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Hoffmann, A.; Levchenko, A.; Scott, M.L.; Baltimore, D. (2002) The IκB-NF-κB singaling module: temporal control and selective gene activation Science, 298, 1241-1245. Abstract
NF-κB is a mammalian transcription factor involved in the regulation of many cellular processes including cell cycle, inflammation and immune response. NF-κB is sequestered in the cytosol associated with IκB. Upon activation of the NF-κB signaling pathway, IκB kinases target IκB for degradation and NF-κB migrates to the nucleus where it triggers gene expression. An important aspect is that one of the IκB proteins (IκBα) is itself a target gene of NF-κB, establishing a feed-back process. Due to such feed-back, oscillations in the levels of NF-κB in the nucleus were predicted theoretically and were confirmed experimentally by Hoffmann et al.. The authors used a moderate detailed computational model to address the function of each of the three elements of the IκB family (IκBα, IκBβ , and IκBε) in the control of nuclear NF-κB oscillations. The model, composed of 64 of reactions and 26 variables, includes several aspects of the NF-κB signaling pathway such as the formation of complexes between NF-κB, IκB and IKK, degradation of IκB, transport in and out of the nucleus for IκB and NF-κB, and formation of IκB transcripts and their translation. Simultaneously, the authors studied NF-κB activation in three knockout cell lines in which only one of the IκB proteins is active. Results from both the computational model and the experiments show that IκBα mediates sustained oscillatory dynamics of NF-κB, while IκBβ and IκBε mediate damping of oscillations.
This computational model provides an important tool to study NF-κB associated events and has been subsequently used in part or totally by others (Lipniacki, T et al. (2004) J. Theor. Biol. 228, 195-215; Nelson et al. (2004) Science 306, 704-708; and Ihekwaba, A.E.C. et al. (2004) Sys. Biol. 1, 93-103). Lipniacki et al. have pointed out three limitations of the original model and amended it accordingly. The main issue deals with the correct implementation of multi-compartmentation, which in the original version of the model assumes that the nucleus and the cytosol have the same volume. Lipniacki corrected this aspect of the model and found that the ratio of cytosolic and a nuclear volumes influences the oscillatory dynamics of NF-κB.
Overall, this cross-disciplinary work provides an excellent example of how a close interplay between computational modelling and experiments can lead to important advancements. 