A splice variant of estrogen receptor beta missing exon 3 displays alteredsubnuclear localization and capacity for transcriptional activation

There are two separate estrogen receptors (ERs), ER alpha and ER beta. The ER beta gene is variably spliced, and in some cases variant expression is h igh. Besides the full-length ER beta (equivalent to ER beta1), splice varia nts can encode proteins bearing an insert within the ligand-binding domain (beta2), a deletion of exon 3 (ER beta1 delta3) disrupting the DNA-binding domain, or both (ER beta2 delta3). Here we examine the intracellular locali zation and transcriptional properties of each of the ER beta splice variant s heterologously expressed in cultured cells. In accordance with ER alpha, ER beta1 and ER beta2 are both distributed in a reticular pattern within th e nucleus after exposure to ligand. In contrast, ER beta1 delta3 and ER bet a2 delta3 localize to discrete spots within the nucleus in the presence of ER agonists. In the presence of ER antagonists, the delta3 variants are dis tributed diffusely within the nucleus. We also show that the spots are stab le nuclear structures to which the delta3 variants localize in a ligand-dep endent manner. Coactivator proteins of ER colocalize with delta3 variants i n the spots in the presence of agonists. The delta3 variants of ER beta can activate luciferase reporter constructs containing an activator protein co mplex-1 site, but not an estrogen response element (ERE). These data sugges t that without an intact DNA-binding domain, ER beta is functionally altere d, allowing localization to discrete nuclear spots and activation from acti vator protein-1-containing reporter genes.