Chemical approaches to cell division
How do cells divide? Chromosomes divide during mitosis and cells physically divide during cytokinesis. Cytokinesis, the final step in cell division, involves the coordinated action of the cytoskeleton, the cell cycle engine and membrane transport machineries. Traditionally, cytokinesis has been difficult to study because it is a very rapid and dynamic process that occupies only a small portion of the cell cycle. Many key cytokinesis proteins also perform essential functions earlier in the cell cycle and their removal leads to an arrest prior to cytokinesis. Since small molecules act rapidly and reversibly and can be added at specific points in the cell cycle for live analysis, they are ideal to study cytokinesis. We use a combination of chemical genetics and RNAi to generate new small molecule tools that affect cytokinesis.
We discovered several promising small molecule inhibitors of cytokinesis by high-throughput screening and we are currently identifying and characterizing their cellular targets. A major focus is to use these novel drugs to probe cytokinesis mechanism by a variety of techniques including live imaging and biochemistry.
In addition to small molecules that affect a process (cytokinesis) and specific proteins (small molecule targets), we are excited about developing chemical tools to study biological pathways. The Rho pathway is responsible for regulating many important cellular events, including cytokinesis, but little is known about the mechanisms involved. We combine chemical approaches and RNAi to develop small molecules and to identify proteins that affect the Rho pathway.
A first step towards understanding a process is to know which proteins are involved. We made the first comprehensive list of cytokinesis proteins by genome-wide RNAi screening and found many new proteins with interesting cytokinesis phenotypes. We are interested in elucidating the functions of some of these proteins, possibly by using specific small molecule inhibitors.
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