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

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Abstract
There are two separate estrogen receptors (ERs), ERa and ERb. The ERb gene is variably spliced, and in some cases variant expres- sion is high. Besides the full-length ERb (equivalent to ERb1), splice variants can encode proteins bearing an insert within the ligand- binding domain (b2), a deletion of exon 3 (ERb1d3) disrupting the DNA-binding domain, or both (ERb2d3). Here we examine the intra- cellular localization and transcriptional properties of each of the ERb splice variants heterologously expressed in cultured cells. In accor- dance with ERa ,E Rb1 and ERb2 are both distributed in a reticular pattern within the nucleus after exposure to ligand. In contrast, ERb1d3 and ERb2d3 localize to discrete spots within the nucleus in the presence of ER agonists. In the presence of ER antagonists, the d3 variants are distributed diffusely within the nucleus. We also show that the spots are stable nuclear structures to which the d3 variants localize in a ligand-dependent manner. Coactivator proteins of ER colocalize with d3 variants in the spots in the presence of agonists. The d3 variants of ERb can activate luciferase reporter constructs con- taining an activator protein complex-1 site, but not an estrogen re- sponse element (ERE). These data suggest that without an intact DNA-binding domain, ERb is functionally altered, allowing localiza- tion to discrete nuclear spots and activation from activator protein- 1-containing reporter genes. (Endocrinology 142: 2039 -2049, 2001)

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