Gastrin transcriptionally regulates trefoil family factor 2

The trefoil family factor 2, also know as spasmolytic peptide containing a dual-trefoil domain, is secreted by mucous neck cells of stomach and proposed to be the principal cytoprotective tretbil peptide. ]'he antral hormone gastrin was known tot its acid stimulating properties and inducing proliferation of the acid secreting mucosa. The recent TFF2-deficient mice demonstrating a decreased thickness and proliferation rate of the gastric mucosa prompt us investigating whether gastrin is a mediator of TFF2. In gastrin-deficient mice, TFF2 is lound to he siguificant decreased expression in fundus of the stomach, as determined by immunohistochemistry with an antibody specifically recognizing the whole mouse TFF2 protein. Furthermore, TFF2 mRNA expression was rapidly and potently" induced by gastrin in AGS ceils that are stablely introduced the gastrin/CCKB receptor. A series of deletion mutants containing mouse promoter sequence are constructed in a dual-luciferase reporter to map gastrin t~spons~ve elements. Cells co-transfected with prompter constructs and internal control, treated with 10-7M of gastrin for 18 h are subsequently measured the ludterase activities. The results indicate that gastrin-treated cells show much higher hiciferase acti~aty while had little effect on the reporter vector itself. P-46 and P-306, containing 46bp and 306bp of upstream sequence of the transcriptional start site, respectively, have a 38 and 59 fold increase in luciferase activity' over those non-treated AGS cells. The increases in lucilerase activity are largely abolished when 10-6 M of YF476, a chemical antagonist of gastrin/CCKg receptor were added with gastrin, suggesting that increase of TFF2 promoter activity is gastrin-specific mediation through its receptor. These results indicate that multiple gastrin responsive elements are located within these regions. In conclusion, our data suggest that gasmn is manscriptionally regulating TFF2 thus may play an important role in mediating the physiological function of trefoil family factors.