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Drug-induced regulation of target expression

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Item Type:Article
Title:Drug-induced regulation of target expression
Creators Name:Iskar, M. and Campillos, M. and Kuhn, M. and Jensen, L.J. and van Noort, V. and Bork, P.
Abstract:Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments. In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention.
Keywords:Drug Discovery, G-Protein-Coupled Receptors, Genetic Databases, Gene Expression Profiling, Genomics, HL-60 Cells, Messenger RNA, Molecular Targeted Therapy, Nonparametric Statistics, Oligonucleotide Array Sequence Analysis, Pharmaceutical Preparations, Pharmacological Processes, Physiological Feedback, Proteins, Systems Biology, Tumor Cell Line
Source:PLoS Computational Biology
Publisher:Public Library of Science
Page Range:e1000925
Date:9 September 2010
Official Publication:https://doi.org/10.1371/journal.pcbi.1000925
PubMed:View item in PubMed

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