期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2006
卷号：103
期号：35
页码：13162-13167
DOI：10.1073/pnas.0605676103
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Estrogen receptor beta (ER-[beta]) regulates diverse physiological functions in the human body. Current studies are confined to ER-[beta]1, and the functional roles of isoforms 2, 4, and 5 remain unclear. Full-length ER-[beta]4 and -[beta]5 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-[beta]1 has a full-length helix 11 and a helix 12 that assumes an agonist-directed position. In ER-[beta]2, the shortened C terminus results in a disoriented helix 12 and marked shrinkage in the coactivator binding cleft. ER-[beta]4 and -[beta]5 completely lack helix 12. We further demonstrated that ER-[beta]1 is the only fully functional isoform, whereas ER-[beta]2, -[beta]4, and -[beta]5 do not form homodimers and have no innate activities of their own. However, the isoforms can heterodimerize with ER-[beta]1 and enhance its transactivation in a ligand-dependent manner. ER-[beta]1 tends to form heterodimers with other isoforms under the stimulation of estrogens but not phytoestrogens. Collectively, these data support the premise that (i) ER-[beta]1 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-[beta]1 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.
关键词：estrogen responsive element ; heterodimerization ; molecular modeling ; steroid receptor coactivator ; type I nuclear receptor
