Drug-induced regulation of target expression
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Drug-induced regulation of target expression. / Iskar, Murat; Campillos, Monica; Kuhn, Michael; Jensen, Lars Juhl; van Noort, Vera; Bork, Peer.
In: PLoS Computational Biology, Vol. 6, No. 9, 01.01.2010.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - Drug-induced regulation of target expression
AU - Iskar, Murat
AU - Campillos, Monica
AU - Kuhn, Michael
AU - Jensen, Lars Juhl
AU - van Noort, Vera
AU - Bork, Peer
PY - 2010/1/1
Y1 - 2010/1/1
N2 - 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.
AB - 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.
KW - Cell Line, Tumor
KW - Databases, Genetic
KW - Drug Discovery
KW - Feedback, Physiological
KW - Gene Expression Profiling
KW - Genomics
KW - HL-60 Cells
KW - Humans
KW - Molecular Targeted Therapy
KW - Oligonucleotide Array Sequence Analysis
KW - Pharmaceutical Preparations
KW - Pharmacological Processes
KW - Proteins
KW - RNA, Messenger
KW - Receptors, G-Protein-Coupled
KW - Statistics, Nonparametric
KW - Systems Biology
U2 - 10.1371/journal.pcbi.1000925
DO - 10.1371/journal.pcbi.1000925
M3 - Journal article
C2 - 20838579
VL - 6
JO - P L o S Computational Biology (Online)
JF - P L o S Computational Biology (Online)
SN - 1553-734X
IS - 9
ER -
ID: 33748459