Transcriptional repression of TFF1 in gastric epithelial cells by CCAAT/enhancer binding protein-β

TFFl is a member of a unique family of gastrointestinal peptides. Loss of TFFl expression has been observed in the majority of human gastric cancers and the biological significance of this loss has been demonstrated in a Tffl knockout mouse model. However, few TFFl gene mutations or allelic loss have also been documented. To understand the molecular mechanism repressing the TFFl gene expression, the 5 ' flanking region of the human TFFl gene was characterized. We found a repressor region (-241 to -84), which is active in MKN45 and IMGE5 cells expressing endogenous TFFl gene. A consensus binding site for C/EBP was identified and EMSA analysis demonstrated specific binding of CEBP beta. Mutation of this C/EBP beta element potentiated the transactivation of TFFl by 50% and 145% for MKN45 and lMGE5 cells respectively. Furthermore, co-transfection of C/EBP beta isoforms specifically decreased TFFl promoter activity. These findings suggest that C/EBP beta is involved in the down-regulating of TIFF I gene expression and this mode of repression may account at least in part for the loss of TFFl gene expression in transformed human and mice gastric epithelial cells. (c) 2005 Published by Elsevier B.V.