Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2005) 10 P88

SFE2005 Poster Presentations Steroids to include Cushing's (15 abstracts)

Non-genomic effects of the glucocorticoid receptor - the effect of glucocorticoids on activation of c-src and PKB/Akt

M Kayahara , AA Berry & DW Ray


University of Manchester, Manchester, United Kingdom.


Glucocorticoids (Gc) are potent anti-inflammatory agents, but their clinical use is limited by their significant side effects. The effects of glucocorticoids are mediated by the cytosolic glucocorticoid receptor (GR), which regulates transcription by transactivation or transrepression. Independent of these genomic effects of the GR are other, very rapid non-genomic effects.

The glucocorticoid receptor forms a complex with hsp90, FKBP51, FKBP52 and cyp40 in its inactive form. Hsp90 also forms a complex with other protein kinases such c-src, lck, lyn and raf-1. Evidence suggests that on activation by glucocorticoids, both GR and c-src dissociate from hsp90.

In the current investigation we have studied the effect of dexamethasone on downstream protein targets of GR in A549 cells.

Kinase assays and immunoblots using anti-phospho c-src antibodies have shown that on treatment with 100 nM dexamethasone, c-src was activated within 5 minutes. Dexamethasone also activated PKB/Akt, a downstream target of the PI3K pathway. Phosphorylation of PKB/Akt was seen within 2 minutes of dexamethasone treatment. This effect was abolished when cells were pretreated with PI3K inhibitor LY294002, or with RU486.

Phosphorylation of GR was also observed by immunoblotting using the anti-phospho-GR antibody. Preincubation with GR antagonist RU486 reduced the phosphorylation of GR, but preincubation with c-src inhibitors PP2 and SU6656 did not. This indicates that both c-src and PI3K are potential mediators of the effect of glucocorticoid as they are both activated in response to dexamethasone.

We are currently investigating the effect of knocking down c-src by using siRNA on GR target genes.

Volume 10

196th Meeting of the Society for Endocrinology and Society for Endocrinology joint Endocrinology and Diabetes Day

Society for Endocrinology 

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