title: Trefoil Factor 1 is involved in gastric cell copper homeostasis.
abstract: 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.
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Esposito
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Montefusco
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Ferro
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Monti
authors.affiliation: Department of Chemistry and Biology, University of Salerno, Fisciano, SA, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Baldantoni
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy. Electronic address: tosco@unisa.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tosco
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, SA, Italy.
authors.forename: Liberato
authors.initials: L
authors.lastname: Marzullo
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004220:Disulfides / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013054:Spectrophotometry, Atomic; D014158:Transcription, Genetic / Q000187:drug effects; D000071163:Trefoil Factor-1; D000071165:Trefoil Factor-3; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021601:trans-Golgi Network / Q000187:drug effects / Q000378:metabolism
chemical_list: D004220:Disulfides; D010455:Peptides; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; C051838:TFF1 protein, human; C082495:TFF3 protein, human; D000071163:Trefoil Factor-1; D000071165:Trefoil Factor-3; D025521:Tumor Suppressor Proteins; D003300:Copper; D003545:Cysteine
keywords: Copper; Sp1; TFF1; Trefoil factors