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 Cheng, J. Articles by Shapiro, D. J. Search for Related Content PubMed PubMed Citation Articles by Cheng, J. Articles by Shapiro, D. J.

A Functional Serine 118 Phosphorylation Site in Estrogen Receptor- Is Required for Down-Regulation of Gene Expression by 17ß-Estradiol and 4-Hydroxytamoxifen

Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Address all correspondence and requests for reprints to: David J. Shapiro, Department of Biochemistry, University of Illinois, 413 RAL, Box B4, 600 South Mathews, Urbana, Illinois 61801. E-mail: djshapir{at}uiuc.edu.

To evaluate the contribution of ERK1/2 phosphorylation of estrogen receptor (ER)- to activation and repression of endogenous genes, we produced stably transfected lines of HeLa cells with functional ERK1/2 pathways that express similar levels of wild-type human ER and ER mutated to inactivate the well-known MAPK site at serine 118 (ERS118A). We compared effects of the S118A mutation on 17ß-estradiol (E₂)-mediated transactivation, which is heavily dependent on activation function (AF) 2 of ER and on 4-hydroxytamoxifen (OHT)-mediated transactivation, which is heavily dependent on AF1, which includes S118. To examine whether S118 was the key ERK/MAPK phosphorylation site in ER action, we compared the effects of the S118A mutant and the ERK inhibitor U0126 on expression of endogenous genes. In several estrogen response element-containing genes, the S118A mutation strongly reduced induction by E₂, and U0126 did not further reduce expression. Expression of another group of estrogen response element-containing genes was largely unaffected by the S118A mutation. The S118A mutation had variable effects on genes induced by ER tethering or binding near specificity protein-1 and activator protein-1 sites. For five mRNAs whose expression is strongly down-regulated by E₂ and partially or completely down-regulated by OHT, the S118A mutation reduced or abolished down-regulation by E₂ and nearly abolished down-regulation by OHT. In contrast, for Sma and mothers against decapentaplegic-3-related, which is down-regulated by E₂ and not OHT, the S118A mutation had little effect. These data suggest that there may be distinct groups of genes down-regulated by ER and suggest a novel role for ERK phosphorylation at serine 118 in AF1 in regulating expression of the set of genes down-regulated by OHT.

This article has been cited by other articles:

				G. Giamas, L. Castellano, Q. Feng, U. Knippschild, J. Jacob, R. S. Thomas, R. C. Coombes, C. L. Smith, L. R. Jiao, and J. Stebbing CK1{delta} modulates the transcriptional activity of ER{alpha} via AIB1 in an estrogen-dependent manner and regulates ER{alpha}-AIB1 interactions Nucleic Acids Res., May 1, 2009; 37(9): 3110 - 3123. [Abstract] [Full Text] [PDF]

				M. Zoubir, M. C. Mathieu, C. Mazouni, C. Liedtke, L. Corley, S. Geha, J. Bouaziz, M. Spielmann, F. Drusche, W. F. Symmans, et al. Modulation of ER phosphorylation on serine 118 by endocrine therapy: a new surrogate marker for efficacy Ann. Onc., August 1, 2008; 19(8): 1402 - 1406. [Abstract] [Full Text] [PDF]