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Modeling of p53 Signaling Pathway Regulation

Isaac Barjis, Khalid Samarrai and Ruwaa Samarrai

The 2010 Summer Computer Simulation Conference (SCSC 10)
Ottawa, Canada, July 11-14, 2010


Summary

Loss of control of genomic stability is central in the development of cancer, and p53, by regulating normal responses to DNA damage and other forms of genotoxic stress, is a key element in maintaining genomic stability. It is well known that in great majority of human tumor the p53 pathway is disarmed by oncogenic mutations in p53 itself, expression of viral oncoproteins, or defective p53 upstream regulation p53 i.e. it is not functional or functions incorrectly. Therefore P53 plays a crucial role in the prevention and suppression of tumour development (Vogelstein et al. 2000). The p53 gene is regulated by a negative feedback loop that involves transcriptional target MDM2. The p53 protein is phosphorylated by a member of protein kinases such as CDK7, and stabilized by the protein ARF. The phosphorylation and stabilization of p53 is believed to enhance its transcriptional activity and act simultaneously. Inactivation of p53-dependent pathways can occur at any of several different points and that p53 itself is merely the most common target. For example, the p53 inhibitor MDM2 is over-expressed in tumors independently of the p53 mutation. Several computational models have been proposed to simulate the dynamics of p53-MDM2 loops, the p53 transcriptional activity, and the apoptosis signaling pathway. However none of the research papers represent the complete process that will show the link between p53 regulation, apoptosis and other signaling pathway. In this paper we demonstrate the value of using Petri nets to model, simulate and analyze molecular interactions and mechanisms of p53 signaling pathways. In order to model the p53 signaling pathway we introduce some extensions to the graphical notation of ordinary Petri nets. Then we used the extended Petri net to model, simulate and analyze the p53 signaling pathway and their regulation.


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