THE ROLE OF NOVEL TUMOUR SUPPRESSORS DURING DEVELOPMENT

癌症是一种可能在一生中的某个时候影响1-4人的疾病。因此，了解癌症的病因对医学科学至关重要。癌症通过改变正常细胞增殖控制、分化或凋亡（程序性细胞死亡）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控很感兴趣，并一直在遗传学上适合的动物模型系统果蝇中研究这一点。在所有生物体中控制细胞增殖的核心是细胞周期蛋白依赖性蛋白激酶。细胞周期蛋白E依赖性蛋白激酶是驱动细胞从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，并且许多致癌突变导致这种关键细胞周期调节剂的上调和过早进入细胞周期。我们已经使用了一种遗传方法，使用果蝇细胞周期蛋白E中的弱突变来分离G1到S相变的其他重要调节因子中的突变。我们已经确定了一些基因的作用，负调控细胞周期，其中2个具有典型的肿瘤抑制因子的特征。我们已经确定了3个这些突变的候选基因，所有这些基因编码的新蛋白质相关的哺乳动物蛋白质参与细胞增殖或肿瘤抑制的负调控。在这个建议中，我们试图确定这些蛋白质的功能，以控制果蝇细胞增殖的方式。由于通过进化参与细胞增殖控制的基因的显着保守性，这项研究可能与人类细胞增殖和癌症发展的控制高度相关。

Cancer is a disease that is likely to affect 1-4 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation or apoptosis (programed cell death). 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, Drosophila. Central to the control of cell proliferation in all organisms are the Cyclin dependent protein kinases. Cyclin E-dependent protein kinase 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 and premature entry into the cell cycle. We have used a genetic approach using a weak mutation in Drosophila Cyclin E to isolate mutations in other important regulators of the G1 to S phase transition. We have identified a number of genes that act to negatively regulate the cell cycle, 2 of which have characteristics typical of tumour suppressors. We have identified candidate genes for 3 of these mutations, all of which encode novel proteins related to mammalian proteins involved in negative regulation of cell proliferation or tumour suppressors. In this proposal we seek to determine the way in which these proteins function to control cell proliferation in Drosophila. Due to the remarkable conservation of genes involved in cell proliferation control through evolution, this study is likely to be highly relevant to the control of cell proliferation and the development of cancer in humans.