Estrogen receptor-mediated transcription involves the activation of multiple kinase pathways in neuroblastoma cells

Clark, S., Rainville, J., Zhao, X., Katzenellenbogen, B. S., Pfaff, D. and Vasudevan, N. ORCID: https://orcid.org/0000-0003-4326-3938 (2014) Estrogen receptor-mediated transcription involves the activation of multiple kinase pathways in neuroblastoma cells. Journal of Steroid Biochemistry and Molecular Biology, 139. pp. 45-53. ISSN 0960-0760 doi: 10.1016/j.jsbmb.2013.09.010

Abstract/Summary

While many physiological effects of estrogens (E) are due to regulation of gene transcription by liganded estrogen receptors (ERs), several effects are also mediated, at least in part, by rapid non-genomic actions of E. Though the relative importance of rapid versus genomic effects in the central nervous system is controversial, we showed previously that membrane-limited effects of E, initiated by an estradiol bovine serum albumin conjugate (E2-BSA), could potentiate transcriptional effects of 17beta-estradiol from an estrogen response element (ERE)-reporter in neuroblastoma cells. Here, using specific inhibitors and activators in a pharmacological approach, we show that activation of phosphatidylinositol-3-phosphate kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways, dependent on a Galphaq coupled receptor signaling are important in this transcriptional potentiation. We further demonstrate, using ERalpha phospho-deficient mutants, that E2-BSA mediated phosphorylation of ERalpha is one mechanism to potentiate transcription from an ERE reporter construct. This study provides a possible mechanism by which signaling from the membrane is coupled to transcription in the nucleus, providing an integrated view of hormone signaling in the brain.