SRA coactivation of estrogen receptor-alpha is phosphorylation-independent, and enhances 4-hydroxytamoxifen agonist activity

Biochemical and Biophysical Research Communications
Kevin M ColemanCarolyn L Smith

Abstract

The ability of steroid receptor RNA activator (SRA), an AF-1 coactivator, to contribute to differences in estrogen receptor (ER)-alpha and ERbeta transcriptional activity was tested. In transient transfections, SRA expression increased ERalpha- and ERbeta-dependent gene expression. However, when the receptors' amino-terminal A/B regions were examined as GAL4 DNA binding domain fusions, SRA enhanced the activity of GAL-ABalpha but not GAL-ABbeta. Exogenous SRA also enhanced AF-2 activity for both receptors, indicating that SRA effects are not limited to AF-1. Simultaneously mutating three phosphorylation sites within GAL-ABalpha domain only modestly reduced SRA coactivation of GAL-ABalpha, suggesting that phosphorylation does not play a major role in SRA function relative to this domain. SRA enhanced ERalpha activity stimulated by 4-hydroxytamoxifen, but was unable to convert this mixed antiestrogen to an ERbeta agonist. Thus, SRA is an ERalpha AF-1-specific coactivator that enhances the agonist activity of tamoxifen-bound ERalpha and may contribute to tamoxifen resistance.

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Citations

Mar 1, 2012·Nucleic Acids Research·Irina V NovikovaKarissa Y Sanbonmatsu
Jan 19, 2010·The Journal of Steroid Biochemistry and Molecular Biology·Nicole BorthFrank Hänel
Mar 13, 2009·Critical Reviews in Biochemistry and Molecular Biology·Shane M Colley, Peter J Leedman
Mar 12, 2016·Oncotarget·Rui YanChunhua Song
Jul 31, 2020·ELife·Tiziana SquillaroGiovanni Di Bernardo
Jun 1, 2016·IUBMB Life·Jean-Pierre ObeidJimmy El Hokayem
Jan 14, 2017·Cancer Biomarkers : Section a of Disease Markers·Ping LuoJian-Cheng Tu
Jun 27, 2021·Nature Chemical Biology·Xi-Wen WangQiangfeng Cliff Zhang

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