Design, synthesis, and characterization of a highly effective Hog1 inhibitor: a powerful tool for analyzing MAP kinase signaling in yeast.
Journal article, 2011
The Saccharomyces cerevisiae High-Osmolarity Glycerol (HOG) pathway is a conserved mitogen-activated protein kinase (MAPK) signal transduction system that often serves as a model to analyze systems level properties of MAPK signaling. Hog1, the MAPK of the HOG-pathway, can be activated by various environmental cues and it controls transcription, translation, transport, and cell cycle adaptations in response to stress conditions. A powerful means to study signaling in living cells is to use kinase inhibitors; however, no inhibitor targeting wild-type Hog1 exists to date. Herein, we describe the design, synthesis, and biological application of small molecule inhibitors that are cell-permeable, fast-acting, and highly efficient against wild-type Hog1. These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo. Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress. Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action.
Signal Transduction
drug effects
Saccharomyces cerevisiae Proteins
Saccharomyces cerevisiae
metabolism
Enzyme Inhibitors
pharmacology
antagonists & inhibitors
Mitogen-Activated Protein Kinases
Molecular
Models
enzymology
antagonists & inhibitors
Molecular Structure
metabolism
chemistry
chemical synthesis
Author
Peter Dinér
University of Gothenburg
Jenny Veide Vilg
University of Gothenburg
Jimmy Kjellén
University of Gothenburg
Iwona Migdal
Terese Andersson
University of Gothenburg
Marinella Gebbia
Guri Giaever
Corey Nislow
Stefan Hohmann
University of Gothenburg
Robert Wysocki
Markus J. Tamás
University of Gothenburg
Morten Grötli
University of Gothenburg
PLoS ONE
1932-6203 (ISSN) 19326203 (eISSN)
Vol. 6 5 e20012-Subject Categories
Biochemistry and Molecular Biology
Medicinal Chemistry
Organic Chemistry
DOI
10.1371/journal.pone.0020012
PubMed
21655328