Glycogen synthase kinase-3β is involved in ligand-dependent activation of transcription and cellular localization of the glucocorticoid receptor

Camila Rubio-Patiño, Claudia M. Palmeri, Alba Pérez-Perarnau, Ana M. Cosialls, Cristina Moncunill-Massaguer, Diana M. González-Gironès, Lluís Pons-Hernández, José M. López, Francesc Ventura, Joan Gil, Gabriel Pons, Daniel Iglesias-Serret

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16 Citations (Scopus)

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. © 2012 by The Endocrine Society.
Original languageEnglish
Pages (from-to)1508-1520
JournalMolecular Endocrinology
Volume26
Issue number9
DOIs
Publication statusPublished - 1 Sep 2012

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    Rubio-Patiño, C., Palmeri, C. M., Pérez-Perarnau, A., Cosialls, A. M., Moncunill-Massaguer, C., González-Gironès, D. M., Pons-Hernández, L., López, J. M., Ventura, F., Gil, J., Pons, G., & Iglesias-Serret, D. (2012). Glycogen synthase kinase-3β is involved in ligand-dependent activation of transcription and cellular localization of the glucocorticoid receptor. Molecular Endocrinology, 26(9), 1508-1520. https://doi.org/10.1210/me.2011-1366