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

癌症是一种影响1-3人的疾病，因此，了解癌症发生的机制对医学科学至关重要。癌症通过改变正常细胞增殖控制、分化、细胞死亡或细胞运动的突变的积累而产生。许多与癌症有关的基因已经被鉴定出来，然而，可能还有更多的基因，当被破坏或错误表达时，可能会导致癌症。我们对细胞增殖的调节很感兴趣，并且一直在遗传学上适合的动物模型系统中研究这一点，醋蝇，果蝇。在所有多细胞生物体中，细胞增殖的关键调节因子是细胞周期蛋白E，它是驱动细胞从G1期（静止状态）进入S期（DNA复制发生）所必需的。细胞周期蛋白E的正确控制在限制细胞增殖中是重要的，许多致癌突变导致这种关键细胞周期调节因子的上调。我们已经使用了遗传学的方法来确定新的负调控细胞周期蛋白E。该提案旨在进一步阐明已鉴定的细胞周期蛋白E相互作用物调节细胞周期进程的机制。此外，该提案旨在确定其他细胞周期蛋白E相互作用的编码基因，有望成为新的肿瘤抑制因子。该项目的预期成果是阐明在整个生物体中控制细胞增殖的新基因和机制。由于细胞增殖和信号蛋白的保守性，这一提议与理解人类癌症有关。

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.