Cellular Response To Glucose Starvation

Glucose is the main energy source for eukaryotic cells.Cell proliferation and viability all require stable and abundant glucose supply.Under the condition of glucose limitation and depletion,cell will go through cycle arrest or apoptosis respectively.Understanding the cellular response to glucose starvation subserves better elucidation of the relation between cell proliferation and metabolism.There has been extensive experimental study on the cel-lular outcome under glucose starvation and the signaling pathways that stands out in this process.However,there has been little research on the mechanism of fate decision from the systems biology pespective.In this paper,we integrate the information of several pathways and construct a three-modules model to depict the process of cellular response to glucose star-vation,aiming to reveal the mechanism of fate decision and the crosstalk between different pathways.Here are the main results:1.By conducting numerial simulation with the deterministic ODE model,we recapitu-late the typical cellular outcomes under the condition of glucose starvation,and the reversibility of cell cycle arrest can also be reproduced.In addition,we find our model is robust to parameter fluctuation:the dynamic mode remains the same when all the parameters randomly fluctuate in the range of 80%to 120%of their default values,and the parameter fluctuation is one source of cell heterogeneity.2.By bifurcation and network motif analysis,we find that proliferation,cell cycle arrest and apoptosis correspond 3 distinct activation levels of p53,and the switching between them is regulated by two bistable switches:the first one is generated by the coupling of AMPK-p53 positive feedback loop and p53-Mdm2 negative feedback loop;and the second one is generated by the coupling of AMPK-p53 positive feedback loop and p53-PTEN-Akt-Mdm2 positive feedback loop.Under moderate energy stress,as AMPK is partially activated and the p53 level switches to an moderate level,cell cycle is arrested.Under severe energy assults,AMPK is fully activated,and the effect of p53-PTEN-Akt-Mdm2 feedback takes over;the p5 3 level rises to high levels with a transient stay at intermediate level,which dipicts cell apoptosis with a transient cell cycle arrest.We also find out the glucose concentration threshold of different fate:when Cg?1mM,we begin to observe cell cycle arrest in culture;when Cg<0.01mM,the energy shortage begins to induce apoptosis.3.With adaptation of growth factor pathway,we also explained the dynamics of U20S cell line culture experiment results,and further discuss the relation of apoptosis initia-tion time and the mTORC1 expression level under glucose depletion:when mTORC1 is slightly overexpressed,the dephosphorylation of p53 is reinforced,and its accumu-lation slows down,thus delaying apoptosis;when mTORC1 is highly overexpressed,its target S6K are highly activated,represses Akt activation via IRS,thus accelarate apoptosis initiation.This thesis is organized as follows:· Chapter ? is a general introduction to the biological background of our research topics,as well as the numerical simulation methods and techniques we used in our work.· In Chapter ?,we give a thorough description of our model on cellular response to glucose starvation,and we also present the ODE description of our model and list the parameter values.· In Chapter ?,we show the time series dynamics of our model under different condi-tions and the mechanism of cell-fate decision.We also explain experimental results with the U20S cell line and discuss regulation of cell fate by growth factors.· Chapter ? is a summary of this thesis.Also included are several topics that are worth further investigation.