THE ROLE OF NOVEL TUMOUR SUPPRESSORS DURING DEVELOPMENT

癌症是一种疾病，可能会在一生中的某个时候影响1-4个人。因此，了解致癌原因对医学具有重要意义。癌症是通过突变的积累而发生的，这些突变改变了正常的细胞增殖控制、分化或凋亡(程序性细胞死亡)。许多与癌症有关的基因已经被发现，然而，很可能还有更多的基因，当这些基因被干扰或错误表达时，可能会导致癌症。我们对细胞增殖的调控很感兴趣，并一直在基因顺从的动物模型系统--果蝇中研究这一点。在所有生物体中，控制细胞增殖的中心是细胞周期蛋白依赖蛋白激酶。细胞周期蛋白E依赖的蛋白激酶是细胞从G1期(静息状态)进入S期(发生DNA复制)所必需的。对Cyclin E的正确控制对于限制细胞增殖非常重要，许多致癌突变会导致这种关键的细胞周期调节因子上调，并过早进入细胞周期。我们使用了一种遗传方法，利用果蝇Cyclin E中的一个弱突变来分离G1到S相变的其他重要调控因子的突变。我们已经确定了一些负调控细胞周期的基因，其中两个具有典型的肿瘤抑制基因的特征。我们已经确定了其中3个突变的候选基因，所有这些突变都编码与哺乳动物蛋白相关的新蛋白，这些蛋白参与细胞增殖的负调控或肿瘤抑制。在这项建议中，我们试图确定这些蛋白质控制果蝇细胞增殖的功能。由于参与细胞增殖控制的基因在进化过程中得到了显著的保存，这项研究很可能对控制细胞增殖和人类癌症的发展具有高度的相关性。

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.