Zinc ions upregulate the hormone gastrin via an E-box motif in the proximal gastrin promoter

Abstract

Gastrin and its precursors act as growth factors for the normal and neoplastic gastrointestinal mucosa. As the hypoxia mimetic cobalt chloride upregulates the gastrin gene, the effect of other metal ions on gastrin promoter activity was investigated. Gastrin mRNA was measured by real-time PCR, gastrin peptides by RIA, and gastrin promoter activity by dual-luciferase reporter assay. Exposure to Zn2+ions increased gastrin mRNA concentrations in the human gastric adenocarcinoma cell line AGS in a dose-dependent manner, with a maximum stimulation of 55±14-fold at 100 μM (P<0.05). Significant stimulation was also observed with Cd2+and Cu2+, but not with Ca2+, Mg2+, Ni2+, or Fe3+ions. Activation of MAPK and phosphatidylinositol 3-kinase pathways is necessary but not sufficient for gastrin induction by Zn2+. Deletional mutation of the gastrin promoter identified an 11 bp DNA sequence, which contained an E-box motif, as necessary for Zn2+-dependent gastrin induction. The fact that E-box binding transcription factors play a crucial role in the epithelial–mesenchymal transition (EMT), together with our observation that Zn2+ions upregulate the gastrin gene in AGS cells by an E-box-dependent mechanism, suggests that Zn2+ions may induce an EMT, and that gastrin may be involved in the transition.