The mammalian intestinal epithelium is a tissue in which cell proliferation is closely linked to differentiation and programmed cell death. Recent studies have implicated several signaling pathways, including Wnt, Notch, Hedgehog, and TGF-beta family, as crucial regulators of intestinal epithelial homeostasis. However, the intracellular mediators for many of these pathways are not fully identified. The project supported by the grant on which this continuation application is based helped established the role played by two related Kruppel-like factors (KLFs), KLF4 and KLF5, in regulating intestinal epithelial proliferation and differentiation. KLF4 and 5 exhibit very different, at times opposite, biological activities. For example, KLF4 inhibits and KLF5 promotes cells proliferation, suggesting that KLF4 and KLF5 function to coordinate proliferation of intestinal epithelial cells. In the project period, we obtained exciting information about several novel aspects of the mechanism of action for the pro-proliferative KLF5 in mediating a number of physiologically relevant signaling processes. We showed that KLF5 is a crucial downstream mediator for the transforming effects of activated (oncogenic) H-Ras and K-Ras. We also obtained evidence that KLF5 is an important mediator for the pro-inflammatory response in intestinal epithelial cells elicited by Toll-like receptor (TLR) signaling, including bacterial lipopolysaccharide (LPS). Lastly, we identified a number of interacting proteins of KLF5 that might help explain its pro-proliferative and pro-inflammatory action. The central hypothesis of this proposal is that KLF5 is an essential mediator for the pro-proliferative and pro-inflammatory responses of intestinal epithelial cells to physiologic stimuli. We propose the following three specific aims in this continuation application: (1) To establish the function of KLF5 in mediating the oncogenic effect of activated K-Ras on intestinal epithelial cells, (2) To determine the role of KLF5 in mediating the pro-proliferative and pro-inflammatory responses to Toll-like receptor (TLR) signaling in intestinal epithelial cells, and (3) To investigate the role of a KLF5-interacting protein, protein inhibitor of activated STAT1 (PIAS1), in regulating KLFS's biological activities. Significance: The understanding of the mechanisms regulating proliferation and differentiation of the intestinal epithelium has the wide-range implication of gaining insights into the pathophysiology underlying many Gl diseases including cancer, infection, inflammatory bowel diseases, and a multitude of developmental disorders. The proposed project will characterize in detail the role of KLF5 in mediating signals that eventually result in the pro-proliferative or pro-inflammatory response of intestinal epithelial cells to various stimuli. A thorough delineation of KLF5's function in modulating these important biological processes may also help establish the foundation for potential therapeutic approaches for treating Gl diseases such as cancer and inflammatory bowel diseases. ? ? ? ?
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