Opposite effects of serum- and glucocorticoid-regulated kinase-1 and glucocorticoids on POMC transcription and ACTH release

Am J Physiol Endocrinol Metab. 2011 Aug;301(2):E336-41. doi: 10.1152/ajpendo.00155.2011. Epub 2011 May 17.

Abstract

Serum- and glucocorticoid-regulated kinase-1 (SGK1) is a glucocorticoid early-response gene; its function, however, has been elucidated mainly in the context of mineralocorticoid signaling. Here, we investigate the expression and function of SGK1 in the pituitary gland, one of the primary glucocorticoid targets. SGK1 is expressed in the human pituitary gland and colocalizes to ACTH. The AtT-20 murine corticotroph cell line was used for functional experiments. Glucocorticoids upregulated SGK1 mRNA and protein levels, parallel to decreasing proopiomelanocortin (POMC) transcription and ACTH release. Dexamethasone-induced changes in SGK1 protein were abolished by the steroid receptor antagonist RU-486 and reduced by the inhibition of PI 3-kinase with LY-294002. SGK1 overexpression increased CREB- and activator protein-1-dependent transcription, POMC transcription, and ACTH secretion but did not influence intracellular cAMP levels. SGK1 overexpression and corticotropin-releasing hormone had additive effects on POMC promoter activity but not on ACTH secretion. SGK1 knockdown by RNA interference decreased POMC promoter activity, demonstrating the importance of SGK1 for basal POMC signaling. In summary, SGK1 is strongly stimulated by glucocorticoids in pituitary corticotrophs; however, its effects on POMC transcription are antagonistic to the classical inhibitory glucocorticoid action, suggesting a cell-regulated counterregulatory mechanism to potentially detrimental glucocorticoid effects.

MeSH terms

  • Adrenocorticotropic Hormone / metabolism*
  • Animals
  • CREB-Binding Protein / metabolism
  • Cell Line, Tumor
  • Corticotropin-Releasing Hormone / pharmacology
  • Cyclic AMP / metabolism
  • Dexamethasone / pharmacology
  • Drug Synergism
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Glucocorticoids / pharmacology
  • Immediate-Early Proteins / genetics*
  • Immediate-Early Proteins / metabolism*
  • Mice
  • Pituitary Gland / cytology
  • Pituitary Gland / physiology
  • Pro-Opiomelanocortin / genetics*
  • Pro-Opiomelanocortin / metabolism*
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Glucocorticoid / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Transcription Factor AP-1 / metabolism

Substances

  • Glucocorticoids
  • Immediate-Early Proteins
  • Receptors, Glucocorticoid
  • Transcription Factor AP-1
  • Pro-Opiomelanocortin
  • Dexamethasone
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Cyclic AMP
  • CREB-Binding Protein
  • Crebbp protein, mouse
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase