PMC:4331679 / 9554-14652 JSONTXT

{"project":"2_test","denotations":[{"id":"25707537-22579283-14870715","span":{"begin":178,"end":179},"obj":"22579283"},{"id":"25707537-22579283-14870716","span":{"begin":198,"end":199},"obj":"22579283"},{"id":"25707537-19641508-14870717","span":{"begin":1949,"end":1950},"obj":"19641508"},{"id":"25707537-16874066-14870718","span":{"begin":2082,"end":2083},"obj":"16874066"},{"id":"25707537-12052897-14870719","span":{"begin":2215,"end":2217},"obj":"12052897"},{"id":"25707537-19180116-14870720","span":{"begin":3430,"end":3432},"obj":"19180116"},{"id":"25707537-22485198-14870721","span":{"begin":3433,"end":3435},"obj":"22485198"},{"id":"25707537-22504301-14870722","span":{"begin":3804,"end":3806},"obj":"22504301"},{"id":"25707537-7626804-14870723","span":{"begin":4116,"end":4118},"obj":"7626804"},{"id":"25707537-11350724-14870724","span":{"begin":4569,"end":4571},"obj":"11350724"},{"id":"25707537-14967141-14870725","span":{"begin":4753,"end":4755},"obj":"14967141"},{"id":"25707537-16940186-14870726","span":{"begin":4979,"end":4981},"obj":"16940186"},{"id":"25707537-20221256-14870727","span":{"begin":5095,"end":5096},"obj":"20221256"}],"text":"Apoptosis network construction\nWe constructed a generic apoptosis network consisting of 22 signalling proteins including 18 proteins from the biological experiment conducted in [5]. The authors of [5] provided Variable Importance in Projection (VIP) scores for different selected proteins to demonstrate how the selected proteins were useful for predicting apoptosis of different cell lines. For example, proteins with VIP score \u003e 1 were important variables, proteins with VIP score \u003c 0.5 were unimportant variables. Since our goal is to test the goodness of fit of our model with Yaffe's data, we selected proteins that have been measured in the experiment. Also, our signalling network includes molecules based on the prior knowledge from several pathways playing critical roles in inducing cell death, which include DNA damage response and cell death pathways, stress response pathways, etc.\nThe network diagram is shown in Figure 1. We constructed connections between various signalling proteins in our basic apoptosis network using the existing literature. HER2 is a cell transmembrane receptor which plays a significant role in breast cancer by suppression of tumour growth. It provides growth signals in PI3KAKT and Ras-MAPK pathways. HER2 also suppresses p53-mediated apoptosis by upregulation of MDM2 by activation of AKT. p53 also participates in promoting apoptosis by sensing DNA damage and can upregulate pro-apoptotic Bcl-2 proteins (e.g. PUMA) as well as suppress IAPs (e.g. survivin) [6]. PUMA is a pro-apoptotic protein and plays crucial roles in apoptosis. Tumour suppressor gene p53 regulates the expression of PUMA. Once activated, PUMA frees the apoptosis regulator Bax and Bak owing to its high affinity with Bcl-2 oncogenic group of proteins. The freed proteins further transduce the apoptotic signals to the mitochondria. This causes the Caspases to be activated and the activated caspases eventually lead to the cell death [7]. Activation of pro-apoptotic BAX/Bak facilitates heme protein cytochrome c being released from the inner mitochondria membrane [8,9]. The cytochrome c further stimulates Casp9, which then stimulates Casp3 and Casp7, which eventually lead to apoptotic cell death [10]. Up-regulation of DAPK induces apoptosis by enhancing response of tumour suppressor p53 whereas down-regulation of DAPK reduces the response of p53 to several oncogenes including c-Myc and E2F-1. The activated form of DAPK further activates the Beclin-1 by phosphorylation. Beclin-1 activation is crucial for Autophagy and also for its crosstalk with apoptosis.\nFigure 1 Basic apoptosis network and various rewiring events. Basic apoptotic network contained all edges except the broken edges (green and blue). Edges represented by thick red colour were deleted by Genetic Algorithm while inferring N2 from N1. Broken edges represented by green colour were inserted by Genetic Algorithm while inferring N2 from N1. Edges represented by magenta colour were deleted by Genetic Algorithm while inferring N3 from N2. Broken edges represented by blue colour were inserted by Genetic Algorithm while inferring N3 from N2. Beclin-1 is an autophagy protein that interacts with Bcl-2, an anti-apoptotic protein, and they form a complex, to facilitate a switch from autophagy to apoptosis and vice-versa. The activity of Beclin-1, owing to the complex formation of Bcl-2:Beclin-1 complex, is suppressed by Bcl-2 protein [11,12]. STAT3 is an important gene due to its roles in regulating cell fate including cell survival and cell growth. Experimental results have shown that a decreased level of STAT3 leads to a reduced level of Bcl-2 [13]. Activation of STAT3 gene stimulates transcription of quite a few cell fate controlling genes, which include some of the members of Bcl-2 protein family [14]. The proteins Wee1 and Cdk1 (Cyclin-dependent kinase 1) play very important roles in regulating cell cycle. During mitosis, the size of a cell is controlled by the inhibition of Cdk1 by Wee1 which prevents the cell from going into mitosis. The suppression of Cdk1 by Wee1 is done by phosphorylation of Cdk1 [15]. Cdk1 in turn phosphorylates Bcl-2 and suppresses its activity [16]. The EGF receptor (EGFR) is a cell membrane protein receptor with high affinity for several specific proteins (ligands) including Epidermal Growth Factor (EGF). EGFR further activates many targets including Jun N-terminal kinases (JNKs). Mutation in EGFR may lead to its uncontrolled expression which can potentially cause uncontrolled cell growth, which is a hall mark of cancer [17]. The Bcl-2-associated death promoter (BAD), another member protein from Bcl-2 group of proteins, is highly pro-apoptotic. JNK can inhibit apoptosis by phosphorylating BAD protein [18]. Trimeric Tumor Necrosis Factor (TNF) activates multiple signalling pathways which in turn lead to apoptosis. TNF interacts with death domain (DD) protein TRADD. TRADD in turn has been shown to have high affinity for RIP [19]. Casp3 mediates cleavage of multiple proteins and causes DNA fragmentation which eventually leads to apoptosis [2]."}