Serum and glucocorticoid-regulated kinase 1 (Sgk1) is a glucocorticoid early response gene; its function however has mainly been elucidated in the context of mineralocorticoid signaling.
Here we investigated the expression and function of Sgk1 in the pituitary gland, which is one of the primary glucocorticoid targets. We found that Sgk1 is highly expressed in the human pituitary gland and co-localises to ACTH. In the AtT-20 murine corticotroph cell line, glucocorticoids up-regulated Sgk1 mRNA and protein levels, whilst decreasing POMC transcription and ACTH release. The dexamethasone-induced increase in Sgk1 protein was abolished by the steroid receptor antagonist RU 486 and reduced by the PI3K inhibitor LY-294002.
Sgk1 overexpression increased CREB- and AP-1-dependent transcription, POMC transcription and ACTH secretion, but did not influence intracellular cAMP levels, suggesting a regulation of POMC transcription and ACTH release by Sgk1 via the PKA and MAPK pathways. Sgk1 overexpression and CRH had additive effects on POMC promoter activity, but not on ACTH secretion. Sgk1 knockdown by siRNA decreased POMC promoter activity, demonstrating the significance of Sgk1-dependent signalling for basal POMC expression.
In summary, Sgk1 is strongly stimulated by glucocorticoids in pituitary corticotrophs; however it enhances AP-1 and CRE activity downstream of PKA, thereby increasing POMC transcription under basal conditions as well as ACTH secretion following glucocorticoid stimulation. These data represent the first direct evidence that Sgk1 effects are antagonistic to the classical glucocorticoid properties. We suggest that Sgk1 integrates different pathways such as the glucocorticoid pathway, the PI3K pathway and the downstream part of the PKA pathway, and acts as a cell-regulated counter regulatory mechanism aiming to weaken the potentially detrimental glucocorticoid effects. The therapeutical targeting of the Sgk1 pathway might open new possibilities for the treatment of Cushing's disease.