title: Glycogen synthase kinase-3β is involved in ligand-dependent activation of transcription and cellular localization of the glucocorticoid receptor.
abstract: Glucocorticoids (GC) induce cell cycle arrest and apoptosis in different cell types and therefore are widely used to treat a variety of diseases including autoimmune disorders and cancer. This effect is mediated by the GC receptor (GR), a ligand-activated transcription factor that translocates into the nucleus where it modulates transcription of target genes in a promoter-specific manner. Glycogen synthase kinase-3 (GSK3) regulates GR response by genomic and nongenomic mechanisms, although the specific role of each isoform is not well defined. We used GSK3 pharmacological inhibitors and isoform-specific small interfering RNA to evaluate the role of GSK3 in the genomic regulation induced by GC. GSK3 inhibition resulted in the reduction of GC-induced mRNA expression of GC-induced genes such as BIM, HIAP1, and GILZ. Knockdown of GSK3β but not GSK3α reduced endogenous GILZ induction in response to dexamethasone and GR-dependent reporter gene activity. Chromatin immunoprecipitation experiments revealed that GSK3 inhibition impaired the dexamethasone-mediated binding of GR and RNA polymerase II to endogenous GILZ promoter. These results indicate that GSK3β is important for GR transactivation activity and that GSK3β inhibition suppresses GC-stimulated gene expression. Furthermore, we show that genomic regulation by the GR is independent of known GSK3β phosphorylation sites. We propose that GC-dependent transcriptional activation requires functional GSK3β signaling and that altered GSK3β activity influences cell response to GC.
authors: Departament de Ciències Fisiològiques II, Institut d'Investigació Biomèdica de Bellvitge, Universitat de Barcelona, Barcelona, Spain.
authors: Camila
authors: C
authors: Rubio-Patiño
authors: Claudia M
authors: CM
authors: Palmeri
authors: Alba
authors: A
authors: Pérez-Perarnau
authors: Ana M
authors: AM
authors: Cosialls
authors: Cristina
authors: C
authors: Moncunill-Massaguer
authors: Diana M
authors: DM
authors: González-Gironès
authors: Lluís
authors: L
authors: Pons-Hernández
authors: José M
authors: JM
authors: López
authors: Francesc
authors: F
authors: Ventura
authors: Joan
authors: J
authors: Gil
authors: Gabriel
authors: G
authors: Pons
authors: Daniel
authors: D
authors: Iglesias-Serret
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D018613:Microscopy, Confocal; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011965:Receptors, Glucocorticoid; C417521:SB 216763; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3