Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1096/fj.09-139998

Type

Journal article

Journal

FASEB J

Publication Date

06/2010

Volume

24

Pages

1700 - 1713

Keywords

Adaptor Proteins, Signal Transducing, Blotting, Western, Bone Morphogenetic Protein Receptors, Type II, Cells, Cultured, Computational Biology, Fluorescent Antibody Technique, Glucocorticoids, Humans, Immunoblotting, Immunoenzyme Techniques, Immunoprecipitation, Lung Neoplasms, NF-kappa B, Nuclear Proteins, Phosphoproteins, Phosphorylation, Promoter Regions, Genetic, RGS Proteins, RNA, Messenger, Receptors, Glucocorticoid, Reverse Transcriptase Polymerase Chain Reaction, Transcriptional Activation