Regulation of NF-κB Oscillation by Nuclear Transport: Mechanisms Determining the Persistency and Frequency of Oscillation.

The activated transcription factor NF-κB shuttles between the cytoplasm and the nucleus resulting in the oscillation of nuclear NF-κB (NF-κBn). The oscillation pattern of NF-κBn is implicated in the regulation of gene expression profiles. Using computational models, we previously reported that spatial parameters, such as the diffusion coefficient, nuclear to cytoplasmic volume ratio, transport through the nuclear envelope, and the loci of translation of IκB protein, modified the oscillation pattern of NF-κBn. In a subsequent report, we elucidated the importance of the "reset" of NF-κBn (returning of NF-κB to the original level) and of a "reservoir" of IκB in the cytoplasm. When the diffusion coefficient of IκB was large, IκB stored at a distant location from the nucleus diffused back to the nucleus and "reset" NF-κBn. Herein, we report mechanisms that regulate the persistency and frequency of NF-κBn oscillation by nuclear transport. Among the four parameters of nuclear transport tested in our spatio-temporal computational model, the export of IκB mRNA from the nucleus regulated the persistency of oscillation. The import of IκB to the nucleus regulated the frequency of oscillation. The remaining two parameters, import and export of NF-κB to and from the nucleus, had virtually no effect on the persistency or frequency. Our analyses revealed that lesser export of IκB mRNA allowed NF-κBn to transcript greater amounts of IκB mRNA, which was retained in the nucleus, and was subsequently exported to the cytoplasm, where large amounts of IκB were synthesized to "reset" NF-κBn and drove the persistent oscillation. On the other hand, import of greater amounts of IκB led to an increase in the influx and the efflux of NF-κB to and from the nucleus, resulting in an increase in the oscillation frequency. Our study revealed the importance of nuclear transport in regulating the oscillation pattern of NF-κBn.