Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2

Salvatore Papa, Francesca Zazzeroni, Concetta Bubici, Shanthi Jayawardena, Kellean Alvarez, Shuji Matsuda, Dung U. Nguyen, Can G. Pham, Andreas H. Nelsbach, Tiziana Melis, Enrico De Smaele, Wei Jen Tang, Luciano D'Adamio, Guido Franzoso

Research output: Contribution to journalArticle

265 Citations (Scopus)

Abstract

NF-κB/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 α (TNFα)-induced killing. With regard to TNFα, the anti-apoptotic activity of NF-κB involves suppression of the c-Jun N-terminal kinase (JNK) cascade. Using an unbiased screen, we have previously identified Gadd45β/Myd118, a member of the Gadd45 family of inducible factors, as a pivotal mediator of this suppressive activity of NF-κB3. However, the mechanisms by which Gadd45β inhibits JNK signalling are not understood. Here, we identify MKK7/JNKK2 - a specific and essential activator of JNK - as a target of Gadd45β, and in fact, of NF-κB itself. Gadd45β binds to MKK7 directly and blocks its catalytic activity, thereby providing a molecular link between the NF-κB and JNK pathways. Importantly, Gadd45β is required to antagonize TNFα-induced cytotoxicity, and peptides disrupting the Gadd45β/MKK7 interaction hinder the ability of Gadd45β, as well as of NF-κB, to suppress this cytotoxicity. These findings establish a basis for the NF-κB control of JNK activation and identify MKK7 as a potential target for anti-inflammatory and anti-cancer therapy.

Original languageEnglish (US)
Pages (from-to)146-153
Number of pages8
JournalNature Cell Biology
Volume6
Issue number2
DOIs
StatePublished - Feb 2004

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JNK Mitogen-Activated Protein Kinases
Tumor Necrosis Factor-alpha
Aptitude
Neoplasms
Carcinogenesis
Cell Death
Anti-Inflammatory Agents
Transcription Factors
Apoptosis
Peptides

ASJC Scopus subject areas

  • Cell Biology

Cite this

Papa, S., Zazzeroni, F., Bubici, C., Jayawardena, S., Alvarez, K., Matsuda, S., ... Franzoso, G. (2004). Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2. Nature Cell Biology, 6(2), 146-153. https://doi.org/10.1038/ncb1093

Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2. / Papa, Salvatore; Zazzeroni, Francesca; Bubici, Concetta; Jayawardena, Shanthi; Alvarez, Kellean; Matsuda, Shuji; Nguyen, Dung U.; Pham, Can G.; Nelsbach, Andreas H.; Melis, Tiziana; De Smaele, Enrico; Tang, Wei Jen; D'Adamio, Luciano; Franzoso, Guido.

In: Nature Cell Biology, Vol. 6, No. 2, 02.2004, p. 146-153.

Research output: Contribution to journalArticle

Papa, S, Zazzeroni, F, Bubici, C, Jayawardena, S, Alvarez, K, Matsuda, S, Nguyen, DU, Pham, CG, Nelsbach, AH, Melis, T, De Smaele, E, Tang, WJ, D'Adamio, L & Franzoso, G 2004, 'Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2', Nature Cell Biology, vol. 6, no. 2, pp. 146-153. https://doi.org/10.1038/ncb1093
Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K, Matsuda S et al. Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2. Nature Cell Biology. 2004 Feb;6(2):146-153. https://doi.org/10.1038/ncb1093
Papa, Salvatore ; Zazzeroni, Francesca ; Bubici, Concetta ; Jayawardena, Shanthi ; Alvarez, Kellean ; Matsuda, Shuji ; Nguyen, Dung U. ; Pham, Can G. ; Nelsbach, Andreas H. ; Melis, Tiziana ; De Smaele, Enrico ; Tang, Wei Jen ; D'Adamio, Luciano ; Franzoso, Guido. / Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2. In: Nature Cell Biology. 2004 ; Vol. 6, No. 2. pp. 146-153.
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abstract = "NF-κB/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 α (TNFα)-induced killing. With regard to TNFα, the anti-apoptotic activity of NF-κB involves suppression of the c-Jun N-terminal kinase (JNK) cascade. Using an unbiased screen, we have previously identified Gadd45β/Myd118, a member of the Gadd45 family of inducible factors, as a pivotal mediator of this suppressive activity of NF-κB3. However, the mechanisms by which Gadd45β inhibits JNK signalling are not understood. Here, we identify MKK7/JNKK2 - a specific and essential activator of JNK - as a target of Gadd45β, and in fact, of NF-κB itself. Gadd45β binds to MKK7 directly and blocks its catalytic activity, thereby providing a molecular link between the NF-κB and JNK pathways. Importantly, Gadd45β is required to antagonize TNFα-induced cytotoxicity, and peptides disrupting the Gadd45β/MKK7 interaction hinder the ability of Gadd45β, as well as of NF-κB, to suppress this cytotoxicity. These findings establish a basis for the NF-κB control of JNK activation and identify MKK7 as a potential target for anti-inflammatory and anti-cancer therapy.",
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