Metabolic regulation of cellular junction proteins

细胞连接蛋白的代谢调节

基本信息

批准号：
9060269
负责人：
Xu Wu
金额：
$ 35.23万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-14 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9060269
关键词：
5&apos -AMP-activated protein kinase AMOTL1 gene Binding Cell Polarity Cell Proliferation Colon Carcinoma Complex Consensus Development Epithelial Cells Genetically Engineered Mouse Goals Health Hypertrophy In Vitro Knock-out Lead Light Liver Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Mediating Metabolic Metabolic stress Metabolism Molecular Mutation Neurofibromin 2 Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Organ Size Pathway interactions Phenformin Phosphorylation Phosphorylation Site Phosphotransferases Play Primary carcinoma of the liver cells Protein Dephosphorylation Protein Inhibition Proteins Regulation Role STK11 gene Signal Transduction Testing Therapeutic Tight Junctions Transcription Coactivator Tumor Suppressor Proteins base cancer cell cell growth regulation epithelial to mesenchymal transition in vivo inhibitor/antagonist insight mouse model mutant novel overexpression protein activation sensor small molecule small molecule inhibitor tumor growth tumor metabolism tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Hippo signaling is an emerging tumor suppressor pathway that plays key roles in organ size control and tumorigenesis. Hippo signaling inhibits the transcription co-activator Yes-Associated Protein (YAP), an oncogene amplified in multiple cancers, including hepatocellular carcinoma, colon and ovarian cancer. YAP promotes cell proliferation, epithelial-to-mesenchymal transition (EMT), survival and chemoresistance. Therefore, it is important to understand how YAP activity is regulated for the development of novel cancer therapeutics. We recently discovered that cellular energy level is a novel upstream signal regulating Hippo pathway, through the central metabolic sensors LKB1 and AMP-activated protein kinase (AMPK). Consistently, small molecule activators of AMPK inhibit YAP activity; and YAP is activated in LKB1-deficient cancers. Further understanding this novel signaling mechanism will shed light on how cellular metabolism regulates YAP oncogene. Our specific aims of this proposal include: (1) To determine the mechanism(s) of metabolic regulation of tight junctions and Hippo signaling. (2) To investigate the roles of tight junction proteins as the central signaling node in regulation of YAP; and to investigate YAP as a downstream oncogenic factor in LKB1-deficient lung cancer. (3) To determine whether activation of AMPK inhibits YAP in vivo; and to target LKB1-deficient lung cancer cells in vitro and in vivo using small molecule inhibitor of YAP-TEAD interaction.

描述（由申请人提供）：河马信号传导是一种新兴的肿瘤抑制途径，在器官尺寸控制和肿瘤发生中起关键作用。河马信号传导抑制转录共激活因子相关蛋白（YAP），这是一种在包括肝细胞癌，结肠癌和卵巢癌在内的多种癌症中扩增的癌基因。 YAP促进细胞增殖，上皮到间质转变（EMT），存活率和化学抗性。因此，重要的是要了解如何调节YAP活动以开发新的癌症治疗剂。我们最近发现，通过中央代谢传感器LKB1和AMP激活的蛋白激酶（AMPK），细胞能级是调节河马途径的新型上游信号。一致地，AMPK的小分子激活剂抑制YAP活性。 YAP在LKB1缺陷型癌症中被激活。进一步了解这种新颖的信号传导机制将阐明细胞代谢如何调节YAP癌基因。该提案的具体目的包括：（1）确定紧密连接和河马信号的代谢调节机制。（2）研究紧密连接蛋白作为中央信号节点在调节YAP中的作用；并研究YAP是LKB1缺陷肺癌的下游致癌因子。（3）确定AMPK的激活是否抑制体内YAP；并使用YAP-TEAD相互作用的小分子抑制剂在体外和体内靶向LKB1缺陷型肺癌细胞。