Back
Acta Physiologica 2009; Volume 195, Supplement 669
The 88th Annual Meeting of The German Physiological Society
3/22/2009-3/25/2009
Giessen, Germany
THE ROLE OF SGK1 IN THE GLUCOCORTICOID-INDUCED ACTIVATION OF THE -ENACGENE PROMOTER
Abstract number: O97
Wilson1 S., McTavish1 N., Getty1 J., Burchell1 A.
1Ninewells Hospital and Medical School, Centre for Cardiovascular and pulmonary Research, Dundee, United Kingdom (Dundee, UK);
The role of serum and glucocorticoid-inducible kinase 1 (SGK1) in the glucocorticoid-induced activation of the a-ENaC gene promoter was explored by monitoring the activity of a luciferase-linked reporter construct (pGL3-KR1) transiently expressed in H441 airway epithelial cells. Dexamethasone, a synthetic glucocorticoid, caused concentration-dependent (EC50~3 mM) activation via a mechanism dependent upon a glucocorticoid response element in the a-ENac gene promoter, and also activated endogenous SGK1. However, artificially increasing cellular SGK1 activity by transiently expressing a constitutively active SGK1 mutant (SGK1-S422D) in hormone-deprived cells did not affect pGL3-KR1 activity, whilst a catalytically inactive SGK1 mutant (SGK1-K127A) suppressed the hormonal activation of endogenous SGK1 without affecting the control of pGL3-KR1. Increasing cellular PI3K activity by expressing a membrane-anchored form of the catalytic P110a subunit also activated endogenous SGK1 in hormone-deprived cells but had no effect upon pGL3-KR1, whilst a catalytically inactive form of this subunit (R1130P) suppressed the dexamethasone-induced activation of SGK1 without affecting the control of pGL3-KR1. Despite these clear findings, SGK1-S422D and P110a both enhanced the transcriptional responses to maximally effective concentrations of dexamethasone. These effects occurred with no change in EC50. Dexamethasone-induced (0.3 300 nM) activation of the a-ENaC gene promoter was also unaffected by inhibitors of PI3K (PI-103 and wortmanin) and by rapamycin, a selective inhibitor of the TORC1 signalling complex. Dexamethasone-induced activation of the a-ENaC gene promoter can thus occur independently of SGK1 / PI3K cells although this pathway does provide a mechanism that allows the transcriptional response to dexamethasone to be enhanced.
To cite this abstract, please use the following information:
Acta Physiologica 2009; Volume 195, Supplement 669 :O97