Visit our Expo - Redox and Inflammation signaling 2012

VIII. Inflammation specific signaling Poster VIII, 35
Stimulus Specificity of Gene Expression Programs Determined by Temporal Control of
IKK activity
Shannon L. Werner, Derren Barken, and Alexander Hoffmann
Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University
of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0375, USA
Email: slwerner@ucsd.edu; dbarken@ucsd.edu; ahoffmann@ucsd.edu
The transcription factor nuclear factor-kappa B (NF-kB) regulates genes having critical roles
in cellular stress responses, adaptive and innate immunity, lymphoid organ development, cell
growth, survival, and apoptosis. Misregulation of NF-kB plays a role in chronic
inflammatory diseases and cancers. Many different stimuli induce the NF-kB, including
inflammatory cytokines (TNF, IL-1), bacterial endotoxin (LPS), oxidative stress, UVirradiation,
and chemotherapeutic drugs. This begs the question: how do different stimuli
elicit unique gene expression programs by activating the same signaling pathway? One
possibility is that the same signaling pathway can transmit temporally distinct signals that
have different physiological effects.
NF-kB-inducing stimuli utilize specific signaling pathways that converge at IKK (inhibitor of
kappaB kinase). Do different stimuli result in unique IKK activity profiles? Do these, in
turn, generate temporally distinct, stimulus-specific nuclear NF-kB activity and gene
expression profiles? This study provides evidence that the temporal control of IKK is
modulated by stimulus-specific signal processing mechanisms that play a role in determining
downstream specificity in gene expression. While TNF-induced IKK activity is rapidly
attenuated by negative feedback by the A20 protein, LPS-signaling and LPS-specific gene
expression programs are dependent on a cytokine-mediated positive feedforward mechanism.
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