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| Item Type: | Article |
|---|---|
| Title: | Drug-induced regulation of target expression |
| Creators Name: | Iskar, M., Campillos, M., Kuhn, M., Jensen, L.J., van Noort, V. and Bork, P. |
| 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. |
| Keywords: | Drug Discovery, G-Protein-Coupled Receptors, Genetic Databases, Gene Expression Profiling, Genomics, HL-60 Cells, Messenger RNA, Molecular Targeted Therapy, Nonparametric Statistics, Oligonucleotide Array Sequence Analysis, Pharmaceutical Preparations, Pharmacological Processes, Physiological Feedback, Proteins, Systems Biology, Tumor Cell Line |
| Source: | PLoS Computational Biology |
| ISSN: | 1553-734X |
| Publisher: | Public Library of Science |
| Volume: | 6 |
| Number: | 9 |
| Page Range: | e1000925 |
| Date: | 9 September 2010 |
| Official Publication: | https://doi.org/10.1371/journal.pcbi.1000925 |
| PubMed: | View item in PubMed |
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