Mathematical modelling of the core regulatory feedback mechanisms of p53 protein that decide cell fate

摘要: Cells defence against stresses that can cause DNA damage (single-strand breaks, double-strand breaks) is crucial in safeguarding the integrity of genome and survival organism as a whole. One genes plays pivotal role maintaining stability humans p53, which encodes its product p53 protein. The regulation activation extremely complex, molecular cell biology has gathered parts pieces whole pathway. Mental intuition this complex challenging; therefore, it requires different method to quantitatively model analyse enhance current understanding. This thesis attempted create two quantitative models mechanisms regulate basal levels appropriate stress response deciding fate by either cycle arrest (to stop proliferation DNA-damaged cells) or apoptosis (programmed death) eliminate damaged cells. In first part research, modified improved from Sun et al. (2011) deterministic proposed explain dynamics due breaks. form delay differential equations incorporates most recently found interactions hypothesis: core regulators consist ATM, Mdm2, MdmX, Wip1 p53. ATM transducer, amplifies signal activates inhibits Mdm2 MdmX. network structure consists positive feedback loops (p53 auto-regulation auto-activation), three negative (Mdm2, MdmX Wip1) interplay have successfully captured (spontaneous pulses under non-stressed conditions) (repeated oscillations stressed conditions). simulation results show spontaneous are intrinsic involving low number breaks; an important contributing threshold generating whether repeated. It also shows excitable, in once initiated, completes pulse even if inhibited. Bifurcation analysis revealed spectrum behaviour conditions characterised Type II excitability (oscillations arises non-zero frequency). Most importantly, we reveal some novel findings on mechanism pulsatile oscillatory for physiological function transcription factor guardian genome. The second extension incorporating initiation module Zhang (2009a) with parameter values modelling regulatory protein apoptotic switch high The…