The long range objective of this research is to understand in molecular detail how progression through the eukaryotic cell cycle is regulated and how extracellular signals influence these regulatory events. This work will help to elucidate how cancer cells overcome the normal constraints on proliferation and may suggest points in the cell cycle where intervention to inhibit proliferation would be most effective. The major controlling element of the eukaryotic cell cycle progression is a 34 kD protein-serine/threonine kinase which in fission yeast is encoded by the cdc2 gene. The activation of this protein kinase triggers all of the events of mitosis including chromosome condensation, nuclear envelope break-down and formation of the mitotic spindle. The eventual inactivation of this complex must occur in order for cells to re-enter an interphase state. To ensure that this protein kinase is not triggered randomly, it is regulated in a complex manner. Activation of p34cdc2 requires that it be associated with a member of the cyclin family of proteins and that it be correctly phosphorylated. Our project proposes to examine the role played by cyclin phosphorylation in this activation process. Phosphorylation of cyclin might be involved in either association with p34cdc2, activation of the complex, or degradation of the complex. We also propose to identify and characterize other proteins which p34cdc2 must interact with in order to bring about the events of mitosis. We will approach this genetically by isolating suppressors of dominant negative p34cdc2 mutants. We are also proposing experiments to examine the function of another gene product which is required for cell cycle progression in Schizosaccharomyces pombe, the cdc5 gene product.
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