title: Pb2+ induces gastrin gene expression by extracellular signal-regulated kinases 1/2 and transcription factor activator protein 1 in human gastric carcinoma cells.
abstract: Divalent lead ions (Pb(2+) ) are toxic environmental pollutants known to cause serious health problems in humans and animals. Absorption of Pb(2+) from air, water, and food takes place in the respiratory and digestive tracts. The ways in which absorbed Pb(2+) 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 Pb(2+) 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 Pb(2+) . MitogIen-activated protein kinase (MAPK)/ERK kinase inhibitor PD98059 suppressed the Pb(2+) -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 Pb(2+) 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 Pb(2+) on gastrin gene activity in cell culture.
authors.affiliation: Transplant Medicine and Surgery Research Centre, Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Chien-Pin
authors.initials: CP
authors.lastname: Chan
authors.forename: Yao-Ting
authors.initials: YT
authors.lastname: Tsai
authors.forename: Yao-Li
authors.initials: YL
authors.lastname: Chen
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Hsu
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Tseng
authors.forename: Hung-Yi
authors.initials: HY
authors.lastname: Chuang
authors.forename: Robert
authors.initials: R
authors.lastname: Shiurba
authors.forename: Mei-Hsien
authors.initials: MH
authors.lastname: Lee
authors.forename: Jaw-Yuan
authors.initials: JY
authors.lastname: Wang
authors.forename: Wei-Chiao
authors.initials: WC
authors.lastname: Chang
mesh_terms: D045744:Cell Line, Tumor; D063185:Epigenetic Repression / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005755:Gastrins / Q000096:biosynthesis* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007854:Lead / Q000633:toxicity*; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000187:drug effects*
chemical_list: D005755:Gastrins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D007854:Lead; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ERK; c-Jun; gastrin; lead (Pb2+)