This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mendez, P. Articles by Garcia-Segura, L. M. Search for Related Content PubMed PubMed Citation Articles by Mendez, P. Articles by Garcia-Segura, L. M. Pubmed/NCBI databases Substance via MeSH

Phosphatidylinositol 3-Kinase and Glycogen Synthase Kinase 3 Regulate Estrogen Receptor-Mediated Transcription in Neuronal Cells

Instituto Cajal, Consejo Superior de Investigaciones Cientificas, E-28002 Madrid, Spain

Address all correspondence and requests for reprints to: Dr. L. M. Garcia-Segura, Instituto Cajal, Avenida Doctor Arce 37, E-28002 Madrid, Spain. E-mail: lmgs{at}cajal.csic.es.

In addition to 17ß-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 ER activity in N2a neuroblastoma cells. LiCl, sodium valproate, and SB415286, three inhibitors of GSK3, dose-dependently blocked ER-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 ER-mediated transcription, and this effect was blocked by GSK3 inhibitors. As in other cell types, IGF-I increased ER activity in absence of estradiol by a mechanism independent of PI3K. In contrast, IGF-I decreased ER activity in the presence of estradiol, and this effect was mediated by PI3K. We also observed a regulated interaction between ß-catenin, one of the main GSK3 nuclear targets, and ER. Transfection with a nondegradable mutant of ß-catenin blocked the increase in ER transcriptional activity induced by the PI3K inhibitor wortmannin, suggesting a role for ß-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 ER 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.

This article has been cited by other articles:

				T. A. Roepke, C. Xue, M. A. Bosch, T. S. Scanlan, M. J. Kelly, and O. K. Ronnekleiv Genes Associated with Membrane-Initiated Signaling of Estrogen and Energy Homeostasis Endocrinology, December 1, 2008; 149(12): 6113 - 6124. [Abstract] [Full Text] [PDF]

				J. Grisouard, S. Medunjanin, A. Hermani, A. Shukla, and D. Mayer Glycogen Synthase Kinase-3 Protects Estrogen Receptor {alpha} from Proteasomal Degradation and Is Required for Full Transcriptional Activity of the Receptor Mol. Endocrinol., October 1, 2007; 21(10): 2427 - 2439. [Abstract] [Full Text] [PDF]

				J. C. Hunter, J. C. Kostyak, J. L. Novotny, A. M. Simpson, and D. H. Korzick Estrogen deficiency decreases ischemic tolerance in the aged rat heart: roles of PKC{delta}, PKC{epsilon}, Akt, and GSK3beta Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R800 - R809. [Abstract] [Full Text] [PDF]