Drug-induced regulation of target expression
Research output: Contribution to journal › Journal article › Research › peer-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.
|Journal||PloS Computational Biology|
|Publication status||Published - 1 Jan 2010|
- 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