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MUCOSAL BIOLOGY

KLF4 gene expression is inhibited by the notch signaling pathway that controls goblet cell differentiation in mouse gastrointestinal tract

¹Departmen of Pathology, Microbiology and Immunology, University of South Carolina, Columbia, South Carolina; ²Division of Gastroenterology, School of Clinical Sciences, University of Liverpool, Liverpool, United Kingdom; ³Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York; and ⁴Sealy Center for Cancer Cell Biology and Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas

Submitted 23 June 2008 ; accepted in final form 17 December 2008

In Kruppel-like factor (KLF)-4-deficient mice, colonic goblet cell numbers are significantly reduced. Goblet cell development is regulated by the Notch signaling pathway. The aim of this study was to examine whether Notch represses KLF4 expression to regulate goblet cell differentiation. We first detected that KLF4 gene expression was upregulated in a human progastrin-overexpressing mouse model where goblet cell hyperplasia has been observed. We then found that mice treated with a -secretase inhibitor (compound E, 10 µmol/kg) for 24 h, which inhibits the Notch signaling pathway, had significantly increased KLF4 mRNA levels in small intestine and colon, accompanied by an increased number of KLF4-expressing cells at the bottom of crypts in small intestine and colon. In a colon cancer cell line (HCT116 cells), KLF4 promoter activity was inhibited by a constitutively active form of Notch1 (ICN1) by transient cotransfection assays. This inhibition was significantly compromised by a dominant-negative RBPjk, a repressive mediator of the Notch signaling pathway. An ICN1-responsive element was then mapped in the human KLF4 promoter between –151 and –122 nucleotides upstream of the transcriptional start site. It was also found that an intact ICN1-responsive element is required for ICN1 to inhibit KLF4 promoter activity by transient cotransfection assays. Our findings thus reveal a possible mechanism by which KLF4 is inhibited by Notch, which controls goblet cell differentiation in mouse gastrointestinal tract.

Kruppel-like factor-4; notch signaling; gene expression; goblet cells

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