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The Naturally Occurring Variant of Estrogen Receptor (ER) ERE7 Suppresses Estrogen-Dependent Transcriptional Activation by Both Wild-Type ER and ERß

Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología Principado de Asturias, Universidad de Oviedo, 33071 Oviedo, Spain

Address all correspondence and requests for reprints to: S. Ramos, Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología Principado de Asturias, Universidad de Oviedo, 33071 Oviedo, Spain. E-mail: sramos{at}correo.uniovi.es.

We have isolated and functionally characterized the exon 7-skipped variant (ERE7) of estrogen receptor (ER), which has emerged as the predominant variant expressed in multiple normal and tumoral tissues. However, to date no function has been established for this variant in mammalian cells. ERE7 exhibits a negligible ability to bind ligands, insensitivity to allosteric modulation by estrogen and antiestrogens, and loss of estrogen-dependent interaction with p160 coactivators such as SRC-1 and AIB1. ERE7 is able to form heterodimers with both ER and ERß in a ligand-independent manner. Transient expression experiments in HeLa cells show that increasing amounts of ERE7 result in a progressive inhibition of the estrogen-dependent transcriptional activation by both wild-type ER and ERß on estrogen response element-driven promoters. The inhibitory effect of ERE7 is due to the inhibition of binding of wild-type receptors to their responsive elements. Surprisingly, the activation function (AF)-1-dependent transactivation triggered by epithelial growth factor and phorbol-12-myristate-13-acetate is also abolished in ERE7 despite AF1 integrity, suggesting a cross-talk between AF1 and AF2 regions of the receptor. These results indicate that the naturally occurring variant ERE7 is a dominant negative receptor that, when expressed at high levels relative to wild-type ERs, might have profound effects on several estrogen-dependent functions.