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Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2.

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.

Pubmed ID: 14743220

Authors

  • 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

Journal

Nature cell biology

Publication Data

February 2, 2004

Associated Grants

  • Agency: NCI NIH HHS, Id: R01-CA098583
  • Agency: NCI NIH HHS, Id: R01-CA84040

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Antigens, Differentiation
  • Apoptosis
  • Cells, Cultured
  • Enzyme Activation
  • Fibroblasts
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 7
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases
  • Mitogen-Activated Protein Kinases
  • Molecular Sequence Data
  • NF-kappa B
  • Peptides
  • Protein Binding
  • Sequence Alignment
  • Signal Transduction
  • Tumor Necrosis Factor-alpha