PROJECT 2: Oncogenic Transformation via the PP2A/YAP/Hippo pathway

项目总结 这项应用寻求YAP/TAZ在癌症中作用的潜在机制。种类繁多的 人类癌症改变了通常与预后有关的YAP/TAZ信号。YAP和它的表亲 TAZ是河马途径的主要效应者，它控制器官的大小，细胞的运动，增殖和 生死存亡。该通路还调节其他重要的信号通路(Hedgehog、Notch、转化生长因子β和Wnt)。 我们将使用小鼠多瘤病毒(MuPyV)来检测YAP功能。MuPyV可引起广泛的肿瘤。它的 研究阐明了酪氨酸磷酸化和PI3激酶在癌症中的作用。它继续指向 重要的问题，如PP2Aβ亚型在癌症中的作用。最近，我们报道了穆皮夫的小T 抗原(ST)直接与YAP结合，通过促进YAP的磷酸化、稳定性和功能改变其功能。 与PP2A的关联。这种相互作用允许ST在几个系统中阻止分化。广泛性 关于MuPyV的癌基因MT的初步数据表明，MT也与YAP有关。这一关联是 对于MT驱动的肿瘤转化很重要。MT也影响YAP的磷酸化，但MT的影响是 与圣彼得堡不同。我们的第一个目标是研究ST对干细胞分化的调控。自.以来 我们知道ST也与TAZ相互作用，我们将测试它是否对表型有贡献。这一目标将 包括对所涉及的转录机制和YAP效应蛋白关联的确定 ST用来实现这些改变。我们的第二个目标是研究YAP在MT驱动中的作用 转型。在这里，我们也将对基因表达和蛋白质-蛋白质关联的变化感兴趣。 在我们的最后一个目标中，我们试图检查YAP在MuPyV MT介导的体内转化中的作用 转基因和基因敲除小鼠。 在这个计划项目的背景下，我们有一个很好的机会来利用病毒的相互作用来获得 更深入地了解河马信号在人类肿瘤发生中的作用。通过比较我们对MuPyV的影响的结果 关于PP2A/YAP/TAZ的ST/MT，以及我们与SV40 ST和Merkel ST合作的同事以及 哈恩实验室在K-RAS驱动的人类癌症中研究YAP，我们应该能够确定 YAP对细胞信号的影响确实很重要，极大地增强了我们数据的影响。理想情况下，这些 研究将引导我们实现将我们的工作转化为人类癌症治疗的最终目标，就像我们所做的那样 之前做过的是PI3激酶。

PROJECT SUMMARY 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, TGFβ 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 Aβ 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 is 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.