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.
Original language | English |
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Journal | PLoS Computational Biology |
Volume | 6 |
Issue number | 9 |
ISSN | 1553-734X |
DOIs | |
Publication status | Published - 1 Jan 2010 |
Keywords
- 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