Regulation of esophageal gene expression and function by KLF5 and p53

描述（由申请人提供）：食道内膜经常暴露于刺激物，如酒精、香烟烟雾、热饮、膳食亚硝基化合物和胃-十二指肠内容物的反流，食道疾病在美国和全世界都是重要的健康问题。例如，胃食管反流病（GERD）每年导致890万美国诊所就诊，食管癌是全球第六大最常见的癌症死亡原因。在食管上皮中，关键的转录调节因子KLF5促进正常的增殖和迁移，正如我们所表明的那样，我们最近发现了KLF5和食管上皮细胞p53之间的新关系，其中p53作为KLF5的“分子开关”。原代人食管角化细胞中p53突变将KLF5从促增殖转化为抗增殖，这一作用主要由p21Waf1/Cip1介导，当p53突变而非野生型p53时，KLF5转录激活角化细胞肿瘤抑制因子NOTCH1。在其他初步数据中，我们证明了KLF5抑制食管角化细胞中的p53，并为KLF5和p53的全基因组协调调节提供了证据。我们的总体假设是KLF5和p53在食管角化细胞中协调广泛的转录程序，控制增殖、生长停滞、凋亡和转化。为了验证这一假设，我们将追求以下相关的具体目标：1。我们将描述

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.