title: Interferon-inducible factor 16 is a novel modulator of glucocorticoid action.
abstract: Previously, we used cDNA expression profiling to identify genes associated with glucocorticoid (Gc) sensitivity. We now identify which of these directly influence Gc action. Interferon-inducible protein 16 (IFI16), bone morphogenetic protein receptor type II (BMPRII), and regulator of G-protein signaling 14 (RGS14) increased Gc transactivation, whereas sialyltransferase 4B (SIAT4B) had a negative effect. Amyloid beta (A4) precursor-protein binding, family B, member 1 (APBB1/Fe65) and neural cell expressed developmentally down-regulated 9 (NEDD9) were without effect. Only IFI16 potentiated Gc repression of NF-kappaB. In addition, IFI16 affected basal expression, and Gc induction of endogenous target genes. IFI16 did not affect glucocorticoid receptor (GR) expression, ligand-dependent repression of GR expression, or the ligand-dependent induction of GR phosphorylation on Ser-211 or Ser-203. Coimmunoprecipitation revealed an interaction, suggesting that IFI16 modulation of GR function is mediated by protein crosstalk. Transfection analysis with GR mutants showed that the ligand-binding domain of GR binds IFI16 and is the target domain for IFI16 regulation. Analysis of human lung sections identified colocalization of GR and IFI16, suggesting a physiologically relevant interaction. We demonstrate that IFI16 is a novel modulator of GR function and show the importance of analyzing variation in Gc sensitivity in humans, using appropriate technology, to drive discovery.
authors.affiliation: Arthritis Research Campaign Epidemiology Unit, University of Manchester, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Berry
authors.forename: L
authors.initials: L
authors.lastname: Matthews
authors.forename: M
authors.initials: M
authors.lastname: Jangani
authors.forename: J
authors.initials: J
authors.lastname: Plumb
authors.forename: S
authors.initials: S
authors.lastname: Farrow
authors.forename: N
authors.initials: N
authors.lastname: Buchan
authors.forename: P A
authors.initials: PA
authors.lastname: Wilson
authors.forename: D
authors.initials: D
authors.lastname: Singh
authors.forename: D W
authors.initials: DW
authors.lastname: Ray
authors.forename: R P
authors.initials: RP
authors.lastname: Donn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019295:Computational Biology; D005455:Fluorescent Antibody Technique; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005938:Glucocorticoids; C099942:NEDD9 protein, human; D016328:NF-kappa B; D009687:Nuclear Proteins; D010750:Phosphoproteins; D020710:RGS Proteins; C491400:RGS14 protein, human; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C076700:IFI16 protein, human; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II