THE ROLE OF A NOVEL NEGATIVE CELL CYCLE REGULATORY PATHWAY DURING ANIMAL 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。这项建议的重点是这些调节因子之一，PHYL，以及与之起作用的蛋白质Sina和Ebi，它们作用于靶向并导致关键蛋白质的降解，这些蛋白质对分化起负面调节作用，并促进细胞增殖。在这项提案中，我们试图了解Ebi-Phyl-Sina蛋白复合体如何在果蝇中控制细胞增殖。此外，我们还将研究新浪复合体是否也能抑制小鼠的细胞增殖。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守，这项研究直接关系到人类细胞增殖的控制和癌症的发展。

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. This proposal focuses on one of these regulators, Phyl, and the proteins that function with it, Sina and Ebi, which act to target and lead to the degradation of key proteins that negatively regulate differentiation and that promote cell proliferation. In this proposal we seek to understand how the Ebi-Phyl-SIna protein complex functions to control cell proliferation in Drosophila. In addition, we will examine whether the Sina complex also acts to inhibit cell proliferation in the mouse. Due to the remarkable conservation of genes involved in cell proliferation control through evolution, this study is directly relevant to the control of cell proliferation and the development of cancer in humans.