Keratinocyte growth factor promotes goblet cell differentiation through regulation of goblet cell silencer inhibitor.
OBJECTIVE
Keratinocyte growth factor (KGF) is an epithelial cell-specific growth factor. Previous reports demonstrated that KGF induces differentiation of epithelial cells of gastrointestinal tract in vivo, especially goblet cell-specific lineage stimulation. Intestinal trefoil factor (ITF) is selectively expressed in intestinal goblet cells and its expression correlates with intestinal goblet cell differentiation. In this study, we analyzed the mechanism of KGF modulation of goblet cell differentiation through characterization of its effects on ITF gene expression.


METHODS
Subclone H2 of the human colonic epithelial cell line HT-29, which can be induced to intestinal goblet cells, was treated with KGF and characterized by Northern and Western blot analyses, transient transfection assays, and electrophoretic mobility shift assays (EMSAs).


RESULTS
KGF promoted differentiation of H2 cells to goblet cells as reflected by induced ITF expression. Transient transfection assays revealed that KGF regulates mouse ITF transcription through the goblet cell silencer inhibitor (GCSI) element, which is essential for goblet cell-specific expression of ITF. EMSAs showed that KGF induces GCSI binding protein (GCSI-BP).


CONCLUSIONS
KGF promotes goblet cell differentiation through the induction of GCSI-BP, a goblet cell-specific transcription factor. GCSI-BP may play a central role in intestinal goblet cell differentiation.
Iwakiri
D
D
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Podolsky
D K
DK
D002454:Cell Differentiation / Q000187:drug effects; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D020868:Gene Silencing; D020397:Goblet Cells / Q000166:cytology / Q000187:drug effects*; D006133:Growth Substances / Q000235:genetics*; D019073:HT29 Cells; D006801:Humans; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3
C496453:FGF7 protein, human; D006133:Growth Substances; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; C099037:TFF3 protein, rat; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor