Modelling and analysis of an ensemble of eukaryotic translation initiation models

Programmed protein synthesis plays an important role in the cell cycle. Deregulated translation has been observed in several cancers. In this study, the authors constructed an ensemble of mathematical models describing the integration of growth factor signals with translation initiation. Using these models, the authors estimated critical structural features of the translation architecture. Sensitivity and robustness analysis with and without growth factors suggested that a balance between competing regulatory programmes governed translation initiation. Proteins such as Akt and mTor promoted initiation by integrating growth factor signals with the assembly of the 80S initiation complex. However, negative regulators such as PTEN and 4EBP1 restrained initiation in the absence of stimulation. Other proteins such as eIF4E were also found to be structurally critical as deletion of amplification of these components resulted in a network incapable of nominal operation. These findings could help understand the molecular basis of translation deregulation observed in cancer and perhaps lead to new anti-cancer therapeutic strategies. [Includes supplementary material].