In the field of cancer biology, numerous genes or proteins form extremely complex regulatory network, which determines cancer cell fate and cancer cell survival. p53 is a major tumor suppressor that is lost in more than 50% of human cancers. It has been well known that a variety of proteins regulate its protein stability, which is essential for its tumor suppressive function. It remains elusive how we could understand and target p53 stabilization process through network analysis. In this paper we discuss the use of random walk and stationary distribution to measure the compound effect of a network of genes or proteins. This method is applied to the network of nine proteins that influence the protein stability of p53 via regulating the interaction between p53 and its regulator MDM2. Our study identifies that some proteins such as HDAC1 in the network of p53 regulators may have more profound effects on p53 stability, agreeing with the established findings on HDAC1. This work shows the importance of using mathematical analysis to dissect the complexity of biology networks in cancer. 1. Introduction The tumor suppressor p53 is the master transcriptional regulator whose expression prevents the development of cancer [1]. Functional p53 expression is lost in about 50% of human cancer cases [2]. The MDM2 gene, a cellular protooncogene that is amplified in more than 7% of all human cancer cases [3], interacts with p53 and counteracts the tumor-suppressive function of p53 protein through various mechanisms, including blocking its transcriptional activity, exporting it into the cytoplasm and most importantly promoting its degradation [4]. MDM2 activities include those of a ubiquitin ligase, making it capable of targeting uniquitination of p53, which leads to p53 degradation [5, 6]. The ability of MDM2 to associate with and target p53 degradation depends highly on proteins that interact with MDM2 and p53, which provide an important mechanism of regulating p53 protein stability and expression [7]. The number of proteins implicated in regulation of p53 protein stability and degradation by modulating p53-MDM2 interaction is growing [8, 9]. By regulating this interaction, these proteins function as p53 degradation-promoting or -protecting molecules [10]. According to a categorized search of the literature using the IPA software program (Ingenuity Systems), 366 studies reported molecular regulators of p53 degradation, and 284 studies reported molecular regulators of p53 stabilization. These proteins participate in a variety of cellular processes, including
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