This application seeks the mechanisms underlying the roles of YAP/TAZ in cancer. A wide variety of human cancers have altered YAP/TAZ signaling that is generally connected to prognosis. YAP and its cousin TAZ are the major effectors of Hippo pathway that controls organ size, cell movement, proliferation and survival. This pathway also regulates other important signaling pathways (Hedgehog, Notch, TGF? and Wnt). We will use murine polyomavirus (MuPyV) to probe YAP function. MuPyV causes a broad range of tumors. Its study has illuminated the roles of tyrosine phosphorylation and PI3 kinase in cancer. It continues to point to important issues, such as the role of PP2A A? isoform, in cancer. Recently, we reported that MuPyV's small T antigen (ST) directly binds YAP and alters its phosphorylation, stability, and function by promoting its association with PP2A. This interaction allows ST to block differentiation in several systems. Extensive preliminary data on MT, the oncogene of MuPyV, show that MT also associates with YAP. This association is important for MT driven neoplastic transformation. MT also affects YAP phosphorylation, but MT's effects are different than those of ST.
Our first aim i s to study ST regulation of the differentiation of stem-like cells. Since we know that ST also interacts with TAZ, we will test whether it contributes to the phenotype.
This aim will include a determination of the transcriptional mechanisms involved and the YAP effector protein associations that ST uses to achieve these alterations.
Our second aim will be to study the roles of YAP in MT driven transformation. Here too we will be interested in changes in gene expression and protein-protein associations. In our last aim we seek to examine the roles of YAP in MuPyV MT mediated transformation in vivo using transgenic and knockout mice. In the context of this Program Project, we have a great opportunity to exploit the virus interactions to gain a deeper insight into Hippo signaling in human oncogenesis. By comparing our results on the effects of MuPyV ST/MT on PP2A/YAP/TAZ with the results of our colleagues working with SV40 ST and Merkel ST and those of the Hahn lab working on YAP in K-Ras driven human cancers, we should be able to determine which of YAP's effects on cellular signaling are truly important, greatly enhancing the impact of our data. Ideally, these studies will lead us to our ultimate goal of translating our work into human cancer therapy, as we have previously done for PI3 kinase.
The polyoma virus ST/MT antigens regulate YAP phosphorylation, stability and function by altering its interaction with PP2A. Notably these YAP/TAZ/PP2A interaction are essential for oncogenesis. This grant will determine the mechanisms linking viral oncogenesis via PP2A/YAP/TAZ and human cancer to improve therapy.
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