Genetic and Biochemical Studies of a Yeast CDK.inhibitor Interaction

This research will examine two aspects of the interaction between a yeast cyclin dependent kinase (CDK), an enzyme that controls passage through the cell division cycle, and its natural inhibitor. The first half of the project will use genetic approaches to investigate how the inhibitor physically interacts with the kinase. It is expected that this work will identify important regions on the surface of the kinase with which both inhibitors and natural substrates of the kinase interact which, in turn, will be useful in the identification of novel inhibitors specific for this enzyme and in the identification of new classes of CDK targets. The second half of the project will explore the hypothesis that a new and unsuspected level of control involving natural chemical modifications is involved in the regulation of the interaction of the CDK with its inhibitor. A revolution in the understanding of how cells reproduce themselves has come in the last 15 years with the discovery of the CDKs and the study of their regulation. The essential use of yeast as a model organism for the development of this work was recognized in 2000 with the award of Nobel prizes to a trio of yeast researchers that made fundamental contributions. This foundation has generated an explosion of studies on related proteins in mammalian cells that has had a profound impact on how we think of natural processes such as differentiation, development and the response to environmental stresses and signals and on disease states such as cancer. This project will extend these studies by providing guides to the identification of new control routes for these important cellular proteins. Furthermore, this project is expected to have a significant regional impact on science education as it initiates a new collaborative program that will pair talented undergraduates chosen by the Biology Department at Berea College with doctoral level researchers at the University of Kentucky. Berea College is a unique institution that has successfully targeted an Appalachian population that, traditionally, has had limited access to higher education. Increasing the exposure of talented members of this population to modern problems in biology is expected to have long term, positive impacts on the educational andeconomic opportunities available to the people of this region.