Microarray-based method for monitoring yeast overexpression strains reveals small-molecule targets in TOR pathway

Rebecca A. Butcher, Bhupinder S. Bhullar, Ethan O. Perlstein, Gerald Marsischky, Joshua LaBaer, Stuart L. Schreiber

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Identification of the cellular targets of small-molecule hits in phenotypic screens is a central challenge in the development of small molecules as biological tools and potential therapeutics. To facilitate the process of small-molecule target identification, we developed a global, microarray-based method for monitoring the growth of pools of yeast strains, each overexpressing a different protein, in the presence of small molecules. Specifically, the growth of Saccharomyces cerevisiae strains harboring ∼3,900 different overexpression plasmids was monitored in the presence of rapamycin, which inhibits the target of rapamycin (TOR) proteins. TOR was successfully identified as a candidate rapamycin target, and many additional gene products were implicated in the TOR signaling pathway. We also characterized the mechanism of LY-83583, a small-molecule suppressor of rapamycin-induced growth inhibition. These data enabled functional links to be drawn between groups of genes implicated in the TOR pathway, identified several candidate targets for LY-83583, and suggested a role for mitochondrial respiration in mediating rapamycin sensitivity.

Original languageEnglish (US)
Pages (from-to)103-109
Number of pages7
JournalNature Chemical Biology
Volume2
Issue number2
DOIs
StatePublished - Feb 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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