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A Splice Variant of Estrogen Receptor ß Missing Exon 3 Displays Altered Subnuclear Localization and Capacity for Transcriptional Activation¹

Department of Cell Biology, Neurobiology, and Anatomy, Loyola University Chicago (R.H.P.), Maywood, Illinois 60153; Department of Anatomy and Neurobiology, Colorado State University (R.H.P., C.A.B., R.J.H.), Fort Collins, Colorado 80523; and Metabolic Research Unit, University of California (P.W., R.U., P.K.), San Francisco, California 94143

Address all correspondence and requests for reprints to: Dr. Robert J. Handa, Department of Anatomy and Neurobiology, Colorado State University, Fort Collins, Colorado 80523. E-mail: rhanda{at}cvmbs.colostate.edu

There are two separate estrogen receptors (ERs), ER and ERß. The ERß gene is variably spliced, and in some cases variant expression is high. Besides the full-length ERß (equivalent to ERß1), splice variants can encode proteins bearing an insert within the ligand-binding domain (ß2), a deletion of exon 3 (ERß13) disrupting the DNA-binding domain, or both (ERß23). Here we examine the intracellular localization and transcriptional properties of each of the ERß splice variants heterologously expressed in cultured cells. In accordance with ER, ERß1 and ERß2 are both distributed in a reticular pattern within the nucleus after exposure to ligand. In contrast, ERß13 and ERß23 localize to discrete spots within the nucleus in the presence of ER agonists. In the presence of ER antagonists, the 3 variants are distributed diffusely within the nucleus. We also show that the spots are stable nuclear structures to which the 3 variants localize in a ligand-dependent manner. Coactivator proteins of ER colocalize with 3 variants in the spots in the presence of agonists. The 3 variants of ERß can activate luciferase reporter constructs containing an activator protein complex-1 site, but not an estrogen response element (ERE). These data suggest that without an intact DNA-binding domain, ERß is functionally altered, allowing localization to discrete nuclear spots and activation from activator protein-1-containing reporter genes.

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