P34 CDC2 AND CELL CYCLE CONTROL

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One of the necessary components in the understanding and treatment of cancer is the knowledge of how cells reproduce themselves in a highly controlled and regulated manner. Within the past few years, tremendous advancements have been made in our understanding of how the eukaryotic cell cycle is regulated. In species as diverse as yeast and man, proteins with remarkable conservation in both structure and function have been identified. The subject of this proposal is one of these key cell-cycle regulators, a serine/threonine protein kinase referred to as p34cdc2 are regulated throughout the cell cycle. p34cdc2 as well as several of its regulators have been overproduced in insect cells using a baculoviral expression system. These regulators include the wee1+ gene product (a negative regulator of mitosis) and cyclins A and B (positive regulators of mitosis). We have made the novel observation that p34cdc2 becomes phosphorylated on tyrosine when co-produced with the wee1+ gene product in insect cells. Further, the tyrosine phosphorylation of p34cdc2 increases dramatically when cyclin is also present. These results suggest a role for both p107wee1 and cyclin in the regulation of p34cdc2 by tyrosine phosphorylation. This proposal utilizes recently developed techniques and unique reagents to analyze in detail how the phosphorylation and kinase activity of p34cdc2 is regulated by p107wee1 and the cyclins. This information is expected to contribute significantly to our understanding of cell cycle control. In addition, important information regarding both the mechanisms that operate to control cell growth and the identification of pathways that are disrupted during oncogenic transformation may be obtained.