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

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.

• Authors: 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
• Journal: Nature cell biology (Nat Cell Biol) Vol. 6 Issue 2 Pg. 146-53 (Feb 2004) ISSN: 1465-7392 [Print] England
• PMID: 14743220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, Differentiation
• GADD45B protein, human
• Gadd45b protein, mouse
• NF-kappa B
• Peptides
• Tumor Necrosis Factor-alpha
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 7
• MAP2K7 protein, human
• Map2k7 protein, mouse
• Mitogen-Activated Protein Kinase Kinases

Topics

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