Analysis of the Scrib, Dlg and Lgl tumour suppressors in cell cycle regulation using the Drosophila animal model system

癌症是一种可能影响1-3人一生的疾病。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、细胞死亡或细胞运动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，并且一直在研究这方面的遗传适应性动物模型系统，醋蝇，果蝇。在所有多细胞生物中，细胞增殖的一个关键调节因子是细胞周期蛋白E，它是驱使细胞从G1（静息状态）进入S期（DNA复制发生）所必需的。正确控制细胞周期蛋白E对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。我们使用遗传方法鉴定了Cyclin e的新的负调节因子，该建议侧重于这些调节因子中的一组，果蝇肿瘤抑制因子，Scrib， Dlg和Lgl，它们在一个共同的遗传途径中起作用，将细胞极性（细胞形状）与细胞增殖联系起来。在这些基因的突变体中，细胞周期蛋白E被上调，发生不适当的细胞增殖。本研究的目的是确定scrib-dlg-lgl突变体中细胞周期蛋白E上调的信号通路和转录因子。我们将利用果蝇强大的遗传学来检测候选基因，并筛选scrib-dlg-lgl突变体中参与细胞周期蛋白E上调的新基因。该项目的预期结果是阐明Scrib-Dlg-Lgl如何控制细胞增殖。Scrib、DLG和LGL存在于哺乳动物中，因此本研究与人类细胞增殖的控制和癌症的发生有直接关系。

Cancer is a disease that is likely to affect 1-3 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, 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 focuses on a group of these regulators, the Drosophila tumour suppressors, Scrib, Dlg and Lgl, which act in a common genetic pathway to link cell polarity (cell shape) to cell proliferation. In mutants of these genes, cyclin E is up-regulated and inappropriate cell proliferation occurs. The aims of this proposal are to determine the signalling pathway and the transcription factors that act to upregulate cyclin E in scrib-dlg-lgl mutants. We will use the powerful genetics of Drosophila to examine candidate genes and to screen for novel genes involved in the upregulation of cyclin E in scrib-dlg-lgl mutants. The expected outcome of this project is to elucidate how Scrib-Dlg-Lgl act to control cell proliferation. scrib, dlg and lgl are present in mammals, therefore, this study is directly relevant to the control of cell proliferation and the development of cancer in humans.