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：
8737255
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/8737255
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

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（由申请人提供）：食道内壁经常暴露于刺激物，如酒精、香烟烟雾、热饮料、膳食亚硝基化合物和胃十二指肠内容物反流物，食道疾病在美国是严重的健康问题。例如，美国因胃食管反流病 (GERD) 就诊的人数达到 890 万人次。每年，食管癌是全球第六大最常见的癌症死亡原因，而食管上皮是关键的转录调节因子 Kr¿正如我们所表明的，ppel 样因子 5 (KLF5) 促进正常增殖和迁移，并且我们最近在食管上皮细胞中发现了 KLF5 和 p53 之间的新关系，因此 p53 充当 KLF5 突变的“分子开关”。原代人食管角质形成细胞将 KLF5 从促增殖转变为抗增殖，这种作用主要由当 p53 突变但野生型 p53 不存在时，p21Waf1/Cip1 和 KLF5 转录激活角质形成细胞肿瘤抑制因子 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，并为 KLF5 的全基因组协调调节提供证据。我们的总体假设是 KLF5 和 p53 协调了广泛的转录程序。控制增殖、生长停滞、凋亡和转化的食管角质形成细胞为了检验这一假设，我们将追求以下相互关联的具体目标： 1. 我们将描述 KLF5 调节 p53 水平和功能的机制~ 2. 我们将定义 KLF5 在 p21Waf1/Cip1 上功能切换的机制~ 3. 我们将在野生型和突变型 p53~ 和 4 的背景下确定 KLF5 的常见和排他靶点我们将确定体内 KLF5 丢失和 p53 突变的功能后果，这些补充方法得到我们已发表和未发表的可靠初步数据的支持。一位经验丰富的调查员，是 Kr¿ 方面的专家ppel 样因子 (KLF)、转录调控、胃肠道疾病动物模型和食管鳞状细胞生物学，正如近期《Cancer Research》、《PLoS One》、《Cell Cycle》和《Neoplasia》上的相关通讯作者出版物所证明的那样。 PI 得到了一支优秀研究团队的支持，辅之以专家合作者，以及宾夕法尼亚大学和 NIH 资助的分子研究中心的卓越资源、设施和智力环境。总体而言，拟议的研究将为食管上皮稳态的转录调节以及食管良性和恶性疾病的分子途径提供重要见解。