Modulator Recognition Factor 1, an AT-Rich Interaction Domain Family Member, Is a Novel Corepressor for Estrogen Receptor α

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Abstract
Cardiovascular tissues are important targets of estrogen action. Vascular cells express the two known estrogen receptors (ERs), ERα and ERβ, ligand-activated transcription factors that regulate gene transcription through interactions with both coactivator and corepressor molecules. To isolate ERα coregulators in vascular cells, we performed a yeast two-hybrid screen for ERα-interacting proteins using a human aorta library. Here we report the identification of modulator recognition factor 1 (MRF1) as an ERα-interacting corepressor protein. Full-length MRF1 binds to both the N terminus and the C terminus of ERα. ERα and MRF1 coimmunoprecipitate in an estradiol-independent manner, and recombinant ERα binds to both full-length and COOH-terminal MRF1 in the absence of estradiol. MRF1 also interacts in a ligand-dependent manner with thyroid receptor α, retinoid X receptor α, and androgen receptor, and in a ligand-independent manner with ERβ and the retinoic acid receptor. MRF1 RNA is highly expressed in aorta, heart, skeletal muscle, and liver. MRF1 has intrinsic repressor activity in an in vitro GAL reporter assay. Transient transfection studies show that MRF1 represses transcription by ERα activated by estradiol in a dose-dependent manner, as well as by the selective ER modulators 4-hydroxy-tamoxifen and raloxifene. MRF1 repression is not influenced by pharmacological inhibition of histone deacetylase. These data identify MRF1 as a repressor of ERα-mediated transcriptional activation and support a role for MRF1 in regulating ER-dependent gene expression in cardiovascular and other cells.