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Glycogen Synthase Kinase-3-beta Regulates Glucocorticoid Signaling by Phosphorylating the Glucocorticoid Receptor

ABSTRACT: Glucocorticoids (GCs) bind to the glucocorticoid receptor (GR) to regulate diverse biological functions from cell growth to apoptosis. Drugs that mimic their action are the most commonly prescribed therapeutic agents in the world and are currently used for the treatment of many diseases including asthma, autoimmune disorders, and some cancers. However, the mechanisms by which one hormone, via one receptor, modulates such diverse biological functions remain unclear. We hypothesized that epigenetic alteration to the GR may contribute to its signaling diversity, and here we demonstrate that Glycogen Synthase Kinase-3-beta phosphorylates GR on Serine 404 in a glucocorticoid-dependent manner. U-2 OS cells expressing a mutant GR that is incapable of Ser404 phosphorylation have enhanced global transcriptional responses, stronger NF-kappaB transrepression, and enhanced cell death in response to dexamethasone. Conversely, presence of Ser404 phosphorylation on the GR inhibits glucocorticoid-dependent NF-kappaB transrepression and cell death of these osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3-beta pathway with the GR resulting in altered glucocorticoid regulated signaling. Our results also provide a mechanism by which the phosphorylation status of Ser404 in GR can dictate how cells will ultimately respond to GCs. Keywords: Glucocorticoid Receptor; GSK-3-beta; NF-kappaB Transrepression; Phosphorylation Overall design: U-2 OS cells with stable WT- or S404A-GR expression were treated, in triplicate, with either vehicle or 100nM Dex for 6 hrs and cytoplasmic RNA was harvested (QIAGEN, Valencia, CA). Gene expression analysis was conducted using Agilent Whole Genome Genome 4x44 multiplex format oligo arrays (014850) (Agilent Technologies, Santa Clara, CA) following the Agilent 1-color microarray-based gene expression analysis protocol. Starting with 500ng of total RNA, Cy3 labeled cRNA was produced according to manufacturer’s protocol. For each sample, 1.65ug of Cy3 labeled cRNAs were fragmented and hybridized for 17 hours in a rotating hybridization oven. Slides were washed and then scanned with an Agilent Scanner. Data was obtained using the Agilent Feature Extraction software (v9.5), using the 1-color defaults for all parameters. The Agilent Feature Extraction Software performed error modeling, adjusting for additive and multiplicative noise.

INSTRUMENT(S): Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version)

SUBMITTER: NIEHS Microarray Core  

PROVIDER: GSE11205 | GEO | 2008-11-24



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Glycogen synthase kinase 3beta-mediated serine phosphorylation of the human glucocorticoid receptor redirects gene expression profiles.

Galliher-Beckley Amy Jo AJ   Williams Jason Grant JG   Collins Jennifer Brady JB   Cidlowski John Anthony JA  

Molecular and cellular biology 20081006 24

Aberrant glycogen synthase kinase 3beta (GSK-3beta) activity is associated with the progression of several pathological conditions such as diabetes, Alzheimer's, and cancer. GSK-3beta regulates cellular processes by directly phosphorylating metabolic enzymes and transcription factors. Here, we discovered a new target for GSK-3beta phosphorylation: the human glucocorticoid receptor (GR). Glucocorticoid signaling is essential for life and regulates diverse biological functions from cell growth to  ...[more]

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