The role of Klf5 in GI epithelial homeostasis and disease

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DESCRIPTION (provided by applicant): The University of Pennsylvania School of Medicine contributes substantially to the local economy. In 2008, the School created 37,000 jobs and $5.4 billion in regional economic activity, with the area's highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. The current proposal will involve the creation of one new job, a postdoctoral researcher hired specifically for this competitive revision. This proposal will also meet the specific goals of the ARRA by accelerating the tempo of scientific research. Kruppel-like factor 5 (KLF5; IKLF; BTEB2) is a key regulator of proliferation in gastrointestinal epithelia. In the esophagus, Klf5 is expressed specifically in the proliferative basal layer, and transgenic expression of Klf5 in mice increases esophageal epithelial proliferation. Yet, KLF5 inhibits proliferation, promotes anoikis, and decreases invasion of esophageal squamous cancer cells. Moreover, Klf5 promotes proliferation and activates cyclin D1 in non-tranformed IEC-18 and IMCE intestinal cells but inhibits proliferation and fails to activate cyclin D1 following Ras-mediated transformation. KLF5 is also deleted or down-regulated in breast and prostate cancers. These studies highlight a context dependent role for KLF5. p53 gene mutations are common in esophageal squamous cancers. Yet epithelial cancers are rarely seen in mice and humans with loss of p53 or p53 mutation alone. In preliminary data, we show that loss of functional KLF5 and p53 in combination, but not individually, is sufficient to transform human primary esophageal keratinocytes. We hypothesize that p53 and KLF5 coordinately regulate esophageal tumorigenesis. Moreover, we identify Notch1, a tumor suppressor and p53 target in skin keratinocytes, as a transcriptional target of KLF5. Thus, we propose the following Specific Aim: to examine transformation and the coordinate regulation of the Notch1 gene in esophageal keratinocytes by KLF5 and p53. While building upon the Specific Aims of the parent R01 ("The role of Klf5 in GI epithelial homeostasis and disease"), this competitive revision represents a significant expansion of the scope or research protocol of the funded R01. As such, this proposal requests costs to support new research objectives and aims that are outside of the scope of the approved parent grant. Overall, we anticipate that these studies will define a key role for KLF5 in malignant transformation in the esophagus and provide new approaches to the diagnosis and treatment of esophageal squamous cell cancer, one of the deadliest cancers in the U.S. and throughout the world. PUBLIC HEALTH RELEVANCE: This proposal will result in the creation of one new job, a postdoctoral researcher hired specifically for this competitive revision. Moreover, the studies proposed here will provide new approaches to the diagnosis and treatment of esophageal squamous cell cancer, one of the deadliest cancers in the U.S. and throughout the world.