In broad terms our research is directed at control mechanisms for cell division: both the events of mitosis and the cell cycle regulation for entry into and exit from mitosis. This proposal describes a number of studies centered on the interrelationship between centrosomes and the cell cycle with an emphasis on checkpoint control mechanisms. Using echinoderm zygotes, frog egg extracts, and cultured cells as model systems, we will: 1. Test the existence of a proposed checkpoint for entry into mitosis that monitors centrosome/centriole duplication. 2. Investigate how centrosome reproduction is coordinated with the nuclear cell cycle. 3. Investigate how centriole duplication is controlled during the cell cycle. 4. Continue our characterization of how the checkpoint for the metaphase/anaphase transition functions in sea urchin zygotes. 5. Continue our studies of the control of nuclear envelope breakdown and the checkpoint for the completion of DNA synthesis. 6. Investigate how the reproductive capacity of maternal centrosomes is controlled in starfish eggs. By characterizing the functional properties of control mechanisms in living cells, we can address issues that are not readily amenable to biochemical analysis. The health relevance of this work is that an essential characteristic of malignant cells is abnormal regulation of the proliferative cycle. Thus, a better understanding of how the mitosis portion of the cell cycle is controlled is necessary for the development of practical strategies to control cancer. Indeed, a number of currently used chemotherapeutic drugs exploit defects that transformed cells have in the checkpoint mechanisms that control entry into mitosis and control exit from mitosis at the metaphase/anaphase transition.
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