Journal
ENDOCRINOLOGY
Volume 148, Issue 10, Pages 4634-4641Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2007-0148
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Funding
- NCI NIH HHS [CA 90371] Funding Source: Medline
- NICHD NIH HHS [HD 16720] Funding Source: Medline
- NIDDK NIH HHS [DK 071909] Funding Source: Medline
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To evaluate the contribution of ERK1/2 phosphorylation of estrogen receptor (ER)-alpha 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 alpha and ER alpha mutated to inactivate the well-known MAPK site at serine 118 (ER alpha S118A). We compared effects of the S118A mutation on 17 beta-estradiol (E-2)-mediated transactivation, which is heavily dependent on activation function (AF) 2 of ER alpha 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 alpha 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 alpha 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.
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