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

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 killing1,2. With regard to TNFα, the anti-apoptotic activity of NF-κB involves suppression of the c-Jun N-terminal kinase (JNK) cascade3,4,5. Using an unbiased screen, we have previously identified Gadd45β/Myd118, a member of the Gadd45 family of inducible factors6, 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 JNK7,8 — 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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Figure 1: Gadd45β physically interacts with kinases in the JNK pathway.
Figure 2: Gadd45β and NF-κB specifically inhibit MKK7 in vivo.
Figure 3: Gadd45β is a direct inhibitor of MKK7.
Figure 4: Gadd45β blocks MKK7 by contacting a peptidic region in its catalytic domain.
Figure 5: Gadd45β-mediated suppression of MKK7 is required to block TNFα-induced apoptosis.

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Acknowledgements

We thank M. Peter, H. Singh, C.-R. Wang, and P. Ashton-Rickardt for critical comments on the manuscript. We are grateful to H. Ichijo, J. Landry, A. Leonardi, P. Vito, H. Gram, R. Vaillancourt, T.H. Wang, and J. Wimalasena for plasmids, and G. Taroli for help with manuscript preparation. We also thank L. Degelstein of the Transgenic and Knockout facility and C. McShan of the Monoclonal Antibody facility, both at the University of Chicago, for help with the generation of Gadd45β knockout mice and the anti-Gadd45β antibody, 5D2.2, respectively. This work was supported in part by the Damon Runyon Scholar Award of the Cancer Research Fund and National Institutes of Health grants R01-CA84040 and R01-CA098583.

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Correspondence to Guido Franzoso.

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Papa, S., Zazzeroni, F., Bubici, C. et al. Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2. Nat Cell Biol 6, 146–153 (2004). https://doi.org/10.1038/ncb1093

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