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Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology. Here we introduce a computational method (MEDICI) to predict PPI essentiality by combining gene knockdown studies with network models of protein interaction pathways in an analytic framework. Our method uses network topology to model how gene silencing can disrupt PPIs, relating the unknown essentialities of individual PPIs to experimentally observed protein essentialities. This model is then deconvolved to recover the unknown essentialities of individual PPIs. We demonstrate the validity of our approach via prediction of sensitivities to compounds based on PPI essentiality and differences in essentiality based on genetic mutations. We further show that lung cancer patients have improved overall survival when specific PPIs are no longer present, suggesting that these PPIs may be potentially new targets for therapeutic development. Software is freely available at https://github.com/cooperlab/MEDICI. Datasets are available at https://ctd2.nci.nih.gov/dataPortal.
Pubmed ID: 28118365 RIS Download
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Repository where scientists and organizations can share, store, manipulate, and publish biological network data. Users can also run their own copies of NDEx Server software in cases where stored networks must be kept in highly secure environment (such as for HIPAA compliance) or where high application load is incompatible with shared public resource. Open source software system that is part of Cytoscape family. Project of Cytoscape Consortium in conjunction with Ideker lab at UCSD School of Medicine. Public forum where biologists can exchange and publish computable network models in many types and formats. NDEx is based on REST web API which can be accessed by any application, including NDEx website and NDEx Cytoscape App. NDEx networks are assigned stable, globally unique URIs and so can be referenced by publications, by other networks, and by analytic applications.
View all literature mentionsTHIS RESOURCE IS NO LONGER IN SERVICE, documented on July 27, 2016. Curated database of information about known biomolecular interactions and key cellular processes assembled into signaling pathways. All interactions are assembled into pathways, and can be accessed by performing searches for biomolecules, or processes, or by viewing predefined pathways. This was a collaborative project between the NCI and Nature Publishing Group (NPG) from 2006 until September 22nd, 2012, and is no longer being updated. PID is aimed at the cancer research community and others interested in cellular pathways, such as neuroscientists, developmental biologists, and immunologists. The database focuses on the biomolecular interactions that are known or believed to take place in human cells. It can be browsed as an online encyclopedia, used to run computational analyses, or employed in ways that combine these two approaches. In addition to PID''''s predefined pathways, search results are displayed as dynamically constructed interaction networks. These features of PID render it a useful tool for both biologists and bioinformaticians. PID offers a range of search features to facilitate pathway exploration. Users can browse the predefined set of pathways or create interaction network maps centered on a single molecule or cellular process of interest. In addition, the batch query tool allows users to upload long list(s) of molecules, such as those derived from microarray experiments, and either overlay these molecules onto predefined pathways or visualize the complete molecular connectivity map. Users can also download molecule lists, citation lists and complete database content in extensible markup language (XML) and Biological Pathways Exchange (BioPAX) Level 2 format. The database is supplemented by a concise editorial section that includes specially written synopses of recent important research articles in areas related to cancer research, and specially commissioned Bioinformatics Primers that provide practical advice on how to make the most of other relevant online resources. The database and editorial content are updated monthly, and users can opt to receive a monthly email alert to stay informed about new content. Note: as of September 23, 2012 the PID is no longer being actively curated. NCI will maintain the PID website and data for twelve months beyond September 2012 to allow interested parties to obtain the previously curated data before the site is retired in September 2013.
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