Eckpoint kinase 2) up-regulation [202]. 146 nodes functioned as p53 target genes, such as effectively studied pro apoptotic genes which include BAX [9] and CDKN1A that controls cell cycle arrest [23]. 11 genes functioned both as upstream and downstream nodes of p53 and were involved in two step feedback loops. We calculated the connectivity degree from the 206 nodes Ang2 Inhibitors products inside the network (Figure three). The connectivity degree of a gene indicates the number of interactions for this gene. The most connected gene was p53, which participated in 225 interactions inside the PKT206 model. There were 30 genes with connectivity degree in between 10 and 100 plus the remaining genes were involved in less than 10 interactions. The network contains 30 two-step feedback loops in total, with 14 involving p53. A few of them play a considerable part in p53 regulation; as an example, the feedback loops involving p53, MDM2 and MDM4 (Mdm4 p53 binding protein homolog (mouse)), which incorporate 5 interactions: p53 activates MDM2; MDM2 inhibitsp53; MDM2 inhibits MDM4; MDM4 activates MDM2 and MDM4 inhibits MDM2 [24]. Feedback loops play a important role in p53 regulation and are thought to raise the robustness in the program in response to perturbations [25]. P53 has been implicated in quite a few cellular responses to tension like IR (ionizing radiation), UV, oncogene activation, and hypoxia. For this model to become in a position to predict cellular fate in response to strain, we linked 20 nodes for the input signal DNA damage (Table S3 in File S1). Most of the hyperlinks from DNA damage are activations and only three are inhibitions (DNA harm inhibits PTTG1 (pituitary tumour-transforming 1), MYC (v-myc, myelocytomatosis viral oncogene homolog (avian)) and AURKA (aurora kinase A). Similarly, p53 controls numerous cellular responses to tension for example cell cycle arrest, DNA damage repair, Fenobucarb Autophagy senescence and apoptosis. We discovered 95 links among downstream gene nodes and apoptosis and 77 nodes interact together with the apoptosis node. Among them, 18 nodes each promoted and prevented apoptosis, 38 nodes only induced apoptosis and 21 nodes only had anti-apoptotic function. We found 52 genes connected to senescence by 61 hyperlinks, among which 28 market and 33 avoid senescence.Analysis of dependencies in the p53 modelLogical dependencies among genes/proteins are represented by the dependency matrix [14], which represents the effects in between all pairs of nodes within the model. Six forms of effects are defined by CellNetAnalyzer based on the existence (or not) of good and unfavorable paths among two nodes: no impact, ambivalent issue, weak inhibitor, weak activator, powerful inhibitor, and powerful activator (see Methods for particulars). You can find 42,436 (2066206) components within the dependency matrix, of which 23,468 correspond to interactions having no effect; 16,540 are ambivalent factors; 1100 are weak inhibitors; 1240 are weak activators; 33 are strong inhibitors and 55 are strong activators (Table S6 in File S1). The majority of dependency matrix components are no effect or ambivalent factors. The huge quantity of ambivalent things is dueFigure 3. Connectivity degree distribution of 206 nodes. The degree distribution of 206 nodes in the model was obtained by the NetworkAnalyzer plugin for Cytoscape; both axes inside the figure are in logarithmic scale. doi:10.1371/journal.pone.0072303.gPLOS One | plosone.orgDNA Harm Pathways to Cancerto the complexity of regulatory effects among nodes, which are impacted by both positive and negative fee.