CELL CYCLE CONTROL BY THE CAMP PKA SIGNAL TRANSDUCTION

Columbia University Health Sciences, New York NY

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Abstract

Our studies of cycling Xenopus egg extracts have demonstrated oscillations in the levels of cAMP and thus, in the activity of protein kinase A (PKA). We will analyze how PKA controls DNA replication in particular the regulation and the activity of cdc6 protein and of the mini chromosome maintenance proteins, required for initiation of DNA replciation. We will determine how cdc2 protein kinase increases cAMP levels and why this is blocked at the mitosis exit checkpoint. Finally, we will study PKA induction of cyclin degradation using defined components of both the cAMP-PKA and the anaphase promoting complex pathways. Our work will focus on the events that coordinate the completion of mitosis to the initiation of DNA replication. Such coordination is critical to understand how the proper order of cell cycle phases is maintained throughout successive cell divisions. PKA has emerged as a key component for the regulation of that transition and we wish to determine the biochemical mechanism of its action. The identification of the relevant cdc2 and PKA substrates is essential to an understanding of cell cycle progression. We anticipate that our studies of PKA function in the sample embryonic cell cycles of Xenopus will allow us to understand the roles of PKA in cell cycle control in a system that is not subjected to growth control. This unique approach will help elucidate how PKA coordinates cell cycle progression in concert with other protein kinases in more complex, i.e. growth regulated systems.