Mechanisms controlling cell cycle exit upon terminal differentiation

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): I am currently completing my fourth year as a post-doctoral fellow at the Fred Hutchinson Cancer Research Center (FHCRC). My career goals are to: develop a research program examining how developmental signals control cell cycle exit, secure a tenure-track faculty position in a leading academic institution within the next 2 years, build a productive lab where I mentor students and postdocs, and obtain independent funding from the NIH or other sources. Toward achieving these goals, I have developed an independent research and career development plan, and will engage in a job search beginning in the fall of 2008. The goal of my research plan is to determine how terminal differentiation signals control the cell cycle machinery to induce and maintain a stable post-mitotic state. I test the hypothesis that differentiation signals initiate cell cycle exit by inhibiting E2F and/or Cyclin E activities, but stably maintain exit by repressing both in parallel, thereby disrupting the positive regulatory loop that normally exists between them. This ensures that cell cycle exit is robust to the de-regulation of a single cell cycle factor and is somehow bypassed in tumorigenesis. While this hypothesis is based upon my previous work in Drosophila, in the research proposed here, I use a combination of genetic and biochemical approaches in Drosophila and mammalian cells to delineate the conserved pathways that control cell cycle exit. By taking advantage of the unique benefits of each model system I strive to develop a creative and exciting independent research project examining cell cycle exit. The research proposed here draws upon the expertise I have gained in Dr. Bruce Edgar's lab in using Drosophila as a model organism, but also requires building expertise with a new system, in vitro differentiation of mammalian cells. To aid me in developing this new aspect to my research I have enlisted two experts to co- mentor me along with Bruce Edgar, my primary mentor. They are, Dr. Steve Collins, an expert in terminal differentiation of hematopoietic cells and Dr. James Roberts, an eminent researcher in the mammalian cell cycle field. Both are faculty at the FHCRC, and the close proximity of our labs will allow extensive interactions during the mentored phase of this project. RELEVANCE: Uncontrolled cell division is a hallmark of cancer. My research addresses how mature cells block the cell cycle to prevent inappropriate division. My proposed research will identify signals that when activated, give the wrong directions to mature cells and cause excessive division, mimicking cancer. By understanding how cell division can be improperly instructed, we hope to identify new targets for the treatment of cancer.