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PLoS Comput Biol. 2010 Sep 9;6(9). pii: e1000925. doi: 10.1371/journal.pcbi.1000925.

Drug-induced regulation of target expression.

Author information

  • 1Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.

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.

PMID:
20838579
[PubMed - indexed for MEDLINE]
PMCID:
PMC2936514
Free PMC Article

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