Dynamic NF-κB and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation

Dynamic cellular systems reprogram gene expression to ensure appropriate cellular fate responses to specific extracellular cues. Here we demonstrate that the dynamics of Nuclear Factor kappa B (NE-kappa B) signalling and the cell cycle are prioritised differently depending on the timing of an inflammatory signal. Using iterative experimental and computational analyses, we show physical and functional interactions between NE-kappa B and the E2 Factor 1 (E2F-1) and E2 Factor 4 (E2F-4) cell cycle regulators. These interactions modulate the NE-kappa B response. In S-phase, the NE-kappa B response was delayed or repressed, while cell cycle progression was unimpeded. By contrast, activation of NE-kappa B at the G1/S boundary resulted in a longer cell cycle and more synchronous initial NE-kappa B responses between cells. These data identify new mechanisms by which the cellular response to stress is differentially controlled at different stages of the cell cycle.