The normalized http://www.selleckchem.com/products/azd9291.html sensitivity coefficients for NF B acti vation were solved and plotted as heat maps to illustrate the dynamic relationship between the signaling compo nents and the system response. The sensitivity results clearly show that the NF B response is nearly completely insensitive to variations in some rate parameters, but also moderately or highly sensitive to others, consistent with earlier results which found that only a relatively small number of network parameters signifcantly influenced NF B activity. A notable feature of our analysis is that, with the excep tion of the NF B nuclear shuttling rates for which the sensitivity scores remain high throughout the entire response, NF B activity exhibits highly dynamic sensitivity with respect to most other para meters.

In other words, there is a strong temporal com ponent to the regulation of NF B activity, where variations in different parameters can exhibit great influ ence over certain phases of activity but have only mar ginal effects on activation during other time intervals. The first 20 min of NF B activity is predominantly influenced by the rates for IKK induced phosphorylation, ubiquitina tion and degradation and also IKK activation, with little contribution from the feedback parameters. As I Ba is degraded and free NF B ascends towards its maximal activity, the nuclear shuttling rates of free NF B have the greatest effect. However, the system shows extreme sensitivity to rates controlling the inner and outer feedback loops.

The system is very senstive to the rates for induced I Ba synthesis and its association with NF B during a time period coinciding with the decline of the first peak, with synthesis and binding rates negatively affecting NF B activation. The rate of conversion of inactivated IKK back to native IKK also is among the most signifi cant parameters in the attenuation of NF B activity. While NF B activity is at its lowest levels Brefeldin_A between 60 90 min, the stability of the remaining I Ba transcripts and the induced phosphorylation, ubiquitination and gradation of I Ba exert more influence on free NF B levels. The second peak of NF B activity is regulated greatly by the nuclear import rate of free I Ba, as evi denced by the high sensitivity of ki3a only during this time period. Feedback from I Ba again has highly sig nificant contributions to the dynamics of the second peak, with induced synthesis of I Ba and its affinity to unbound I Ba having very high sensitivities. The NF B response is also highly sensitive to the outer A20 feedback loop in a time dependent manner. The rates for IKK inactivation by A20 significantly affect the termination of initial NF B activity as well as the second phase of activity.