The Kruppel-like KLF4 transcription factor, a novel regulator of urokinase receptor expression, drives synthesis of this binding site in colonic crypt luminal surface epithelial cells.
The urokinase-type plasminogen activator receptor (u-PAR) plays a central role in cell migration, growth, and invasion and is regulated, in part, transcriptionally. In mice, u-PAR expression is restricted to a few tissues, one of which is the colon. We therefore screened a colon expression library for regulators of u-PAR promoter activity and identified a zinc finger protein bearing consensus sequences to the Kruppel-like family of transcription factors and showing partial homology with one of the members, KLF4. Like u-PAR, KLF4 expression is predominant in the luminal surface epithelial cells of the colonic crypt, and we hypothesized that u-PAR synthesis in these cells is directed by this transcription factor. Colon cells from KLF4 null mice showed a dramatic reduction in u-PAR protein compared with wild-type mice. Conversely, KLF4 expression in HCT116 colon cancer cells increased the amount of u-PAR protein/mRNA. Transient transfection of KLF4 with a reporter driven by 5'- deleted u-PAR promoter fragments indicated the requirement of the proximal 200 base pairs for optimal expression. Mobility-shifting experiments demonstrated binding of KLF4 to multiple regions of the u-PAR promoter (-154/-128, -105/-71, and -51/-24), and chromatin immunoprecipitation assays confirmed the binding of KLF4 to the endogenous promoter. Deletion of the -144/-123 promoter region diminished but did not eliminate the ability of KLF4 to transactivate the u-PAR promoter, suggesting cooperativity of these binding sites with respect to activation of gene expression. In conclusion, we have identified KLF4 as a novel regulator of u-PAR expression that drives the synthesis of u-PAR in the luminal surface epithelial cells of the colon.[1]References
- The Kruppel-like KLF4 transcription factor, a novel regulator of urokinase receptor expression, drives synthesis of this binding site in colonic crypt luminal surface epithelial cells. Wang, H., Yang, L., Jamaluddin, M.S., Boyd, D.D. J. Biol. Chem. (2004) [Pubmed]
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