%0 Journal Article %1 Iskar2010Druginduced %A Iskar, Murat %A Campillos, Monica %A Kuhn, Michael %A Jensen, Lars Juhl J. %A van Noort, Vera %A Bork, Peer %D 2010 %I Public Library of Science %J PLoS computational biology %K drug-targets gene-expression perturbations %N 9 %P e1000925+ %R 10.1371/journal.pcbi.1000925 %T Drug-induced regulation of target expression. %U http://dx.doi.org/10.1371/journal.pcbi.1000925 %V 6 %X 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.

@article{Iskar2010Druginduced, 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.}, added-at = {2018-12-02T16:09:07.000+0100}, author = {Iskar, Murat and Campillos, Monica and Kuhn, Michael and Jensen, Lars Juhl J. and van Noort, Vera and Bork, Peer}, biburl = {https://www.bibsonomy.org/bibtex/2f076e69aac83412778f07060d9e6f9d1/karthikraman}, citeulike-article-id = {7817780}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pcbi.1000925}, citeulike-linkout-1 = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936514/}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/20838579}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=20838579}, day = 9, doi = {10.1371/journal.pcbi.1000925}, interhash = {2dfa7793af41c51e1e4559b056677ec6}, intrahash = {f076e69aac83412778f07060d9e6f9d1}, issn = {1553-7358}, journal = {PLoS computational biology}, keywords = {drug-targets gene-expression perturbations}, month = sep, number = 9, pages = {e1000925+}, pmcid = {PMC2936514}, pmid = {20838579}, posted-at = {2010-09-16 15:03:55}, priority = {2}, publisher = {Public Library of Science}, timestamp = {2018-12-02T16:09:07.000+0100}, title = {Drug-induced regulation of target expression.}, url = {http://dx.doi.org/10.1371/journal.pcbi.1000925}, volume = 6, year = 2010 }