Using chemical biology to probe the regulation of cell division.

摘要

The division of one cell into two was one of the first cellular behaviors observable to 19th century biologists, and has captivated our imagination ever since. As technology advanced, an increasingly large number of techniques and approaches have been used to try and understand how the cell cycle ensures that each daughter cell receives an equal complement of chromosomes and cytoplasm. Chemical biology involves the application of organic chemical techniques to generate tools to study different aspects of cell structure and function, and we have employed this technique to understand two basic questions of cell cycle- and cytoskeletal regulation. We have implemented chemical biology as both a tool to study two biological questions whose answers have thus far evade other standard approaches. Our first study used a small molecule inhibitor to study a mechanism by which oocytes rapidly progress through meiotic divisions prior to fertilization. Oocytes were arrested in the interkinesis between MI and MII, and three kinases involved in chromatin condensation were inhibited with small molecule inhibitors. Only one kinase, Aurora B, was found to be required for the maintenance of chromatin condensation during interkinesis. In the second study, we examined the effects of a ubiquitous small molecule whose release into the environment has been cause for concern based on its endocrine effects, but upon closer examination may also cause defects in early development by disrupting cell division. Our efforts include morphological analysis and synthesizing probes to identify the cellular targets of this small molecule. We propose a novel mechanism by which Bisphenol A affects the nucleation of microtubules, by disrupting the tight spatial control associated with normal chromosome segregation and resulting in aneuploidy. Together, these studies provide examples of how the merging of chemical- and cell biological approaches may be applied to better understand the basic mechanisms of cell division.