The Retinoblastoma Protein Pathway in Differentiation, Senescence and Cancer

Our research is focused on G1 cell cycle control and its dysregulation in cancer cells. Specifically, we are investigating the function of the retinoblastoma protein, (pRb), D-type cyclins, cdk4 and cdk6 in programs of cell cycle exit. Together, along with p16INK4a, a negative regulator of cdk4 and cdk6, these proteins regulate a critical decision making point in progression to S phase and thus DNA replication. In almost all human tumors, one of these proteins is lost or overexpressed, thus favoring proliferation and tumor growth. Although these proteins regulate S phase in response to genome integrity (DNA damage), we and others have shown that they are also critically involved in the permanent cell cycle withdrawal associated with differentiation and senescence. Using complementary approaches incorporating biochemical methods, cell culture of primary and established cells, and animal models of development and cancer, we aim to identify key regulators of tumorigenesis with particular emphasis on breast cancer and osteosarcoma.