PROJECT SUMMARY Gain-of-function mutations of oncogenes and loss-of-function mutations of tumor suppressor genes drive the initiation and progression of human cancer. These genes also play critical roles in normal development and cellular differentiation. Genetic or epigenetic alterations in the Rb pathway are required for the initiation and progression of most types of human cancer. The three inter-related projects in this program will address major outstanding fundamental questions about the functioning of key proteins in the Rb pathway: Cyclin D-Cdk4/6 oncoproteins that regulate Rb by phosphorylation, the Rb family of tumor suppressors that act as transcriptional regulators, and the E2F family of transcription factors that interact with and are directly regulated by the Rb family proteins and control the transcription of genes important for cell cycle progression. A major goal of this program project is to investigate the Rb pathway using an interdisciplinary approach. The major goal of this Core is to provide an administrative framework to help implement the scientific goals and disseminate the results of the proposed experiments. Specifically, the Administrative Core will have three goals. The first goal will be to promote scientific interactions among the Project Leaders and laboratory members involved in the three main Projects and two Scientific Cores. The second goal will be to provide scientific and financial guidance and oversight, including in conjunction with an Internal Advisory Committee and an External Scientific Advisory Board. The third goal will be to facilitate communication among the members of the Projects and Cores themselves and to the greater scientific community and the public. To achieve these goals, the Leader for this Administrative Core, will work closely with the Leaders of each of the Projects and Scientific Cores. Regular scientific interactions to exchange ideas and results, feedback from members of the internal advisory committee and the external scientific advisory board, and specific metrics to monitor progress, will all be critical to help uncover novel fundamental mechanisms underlying cell cycle progression.