THE ROLE OF A NOVEL NEGATIVE CELL CYCLE REGULATORY PATHWAY DURING ANIMAL DEVELOPMENT

癌症是一种可能影响1-4人的疾病。因此，了解导致癌症的原因对医学至关重要。癌症是通过改变正常细胞增殖控制、分化或细胞凋亡（程序性细胞死亡）的突变积累而产生的。许多与癌症有关的基因已经被确定，然而，可能还有更多的基因，当它们被破坏或错误表达时，就会导致癌症。我们对细胞增殖的调控很感兴趣，并一直在果蝇这一基因可调节的动物模型系统中进行研究。在所有生物体中，细胞周期蛋白依赖蛋白激酶是控制细胞增殖的核心。细胞周期蛋白e依赖性蛋白激酶需要驱动细胞从G1（静息状态）进入S期（DNA复制发生的地方）。正确控制Cyclin E对于限制细胞增殖很重要，许多致癌突变导致这个关键的细胞周期调节因子上调和过早进入细胞周期。我们使用了一种遗传学方法，利用果蝇周期蛋白E中的一个弱突变来分离G1期到S期转变的其他重要调节因子的突变。本研究的重点是这些调节因子之一Phyl，以及与之一起起作用的蛋白Sina和Ebi，它们的作用是靶向并导致负调控分化和促进细胞增殖的关键蛋白的降解。在本研究中，我们试图了解Ebi-Phyl-SIna蛋白复合物如何控制果蝇细胞增殖。此外，我们将研究Sina复合体是否也能抑制小鼠细胞增殖。由于参与细胞增殖控制的基因在进化过程中具有显著的保守性，因此本研究与人类细胞增殖的控制和癌症的发生直接相关。

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. 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.