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：
9127223
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/9127223
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 TP53 gene 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 knock-down migration mouse model mutant new therapeutic target novel novel diagnostics novel strategies programs response stressor

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由适用提供）：食管衬里定期暴露于诸如酒精，香烟烟雾，热品种，饮食中的硝基化合物和Reflectophagus之类的刺激物中，在美国和全世界都是重大的健康问题。例如，胃食管反射酶疾病（GERD）每年可进行890万次美国诊所就诊，而食管癌是全球癌症死亡的第六个最常见原因。如我们所表明的那样，在食道上皮中，关键的转录调节剂KRPPEL样因子5（KLF5）促进了正常的增殖和迁移，并且我们最近确定了食管上皮细胞中KLF5和P53之间的新型关系，其中p53在p53中起着“分子开关的KLF5”。原代人食道角质形成细胞中的p53突变将KLF5从促生产转化为抗增殖，这是由p21waf1/cip1介导的效果，而KLF5转录在p53中激活了p53时p53是突变的p53。在其他初步数据中，我们证明了KLF5在食管角质形成细胞中抑制p53，并为KLF5和p53提供了全基因组坐标调节的证据。我们的总体假设是，KLF5和p53在食管角质形成细胞中策划了一个广泛的转录程序，该程序控制着增殖，生长停滞，凋亡和转化。为了检验这一假设，我们将追求以下相互关联的具体目的：1。我们将描述 KLF5调节p53水平和功能〜2的机制。我们将在p21WAF1/CIP1〜3上定义KLF5功能转换的机制。我们将在野生型和突变体p53〜和4中确定KLF5的常见和独家目标，我们将确定KLF5损耗的功能损失和p55损失。这些完整的方法得到了我们强大的初步数据的支持，这些数据均已发布和未发表。此外，PI是一位经验丰富的研究者，他是Krppel样因素（KLF），转录调节，胃肠道疾病的动物模型和食管鳞状细胞生物学的动物模型，如最近的，相关的相应的授权人在癌症研究中，PLOS One，Cell Cyce Cycle和Neoplasia中的相关相应的作者。此外，PI得到了一支精湛的研究团队的支持，由专家合作者完成，以及宾夕法尼亚大学的杰出资源，设施和知识环境以及NIH资助的消化和肝病分子研究中心。总体而言，拟议的研究将为食管上皮稳态的转录调节以及基于良性和恶性食管疾病的分子途径提供关键见解。