The control of cell proliferation is important in normal growth and development, and its disruption has health consequences extending from psoriasis to cancer. Cell doubling involves a myriad of events, all accurately coordinated to avoid genetically destabilizing errors that can be oncogenic. The discovery of master cell cycle regulators, cyclins, cyclin dependent kinases (Cdks) and their modulators, was a major advance that provided insight into mechanism. We hope to extend the insights by exploring mysteries surrounding the resulting kernel of understanding. We are asking - How is the cell cycle machine regulated to mold structure and form during development of metazoans, and how do the cell cycle regulators direct the myriad of cell biological processes that duplicate a cell? Cell cycle studies in the model organism Drosophila melanogaster have shown that early developmental transitions trigger dramatic changes in the regulation of cyclin:Cdk complexes and that these changes direct major restructuring of the cell cycle during embryogenesis. We are using genetics and modern real-time imaging to explore three regulatory events in this context. Exponential expansion of nuclei in early embryos titrates cell cycle regulators, and trips a reinforcing regulatory loop, the mid-blastula transition (MET), that introduces a period of quiescence into the cell cycle. We discovered that the MBT also extends S phase by introducing late replication and we are investigating the mechanisms leading to this change. Later in development, further reduction in cyclin:Cdk destabilizes the normal mitotic cell cycle and creates an endocycle in which S phases are truncated so that late replicating sequences fail to replicate at all. We have created a cell culture model of the endocycle by manipulating gene function using RNAi and we are dissecting the mechanisms that reshape the cell cycle. In cells that continue in a mitotic cycle, the destruction of cyclins at mitosis serves as a coordinating signal to guide the processes that divide the cell in two. Using real-time visualization of tagged proteins and RNAi we are detailing the interactions between cyclin:Cdk and the cytokinetic machinery.
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