title: An estrogen receptor beta isoform that lacks exon 5 has dominant negative activity on both ERalpha and ERbeta.
abstract: An alternatively spliced isoform of human estrogen receptor beta (ERbeta) has been isolated from normal human testis mRNA that is coexpressed with wild-type ERbeta by reverse transcription polymerase chain reaction (RT-PCR). Sequence analysis of the ERbeta isoform PCR product reveals the absence of 139 bp that corresponds to the entire exon 5 of wild-type ERbeta, which predicts to lack part of the hormone-binding domain. The transient expression of the exon 5-deleted isoform of ERbeta (ERbetaDelta5) had no effect on basal transactivation activity of an estrogen-responsive luciferase reporter gene. This finding was in contrast to the previous reports that the exon 5-deleted isoform of ERalpha (ERalphaDelta5) acts as a dominant positive receptor, increasing basal gene transactivation itself. Moreover, when ERbetaDelta5 was cotransfected with the wild-type ERalpha or ERbeta, it behaved as a dominant negative receptor that inhibited not only estradiol-stimulated transactivation by ERbeta but also that by ERalpha. The ligand-independent nuclear localization of ERbetaDelta5 was confirmed by immunohistochemistry, and the coexpression of the isoform and the wild-type receptors could be observed in a single cell that transfected with both receptor cDNAs. These findings indicate that ERbetaDelta5 has a potential as a dominant negative receptor that blocks both ERalpha and ERbeta signaling pathways, suggesting some physiological roles of this isoform as an "ER inhibitor".
authors.affiliation: Department of Geriatric Medicine, Department of Obstetrics and Gynecology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. inoworld-tky@umin.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Inoue
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.forename: K
authors.initials: K
authors.lastname: Horie
authors.forename: S
authors.initials: S
authors.lastname: Hoshino
authors.forename: W
authors.initials: W
authors.lastname: Goto
authors.forename: T
authors.initials: T
authors.lastname: Hosoi
authors.forename: O
authors.initials: O
authors.lastname: Tsutsumi
authors.forename: M
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Y
authors.initials: Y
authors.lastname: Ouchi
mesh_terms: D017398:Alternative Splicing; D002467:Cell Nucleus / Q000378:metabolism; D047629:Estrogen Receptor beta; D005091:Exons / Q000235:genetics; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D047629:Estrogen Receptor beta; D020033:Protein Isoforms; D012333:RNA, Messenger; D011960:Receptors, Estrogen