title: Signal transducer and activator of transcription 1 (STAT1) is essential for chromium silencing of gene induction in human airway epithelial cells.
abstract: Hexavalent chromium (Cr(VI)) promotes lung injury and pulmonary diseases through poorly defined mechanisms that may involve the silencing of inducible protective genes. The current study investigated the hypothesis that Cr(VI) actively signals through a signal transducer and activator of transcription 1 (STAT1)-dependent pathway to silence nickel (Ni)-induced expression of vascular endothelial cell growth factor A (VEGFA), an important mediator of lung injury and repair. In human bronchial airway epithelial (BEAS-2B) cells, Ni-induced VEGFA transcription by stimulating an extracellular regulated kinase (ERK) signaling cascade that involved Src kinase-activated Sp1 transactivation, as well as increased hypoxia-inducible factor-1 alpha (HIF-1 alpha) stabilization and DNA binding. Ni-stimulated ERK, Src, and HIF-1 alpha activities, as well as Ni-induced VEGFA transcript levels were inhibited in Cr(VI)-exposed cells. We previously demonstrated that Cr(VI) stimulates STAT1 to suppress VEGFA expression. In BEAS-2B cells stably expressing STAT1 short hairpin RNA, Cr(VI) increased VEGFA transcript levels and Sp1 transactivation. Moreover, in the absence of STAT1, Cr(VI), and Ni coexposures positively interacted to further increase VEGFA transcripts. This study demonstrates that metal-stimulated signaling cascades interact to regulate transcription and induction of adaptive or repair responses in airway cells. In addition, the data implicate STAT1 as a rate limiting mediator of Cr(VI)-stimulated gene regulation and suggest that cells lacking STAT1, such as many tumor cell lines, have opposite responses to Cr(VI) relative to normal cells.
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
authors.forename: Antonia A
authors.initials: AA
authors.lastname: Nemec
authors.forename: Aaron
authors.initials: A
authors.lastname: Barchowsky
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D002857:Chromium / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D020868:Gene Silencing / Q000187:drug effects*; D016391:Genes, src / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008670:Metals / Q000633:toxicity; D009532:Nickel / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008670:Metals; D011084:Polycyclic Aromatic Hydrocarbons; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D042461:Vascular Endothelial Growth Factor A; D002857:Chromium; D012313:RNA; D009532:Nickel; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases