Lack of differentiation is a hallmark of many cancer cells. Because differentiation is often coordinated with exit from the cell cycle, loss of differentiation may contribute to the transformed phenotype. Cancer therapies that initiate differentiation pathways and result in a loss of proliferative capacity provide a novel approach to cancer control. Many cancers, however, are refractory to differentiation therapy or acquire resistance to currently utilized drugs. A lack of understanding about the signaling pathways that regulate differentiation and the inverse relationship that exists between differentiation and proliferation hinders the design of novel differentiation-inducing molecules. We propose to contribute to the understanding of these pathways by testing the hypothesis that oncogenic Src family kinases aberrantly activate signaling pathways that inhibit differentiation of pluripotent cells. Understanding differentiation and cell cycle exit in normal cells is vital for understanding the changes that occur in transformed cells and mouse embryonic stem (ES) cells provide an ideal system for studying these signaling pathways. Our work will involve three specific aims. First, we will test the hypothesis that cellular Src kinases normally coordinate exit from the cell cycle with differentiation in murine ES cells. Second, we will test the hypothesis that oncogenic Src kinases aberrantly activate Stat transcription factors and other pathways that suppress differentiation in ES cells as seen in many cancer cells. Third, we will test the hypothesis that elevated Src kinase activity commonly observed in colon cancer cells contributes to the inhibition of differentiation, in some cases through a Stat-dependent mechanism. In addition to the research plan, a proposal for the development of the Applicant's expertise in the field of cell signaling in human cancer is presented. Together, completion of these goals will serve to transition the Applicant to an independent career in the basic research of human cancer cell biology. ? ? Relevance: Drugs that induce cellular differentiation have been successfully used in the treatment of a limited number of cancers. The work proposed here seeks to identify biochemical pathways that prevent the differentiation of cancer cells. Understanding these pathways can aid in the design of novel therapeutic agents with the hope of expanding this type of therapy to new types of cancer. ? ? ? ?
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