Regulation of signal transduction by spatial parameters: a case in NF-kappa B oscillation

NF-kappa B is a transcription factor regulating expression of more than 500 genes, and its dysfunction leads to the autoimmune and inflammatory diseases. In malignant cancer cells, NF-kB is constitutively activated. Thus the elucidation of mechanisms for NF-kB regulation is important for the establishment of therapeutic treatment caused by incorrect NF-kB responses. Cytoplasmic NF-kB translocates to the nucleus by the application of extracellular stimuli such as cytokines. Nuclear NF-kB is known to oscillate with the cycle of 1.5-4.5h, and it is thought that the oscillation pattern regulates the expression profiles of genes. In this review, first we briefly describe regulation mechanisms of NF-kB. Next, published computational simulations on the oscillation of NF-kB are summarised. There are at least 60 reports on the computational simulation and analysis of NF-kB oscillation. Third, the importance of a space' for the regulation of oscillation pattern of NF-kB is discussed, showing altered oscillation pattern by the change in spatial parameters such as diffusion coefficient, nuclear to cytoplasmic volume ratio (N/C ratio), and transport through nuclear membrane. Finally, simulations in a true intracellular space (TiCS), which is an intracellular 3D space reconstructed in a computer with organelles such as nucleus and mitochondria are discussed.