Characterization of novel inhibitors of G1-S phase progression in Drosophila

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Cancer is a disease that affects 1-3 people and therefore, understanding the mechanisms by which cancer arises is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. Many genes involved in cancer have been identified, however, there are likely to be many more genes, that when disrupted or misexpressed can lead to cancer. We are interested in the regulation of cell proliferation, and have been studying this in the genetically amenable animal model system, the vinegar fly, Drosophila. A key regulator of cell proliferation in all multicellular organisms is Cyclin E, which is required to drive cells from the G1 (resting state) into S phase (where DNA replication occurs). Correct control of Cyclin E is important in limiting cell proliferation and many cancer-causing mutations result in up-regulation of this critical cell cycle regulator. We have used a genetic approach to identify novel negative regulators of Cyclin E. This proposal seeks to further clarify the mechanism by which the identified Cyclin E interactors regulate cell cycle progression. In addition, this proposal seeks to identify the genes encoding other cyclin E interactors, expected to be novel tumor suppressors. The expected outcome of this project is to elucidate novel genes and mechanisms that control cell proliferation in the context of a whole organism. Due to the conservation of cell proliferation and signalling proteins, this proposal is relevant to understanding human cancer.