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

• 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
• 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

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 食管内膜经常暴露于刺激物，如酒精、香烟烟雾、热饮、饮食 亚硝基化合物、胃十二指肠内容物反流和食管疾病是重要的 美国和全世界的健康问题。 例如，胃食管反流病（GERD） 导致每年890万美国诊所就诊，食管癌是第六大最常见的癌症原因 全世界的死亡 在食管上皮中，关键的转录调节因子Kr <$ppel样因子5（KLF 5） 促进正常的增殖和迁移，正如我们所展示的，我们最近发现了一种新的关系， 在食管上皮细胞中，KLF 5和p53之间存在联系，p53作为KLF 5的“分子开关”。 p53 原代人食管角化细胞中的突变将KLF 5从促增殖转化为抗增殖， 主要由p21 Waf 1/Cip 1介导的作用，KLF 5转录激活角质形成细胞肿瘤 当p53是突变型时，抑制子NOTCH 1，但不与野生型p53。 在初步数据中，我们 证明KLF 5抑制食管角化细胞中的p53，并为全基因组研究提供证据。 通过KLF 5和p53协调调节。 我们的总体假设是KLF 5和p53协调了一个广泛的 食管角化细胞中控制增殖、生长停滞、凋亡和 转型 为了验证这一假设，我们将追求以下相互关联的具体目标：1。我们 将描述KLF 5调节p53水平和功能的机制。我们将定义 p21 Waf 1/Cip 1 ~ 3上KLF 5功能切换的机制。我们将确定共同的和排他性的目标， KLF 5在野生型和突变型p53-和4.我们将确定的功能后果 体内KLF 5缺失和p53突变。 这些互补的方法得到了我们强大的 初步数据，包括已发表和未发表的数据。 此外，PI是一名经验丰富的研究者， Kr <$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，如最近的相关通讯作者出版物所示 《癌症研究》、《公共科学图书馆·综合》、《细胞周期》和《肿瘤》。 此外，PI还得到了一个极好的 研究团队，辅以专家合作者，并通过特殊的资源，设施， 宾夕法尼亚大学和美国国立卫生研究院资助的分子研究中心的知识环境， 消化和肝脏疾病。 总的来说，拟议的研究将提供关键的见解转录 食管上皮内环境稳定的调节和食管癌发生的分子途径 良性和恶性疾病。