Regulation and Functional Dissection of YAP in Mitosis

YAP 在有丝分裂中的调控和功能解析

• 批准号: 8614249
• 负责人: Jixin Dong
• 金额: $ 28.6万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-10 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8614249
• 关键词: Aneuploidy; Apoptosis; Biological; CDC2 Protein Kinase; Cancer Etiology; Cell Cycle Regulation; Cell Proliferation; Cells; Chromosomal Instability; Chromosome Segregation; Contact Inhibition; Defect; Dissection; Drug Targeting; Ensure; Future; Genomic Instability; Goals; Human Characteristics; Light; Link; Malignant Neoplasms; Mediating; Mitosis; Mitotic; Mitotic Cell Cycle; Molecular; Oncogene Proteins; Oncogenic; Organ; Outcome; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Property; Proteins; Regulation; Role; Signal Pathway; Site; Stem cells; Testing; Tissues; Tumor Suppressor Proteins; Work; base; cancer type; insight; metaplastic cell transformation; mutant; new therapeutic target; novel; overexpression; protein function; public health relevance; self-renewal; therapeutic development; therapeutic target; tumorigenesis

Abstract Text The Hippo pathway controls cell contact inhibition, stem cell self -renewal, and tumorigenesis through phosphorylating and inactivating the downstream oncoprotein, yes-associated protein (YAP). The PI, along with others, has demonstrated that YAP promotes oncogenesis by stimulating cell proliferation and inhibiting apoptosis. YAP is overexpressed or hyperactivated in many types of cancers. Current studies involving YAP focus on determining its overall oncogenic role in various organs/tissues as well as its role in crosstalk with other signaling pathways. While these studies provide important insight into the oncogenic properties of YAP, however, the underlying molecular mechanisms through which YAP exerts its oncogenic function are poorly understood. The long-term goal of this project is to elucidate the regulatory mechanisms of the Hippo-YAP signaling pathway in mitotic cell-cycle control and oncogenic transformation, thus providing potential therapeutic targets. Our preliminary studies demonstrate that during mitosis YAP is phosphorylated on novel sites and activated in a CDK1-dependent manner. Importantly, mitotic phosphorylation is required for YAP-driven cellular transformation. We have found that YAP is required for the activation of the spindle checkpoint during mitosis. Furthermore, overexpression of YAP, but not of the non - phosphorylatable mutant, hyper-activates the spindle checkpoint and causes mitotic defects. Based on these preliminary studies, we hypothesize that CDK1-mediatd mitotic phosphorylation of YAP is biologically significant in the regulation of the spindle checkpoint activation and subsequent oncogenic transformation. Our central hypothesis will be tested through the following three specific aims: Aim 1: Determine the molecular mechanism of YAP regulation/activation during mitosis; Aim 2: Determine the role of YAP and its phosphorylation in mitotic progression, the spindle checkpoint, and aneuploidy; Aim 3: Determine the functional significance of YAP phosphorylation on its targets. Successful completion of these studies will not only reveal novel roles of YAP in mitosis and genome instability, but will also shed light on the mechanisms involved in YAP-driven oncogenesis.

摘要文本 Hippo通路控制细胞接触抑制、干细胞自我更新和肿瘤发生 通过磷酸化和灭活下游癌蛋白，是相关蛋白 （雅普）。PI和其他人沿着已经证明雅普通过以下方式促进肿瘤发生： 刺激细胞增殖和抑制凋亡。雅普在细胞中过度表达或过度活化， 多种癌症。目前涉及雅普的研究集中在确定其 在各种器官/组织中的总体致癌作用以及其在与其他组织/组织的相互干扰中的作用 信号通路虽然这些研究提供了重要的洞察致癌特性 然而，雅普的潜在分子机制，通过它雅普发挥其作用， 致癌功能知之甚少。本项目的长期目标是阐明 Hippo-YAP信号通路在有丝分裂细胞周期控制中的调节机制， 致癌转化，从而提供潜在的治疗靶点。 我们的初步研究表明，在有丝分裂过程中，雅普在新的位点被磷酸化 并以CDK 1依赖性方式激活。重要的是，有丝分裂磷酸化是必需的， YAP驱动的细胞转化。我们已经发现，雅普是激活 纺锤体检查点。此外，雅普的过表达，而非YAP的过表达， 在一些实施方案中，可磷酸化的突变体过度激活纺锤体检查点并导致有丝分裂缺陷。 基于这些初步研究，我们假设CDK 1介导的有丝分裂磷酸化 雅普在调节纺锤体检查点激活方面具有生物学意义， 随后的致癌转化。我们的中心假设将通过 具体目标有以下三个：目标1：明确雅普的分子机制 目的2：确定雅普及其磷酸化在有丝分裂中的作用， 有丝分裂进程、纺锤体检查点和非整倍体;目的3：确定功能性 雅普磷酸化对其靶点的重要性。成功完成这些研究将 不仅揭示了雅普在有丝分裂和基因组不稳定性中的新作用， 参与YAP驱动的肿瘤发生的机制。