Design, synthesis, and characterization of a highly effective Hog1 inhibitor: a powerful tool for analyzing MAP kinase signaling in yeast
| Autor: | Stefan Hohmann, Iwona Migdal, Markus J. Tamás, Jimmy Kjellén, Guri Giaever, Peter Dinér, Terese Andersson, Jenny Veide Vilg, Marinella Gebbia, Corey Nislow, Robert W. Wysocki, Morten Grøtli |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
MAPK/ERK pathway
Models Molecular Cell cycle checkpoint Antagonists & inhibitors Saccharomyces cerevisiae Proteins Saccharomyces cerevisiae lcsh:Medicine 03 medical and health sciences Molecular Cell Biology Chemical Biology Signaling in Cellular Processes Kinase activity Enzyme Inhibitors Protein kinase A lcsh:Science Biology 030304 developmental biology 0303 health sciences Multidisciplinary biology Molecular Structure Kinase 030302 biochemistry & molecular biology lcsh:R biology.organism_classification Cell biology Chemistry lcsh:Q Signal transduction Mitogen-Activated Protein Kinases Signal Transduction Research Article |
| Zdroj: | PLoS ONE PLoS ONE, Vol 6, Iss 5, p e20012 (2011) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|