Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling

In addition to coordinating immune and inflammatory responses, NF-kappaB/Rel transcription factors control cell survival(1). Normally, NF-kappaB dimers are sequestered in the cytoplasm by binding to inhibitory I kappaB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteolysis of I kappa Bs(1). Activation of NF-kappaB antagonizes apoptosis or programmed cell death by numerous triggers, including the ligand engagement of 'death receptors' such as tumour-necrosis factor (TNF) receptor(2). The anti-apoptotic activity of NF-kappaB is also crucial to oncogenesis and to chemo- and radio-resistance in cancer(2). Cytoprotection by NF-kappaB involves the activation of pro-survival genes(2); however, its basis remains poorly understood. Here we report that NF-kappaB complexes downregulate the c-Jun aminoterminal kinase (JNK) cascade(3), thus establishing a link between the NF-kappaB and the JNK pathways. This link involves the transcriptional upregulation of gadd45 beta /myd118 (ref. 4), which downregulates JNK signalling induced by the TNF receptor (TNF-R). This NF-kappaB-dependent inhibition of the JNK pathway is central to the control of cell death. Our findings define a protective mechanism that is mediated by NF-kappaB complexes and establish a role for the persistent activation of JNK in the apoptotic response to TNF-alpha.