Visit our Expo - Redox and Inflammation signaling 2012

Session XIV : Transcriptional and translational control Poster XIV, 54
A dynamic equilibrium of IkB metabolism confers NF-kB responsiveness to UV
irradiation
Ellen O’Dea 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: eodea@ucsd.edu; ahoffmann@ucsd.edu
The transcription factor NF-kB (nuclear factor-kappaB) is activated by a variety of stimuli,
the majority of which signal to the IKK (IkappaB kinase) complex that triggers stimulusresponsive
degradation of IkB proteins. Ultraviolet (UV) irradiation activates NF-kB through
a distinctly different mechanism. Previous work reveals that UV-induced NF-kB activation
involves translational inhibition through an ER-stress mediated pathway that induces
phosphorylation of the eukaryotic initiation factor eIF2a.
Even a modest suppression of protein synthesis may result in a disruption of the homeostasis
of the cell and its signaling components. In the context of the NF-kB signaling module, we
utilize a mathematical model to guide our experimental studies of the mechanisms that allow
translational inhibition to result in NF-kB activation. Interestingly, the protein half-lives of
IkB-bound to NF-kB and of the free form are regulated by distinct degradation pathways. We
find that even in unstimulated cells, bound IkB is degraded by the well-characterized IKKmediated
mechanism that is dependent on constitutive IKK activity. Indeed, computational
simulations and experimental results demonstrate that genetic alterations in constitutive IKK
activity or in IkB-responsiveness to IKK alter UV inducibility of NF-kB. In contrast, free
IkB exists as a small pool in the cell that undergoes rapid degradation by a poorly understood
IKK-independent mechanism. Similarly integrated computational/experimental studies reveal
that short half-life control of free IkB is critical to UV responsiveness. Finally, we present
evidence that cells are capable of altering this dynamic equilibrium of rapid IkB degradation
balanced by constitutive synthesis thereby either attenuating or enhancing UV-induced NF-kB
activation. Potential signaling crosstalk mechanisms will be discussed.
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