Roles of 14-3-3β and γ in regulation of the glucocorticoid receptor transcriptional activation and hepatic gluconeogenesis

The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that mediates the effects of glucocorticoids, and plays a crucial role in cell growth, development, inflammation, and gluconeogenesis. The 14-3-3 proteins bind to target proteins via phosphorylation, and influence many cellular events by altering their subcellular localization or by acting as chaperones. However, the mechanisms by which 14-3-3 proteins regulate GR transactivation and their involvement in gluconeogenesis remain uncharacterized. We found that 14-3-3β and γ increased GR transcriptional activity and the promoter activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase in the presence of glucocorticoids. Inhibition of the endogenous 14-3-3β and γ decreased dexamethasone- and cAMP-stimulated PEPCK expression. Further, both 14-3-3β and γ increased glucose production in response to glucocorticoids. Our findings suggest that 14-3-3β and γ function as positive regulators of GR transactivation and glucocorticoid-mediated hepatic gluconeogenesis.