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, which was recognized in this year's Nobel Prize in Medicine, provided insight into mechanism and new avenues of drug design to target cancer cells. However, the links from the master regulators to cell biological events are largely unknown. In addition to triggering cell cycle transitions from one phase to the next, the master regulators appear to govern individual events in the cell cycle, defining when the events occur and enforcing the coordination required for accuracy. Our cell cycle studies in the model organism Drosophila have uncovered previously unrecognized regulatory roles of the cyclins. The mitotic cyclins are well known as activators of cyclin dependent kinase 1 (Cdk1) and as inducers of mitosis. Our results suggest that the accuracy of chromosome segregation at mitosis depends on an increase in the stability of kinetochore attachment to the spindle. This change, which occurs at the transition to anaphase, depends on the timely destruction of cyclin B. Similarly, cytokinesis follows destruction of cyclin B, which otherwise inhibits it. In contrast, cytokinesis occurs in the presence of stable cyclin B3 despite persistence of a spindle and condensed chromosomes. Maintenance of the G2 phase of the cell cycle requires a catalytically repressed cyclin/Cdk1 complex, which, we propose, may specify this cell cycle state by acting as a protein ligand to influence other activities. Disruption of the controls that we are investigating results in segregation and replication defects resembling anomalies that are prominent in cancer cells. We will use genetic and cell biological tools to define the new regulatory pathways and will then pursue their biochemical dissection.
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