TY - JOUR
T1 - Glycogen synthase kinase-3β is involved in ligand-dependent activation of transcription and cellular localization of the glucocorticoid receptor
AU - Rubio-Patiño, Camila
AU - Palmeri, Claudia M.
AU - Pérez-Perarnau, Alba
AU - Cosialls, Ana M.
AU - Moncunill-Massaguer, Cristina
AU - González-Gironès, Diana M.
AU - Pons-Hernández, Lluís
AU - López, José M.
AU - Ventura, Francesc
AU - Gil, Joan
AU - Pons, Gabriel
AU - Iglesias-Serret, Daniel
PY - 2012/9/1
Y1 - 2012/9/1
N2 - 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.
AB - 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.
U2 - 10.1210/me.2011-1366
DO - 10.1210/me.2011-1366
M3 - Article
SN - 0888-8809
VL - 26
SP - 1508
EP - 1520
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 9
ER -