title: Identification of plasminogen activator inhibitor-2 as a gastrin-regulated gene: Role of Rho GTPase and menin.
abstract: OBJECTIVE
  The gastric hormone gastrin regulates acid secretion, gene expression, and the functional development and cellular composition of the gastric mucosa. Using a gene array, we sought to identify major, novel, gastrin-regulated genes.
  
  
  METHODS
  A cancer gene array was probed with samples from the gastric cancer cell line AGS, expressing the gastrin-cholecystokinin(B) receptor and stimulated with gastrin. The expression of gastrin-regulated genes was further characterized by Western blots and enzyme-linked immunosorbent assay in tissue and blood of hypergastrinemic patients. Gene expression was studied using promoter-luciferase reporter constructs.
  
  
  RESULTS
  Plasminogen activator inhibitor 2 (PAI-2) was identified as a major, previously unknown target of gastrin in the gastric cancer cell line AGS. The relevance was confirmed by showing elevated tissue and plasma PAI-2 in hypergastrinemic patients (pernicious anemia and multiple endocrine neoplasia type 1). PAI-2 promoter-luciferase constructs showed that gastrin stimulated expression via pathways involving Galpha and Gbetagamma subunits, protein kinase C, RhoA, and the transcription factors CREB and AP1. The tumor suppressor menin inhibited transcription. In addition, gastrin stimulated expression in adjacent cells via a paracrine mechanism involving protein kinase C and RhoA but not CREB.
  
  
  CONCLUSIONS
  A gene array showed PAI-2 to be a novel gastrin-regulated gene, stimulated in part through CREB and AP-1 and inhibited by the tumor suppressor menin.
authors.affiliation: Physiological Laboratory, University of Liverpool, Liverpool, England. avarro@liverpool.ac.uk
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
authors.forename: Elaine
authors.initials: E
authors.lastname: Hemers
authors.forename: Debbie
authors.initials: D
authors.lastname: Archer
authors.forename: Adelina
authors.initials: A
authors.lastname: Pagliocca
authors.forename: Chris
authors.initials: C
authors.lastname: Haigh
authors.forename: Suhail
authors.initials: S
authors.lastname: Ahmed
authors.forename: Rod
authors.initials: R
authors.lastname: Dimaline
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Dockray
mesh_terms: D000368:Aged; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D019899:Paracrine Communication; D017396:Plasminogen Activator Inhibitor 2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D014407:Tumor Cells, Cultured; D020741:rho GTP-Binding Proteins / Q000502:physiology*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D005755:Gastrins; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D017396:Plasminogen Activator Inhibitor 2; D011518:Proto-Oncogene Proteins; D018808:Transcription Factor AP-1; D008156:Luciferases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins