Trefoil Factor 1 is involved in gastric cell copper homeostasis

Trefoil Factor 1 belongs to a group of small secreted proteins (the Trefoil Factor Family proteins), that arelocalized within the mucous granules and are expressed and secreted by epithelial cells that line mucousmembranes. Trefoil factors are mainly expressed in the gastrointestinal tract, where they normally con-tribute to maintain the integrity of the mucosa. We recently demonstrated a selective binding abilityof Trefoil Factor 1 for copper ions, through its carboxy-terminal tail, and we also observed that copperlevels influence the equilibrium between the monomeric and homodimeric forms of Trefoil Factor 1, thus modulating its biological activity. Here we report that transcriptional regulation of Trefoil Factor 1 is also affected by copper levels, through the modulated binding of the copper-sensing transcription factor Sp1 onto the responsive elements present in the regulatory region of the gene. In addition we demonstrate that copper overload causes an accumulation of the trefoil protein in the Trans-Golgi Network and that Trefoil Factor 1 levels can influence copper excretion and copper related toxicity. These findings suggest that the protein might play a role in the overall complex mechanisms of copper homeostasis in the gastrointestinal tissues.