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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




Journal article



Publication Date





1700 - 1713


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