Esposito Roberta, Montefusco Sandro, Ferro Piera, Monti Maria Chiara, Baldantoni Daniela, Tosco Alessandra, Marzullo Liberato
Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
Int J Biochem Cell Biol. 2015 Feb;59:30-40. doi: 10.1016/j.biocel.2014.11.014. Epub 2014 Dec 5.
Trefoil Factor 1 belongs to a group of small secreted proteins (the Trefoil Factor Family proteins), that are localized within the mucous granules and are expressed and secreted by epithelial cells that line mucous membranes. Trefoil factors are mainly expressed in the gastrointestinal tract, where they normally contribute to maintain the integrity of the mucosa. We recently demonstrated a selective binding ability of Trefoil Factor 1 for copper ions, through its carboxy-terminal tail, and we also observed that copper levels 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.
三叶因子1属于一组小分泌蛋白（三叶因子家族蛋白），它们定位于黏液颗粒内，由黏膜内衬的上皮细胞表达和分泌。三叶因子主要在胃肠道表达，在那里它们通常有助于维持黏膜的完整性。我们最近证明了三叶因子1通过其羧基末端尾巴对铜离子具有选择性结合能力，并且我们还观察到铜水平会影响三叶因子1单体和同源二聚体形式之间的平衡，从而调节其生物活性。在此我们报告，通过铜感应转录因子Sp1与该基因调控区域中存在的反应元件的结合受到调节，三叶因子1的转录调控也受铜水平影响。此外，我们证明铜过载会导致三叶因子蛋白在反式高尔基体网络中积累，并且三叶因子1的水平会影响铜的排泄和与铜相关的毒性。这些发现表明该蛋白可能在胃肠道组织中铜稳态的整体复杂机制中发挥作用。
