Regulation of esophageal gene expression and function by KLF5 and p53

KLF5 和 p53 对食管基因表达和功能的调节

基本信息

批准号：
8652150
负责人：
JONATHAN P KATZ
金额：
$ 34.8万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2013-09-20 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8652150
关键词：
Ablation Address Alcohols Animal Model Apoptosis Benign Beverages Bile Acids Binding Cancer Etiology Cell Cycle Cell Line Cell Proliferation Cells Cellular Stress Cellular biology Cessation of life ChIP-seq Clinic Visits Complement Data Development Diagnosis Diet Dietary Nitroso Compound Digestive System Disorders Dysplasia Early Diagnosis Environment Epithelial Epithelial Cells Epithelium Esophageal Esophageal Diseases Esophageal Squamous Cell Esophagus Funding Gastroesophageal reflux disease Gastrointestinal Diseases Gene Expression Gene Targeting Genetic Transcription Growth Health Homeostasis Human In Vitro Irritants Lead Liver diseases MDM2 gene Malignant - descriptor Malignant Squamous Cell Neoplasm Malignant neoplasm of esophagus Mediating Messenger RNA Molecular Molecular Target Mutation NOTCH1 gene Neoplasms Nodal Normal Cell Pathway interactions Patients Pennsylvania Post-Translational Protein Processing Protein p53 Proteins Publications Publishing Regulation Research Research Personnel Resources Stomach Sum Survival Rate Testing Transcription Repressor/Corepressor Transcriptional Regulation Tumor Suppressor Proteins United States National Institutes of Health Universities Validation Work anticancer research cell growth cigarette smoking combinatorial experience gene function genome-wide human tissue in vivo insight keratinocyte migration mouse model mutant new therapeutic target novel novel diagnostics novel strategies programs public health relevance response stressor

项目摘要

PROJECT SUMMARY The esophageal lining is regularly exposed to irritants such as alcohol, cigarette smoke, hot beverages, dietary nitroso-compounds, and refluxate of gastro-duodenal contents, and disorders of the esophagus are significant health problems in the U.S. and throughout the world. For example, gastroesophageal reflux disease (GERD) leads to 8.9 million U.S. clinic visits annually, and esophageal cancer is the 6th most common cause of cancer death worldwide. In esophageal epithelia, the key transcriptional regulator Kr¿ppel-like factor 5 (KLF5) promotes normal proliferation and migration, as we have shown, and we recently identified a novel relationship between KLF5 and p53 in esophageal epithelial cells, whereby p53 acts as a "molecular switch" for KLF5. p53 mutation in primary human esophageal keratinocytes converts KLF5 from pro-proliferative to anti-proliferative, an effect mediated predominantly by p21Waf1/Cip1, and KLF5 transcriptionally activates the keratinocyte tumor suppressor NOTCH1 when p53 is mutant but not with wild-type p53. In additional Preliminary Data, we demonstrate that KLF5 suppresses p53 in esophageal keratinocytes and provide evidence for genome-wide coordinate regulation by KLF5 and p53. Our overarching hypothesis is that KLF5 and p53 orchestrate a broad transcriptional program in esophageal keratinocytes that controls proliferation, growth arrest, apoptosis, and transformation. To test this hypothesis, we will pursue the following interrelated Specific Aims: 1. We will delineate the mechanisms through which KLF5 regulates p53 levels and function~ 2. We will define the mechanism for KLF5 functional switching on p21Waf1/Cip1~ 3. We will identify common and exclusive targets of KLF5 in the context of wild-type and mutant p53~ and 4. We will determine the functional consequences of KLF5 loss and p53 mutation in vivo. These complementary approaches are supported by our robust Preliminary Data, both published and unpublished. Moreover, the PI is an experienced investigator who is an expert in the Kr¿ppel-like factors (KLFs), transcriptional regulation, animal models of gastrointestinal diseases, and esophageal squamous cell biology, as demonstrated by recent, relevant corresponding-author publications in Cancer Research, PLoS One, Cell Cycle, and Neoplasia. In addition, the PI is supported by a superb research team, complemented by expert collaborators, and by the exceptional resources, facilities, and intellectual environment of the University of Pennsylvania and the NIH-funded Center for Molecular Studies in Digestive and Liver Diseases. Overall, the proposed studies will provide key insights into the transcriptional regulation of esophageal epithelial homeostasis and the molecular pathways that underlie esophageal diseases, both benign and malignant.

项目摘要食管衬里定期暴露于刺激性，例如酒精，香烟，热卧室，饮食硝基化合物和胃二丁酸含量的反射，食管的疾病很重要美国和世界各地的健康问题。例如，胃食管反射X疾病（GERD）每年可进行890万次美国诊所就诊，食管癌是癌症的第六个最常见原因全球死亡。在食道上皮中，关键转录调节剂kr kr kr类样因子5（KLF5）正如我们所表明的，促进正常的增殖和迁移，我们最近确定了一种新的关系食管上皮细胞中的KLF5和p53之间，p53充当KLF5的“分子开关”。 p53 原发性人类食管角质形成细胞中的突变将KLF5从促生殖转化为抗增殖，主要由p21WAF1/CIP1介导的效应，而KLF5转录激活角质形成细胞肿瘤当p53是突变体而不是野生型p53时，抑制剂notch1。在其他初步数据中，我们证明KLF5抑制食管角质形成细胞中的p53，并提供了全基因组的证据 KLF5和p53的坐标调节。我们的总体假设是KLF5和P53策划了一个广泛的控制增殖，停滞，凋亡和转型。为了检验这一假设，我们将追求以下相互关联的特定目的：1。将描述KLF5调节p53级别和功能〜2的机制。我们将定义 KLF5功能开关的机制在P21WAF1/CIP1〜3上。我们将确定的常见目标和独家目标在野生型和突变体p53〜和4的背景下，KLF5。我们将确定功能后果 KLF5损失和体内p53突变。这些完整的方法得到了我们的强大支持初步数据，均已发布和未发表。此外，PI是一位经验丰富的调查员 kr¿ppel样因素（KLF），转录调节，胃肠道疾病动物模型的专家，和食管鳞状细胞生物学，如最近相关的相应作者出版物所证明在癌症研究中，PLOS ONE，细胞周期和肿瘤。此外，PI由一流的支持研究团队，由专家合作者完成，由卓越的资源，设施和宾夕法尼亚大学的知识环境和NIH资助的分子研究中心消化和肝病。总体而言，拟议的研究将提供对转录的关键见解食管上皮稳态的调节和基于食管的分子途径良性和恶性疾病。