Recent advances in research on the cell cycle have lead to a unifying hypothesis of cell cycle control. Central to this hypothesis is a protein kinase known in budding yeast as Cdc28 and in fission yeast and animal cells as Cdc2. It has been proposed that both the G1 to S-phase and the G2 to M-phase transitions are controlled at the level of activation of this protein kinase. The differential activation of the Cdc28 protein kinase for the different transitions appears to be mediated by association with different classes of positive regulatory subunits known as cyclins as well as by other regulatory elements. This model has largely been confirmed for budding and fission yeast and it is likely to be valid for all eukaryotes. S. cerevisiae presently has the advantage of having many of the elements involved in G1 and G2 control identified and accessible to genetic analysis. Furthermore, it has been possible to prepare active yeast Cdc28 protein kinase from purified components to facilitate high-resolution structural and functional analyses, a unique feature of the yeast system. We plan to continue a number of our past avenues of investigation in the current research plan. Specifically, we wish to perform careful analysis of the properties of pure Cdc28 kinase to better understand how its functions are regulated in vivo. The regulation and properties of both G1 and mitotic cyclins will be investigated. A concerted effort will be applied to finding bot G1 and mitotic critical substrates of the Cdc28 kinase. Finally, a number of other regulatory elements that interact directly or indirectly with the Cdc28 kinase to regulate its G1 and mitotic functions will be characterized. These include MIHI,CKS1 and CDC37. Because of the highly conserved nature of cell cycle control, the information gained in the course of this research is likely to be informative for all eukaryotic organisms, including man.
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