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：
9005838
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/9005838
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 Programming Genetic Recombination Genetically Engineered Mouse Growth Health 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 Second Primary Neoplasms 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 gain of function in vivo loss of function mammary epithelium men overexpression promoter research study self-renewal stem 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）：导致强启动子和ETS家族转录因子ERG之间基因融合的染色体重组是人类前列腺癌中最常见的遗传事件。 ERG 过度表达的意义和 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产生的广泛初步证据的基础上。我们培育了在小鼠前列腺上皮中过表达 ERG 的转基因小鼠，其水平与人类前列腺癌中的 ERG 水平相似，并发现这些动物会患上与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的最重要因素。对 ERG 转基因动物的分析揭示了受 Hippo 信号通路负控制的基因的特异性激活。众所周知，Hippo 通路会限制干细胞和祖细胞的自我更新，并且 Hippo 通路的组成性失活与肝癌、皮肤、肠和乳腺上皮癌有关。 Hippo 通路在前列腺上皮和前列腺癌中的重要性目前尚不清楚。我们证实了人前列腺上皮细胞中 Hippo 基因的 ERG 依赖性激活，并发现 ERG 与 Hippo 转录共激活因子 YAP1/TAZ 结合并增强其转录活性。因此，本申请的中心假设是Hippo途径在正常前列腺体内平衡的调节中发挥重要作用，并且Hippo靶基因的激活是负责前列腺癌中ERG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。在目标 1 中，我们将研究 ERG 和 YAP1/TAZ 蛋白之间的物理和功能联系。在目标 2 中，我们将确定 ERG 对 Hippo 通路转录输出的机制和影响。在目标 3 中，我们将使用基因工程小鼠来揭示 Hippo 通路在正常前列腺稳态和 ERG 介导的前列腺癌中的重要性。总的来说，这项研究将确定 Hippo 通路在正常前列腺中的作用，并揭示导致前列腺癌发生的关键机制。