The Dynamics Of P53 And Associated Proteins Under Different Stresses

p53 is one of the most important tumor suppressors,called the guardian of the genome.p53 mediates the cellular response to various kinds of stresses such as DNA damage and oncogene activation by inducing cell-cycle arrest,senescence and apoptosis.It is increasingly evident that p53 dynamics play a critical role in cell-fate decision.One important frontier in the p53 field is to construct mathematical models of the p53 network and associate network dynamics with the underlying biophysical mechanisms for cellular responses.The current thesis proposes a network model of the p53 core pathway and explores the network dynamics in response to various stresses to reveal the regulatory mechanism for cell-fate decision.The thesis consists of three chapters.In Chapter 1,we introduce backgrounds of biology and common methods for analysis and computation.These include gene expression and regulation,cell cycle,the laws of biochemical reactions,methods for numerical simulation,the history of p53 study,the p53 signaling pathway,and transcriptional activity and posttranslational modifications of p53.In Chapter 2,we build a mathematic model to simulate the dynamics of p53 and associated proteins under different stresses and compare simulation results with experimental observations.Experimentally,etoposide(ETP),nutlin-3 and Wip1 inhibition were applied to cells,and cellular responses were monitored.ETP is toxic so that it can produce DNA damage such as double-strand breaks(DSBs)and activate the ATM protein.The kinase ATMp can phosphorylate p53.Nutlin-3 is a small molecule binding to Mdm2,which is the most important negative regulator of p53.So nutline-3 can inhibit the interaction between p53 and Mdm2,enhancing the stability and activity of p53.Wip1 is a target protein of p53 and is a phosphatase,dephosphorylating ATM and p53.Wip1 is knocked down via RNA interference to inhibit Wip1 activity,called Wip1 KD.Adding Wip1 KD,p53 and ATM can remain in the phosphorylated state once they are phosphorylated.In simulations,the dose of ETP is set to 0,1 and 100.Together,there are eight sets of input signals,and we probe the network dynamics in each case and associate the cellular output with the dynamic characteristics of key proteins.Our simulation results reveal that p53 can exhibit switch-like or oscillatory behaviors,guiding different cell fates.These results are qualitatively consistent with experimental observations.This work provides a coherent picture of the dynamics and functions of the p53 network in response to different combinations of stress signals.In Chapter 3,we present a summary of our results and give some outlooks for further research.