Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling.
In addition to coordinating immune and inflammatory responses, NF-kappaB/Rel transcription factors control cell survival. Normally, NF-kappaB dimers are sequestered in the cytoplasm by binding to inhibitory IkappaB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteolysis of IkappaBs. 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. The anti-apoptotic activity of NF-kappaB is also crucial to oncogenesis and to chemo- and radio-resistance in cancer. Cytoprotection by NF-kappaB involves the activation of pro-survival genes; however, its basis remains poorly understood. Here we report that NF-kappaB complexes downregulate the c-Jun amino-terminal kinase (JNK) cascade, thus establishing a link between the NF-kappaB and the JNK pathways. This link involves the transcriptional upregulation of gadd45beta/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.
De Smaele
E
E
The Gwen Knapp Center for Lupus and Immunology research, The University of Chicago, Illinois 60637, USA.
Zazzeroni
F
F
Papa
S
S
Nguyen
D U
DU
Jin
R
R
Jones
J
J
Cong
R
R
Franzoso
G
G
D016475:3T3 Cells; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival; D003513:Cycloheximide / Q000494:pharmacology; D005786:Gene Expression Regulation; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D003513:Cycloheximide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins