title: Oncostatin M induced alpha1-antitrypsin (AAT) gene expression in Hep G2 cells is mediated by a 3' enhancer.
abstract: alpha(1)-Antitrypsin (AAT) is the major serine proteinase inhibitor (SERPIN A1) in human plasma. Its target proteinase is neutrophil elastase and its main physiological function is protection of the lower respiratory tract from the destructive effects of neutrophil elastase during an inflammatory response. Circulating levels of AAT rise 2-3-fold during inflammation and the liver produces most of this increase. The cytokines oncostatin M (OSM) and interleukin-6 have been shown to be mainly responsible for this effect, which is mediated via the interaction of cytokine-inducible transcription factors with regulatory elements within the gene. In the present study, we report for the first time that OSM stimulation of hepatocyte AAT occurs via an interaction between the hepatocyte promoter and an OSM-responsive element at the 3'-end of the AAT gene. This effect is mediated by the transcription factor signal transducer and activator of transcription 3 ('STAT 3') binding to an OSM-responsive element (sequence TTCTCTTAA), and this site is distinct from, but close to, a previously reported interleukin-6-responsive element.
authors.affiliation: Division of Clinical Chemistry, School of Clinical Laboratory Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.forename: Peter
authors.initials: P
authors.lastname: Marsters
authors.forename: Stephen
authors.initials: S
authors.lastname: Morley
authors.forename: Diana
authors.initials: D
authors.lastname: van Gent
authors.forename: Ala
authors.initials: A
authors.lastname: Hejazi
authors.forename: Matt
authors.initials: M
authors.lastname: Backx
authors.forename: Emma R K
authors.initials: ER
authors.lastname: Thorpe
authors.forename: Noor
authors.initials: N
authors.lastname: Kalsheker
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D004247:DNA; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005091:Exons; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D053683:Oncostatin M; D010455:Peptides / Q000502:physiology*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D015850:Interleukin-6; C508351:OSM protein, human; D010455:Peptides; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D000515:alpha 1-Antitrypsin; D053683:Oncostatin M; D004247:DNA