The evolution of p53 network behavior

Abstract

We study the evolution of the p53 core regulation network across the taxonomic span of humans to protozoans and nematodes. We introduce a new model for the core regulation network in mammalian cells, and conduct a formal analysis of the different network configurations that emerge in the evolutionary path to complexity. Solving the high dimensional equations associated with this model is typically challenging, and we develop a novel algorithm to overcome this problem. A key technical tool used is the representation of the distinct pathways in the core regulation networks as "modules", such that the behavior of the composite of two or more modules can be inferred from the characteristics of each of the individual modules. Apart from simplifying the complexity of the algorithm, this modular representation also allows us to qualitatively compare the distinct types of switching behaviors each network can exhibit. This then allows us to demonstrate how our model for the core regulation network in mammalian cells matches experimentally observed phenomena, and contrast this with the plausible behaviors admitted by the network configurations in putative primordial organisms. We show that the complexity of the p53 core regulation network in vertebrates permits a range of behaviors that can bring about distinct cell fate decisions not possible in the putative primordial organisms. p53 | evolution | modularity | bifurcationsA major cause for the emergence of tumors is genetic mutations that occur when the cellular DNA is damaged and not repaired to its original state. When the mutations interfere with the normal regulation of cell division, then cell proliferation could cause the tumor to become cancerous [1]. While there is abundant evidence that exposure to chemical carcinogens and radiation has had an impact on cancer rates [2], there is also evidence that cancer is a general feature of multi-cellular organisms that has presented a long-standing evolutionary challenge [3].A key component of the DNA damage response mechanism is the T P 53 gene which expresses the p53 tumor suppressor protein, the so-called "guardian of the genome" [4]. p53 and its ancestors have been protecting metazoans from mutations arising from DNA damage for over one billion years [5]. Recent research has shown that p53 plays this role by first sensing DNA damage, and then mediating various downstream processes in response. p53 can promote cell survival by upregulating genes that bring about cell-cycle arrest or DNA repair. However, p53 can also promote cell inactivation or death by bringing about permanent cell-cycle arrest or cell death [6][7][8][9]. How p53 levels and dynamics determine different cell fates in response to DNA damage is a crucial component of an organism's tumor suppression mechanism [10][11][12][13]. It is therefore no surprise that a mutation in p53 is implicated in over 50% of human cancers [14].One of the oldest known mechanisms cells employ in response to DNA damage is programmed cell death, also known as apoptosis [15]. Cell...