Sources of dynamic variability in NF-kappa B 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 IkBa transcription rate constant, e.g. by co-factors, provides the possibility of regulating the NF-kappa B dynamics by crosstalk.