Parallel chemical genetic and genome-wide RNAi screens identify cytokinesis inhibitors and targets

TY - JOUR

T1 - Parallel chemical genetic and genome-wide RNAi screens identify cytokinesis inhibitors and targets

AU - Eggert, Ulrike

AU - Kiger, Amy A

AU - Richter, Constance

AU - Perlman, Zachary E

AU - Perrimon, Norbert

AU - Mitchison, Timothy J

AU - Field, Christine M

PY - 2004/10/5

Y1 - 2004/10/5

N2 - Cytokinesis involves temporally and spatially coordinated action of the cell cycle and cytoskeletal and membrane systems to achieve separation of daughter cells. To dissect cytokinesis mechanisms it would be useful to have a complete catalog of the proteins involved, and small molecule tools for specifically inhibiting them with tight temporal control. Finding active small molecules by cell-based screening entails the difficult step of identifying their targets. We performed parallel chemical genetic and genome-wide RNA interference screens in Drosophila cells, identifying 50 small molecule inhibitors of cytokinesis and 214 genes important for cytokinesis, including a new protein in the Aurora B pathway (Borr). By comparing small molecule and RNAi phenotypes, we identified a small molecule that inhibits the Aurora B kinase pathway. Our protein list provides a starting point for systematic dissection of cytokinesis, a direction that will be greatly facilitated by also having diverse small molecule inhibitors, which we have identified. Dissection of the Aurora B pathway, where we found a new gene and a specific small molecule inhibitor, should benefit particularly. Our study shows that parallel RNA interference and small molecule screening is a generally useful approach to identifying active small molecules and their target pathways.

AB - Cytokinesis involves temporally and spatially coordinated action of the cell cycle and cytoskeletal and membrane systems to achieve separation of daughter cells. To dissect cytokinesis mechanisms it would be useful to have a complete catalog of the proteins involved, and small molecule tools for specifically inhibiting them with tight temporal control. Finding active small molecules by cell-based screening entails the difficult step of identifying their targets. We performed parallel chemical genetic and genome-wide RNA interference screens in Drosophila cells, identifying 50 small molecule inhibitors of cytokinesis and 214 genes important for cytokinesis, including a new protein in the Aurora B pathway (Borr). By comparing small molecule and RNAi phenotypes, we identified a small molecule that inhibits the Aurora B kinase pathway. Our protein list provides a starting point for systematic dissection of cytokinesis, a direction that will be greatly facilitated by also having diverse small molecule inhibitors, which we have identified. Dissection of the Aurora B pathway, where we found a new gene and a specific small molecule inhibitor, should benefit particularly. Our study shows that parallel RNA interference and small molecule screening is a generally useful approach to identifying active small molecules and their target pathways.

KW - Animals

KW - Aurora Kinases

KW - Caenorhabditis elegans

KW - Cell Line

KW - Cytokinesis

KW - Drosophila

KW - Formamides

KW - Genetic Techniques

KW - Genome

KW - Genomics

KW - Microscopy, Fluorescence

KW - Phenotype

KW - Protein-Serine-Threonine Kinases

KW - Pyrazoles

KW - RNA Interference

KW - Saccharomyces cerevisiae

U2 - 10.1371/journal.pbio.0020379

DO - 10.1371/journal.pbio.0020379

M3 - Article

C2 - 15547975

SN - 1544-9173

VL - 2

SP - 2135

EP - 2143

JO - PL o S Biology

JF - PL o S Biology

IS - 12

M1 - e379

ER -