Stress-specific response of the p53-Mdm2 feedback loop

We construct a mathematical model of the negative feedback loop involving p53 and its inhibitor, Mdm2, at the core of this pathway, and use it to examine the effect of different stresses that trigger p53. In response to DNA damage, hypoxia, etc., the model exhibits a wide variety of specific output behaviour - steady states with low or high levels of p53 and Mdm2, as well as spiky oscillations with low or high average p53 levels.We show that even a simple negative feedback loop is capable of exhibiting the kind of flexible stress-specific response observed in the p53 system. Further, our model provides a framework for predicting the differences in p53 response to different stresses and single nucleotide polymorphisms.The tumor suppressor protein, p53, is a transcription factor that regulates the activity of hundreds of genes involved in cell growth and death [1,2]. Over 50% of human cancer cells contain mutations in p53, because of which it has become a key target in cancer research [3]. A wide variety of stress conditions result in the accumulation and activation of p53 - among others: DNA damage, hypoxia, heat shock, nutrient deprivation and oncogene activation. Despite the fact that all these inputs are integrated into a single node, p53, the expression pattern of downstream genes (and hence the physiological response) appears to be specific to each stress. For example, hypoxia invariably leads to apoptosis [4], whereas ribonucleotide depletion leads to reversible cell cycle arrest [5], and UV irradiation can result in either cell cycle arrest or apoptosis depending on the intensity of the damage [6].How does the regulatory network around p53 retain this exibility even though all inputs converge at a single node? We argue in this paper that the particular design of the p53-Mdm2 feedback loop at the core of this network could be the source of this flexibility. p53 is regulated by other proteins at two levels: its stability (e.g., Pirh2, COP1, Mdm2 decrease its hal