Inhibition of JNK activation through NF-kappaB target genes.
Authors:
Journal: Nature
Publication Type: Journal Article
Date: 2001
DOI: 10.1038/35104568
ID: 11713531
Abstract
The proinflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) regulates immune responses, inflammation and programmed cell death (apoptosis). The ultimate fate of a cell exposed to TNF-alpha is determined by signal integration between its different effectors, including IkappaB kinase (IKK), c-Jun N-terminal protein kinase (JNK) and caspases. Activation of caspases is required for apoptotic cell death, whereas IKK activation inhibits apoptosis through the transcription factor NF-kappaB, whose target genes include caspase inhibitors. JNK activates the transcription factor c-Jun/AP-1, as well as other targets. However, the role of JNK activation in apoptosis induced by TNF-alpha is less clear. It is unknown whether any crosstalk occurs between IKK and JNK, and, if so, how it affects TNF-alpha-induced apoptosis. We investigated this using murine embryonic fibroblasts that are deficient in either the IKKbeta catalytic subunit of the IKK complex or the RelA/p65 subunit of NF-kappaB. Here we show that in addition to inhibiting caspases, the IKK/NF-kappaB pathway negatively modulates TNF-alpha-mediated JNK activation, partly through NF-kappaB-induced X-chromosome-linked inhibitor of apoptosis (XIAP). This negative crosstalk, which is specific to TNF-alpha signalling and does not affect JNK activation by interleukin-1 (IL-1), contributes to inhibition of apoptosis.
Chemical List
- NF-kappa B|||Protein Synthesis Inhibitors|||Proteins|||Transcription Factor RelA|||Tumor Necrosis Factor-alpha|||X-Linked Inhibitor of Apoptosis Protein|||XIAP protein, human|||Cycloheximide|||Protein Serine-Threonine Kinases|||CHUK protein, human|||Chuk protein, mouse|||I-kappa B Kinase|||IKBKB protein, human|||IKBKE protein, human|||Ikbkb protein, mouse|||Ikbke protein, mouse|||JNK Mitogen-Activated Protein Kinases|||Mitogen-Activated Protein Kinases