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

NF-kappaB/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(1,2). With regard to TNFalpha, the anti-apoptotic activity of NF-kappaB involves suppression of the c-Jun N-terminal kinase (JNK) cascade(3-5). Using an unbiased screen, we have previously identified Gadd45beta/Myd118, a member of the Gadd45 family of inducible factors(6), as a pivotal mediator of this suppressive activity of NF-kappaB(3). However, the mechanisms by which Gadd45 inhibits JNK signalling are not understood. Here, we identify MKK7/JNKK2 - a specific and essential activator of JNK(7,8) - as a target of Gadd45beta, and in fact, of NF-kappaB itself. Gadd45beta binds to MKK7 directly and blocks its catalytic activity, thereby providing a molecular link between the NF-kappaB and JNK pathways. Importantly, Gadd45 is required to antagonize TNFalpha-induced cytotoxicity, and peptides disrupting the Gadd45beta/MKK7 interaction hinder the ability of Gadd45beta, as well as of NF-kappaB, to suppress this cytotoxicity. These findings establish a basis for the NF-kappaB control of JNK activation and identify MKK7 as a potential target for antiinflammatory and anti-cancer therapy.