Roles of Spatial Parameters on the Oscillation of Nuclear NF-κB: Computer Simulations of a 3D Spherical Cell

摘要

Transcription factor NF-κB resides in the cytoplasm and translocates to the nucleus by application of extracellular stimuli. It is known that the nuclear NF-κB oscillates and different oscillation patterns lead to different gene expression. Nearly forty reports on modeling and simulation of nuclear NF-κB have been published to date. The computational models reported so far are temporal or two-dimensional, and the discussions on spatial parameters have not been involved or limited. Since spatial parameters in cancer cells such as nuclear to cytoplasmic volume (N/C) ratio are different from normal cells, it is important to understand the relationship between oscillation patterns and spatial parameters. Here we report simulations of a 3D computational model for the oscillation of nuclear NF-κB using A-Cell software. First, we found that the default biochemical kinetic constants used in the temporal model cannot replicate the experimentally observed oscillation in the 3D model. Thus, the default parameters should be changed in the 3D model. Second, spatial parameters such as N/C ratio, nuclear transport, diffusion coefficients, and the location of IκB synthesis were found to alter the oscillation pattern. Third, among them, larger N/C ratios resulted in persistent oscillation of nuclear NF-κB, and larger nuclear transport resulted in faster oscillation frequency. Our simulation results suggest that the changes in spatial parameters seen in cancer cells is one possible mechanism for alteration in the oscillation pattern of nuclear NF-κB and lead to the altered gene expression in these cells.