Sources of dynamic variability in NF-κB signal transduction: a mechanistic model

The transcription factor NF-{kappa}B (p65/p50) plays a central role in the coordination of cellular responses by activating the transcription of numerous target genes. The precise role of the dynamics of NF-{kappa}B signalling in regulating gene expression is still an open question. Here, we show that besides external stimulation intracellular parameters can influence the dynamics of NF-{kappa}B. By applying mathematical modelling and bifurcation analyses, we show that NF-{kappa}B is capable of exhibiting different types of dynamics in response to the same stimulus. We identified the total NF-{kappa}B concentration and the I{kappa}B{alpha} transcription rate constant as two critical parameters that modulate the dynamics and the fold change of NF-{kappa}B. Both parameters might vary as a result of cell-to-cell variability. The regulation of the IκBα transcription rate constant, e.g. by co-factors, provides the possibility of regulating the NF-{kappa}B dynamics by crosstalk.