The p53 gene is the most frequently mutated gene in human cancer, and it controls several cellular responses to DNA damage including cell cycle arrest, DNA repair, cellar senescence, and apoptosis. However, why the p53 pathway is complex and the behavior of p53 during DNA damage repair are not clear yet. We decomposed the p53 pathway into several configurations which are derived from the phylogeny of the p53 pathway. No p53 feedback loop or the p53-MDM2 feedback loop, which is found in invertebrates, shows possibly linear relationship between DNA damage and p53 stable equilibrium states. However, more complex configuration, which is found in vertebrates, shows the bistable digram, which could never lead this bistable diagram for any values of the parameters in invertebrates. This complex p53 pathway makes the bistable states of the p53 and allows explaining for DNA repair and apoptosis.
p53 is known as a tumor suppressor gene, which is a hub of cellular signaling networks that is activated by other classes of DNA damage. Thus, it plays a critical role in guarding against cancer development; the loss of p53 function contributes to the development of most human cancers. The p53 pathway is composed of genes and their products that are targeted to respond to stress signals. More than seven negative and three positive feedback loops in the p53 pathway have identified. However, whether or not each of these feedback loops plays an important role in the overall function of the network has not been studies.
The main feedback loop in the p53 pathway consists of p53 and MDM2. It is a negative feedback loop that keeps the p53 protein at low levels in cells under normal conditions. In contrast, the free p53 protein concentration increases in the damaged cells. Also, the PTEN is known as a tumor suppressor protein, which regulates the cellular localization of MDM2. When restricted to the cytoplasm, MDM2 is degraded and this inhibition of MDM2 makes a p53 positive feedback loop. Another positive feedback loop includes ARF. There are two possible ways to keep p53 stabilization. One is MDM2 feedback loop interacting with p53 and another mechanism to stabilize p53 is by inhibition of MDM2 ubiquitin ligase activity through ARF.
Most vertebrates have homologs of each protein in the p53 pathway but at least a few vertebrates, such as common bottle nose dolphin and brandy’s bat do not include the ARF feedback loop. We apply a technique of analyzing the network dynamics based on grouping genes into discrete modules that allows us to understand the qualitative effect of the ARF feedback loop on the dynamics of the p53 network. This analysis suggests that the ARF component can have an effect on organismal fitness and that the transition from an ancestor missing the ARF loop to species containing the ARF loop may have been selected for because of its effect on whole organism fitness in response to the risk of cancer.
ARF and the p53-pathway
The p53-pathway serves as an important tumor surveillance mechanism that responds to oncogenic signals by triggering cell death or cell cycle arrest, and its inactivation is an obligatory step in many cancers. Retinoblastoma was believed to be an exception since no mutation in TP53 has ever been reported. Laurie et al reported MDM4 and MDM2 copy number gain in 63% and 10% of retinoblastomas, respectively, inferring that the p53-pathway is functionally inactivated in these tumors. A key component of the p53-pathway is the upstream activator, ARF, which transmits oncogenic signals to activate p53 by inhibiting the p53-antagonist MDM2.
ARF is frequently inactivated in cancers, resulting in a compromised p53-tumor surveillance pathway. The role of ARF in retinoblastoma was dismissed by Laurie et al., who reported an elevation of ARF mRNA in retinoblastomas compared to normal fetal retinas, and proposed that high ARF ex