Drug-induced Regulation of Target Expression

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Databases, Genetic
  • Drug Discovery / methods*
  • Feedback, Physiological / drug effects*
  • Gene Expression Profiling / methods*
  • Genomics / methods*
  • HL-60 Cells
  • Humans
  • Molecular Targeted Therapy / methods*
  • Oligonucleotide Array Sequence Analysis
  • Pharmaceutical Preparations
  • Pharmacological Phenomena
  • Proteins / metabolism
  • RNA, Messenger / analysis
  • Receptors, G-Protein-Coupled
  • Statistics, Nonparametric
  • Systems Biology / methods*

Substances

  • Pharmaceutical Preparations
  • Proteins
  • RNA, Messenger
  • Receptors, G-Protein-Coupled