Previous investigations on the 3 groups of genes have indicated distinct mechanisms for the differential dy namical our website response. Hao and Baltimore have found lesser presence of AU Rich Element region on the 3UTR of group III genes, targeted by microRNAs and ARE binding proteins that en hance RNA decay processes. Hence, it was postulated as one possible reason for the lower decay response of group Inhibitors,Modulators,Libraries III genes compared with genes from groups I and II. More recently, by studying the kinetics of pre mRNA and mRNA, Hao and Baltimore observed delays in splicing Inhibitors,Modulators,Libraries of groups II and III genes compared to group I genes. The differential delays were suggested as another biological mechanism for the distinct gene profiles. In our extended model, we, therefore, considered both mechanisms to reproduce the temporal profiles of the 3 groups of genes.

Notably, our simulations of pre mRNA and mRNA for all groups of genes matched the data of Hao and Baltimore for the first 60 min. However, subsequently for 12 h, although the simulations of groups I and II genes were recapitulated, Inhibitors,Modulators,Libraries group III simulation was poor. Specifically, reducing the parameter value for the decay term representing lower miRNA and ARE binding pro teins regulating decay processes, and adding intermediates to provide delays in RNA splicing in our model were not sufficient to produce the continuous activation of group III genes. To overcome the shortfall in the model simulations, we hypothesized that novel activation or transcription term may be present to provide additional flux for the continuous increase in group III expressions.

This could result from secondary post transcriptionaltranslational mechanisms through i autocrine signaling such as IL 1, IL 6 or TGF B signaling, or ii cytosolic feed back mechanisms specifically for group III genes. Thus, a novel feedback mechanism pre dominantly affecting Inhibitors,Modulators,Libraries the transcription of group III genes was Inhibitors,Modulators,Libraries added to the TNFR1 model. The modified TNFR1 model with feedback mecha nisms to group III genes produced simulations that matched all 3 groups of gene expression profiles. To scrutinize the feed back mechanism, we re monitored the simulation pro file of sellekchem NF B for 6 hours. The resultant profile mimics the damped oscillatory dynamics of NF B previously observed in murine fi broblasts. Overall, these data suggest that low miRNA regulation and additional delay in RNA spli cing are not sufficient to produce the continuous activation of group III genes, and that a novel tran scription process, possibly through secondary post transcriptionaltranslational autocrine signaling, such as IL 1 signaling or other novel feedback mechanisms that activate NF B, and not MAPK, are required.