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J. Biol. Chem., Vol. 278, Issue 40, 38125-38131, October 3, 2003

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Truncated Estrogen Receptor Product-1 Stimulates Estrogen Receptor Transcriptional Activity by Titration of Repressor Proteins^*

Vicky Y. Lin , Eileen M. Resnick  and Margaret A. Shupnik  ¶

From the Departments of Pharmacology and Internal Medicine, Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, Virginia 22908

The truncated estrogen receptor product-1 (TERP-1, or TERP) is a pituitary-specific isoform of estrogen receptor (ER), and its expression is regulated by estrogen. TERP modulates the transcriptional activity of ER but has no independent effect on transcription of estrogen-response element-containing promoters. At low concentrations, TERP stimulates ER transcriptional activity in transient transfection assays. At TERP concentrations equal to or greater than full-length ER, TERP forms dimers with ER and reduces both ligand-dependent and -independent transcription. A dimerization mutant of TERP, TERP L509R, stimulated ER transcription at all concentrations. We hypothesized that TERP stimulates ER transcriptional activity by titrating suppressors of ER activity. We found that repressor of estrogen receptor activity (REA), originally isolated from human breast cancer cells, is present in mouse pituitary gonadotrope cell lines. Levels of REA vary slightly throughout the rat reproductive cycle, but TERP mRNA and protein vary much more dramatically. In transfection experiments, REA suppressed ER transcriptional activity, and TERP L509R was able to alleviate transcriptional suppression by REA. In glutathione S-transferase pull-down assays, TERP bound to REA more efficiently than did ER at equivalent concentrations, suggesting that REA will preferentially bind to TERP. Our findings suggest that the stimulation of pituitary ER activity by low concentrations of TERP can occur by titration of corepressors such as REA.

Received for publication, April 14, 2003 , and in revised form, July 23, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY319418

^* This work was supported by the National Institutes of Health Grant R01-DK57082 (to M. A. S.) and by a grant to the Molecular Core of the Center for Research in Reproduction, supported by NICHD, National Institutes of Health, through cooperative agreement (U54 HD28934) as part of the Specialized Cooperative Centers Program in Reproduction Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Medicine/Endocrinology, P. O. Box 800578 HSC, University of Virginia, Charlottesville, VA 22908. Tel.: 434-982-0010; Fax: 434-982-0088; E-mail: mas3x{at}virginia.edu.

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