title: Drug-induced regulation of target expression.
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.
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Murat
authors.initials: M
authors.lastname: Iskar
authors.forename: Monica
authors.initials: M
authors.lastname: Campillos
authors.forename: Michael
authors.initials: M
authors.lastname: Kuhn
authors.forename: Lars Juhl
authors.initials: LJ
authors.lastname: Jensen
authors.forename: Vera
authors.initials: V
authors.lastname: van Noort
authors.forename: Peer
authors.initials: P
authors.lastname: Bork
mesh_terms: D045744:Cell Line, Tumor; D030541:Databases, Genetic; D055808:Drug Discovery / Q000379:methods*; D025461:Feedback, Physiological / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods*; D023281:Genomics / Q000379:methods*; D018922:HL-60 Cells; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D004364:Pharmaceutical Preparations; D000069437:Pharmacological Phenomena; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D043562:Receptors, G-Protein-Coupled; D018709:Statistics, Nonparametric; D049490:Systems Biology / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations; D011506:Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled