Our laboratory focuses on preclinical models of cellular proliferation control and its dysregulation in cancer cells. Because the in vivo properties of tumor cells are heavily influenced by the microenvironment, we often rely on mouse models and primary cells derived from them for these studies. Recently, we have been studying oncogenic events in spontaneous and UV-induced melanoma formation in a unique BRAFV600E-driven transgenic mouse strain, with a particular focus on the permanent cell cycle withdrawal associated with terminal differentiation and the immunomodulatory process of senescence. Further, we have developed precisely engineered mouse and human melanoma models to test the role of specific AKT isoforms as collaborators with BRAFV600E and as mechanisms of drug resistance using genetic and pharmacological approaches. These studies complement our longstanding interest in the function of the retinoblastoma protein (pRB), D-type cyclins, cdk4 and cdk6 in programs of cell cycle exit. Although these proteins regulate S phase in response to cellular stress, we and others have shown that they are also critically involved in the permanent cell cycle withdrawal associated with differentiation and senescence. Our current work focuses on the role of this pathway in tissue and tumor progenitor cells in the breast, bone and heart, where it impacts cell fate choices, transcriptional programs, cellular metabolism, and establishment of the postmitotic state.