Systems-Biological Approach to Ras-Mediated Signal Transduction

The analysis of complex intra-cellular signal transduction pathways involving reversible protein modifications and gene regulation requires a mixture of novel experimental and theoretical methods, often characterised as a "systems-biological approach." Mathematical modelling of the dynamics of the dynamics often determines the cellular response. This book gives an overview about existing models and develops new models and methods to investigate signalling pathways downstream of the oncogene Ras. It pays special attention to the MAPK signal transduction cascade, which has been subject of mathematical modelling for over a decade. In the first part the stimulus-response curve of the MAPK cascade is characterised both mathematically and experimentally. First, previous results are reviewed and the effect of feedback loops on the dynamics of the cascade is discussed. Subsequently, the effect of sequestration due to high enzyme concentrations as they are present in this pathway is discussed. Then, it is investigated whether the activation is bistable. In the second part the gene expression changes due to Ras-mediated signalling are investigated. First, expression time-series of well-defined target genes after induction of oncogenic Ras are investigated, and a mathematical model of a feedback via the transcriptional induction of a phosphatase is derived. Second, a method is developed to functionally classify targets genes. Finally, this method is extended to allow for functional prediction of transcription factor targets.