BACKGROUND: Overexpression of trefoil factor 2 (SP/TFF2) is associated with increased cell migration, resistance to apoptosis, and possibly increased gastric cancer invasion. Dysregulation of p53 is frequently observed in preneoplastic conditions of the stomach. Here, we investigated the effect of p53 on the expression and function of TFF2 in gastric cancer cell lines. METHODS: Gene expression was determined by reverse transcription-polymerase chain reaction, and promoter activity was assessed using dual luciferase reporter assays. Binding of nuclear factors to the TFF2 promoter was evaluated by gel shift and chromatin immunoprecipitation assays. Apoptosis was detected by flow cytometry, and cell migration was evaluated using the Boyden Chamber assay. RESULTS: Exogenous expression of p53 dose-dependently inhibited endogenous TFF2 mRNA and promoter activity, and resulted in induction of cell apoptosis and inhibition of cell migration. Downregulation of TFF2 by siRNA sensitized gastric cancer cells to drug-induced p53-dependent apoptosis. Addition of human TFF2 peptide reversed p53-dependent apoptosis and inhibition of cell migration. The p53-responsive element was mapped to an AP-1-like cis-element at -182bp upstream of the TFF2 transcription start site. Mutation of this AP-1-like element abrogated p53-mediated inhibition of TFF2 promoter activity. Gel shift and chromatin immunoprecipitation assays demonstrated that c-Jun and c-Fos bind to this AP-1-like element. Ectopic expression of c-Jun/c-Fos or treatment of cells with phorbol 12-myristate 13-acetate (PMA) stimulated endogenous TFF2 mRNA expression and promoter activity, and p53 inhibited the effects of AP-1 and PMA on TFF2. CONCLUSION: p53 induces cell apoptosis and inhibits cell migration in part by downregulating TFF2 expression through an AP-1-like site, suggesting that TFF2 may be an important downstream target of p53.