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.

Gadd45beta mediates the nf-kappab suppression of jnk signalling by targeting mkk7/jnkk2 / Papa, S; Zazzeroni, F; Bubici, C; Jayawardena, S; Alvarez, K; Matsuda, S; NGUYEN D., U; PHAM C., G; NELSBACH A., H; Melis, T; DE SMAELE, Enrico; TANG W., J; D'Adamio, L; Franzoso, G.. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - STAMPA. - 6(2):(2004), pp. 146-153. [10.1038/ncb1093]

Gadd45beta mediates the nf-kappab suppression of jnk signalling by targeting mkk7/jnkk2

DE SMAELE, Enrico;
2004

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.
2004
NF-kappa B; JNK; TNF-alpha; apoptosis; gadd45beta; mkk7
01 Pubblicazione su rivista::01a Articolo in rivista
Gadd45beta mediates the nf-kappab suppression of jnk signalling by targeting mkk7/jnkk2 / Papa, S; Zazzeroni, F; Bubici, C; Jayawardena, S; Alvarez, K; Matsuda, S; NGUYEN D., U; PHAM C., G; NELSBACH A., H; Melis, T; DE SMAELE, Enrico; TANG W., J; D'Adamio, L; Franzoso, G.. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - STAMPA. - 6(2):(2004), pp. 146-153. [10.1038/ncb1093]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/145361
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