Phosphatidylinositol 3-kinase and glycogen synthase kinase 3 regulate estrogen receptor-mediated transcription in neuronal cells.
In addition to 17beta-estradiol binding, estrogen receptor (ER) transcriptional activity could be controlled by intracellular kinase signaling pathways activated by growth factors. In this report we present evidence suggesting that glycogen synthase kinase 3 (GSK3), an effector kinase of the phosphatidylinositol 3-kinase ( PI3K) pathway, may affect ERalpha activity in N2a neuroblastoma cells. LiCl, sodium valproate, and SB415286, three inhibitors of GSK3, dose-dependently blocked ERalpha-mediated transcription. In contrast, overexpression of wild-type GSK3, but not of a mutant inactive form, increased ER-dependent gene expression. Pharmacological or genetic inhibition of the PI3K/Akt pathway, whose activity is inversely correlated with that of GSK3, increased ERalpha-mediated transcription, and this effect was blocked by GSK3 inhibitors. As in other cell types, IGF-I increased ERalpha activity in absence of estradiol by a mechanism independent of PI3K. In contrast, IGF-I decreased ERalpha activity in the presence of estradiol, and this effect was mediated by PI3K. We also observed a regulated interaction between beta-catenin, one of the main GSK3 nuclear targets, and ERalpha. Transfection with a nondegradable mutant of beta-catenin blocked the increase in ERalpha transcriptional activity induced by the PI3K inhibitor wortmannin, suggesting a role for beta-catenin in estrogen signaling. In addition, we investigated the regulation of ER protein levels as a potential mechanism for its regulation by the PI3K/GSK3 pathway; GSK3 blockade increased ERalpha protein stability, whereas PI3K inhibition decreased it. In summary, our findings suggest that ER-dependent gene expression in N2a cells is controlled by the PI3K/Akt/GSK3 signaling pathway.[1]References
- Phosphatidylinositol 3-kinase and glycogen synthase kinase 3 regulate estrogen receptor-mediated transcription in neuronal cells. Mendez, P., Garcia-Segura, L.M. Endocrinology (2006) [Pubmed]
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