rel transcription factors control apoptosis, also known as programmed cell death. This control is crucial for oncogenesis, cancer chemo-resistance and for antagonizing tumour necrosis factor alpha (TNFalpha)-induced killing. With regard to TNFalpha, the anti-apoptotic activity of NF-kappa B involves suppression of the c-Jun N-terminal kinase (JNK) cascade. Using an unbiased screen, we have previously identified Gadd45 beta/Myd118, a member of the Gadd45 family of inducible factors, as a pivotal mediator of this suppressive activity of NF-kappa B. However, the mechanisms by which Gadd45 beta inhibits JNK signalling are not understood. Here, we identify MKK7/JNKK2--a specific and essential activator of JNK--as a target of Gadd45 beta, and in fact, of NF-kappa B itself. Gadd45 beta binds to MKK7 directly and blocks its catalytic activity, thereby providing a molecular link between the NF-kappa B and JNK pathways. Importantly, Gadd45 beta is required to antagonize TNFalpha-induced cytotoxicity, and peptides disrupting the Gadd45 beta/MKK7 interaction hinder the ability of Gadd45 beta, as well as of NF-kappa B, to suppress this cytotoxicity. These findings establish a basis for the NF-kappa B control of JNK activation and identify MKK7 as a potential target for anti-inflammatory and anti-cancer therapy.
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Antígenos de Diferenciação
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NF-kappa B
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Quinases de Proteína Quinase Ativadas por Mitógeno
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Proteínas Quinases Ativadas por Mitógeno
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article