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


In addition to coordinating immune and inflammatory responses, NF-κB/Rel transcription factors control cell survival1. 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 IκBs1. 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) receptor2. The anti-apoptotic activity of NF-κB is also crucial to oncogenesis and to chemo- and radio-resistance in cancer2. Cytoprotection by NF-κB involves the activation of pro-survival genes2; however, its basis remains poorly understood. Here we report that NF-κB complexes downregulate the c-Jun amino-terminal kinase (JNK) cascade3, 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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Figure 1: gadd45β is a physiological target of NF-κB.
Figure 2: Gadd45β antagonizes TNF-R-induced apoptosis in NF-κB null cells.
Figure 3: Gadd45β blocks apoptotic pathways in NF-κB null cells.
Figure 4: The inhibition of JNK represents a protective mechanism by NF-κB.
Figure 5: Gadd45β is a physiological inhibitor of JNK signalling.


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We thank M. Peter, A. Ma, H. Singh, C.-R. Wang, P. Ashton-Rickardt, M. Rosner and C. G. Pham for comments on the manuscript. We are grateful to L. D'Adamio for advice on the manuscript and the ‘death trap’ system, and for pLTP. We thank D. Baltimore and A. Hoffmann for the RelA-/- MEFs; A. Lin for dominant-negative JNKK2; J. Han for MKK3b; D. Liebermenn and A. Balliet for Gadd45β reagents; and S. Rua for help with manuscript preparation. Supported in part by the Damon Runyon Scholar Award of the Cancer Research Fund and an NIH grant.

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Correspondence to Guido Franzoso.

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De Smaele, E., Zazzeroni, F., Papa, S. et al. Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling. Nature 414, 308–313 (2001).

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