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

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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.