How does the interaction of protein phosphatase 2A and small t antigen lead to activation of the PI3K pathway and subsequent transformation of primary human cells? Determination of the level of interaction and elucidation of the mechanism

在过去的十年中，癌症界已经通过确定哪些突变对这一过程至关重要来了解细胞是如何转化的。一个流行的系统的人乳腺上皮细胞（HMEC）的开发，永生化的人端粒酶和转化的早期区域的SV 40和H-ras的表达。该模型对于理解转化机制的研究具有重要价值，因为它提供了一个明确定义的系统，与其中发生了多个未定义事件的离体癌细胞相反。该项目旨在阐明磷脂酰肌醇3-激酶（PI 3 K）通路的激活机制，该通路对HMEC转化至关重要，最有可能通过小t抗原介导的蛋白磷酸酶PP 2A的抑制来实现，PP 2A参与细胞周期控制和增殖等细胞过程的调节。计划检查PP 2A与PI 3 K通路的元件的相互作用水平以及这种激活的分子机制。对这些过程的详细了解将对理解细胞转化产生重大影响，并有望为识别新的治疗靶点开辟道路。

In the past decade the cancer community has learned a great deal of how cells are transformed by determining which mutations are essential for this process. A popular system of human mammary epithelial cells (HMECs) was developed, immortalized by human telomerase and transformed by expression of the early region of SV40 and H-ras. This model is of great value to research in understanding the mechanisms of transformation as it provides a well defined system in contrast to ex vivo cancer cells in which multiple undefined events have taken place. The presented project aims to elucidate the mechanism of activation of the phosphatidylinositol 3-kinase (PI3K) pathway which is essential for HMEC transformation and is most probably achieved by small t antigen mediated inhibition of a protein phosphatase, PP2A, implicated in regulation of cellular processes such as cell cycle control and proliferation. It is planned to examine both the level of interaction of PP2A with the elements if the PI3K pathway as well as the molecular mechanism of this activation. The detailed knowledge of these processes will provide a high impact on the understanding of cell transformation, and hopefully will open the avenue for the identification of new therapeutic targets.