Abstract
BackgroundCancer is caused by genetic abnormalities, such as mutations of oncogenes or tumor suppressor genes, which alter downstream signal transduction pathways and protein-protein interactions. Comparisons of the interactions of proteins in cancerous and normal cells can shed light on the mechanisms of carcinogenesis.ResultsWe constructed initial networks of protein-protein interactions involved in the apoptosis of cancerous and normal cells by use of two human yeast two-hybrid data sets and four online databases. Next, we applied a nonlinear stochastic model, maximum likelihood parameter estimation, and Akaike Information Criteria (AIC) to eliminate false-positive protein-protein interactions in our initial protein interaction networks by use of microarray data. Comparisons of the networks of apoptosis in HeLa (human cervical carcinoma) cells and in normal primary lung fibroblasts provided insight into the mechanism of apoptosis and allowed identification of potential drug targets. The potential targets include BCL2, caspase-3 and TP53. Our comparison of cancerous and normal cells also allowed derivation of several party hubs and date hubs in the human protein-protein interaction networks involved in caspase activation.ConclusionOur method allows identification of cancer-perturbed protein-protein interactions involved in apoptosis and identification of potential molecular targets for development of anti-cancer drugs.
Highlights
Cancer is caused by genetic abnormalities, such as mutations of oncogenes or tumor suppressor genes, which alter downstream signal transduction pathways and proteinprotein interactions
Genetic mutations, translocations, amplifications, deletions, and viral gene insertions can alter translated proteins and thereby disrupt signal transduction pathways and protein-protein interactions that are essential for apoptosis and other important cellular processes [3]
Apoptosis is necessary for normal human development and survival, in that cells must die in order to prevent uncontrolled growth [7]
Summary
Cancer is caused by genetic abnormalities, such as mutations of oncogenes or tumor suppressor genes, which alter downstream signal transduction pathways and proteinprotein interactions. Comparisons of the interactions of proteins in cancerous and normal cells can shed light on the mechanisms of carcinogenesis. The entire set of molecular interactions within cells, has provided many insights into the etiology and regulation of cancer [1,2]. Genetic mutations, translocations, amplifications, deletions, and viral gene insertions can alter translated proteins and thereby disrupt signal transduction pathways and protein-protein interactions that are essential for apoptosis and other important cellular processes [3]. Inactivation of pro-apoptotic proteins or up-regulation of anti-apoptotic proteins results in unchecked growth of cells and to cancer [4]. Apoptosis requires activation of multiple pathways via regulated protein-protein interac-
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