CDC2-RELATED PROTEINS AND THE CONTROL OF CELL DIVISION

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This application is for a Clinical Investigator Award, to provide support during a period of transition from post-doctoral training to a career as an independent investigator. The applicant received predoctoral training in the NIH-sponsored Medical Scientist Training Program, followed by clinical training in Internal Medicine and Gastroenterology, and has returned to the laboratory to investigate the molecular mechanisms that control human cell division. Substantial progress has recently been made in two related but largely separate areas of investigation, the control of the eucaryotic cell cycle and the mechanisms of malignant transformation. The separation of the two fields has in part been due to a lack of understanding of the molecular events that control cell division in higher eucaryotes. As a result, it has remained unclear how the various oncogenes that have been identified ultimately disrupt the normal controls on cell proliferation. Much of the progress on the cell cycle has come from work in lower eucaryotes. In yeasts a protein kinase designated cell division control protein 2 (cdc2) regulates both major transitions in the cell cycle, entry into DNA synthesis and entry into mitosis. It is now evident that this protein regulates the onset of mitosis in all eucaryotes, including man. However, there has been no evidence for a role for cdc2 in earlier cell cycle events in higher eucaryotes. Recently a closely related protein kinase has been identified in several higher eucaryotes that is essential for DNA synthesis and associates with the principle transforming protein of human adenovirus. These observations establish that at least two closely related protein kinases control cell division in higher eucaryotes and that these enzymes may be targets of malignant transformation. We have recently identified five more protein kinases in human cells that are closely related to cdc2. This proposal is to study the normal function of a subset of these proteins, by analyzing the points in the cell cycle when they are active and the effects on the cell of ablating their activity. This work will further define the normal controls over human cell division and potential targets for transforming proteins.