The Hippo Pathway in Prostate Gland Homeostasis and Prostate Cancer

前列腺稳态和前列腺癌中的 Hippo 通路

基本信息

批准号：
9228337
负责人：
VALERI VASIOUKHIN
金额：
$ 36.21万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9228337
关键词：
Age American Animals Binding Biological Assay Cancer Etiology Cells Cessation of life ChIP-on-chip ChIP-seq Country DNA Sequence Data Development Disease EMSA Epithelial Cells Epithelium Event Family Gene Activation Gene Fusion Gene Targeting Genes Genetic Genetic Recombination Genetic Transcription Genetically Engineered Mouse Growth Homeostasis Human In Vitro Intestines LATS2 gene Laboratories Liver Luciferases Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Molecular Mus Normal tissue morphology Oncogenic Organism Output Pathway interactions Phenotype Phosphorylation Phosphotransferases Play Prostate Proteins Recurrence Regulation Role Signal Pathway Signal Transduction Signal Transduction Pathway Skin Stem cells Tertiary Protein Structure Testing Therapeutic Transcription Coactivator Transcriptional Activation Transcriptional Regulation Transgenic Animals Transgenic Mice Up-Regulation age related base cancer initiation experimental study gain of function in vivo loss of function mammary epithelium men overexpression programs promoter public health relevance self-renewal stem cell division trait transcription factor transcriptome sequencing tumor progression

项目摘要

DESCRIPTION (provided by applicant): Chromosomal recombination resulting in a gene fusion between a strong promoter and an ETS- family transcription factor ERG is the most common genetic event in human prostate cancer. The significance of ERG overexpression and the mechanisms of ERG are not well understood. This application aims at answering these questions and builds on extensive preliminary evidence generated in our laboratory. We generated transgenic mice overexpressing ERG in mouse prostate epithelium at the levels similar to the levels of ERG in human prostate cancer, and found that these animals develop age-related prostate cancer. This is exciting, because age is the most significant factor in development of human prostate cancer. The analyses of ERG transgenic animals revealed specific activation of the genes negatively controlled by the Hippo signaling pathway. Hippo pathway is known to restrict self-renewal of stem and progenitor cells and constitutive inactivation of the Hippo pathway is causally involved in cancer in liver, skin, intestine and breast epithelium. The significance of the Hippo pathway in prostate epithelium and prostate cancer is presently unknown. We confirmed ERG-dependent activation of Hippo genes in human prostate epithelial cells and found that ERG binds to Hippo transcriptional co-activators YAP1/TAZ and potentiates their transcriptional activity. Thus, the central hypothesis of this application is that the Hippo pathway plays an important role in regulation of homeostasis of normal prostate gland and activation of Hippo target genes is the primary pathway responsible for oncogenic function of ERG in prostate cancer. We propose to comprehensively investigate this hypothesis using in vitro and in vivo approaches. In aim 1, we will investigate the physical and functional connection between ERG and YAP1/TAZ proteins. In aim 2, we will determine the mechanisms and the impact of ERG on the transcriptional output of the Hippo pathway. In aim 3, we will use genetically engineered mice to reveal the significance of the Hippo pathway in normal prostate gland homeostasis and ERG- mediated prostate cancer. Overall, this study will determine the role of the Hippo pathway in normal prostate and reveal the pivotal mechanisms responsible for the development of prostate cancer.

描述（由申请人提供）：染色体重组，导致强启动子与ETS-家族转录因子ERG之间的基因融合是人类前列腺癌中最常见的遗传事件。 ERG过表达的意义和ERG的机制尚不清楚。该应用程序旨在回答这些问题，并建立在我们实验室中产生的广泛初步证据的基础上。我们在小鼠前列腺上皮中过表达ERG的转基因小鼠在类似于人类前列腺癌水平的水平上，发现这些动物会发展为年龄相关的前列腺癌。这是令人兴奋的，因为年龄是人类前列腺癌发展中最重要的因素。 ERG转基因动物的分析揭示了由河马信号通路负面控制的基因的特异性激活。已知河马途径限制了茎和祖细胞的自我更新，并且河马途径的组成型失活在肝脏，皮肤，肠和乳房上皮中与癌症有关。目前尚不清楚河马途径在前列腺上皮和前列腺癌中的重要性。我们证实了人类前列腺上皮细胞中河马基因的ERG依赖性激活，发现ERG与河马转录共激活剂YAP1/TAZ结合并增强其转录活性。因此，该应用的中心假设是，河马途径在调节正常前列腺的体内稳态中起重要作用，而河马靶基因的激活是负责ERG在前列腺癌中致癌功能的主要途径。我们建议使用体外和体内方法全面研究这一假设。在AIM 1中，我们将研究ERG和YAP1/TAZ蛋白之间的物理和功能连接。在AIM 2中，我们将确定ERG对河马途径转录输出的机理和影响。在AIM 3中，我们将使用基因工程的小鼠来揭示河马途径在正常前列腺腺体稳态和ERG-介导的前列腺癌中的重要性。总体而言，这项研究将确定河马途径在正常前列腺中的作用，并揭示导致前列腺癌发展的关键机制。