Spatio-temporal modelling of the NF-kappa B intracellular signalling pathway:the roles of diffusion, active transport, and cell geometry

The nuclear factor kappa B (NF-kappa B) intracellular signalling pathway is central to many stressful, inflammatory, and innate immune responses. NF-kappa B proteins themselves are transcription factors for hundreds of genes. Experiments have shown that the NF-kappa B pathway can exhibit oscillatory dynamics a negative feedback loop causes oscillatory nuclear-cytoplasm c translocation of NF-kappa B. Given that cell size and shape are known to influence intracellular signal transduction, we consider a spatio-temporal model of partial differential equations for the NF-kappa B pathway, where we model molecular movement by diffusion and, for several key species including NF-kappa B, by active transport as well.Through numerical simulations we find values for model parameters such that sustained oscillatory dynamics occur. Our spatial profiles and animations bear a striking resemblance to experimental images and movie clips employing fluorescent fusion proteins. We discover.:hat oscillations in nuclear NF-kappa B may occur when active transport is across the nuclear membrane only, or when no species are subject to active transport. However, when active transport is across the nuclear membrane and NF-kappa B is additionally actively transported through the cytoplasm, oscillations ire lost. Hence transport mechanisms in a cell will influence its response to activation of its NF-kappa B pathway. We also demonstrate that sustained oscillations in nuclear NF-kappa B are somewhat robust to changes in the shape of the cell, or the shape, location, and size of its nucleus, or the location of ribosomes. Yet if the cell is particularly flat or the nucleus sufficiently small, then oscillations are lost. Thus the geometry of a cell may partly determine its response to NF-kappa B activation.The NF-kappa B pathway is known to be constitutively active in several human cancers. Our spatially explicit modelling approach will allow us, in future work, to investigate targeted drug therapy of tumours. (C) 2011 Elsevier Ltd. All rights reserved.