drug-induced regulation of target expression药物引起的监管目标表达式.pdfVIP

Drug-Induced Regulation of Target Expression 1 1 1 1,2 1 1,3 Murat Iskar , Monica Campillos , Michael Kuhn , Lars Juhl Jensen , Vera van Noort , Peer Bork * 1 Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany, 2 Novo Nordisk Foundation Center for Protein Research, ¨ Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark, 3 Max-Delbruck-Centre for Molecular Medicine, Berlin, Germany 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