Drug-induced regulation of target expression

Research output: Contribution to journalJournal articlepeer-review

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.
Original languageEnglish
JournalPLoS Computational Biology
Volume6
Issue number9
ISSN1553-734X
DOIs
Publication statusPublished - 1 Jan 2010

    Research areas

  • Cell Line, Tumor, Databases, Genetic, Drug Discovery, Feedback, Physiological, Gene Expression Profiling, Genomics, HL-60 Cells, Humans, Molecular Targeted Therapy, Oligonucleotide Array Sequence Analysis, Pharmaceutical Preparations, Pharmacological Processes, Proteins, RNA, Messenger, Receptors, G-Protein-Coupled, Statistics, Nonparametric, Systems Biology

ID: 33748459