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

The activated transcription factor NF-kappa B shuttles between the cytoplasm and the nucleus resulting in the oscillation of nuclear NF-kappa B (NF-kappa B-n). The oscillation pattern of NF-kappa B-n 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 I kappa B protein, modified the oscillation pattern of NF-kappa Bn. In a subsequent report, we elucidated the importance of the "reset" of NF-kappa B-n (returning of NF-kappa B to the original level) and of a "reservoir" of I kappa B in the cytoplasm. When the diffusion coefficient of I kappa B was large, I kappa B stored at a distant location from the nucleus diffused back to the nucleus and "reset" NF-kappa B-n. Herein, we report mechanisms that regulate the persistency and frequency of NF-kappa Bn oscillation by nuclear transport. Among the four parameters of nuclear transport tested in our spatio-temporal computational model, the export of I kappa B mRNA from the nucleus regulated the persistency of oscillation. The import of I kappa B to the nucleus regulated the frequency of oscillation. The remaining two parameters, import and export of NF-kappa B to and from the nucleus, had virtually no effect on the persistency or frequency. Our analyses revealed that lesser export of I kappa B mRNA allowed NF-kappa Bn to transcript greater amounts of I kappa B mRNA, which was retained in the nucleus, and was subsequently exported to the cytoplasm, where large amounts of I kappa B were synthesized to "reset" NF-kappa B-n and drove the persistent oscillation. On the other hand, import of greater amounts of I kappa B led to an increase in the influx and the efflux of NF-kappa B 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-kappa B-n.