The role of Klf5 in GI epithelial homeostasis

University Of Pennsylvania, Philadelphia PA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Klf5 (IKLF; BTEB2) is a member of the Kruppel-like factor (KLF) family implicated as a positive regulator of cell proliferation with transforming properties in vitro. In gastrointestinal epithelia, Klf5 is expressed in regions of active cell proliferation, including the basal layer of the esophagus, the small intestinal crypts, and the lower third of colonic crypts. In vitro, KLF5 mediates the transforming activity of oncogenic H-Ras and negatively regulates Klf4 (GKLF). We have previously investigated the role of Klf4 in vivo through gene targeting experiments and demonstrated a vital role for Klf4 as a negative regulator of cell proliferation and promoter of normal differentiation in several gastrointestinal epithelia. Nonetheless, Klf5 has also been suggested to be a possible tumor suppressor gene in human breast, prostate, and intestine, leading to conflicting hypotheses of the role of K/f5 in normal epithelial homeostasis and tumorigenesis. Thus, we will investigate the role of Klf5 in gastrointestinal proliferation and differentiation by testing the following hypotheses: (1) increased expression of Klf5 in gastrointestinal epithelia leads to epithelial hyperproliferation and altered differentiation; (2) loss of Klf5 expression in gastrointestinal epithelia results in decreased epithelial proliferation. The following Specific Aims will be pursued: (1) to analyze the function of Klf5 in gastrointestinal proliferation and differentiation in vivo by direct overexpression of Klf5 in murine esophageal and intestinal epithelia using the upstream regulatory elements of ED-L2 and villin respectively; (2) to examine the effects of increased Klf5 expression in gastrointestinal epithelia by overexpressing Klf5 in primary esophageal epithelial cells; (3) to investigate the role of Klf5 in gastrointestinal epithelial homeostasis through loss-of-function studies in primary esophageal epithelial cells. This work will provide important new insights into the regulation of gastrointestinal epithelial proliferation and differentiation and provide a framework to understand the molecular events underlying mucosal injury and malignant transformation. [unreadable] [unreadable]