Cushings tumours are ACTH-producing neoplasms of the pituitary gland. Their ACTH-oversecretion is autonomous and does not respond to the canonical inhibition of the hence also elevated cortisol. Current research in identifying new drug targets is mainly focused on designing therapeuticals that directly inhibit ACTH over-secretion from the adenoma. Serum and glucocorticoid-induced kinase 1 (Sgk1) is an early target gene of glucocorticoids in all cells studied. It is a PKB/Akt-like kinase that acts downstream of the phosphoinositol-3-kinase (PI3K) signal transduction pathway. PI3K is related to increased cell proliferation and hormone secretion in corticotrophs, and a target of recent drugs that reduce ACTH oversecretion.
We present here that Sgk1 is expressed in pituitary corticotrophs and localised in the perinuclear cytosol, as demonstrated by immunohistochemistry. Quantitative RT-PCR reveals that stimulation of the murine corticotroph tumour cell line AtT-20 with dexamethasone induces a rapid increase of Sgk1 transcription, accompanied by a reduction of the transcription of pro-opiomelanocortin (POMC). In parallel, dexamethasone induces a translocation of Sgk1 to the nucleus, as shown by Western blotting. Transient over-expression of Sgk1 in AtT-20 cells is associated with reduced POMC transcription. Moreover, siRNA-mediated down-regulation of Sgk1 causes an increase in POMC mRNA levels.
In summary, Sgk1 is a downstream target of dexamethasone in corticotroph cells. It controls basal and stimulated POMC expression and is a potential drug target for the treatment of Cushings disease. Ongoing investigations are aiming to fully characterise the role of Sgk1 in corticotroph cells.
03 - 07 May 2008
European Society of Endocrinology