| Title: | A genome-wide overexpression screen in yeast for small-molecule target identification |
| Author(s): | Luesch H; Wu TY; Ren P; Gray NS; Schultz PG; Supek F; |
| Address: | "Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA" |
| DOI: | 10.1016/j.chembiol.2004.10.015 |
| ISSN/ISBN: | 1074-5521 (Print) 1074-5521 (Linking) |
| Abstract: | "We describe a multicopy gene suppression screen of drug sensitivity in Saccharomyces cerevisiae that facilitates the identification of cellular targets of small molecules. An array of yeast transformants harboring a multicopy yeast genomic library was screened for resistance to growth inhibitors. Comparison of array growth patterns for several such inhibitors allowed the differentiation of general and molecule-specific genetic suppressors. Specific resistance to phenylaminopyrimidine (1), an inhibitor identified from a kinase-directed library, was associated with the overexpression of Pkc1 and a subset of downstream kinases. Components of two other pathways (pheromone response/filamentous growth and Pho85 kinase) that genetically interact with the PKC1 MAPK signaling cascade were also identified. Consistent with the suppression screen, inhibitor 1 bound to Pkc1 in yeast cell lysate and inhibited its activity in vitro. These results demonstrate the utility of this approach for the rapid deconvolution of small-molecule targets" |
| Keywords: | "Drug Evaluation, Preclinical/methods Drug Resistance, Fungal/genetics *Gene Expression Regulation, Fungal/drug effects Genomic Library MAP Kinase Signaling System/drug effects/physiology Microbial Sensitivity Tests Molecular Structure Molecular Weight Pro;" |
| Notes: | "MedlineLuesch, Hendrik Wu, Tom Y H Ren, Pingda Gray, Nathanael S Schultz, Peter G Supek, Frantisek eng Research Support, Non-U.S. Gov't 2005/01/25 Chem Biol. 2005 Jan; 12(1):55-63. doi: 10.1016/j.chembiol.2004.10.015" |
