Dynamics of th p53 signaling network and its role in cell fate decisions

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The p53 signaling network is the most prominent pathway protecting against tumor formation. The pathway is induced by cellular stress ranging from DNA damage to oncogenic transformation. Upon DNA damage, upstream kinases phosphorylate p53, leading to its stabilization and accumulation in the nucleus. Nuclear p53 activates the expression of target genes involved in DNA repair, cell cycle arrest and apoptosis. Negative feedback loops ensure that p53 becomes deactivated again. The architecture of these feedback loops shapes the dynamic response of the pathway. In the proposed project, I plan to investigate the quantitative relation between DNA damage and the p53 response, in particular whether there is a threshold of damage necessary to induce the signaling pathway. Furthermore, I aim to understand how the architecture of the signaling network shapes its dynamic response to different conditions. Finally, I will determine how the dynamics of p53 influence the cellular response to DNA damage. To achieve these goals, I will quantitatively measure protein dynamics with high temporal resolution in single living human cells and combine the resulting data with mathematical models. For cancer formation, cells have to escape tumor suppression by the p53 network. Therefore, understanding the induction and dynamics of the p53 network in detail may provide novel targets for therapeutic intervention.