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

Enrico De Smaele, Francesca Zazzeroni, Salvatore Papa, Dung U. Nguyen, Rongguan Jin, Joy Jones, Rong Cong and Guido Franzoso ()
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Enrico De Smaele: The Gwen Knapp Center for Lupus and Immunology Research, and The Ben May Institute for Cancer Research, The University of Chicago
Francesca Zazzeroni: The Gwen Knapp Center for Lupus and Immunology Research, and The Ben May Institute for Cancer Research, The University of Chicago
Salvatore Papa: The Gwen Knapp Center for Lupus and Immunology Research, and The Ben May Institute for Cancer Research, The University of Chicago
Dung U. Nguyen: The Gwen Knapp Center for Lupus and Immunology Research, and The Ben May Institute for Cancer Research, The University of Chicago
Rongguan Jin: The Gwen Knapp Center for Lupus and Immunology Research, and The Ben May Institute for Cancer Research, The University of Chicago
Joy Jones: The Gwen Knapp Center for Lupus and Immunology Research, and The Ben May Institute for Cancer Research, The University of Chicago
Rong Cong: The Gwen Knapp Center for Lupus and Immunology Research, and The Ben May Institute for Cancer Research, The University of Chicago
Guido Franzoso: The Gwen Knapp Center for Lupus and Immunology Research, and The Ben May Institute for Cancer Research, The University of Chicago

Nature, 2001, vol. 414, issue 6861, 308-313

Abstract: Abstract 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.

Date: 2001
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DOI: 10.1038/35104560

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