TY - JOUR
T1 - Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2
AU - Papa, Salvatore
AU - Zazzeroni, Francesca
AU - Bubici, Concetta
AU - Jayawardena, Shanthi
AU - Alvarez, Kellean
AU - Matsuda, Shuji
AU - Nguyen, Dung U.
AU - Pham, Can G.
AU - Nelsbach, Andreas H.
AU - Melis, Tiziana
AU - De Smaele, Enrico
AU - Tang, Wei Jen
AU - D'Adamio, Luciano
AU - Franzoso, Guido
N1 - Funding Information:
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.
PY - 2004/2
Y1 - 2004/2
N2 - 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.
AB - 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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U2 - 10.1038/ncb1093
DO - 10.1038/ncb1093
M3 - Article
C2 - 14743220
AN - SCOPUS:1642602694
SN - 1465-7392
VL - 6
SP - 146
EP - 153
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 2
ER -