Metabolic regulation of cellular junction proteins

细胞连接蛋白的代谢调节

• 批准号: 8761052
• 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
• 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/8761052
• 关键词: 5' -AMP-activated protein kinase; Binding; Cell Polarity; Cell Proliferation; Colon; Colon Carcinoma; Complex; Consensus; Development; Epithelial Cells; Genetic Transcription; Genetically Engineered Mouse; Goals; 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; Oncogene Proteins; Oncogenes; Oncogenic; Organ Size; Ovarian; 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; Transcriptional Regulation; 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; public health relevance; sensor; small molecule; tumor growth; tumor metabolism; tumorigenesis

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）：Hippo信号是一种新兴的肿瘤抑制途径，在器官大小控制和肿瘤发生中起关键作用。Hippo信号抑制转录共激活因子Yes-Associated Protein (YAP)，这是一种在多种癌症中扩增的致癌基因，包括肝细胞癌、结肠癌和卵巢癌。YAP促进细胞增殖、上皮-间质转化（EMT）、存活和化疗耐药。因此，了解YAP活性是如何被调控的对于开发新的癌症治疗方法是很重要的。我们最近发现细胞能量水平是一个新的上游信号，通过中枢代谢传感器LKB1和amp活化蛋白激酶（AMPK）调节Hippo通路。一致地，小分子AMPK激活剂抑制YAP活性；而YAP在缺乏lkb1的癌症中被激活。进一步了解这一新的信号机制将有助于揭示细胞代谢如何调节YAP癌基因。我们的具体目标包括：(1)确定紧密连接和Hippo信号的代谢调节机制。(2)探讨紧密连接蛋白作为中心信号节点在YAP调控中的作用；并研究YAP作为lkb1缺失肺癌的下游致癌因子。(3)确定激活AMPK是否在体内抑制YAP；以及在体外和体内使用YAP-TEAD相互作用的小分子抑制剂靶向lkb1缺陷肺癌细胞。