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

P53信号网络是防止肿瘤形成的最重要的途径。该途径是由细胞应激诱导的，从DNA损伤到致癌转化。DNA损伤时，上游蛋白激酶使P53磷酸化，使其稳定并在细胞核内积聚。核P53激活与DNA修复、细胞周期停滞和细胞凋亡相关的靶基因的表达。负反馈循环确保P53再次失活。这些反馈环的架构塑造了路径的动态响应。在拟议的项目中，我计划调查DNA损伤和P53反应之间的定量关系，特别是是否存在诱导信号通路所需的损伤阈值。此外，我的目标是了解信令网络的体系结构如何塑造其对不同条件的动态响应。最后，我将确定P53的动态如何影响细胞对DNA损伤的反应。为了实现这些目标，我将在单个活着的人类细胞中以高时间分辨率定量测量蛋白质动力学，并将所得数据与数学模型相结合。对于癌症的形成，细胞必须逃避P53网络对肿瘤的抑制。因此，详细了解P53网络的诱导和动力学可能会为治疗干预提供新的靶点。

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.