Centrosomes play an important role in the morphogenesis and function of the mitotic apparatus. Defects in the regulation of this organelle, such as over-replication, result in increased genetic instability and are associated with numerous types of human cancer cells. The line of investigation presented in this proposal will result in the characterization of regulatory components of centrosome function, establish a mechanism for the regulation of the termination of centrosome replication and discover new centrosome-associated proteins. The experimental system utilized in these experiments is well suited for the genetic, cytological, and molecular approaches that we propose. Our studies of Slimb in Drosophila are designed to analyze cell cycle functions for this subunit of the SCF complex, and to characterize putative Slimb-interacting centrosome pathway components. Our genetic analyses will reveal additional components of the slimb pathway and begin to elucidate their functions. Because this strategy can potentially identify other components of the slimb pathway besides proteins that come into direct contact with Slimb, our approach compliments existing efforts at biochemical purification of SCF components. Finally, as inroads are made toward a mechanism by which Slimb affects centrosome function, an unbiased genetic screen for additional centrosome-associated proteins will provide additional puzzle pieces in our understanding of the function of centrosomes in cell division. These discoveries will provide new diagnostic or therapeutic targets for the prevention or treatment of cancer.
