p53-Mdm2 loop controlled by a balance of its feedback strength and effective dampening using ATM and delayed feedback.

摘要: When the genomic integrity of a cell is challenged, its fate determined in part by signals conveyed p53 tumour suppressor protein. It was observed recently that such are not simple gradations concentration, but rather counter-intuitive limit-cycle behaviour. Based on careful mathematical interpretation experimental body knowledge, we propose model for signalling network and characterise stability oscillatory dynamics. In our model, ATM, protein senses DNA damage, activates phosphorylation. active state, has decreased degradation rate an enhanced transactivation Mdm2, gene whose product Mdm2 tags degradation. Thus p53-Mdm2 system forms negative feedback loop. However, this loop delayed, as pool molecules being induced at given time will mark some later time, after have been transcribed, exported out nucleus, translated transported back into nucleus. The analysis demonstrates how lag combines with ATM-controlled strength effective dampening to produce oscillations. picture emerges once activated makes oscillator undergo supercritical Hopf bifurcation. This approach yields improved understanding global dynamics bifurcation structure time-delayed, allows predictions behaviour under different perturbations.