Identification of a ligand-induced transient refractory period in nuclear factor-kappaB signaling.
Abstract
In response to a variety of extracellular ligands, nuclear factor-kappaB (NF-kappaB) signaling regulates inflammation, cell proliferation, and apoptosis. It is likely that cells are not continuously exposed to stimulating ligands in vivo but rather experience transient pulses. To study the temporal regulation of NF-kappaB and its major regulator, inhibitor of NF-kappaBalpha (IkappaBalpha), in real time, we utilized a novel transcriptionally coupled IkappaBalpha-firefly luciferase fusion reporter and characterized the dynamics and responsiveness of IkappaBalpha processing upon a short 30-s pulse of tumor necrosis factor alpha (TNFalpha) or a continuous challenge of TNFalpha following a 30-s preconditioning pulse. Strikingly, a 30-s pulse of TNFalpha robustly activated inhibitor of NF-kappaB kinase (IKK), leading to IkappaBalpha degradation, NF-kappaB nuclear translocation, and strong transcriptional up-regulation of IkappaBalpha. Furthermore, we identified a transient refractory period (lasting up to 120 min) following preconditioning, during which the cells were not able to fully degrade IkappaBalpha upon a second TNFalpha challenge. Kinase assays of IKK activity revealed that regulation of IKK activity correlated in part with ...Continue Reading
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Apoptosis
Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis