An important question in our understanding of cancer, a genetic disease, is how chromosomes change in cancer cells. The loss or gain of whole chromosomes or chromosome regions is a condition referred to as aneuploidy. Aneuploidy is one of the first cellular changes associated with cancer cell transformation. How cells become aneuploid is a fundamental unanswered question. Recent discoveries show that the overexpression of a single protein, called Aurora kinase, is sufficient for cells to quickly become aneuploid. Moreover, the gene for Aurora kinase resides at a chromosomal "hot-spot" frequently associated with various human cancers such as those of breast, bladder, colon, ovary, pancreas, head, and neck. We hypothesize that the misregulation of Aurora kinases is a cause of cellular aneuploidy and an initial step in cancer progression. While many cancer genes control a cell¹s decision whether or not to divide, Aurora kinases are master regulators of equal segregation of chromosomes into daughter cells at the end of cell division. Aurora kinases control multiple steps in this process. We have evidence that Aurora kinases are themselves regulated and we have developed a powerful in vitro system to dissect these regulatory pathways. We have also found that Aurora kinases reside in cell-cycle-regulated complexes. The experiments we are propose are designed to 1) identify the cell cycle regulator(s) of Aurora/Ipl1 activity; 2) define the role of Aurora/Ipl1 cell cycle phosphorylation; 3) and identify and characterize the binding partners of Aurora/Ipl1 kinases. This work will define how the events of chromosome segregation are temporally and spatially controlled. Previous work has clearly demonstrated that Aurora kinases are important cellular regulators. The next critical experiments are to identify regulators of Aurora kinases. Better understanding of Aurora kinases and their regulation will be the basis for treating and even preventing cancer.