Induction of gadd45 beta by NF-kappa B downregulates pro-apoptotic JNK signalling

In addition to coordinating immune and inflammatory responses, NF-kappaB/Re l transcription factors control cell survival(1). Normally, NF-kappaB dimer s are sequestered in the cytoplasm by binding to inhibitory I kappaB protei ns, and can be activated rapidly by signals that induce the sequential phos phorylation and proteolysis of I kappa Bs(1). Activation of NF-kappaB antag onizes apoptosis or programmed cell death by numerous triggers, including t he ligand engagement of 'death receptors' such as tumour-necrosis factor (T NF) receptor(2). The anti-apoptotic activity of NF-kappaB is also crucial t o oncogenesis and to chemo- and radio-resistance in cancer(2). Cytoprotecti on by NF-kappaB involves the activation of pro-survival genes(2); however, its basis remains poorly understood. Here we report that NF-kappaB complexe s downregulate the c-Jun aminoterminal kinase (JNK) cascade(3), thus establ ishing a link between the NF-kappaB and the JNK pathways. This link involve s the transcriptional upregulation of gadd45 beta /myd118 (ref. 4), which d ownregulates JNK signalling induced by the TNF receptor (TNF-R). This NF-ka ppaB-dependent inhibition of the JNK pathway is central to the control of c ell death. Our findings define a protective mechanism that is mediated by N F-kappaB complexes and establish a role for the persistent activation of JN K in the apoptotic response to TNF-alpha.