Open AccessGlycogen Synthase Kinase-3β Is Involved in Ligand-Dependent Activation of Transcription and Cellular Localization of the Glucocorticoid Receptor
Author(s) -
Camila Rubio-Patiño,
Claudia Mariela Palmeri,
Alba Pérez-Perarnau,
Ana M. Cosialls,
Cristina Moncunill-Massaguer,
Diana M. González-Gironès,
Lluís Pons-Hernández,
José Manuel López,
Francesc Ventura,
Joan Gil,
Gabriel Pons,
Daniel Iglesias-Serret
Publication year - 2012
Publication title -
molecular endocrinology
Language(s) - English
Resource type - Journals
eISSN - 1944-9917
pISSN - 0888-8809
DOI - 10.1210/me.2011-1366
Subject(s) - transactivation , biology , gsk 3 , glucocorticoid receptor , chromatin immunoprecipitation , gene knockdown , small interfering rna , transcription factor , microbiology and biotechnology , gsk3b , rna polymerase ii , phosphorylation , gene expression , promoter , gene , biochemistry , rna
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.