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Induction Of Gadd45β By NF-κB Downregulates Pro-apoptotic JNK Signalling

E. Smaele, F. Zazzeroni, S. Papa, D. U. Nguyen, R. Jin, Joy Jones, R. Cong, G. Franzoso
Published 2001 · Biology

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In addition to coordinating immune and inflammatory responses, NF-κB/Rel transcription factors control cell survival. Normally, NF-κB dimers are sequestered in the cytoplasm by binding to inhibitory IκB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteolysis of IκBs. Activation of NF-κB antagonizes apoptosis or programmed cell death by numerous triggers, including the ligand engagement of ‘death receptors’ such as tumour-necrosis factor (TNF) receptor. The anti-apoptotic activity of NF-κB is also crucial to oncogenesis and to chemo- and radio-resistance in cancer. Cytoprotection by NF-κB involves the activation of pro-survival genes; however, its basis remains poorly understood. Here we report that NF-κB complexes downregulate the c-Jun amino-terminal kinase (JNK) cascade, thus establishing a link between the NF-κB and the JNK pathways. This link involves the transcriptional upregulation of gadd45β/myd118 (ref. 4), which downregulates JNK signalling induced by the TNF receptor (TNF-R). This NF-κB-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-κB complexes and establish a role for the persistent activation of JNK in the apoptotic response to TNF-α.
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