One of the fundamental questions of cell biology is how eukaryotic cell division is regulated. A thorough knowledge of this process is the first step in elucidating how cancer cells overcome the normal constraints on proliferation and will suggest points in the cell cycle where intervention in the cell division process would be most effective. Understanding this process will also improve our understanding of the basic biological processes of development and cell differentiation. In the last few years, key regulatory elements of the eukaryotic cell cycle have been identified as a family of 34 kDa protein-serine/threonine kinases, the CDKs. The first of these protein kinases to be identified was Cdc2. It was isolated in screens for yeast mutants unable to progress through the cell division cycle. It is now established that the activation of Cdc2 in all eukaryotes triggers the events of mitosis which include chromosome condensation, nuclear envelope breakdown 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 which has been conserved throughout evolution. Activation of Cdc2 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 aspects of the Cdc2 activation process in the yeast, Schizosaccharomyces pombe. We are interested in determining what role cyclin phosphorylation might play in the function of the complex and to identify other cyclin interacting proteins. We also propose to investigate the function of the Cdr2 protein kinase which genetically interacts with cyclin and other mitotic regulatory genes. In addition, we propose experiments aimed at understanding the function of another gene product which is required for entry into mitosis, Cdc5. Our goal is to determine the pathway in which Cdc5 functions and to understand how that pathway is linked with the known mitotic control pathway regulating the activation of Cdc2.
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