Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling.
Estrogen receptor beta (ER-beta) regulates diverse physiological functions in the human body. Current studies are confined to ER-beta1, and the functional roles of isoforms 2, 4, and 5 remain unclear. Full-length ER-beta4 and -beta5 isoforms were obtained from a prostate cell line, and they exhibit differential expression in a wide variety of human tissues/cell lines. Through molecular modeling, we established that only ER-beta1 has a full-length helix 11 and a helix 12 that assumes an agonist-directed position. In ER-beta2, the shortened C terminus results in a disoriented helix 12 and marked shrinkage in the coactivator binding cleft. ER-beta4 and -beta5 completely lack helix 12. We further demonstrated that ER-beta1 is the only fully functional isoform, whereas ER-beta2, -beta4, and -beta5 do not form homodimers and have no innate activities of their own. However, the isoforms can heterodimerize with ER-beta1 and enhance its transactivation in a ligand-dependent manner. ER-beta1 tends to form heterodimers with other isoforms under the stimulation of estrogens but not phytoestrogens. Collectively, these data support the premise that (i) ER-beta1 is the obligatory partner of an ER-beta dimer, whereas the other isoforms function as variable dimer partners with enhancer activity, and (ii) a single functional helix 12 in a dimer is sufficient for gene transactivation. Thus, ER-beta behaves like a noncanonical type-I receptor, and its action may depend on differential amounts of ER-beta1 homo- and heterodimers formed upon stimulation by a specific ligand. Our findings have provided previously unrecognized directions for studying ER-beta signaling and design of ER-beta-based therapies.
Leung
Yuet-Kin
YK
Department of Environmental Health, Division of Environmental Genetics and Molecular Toxicology, College of Medicine, University of Cincinnati, OH 45267, USA.
Mak
Paul
P
Hassan
Sazzad
S
Ho
Shuk-Mei
SM
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D019281:Dimerization; D047629:Estrogen Receptor beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D053766:Presenilin-2; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020539:Sequence Analysis, Protein; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D015003:Yeasts
D047629:Estrogen Receptor beta; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D020033:Protein Isoforms; D012333:RNA, Messenger