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

项目 2：通过 PP2A/YAP/Hippo 途径进行致癌转化

• 批准号: 10227783
• 负责人: THOMAS M ROBERTS
• 金额: $ 33.21万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227783
• 关键词: 1-Phosphatidylinositol 3-Kinase; Ablation; Affect; Alleles; Amyloid beta-Protein; Antigens; Apoptosis; Binding; Breast cancer metastasis; Cell Maintenance; Cell Nucleus; Cell Proliferation; Cell Survival; Cells; Cellular biology; Colorectal Cancer; Cytoplasm; Data; Erinaceidae; Gene Expression; Gene Proteins; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Grant; Human; Journals; KRAS2 gene; Knockout Mice; Lead; Link; Literature; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mammary Neoplasms; Mediating; Merkel cell carcinoma; Modeling; Modification; Mus; Neoplasm Metastasis; Neoplastic Cell Transformation; Oncogenes; Oncogenic; Organ Size; Paper; Pathway interactions; Phenotype; Phosphorylation; Polyomavirus; Population; Post-Translational Protein Processing; Prognosis; Protein Isoforms; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; Publishing; Regulation; Reporting; Role; Serine/Threonine Phosphorylation; Signal Pathway; Signal Transduction; Simian virus 40; Small T Antigen; System; Testing; Transforming Growth Factor beta; Transgenic Mice; Translating; Tyrosine; Tyrosine Phosphorylation; Viral; Virus; WNT Signaling Pathway; Whole Organism; Wild Type Mouse; Work; cancer therapy; cell motility; cell transformation; cellular targeting; experimental study; improved; in vivo; insight; interest; malignant breast neoplasm; mouse polyomavirus; notch protein; programs; protein function; sialosyl-T antigen; stem cell differentiation; stem cell proliferation; stem-like cell; tumor; tumorigenesis

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.

项目摘要 该应用寻求YAP/TAZ在癌症中作用的机制。各种各样的 人类的癌症改变了通常与预后相关的YAP/TAZ信号传导。 yap及其堂兄 TAZ是控制器官大小，细胞运动，增殖和 生存。该途径还调节其他重要的信号通路（刺猬，缺口，TGFβ和WNT）。 我们将使用鼠多瘤病毒（MUPYV）来探测YAP功能。 MUPYV引起广泛的肿瘤。它是 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 重要问题，例如PP2AAβ同工型在癌症中的作用。最近，我们报道了Mupyv的小T 抗原（ST）直接结合YAP并通过促进其磷酸化，稳定性和功能来改变其磷酸化，稳定性和功能 与PP2A的关联。这种相互作用允许ST阻止几个系统中的分化。广泛的 MT的MT癌基因的初步数据表明，MT也与YAP相关联。这个关联是 对于MT驱动肿瘤转化很重要。 MT也影响YAP磷酸化，但MT的影响是 与St的不同。我们的第一个目的是研究茎样细胞分化的ST调节。自从 我们知道ST也与TAZ相互作用，我们将测试它是否有助于表型。这个目标 包括确定所涉及的转录机制和YAP效应蛋白关联 ST用来实现这些改变。我们的第二个目标是研究YAP在Mt Drive中的作用 转型。在这里，我们也会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，我们试图研究Yap在Mupyv mt Mt介导的转换中的作用 转基因和淘汰小鼠。 在该计划项目的背景下，我们有一个很好的机会来利用病毒相互作用以获得 对人肿瘤发生的河马信号传导的深入了解。通过比较我们对MUPYV影响的结果 pp2a/yap/taz上的ST/MT与我们的同事的结果与SV40 ST和Merkel ST一起工作， 在K-Ras驱动人类癌症的Hahn Lab的YAP工作中，我们应该能够确定哪一个 YAP对细胞信号的影响确实很重要，可以很好地增强我们数据的影响。理想情况下，这些 研究将使我们达到将工作转化为人类癌症疗法的最终目标，因为我们 以前用于PI3激酶。