Pb²⁺ induces gastrin gene expression by extracellular signal-regulated kinases 1/2 and transcription factor activator protein 1 in human gastric carcinoma cells

Divalent lead ions (Pb²⁺) are toxic environmental pollutants known to cause serious health problems in humans and animals. Absorption of Pb²⁺ from air, water, and food takes place in the respiratory and digestive tracts. The ways in which absorbed Pb²⁺ affects cell physiology are just beginning to be understood at the molecular level. Here, we used reverse transcription PCR and Western blotting to analyze cultures of human gastric carcinoma cells exposed to 10 μM lead nitrate. We found that Pb²⁺ induces gastrin hormone gene transcription and translation in a time-dependent manner. Promoter deletion analysis revealed that activator protein 1 (AP1) was necessary for gastrin gene transcription in cells exposed to Pb²⁺. MitogIen-activated protein kinase (MAPK)/ERK kinase inhibitor PD98059 suppressed the Pb²⁺-induced increase in messenger RNA. Epidermal growth factor receptor (EGFR) inhibitors AG1478 and PD153035 reduced both transcription and phosphorylation by extracellular signal-regulated kinase (ERK1/2). Cells exposed to Pb²⁺ also increased production of c-Jun protein, a component of AP1, and over-expression of c-Jun enhanced activation of the gastrin promoter. In sum, the findings suggest the EGFR-ERK1/2-AP1 pathway mediates the effects of Pb²⁺ on gastrin gene activity in cell culture.