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Single-Chain Estrogen Receptors (ERs) Reveal that the ER/ß Heterodimer Emulates Functions of the ER Dimer in Genomic Estrogen Signaling Pathways

Xiaodong Li, Jing Huang, Ping Yi, Robert A. Bambara, Russell Hilf, and Mesut Muyan^*

Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York

Received 31 March 2004/ Returned for modification 4 May 2004/ Accepted 1 June 2004

The effects of estrogens, particularly 17ß-estradiol (E2), are mediated by estrogen receptor (ER) and ERß. Upon binding to E2, ERs homo- and heterodimerize when coexpressed. The ER dimer then regulates the transcription of target genes through estrogen responsive element (ERE)-dependent and -independent pathways that constitute genomic estrogen signaling. Although ER and ERß have similar ERE and E2 binding properties, they display different transregulatory capacities in both ERE-dependent and -independent signaling pathways. It is therefore likely that the heterodimerization provides novel functions to ERs by combining distinct properties of the contributing partners. The elucidation of the role of the ER heterodimer is critical for the understanding of physiology and pathophysiology of E2 signaling. However, differentially determining target gene responses during cosynthesis of ER subtypes is difficult, since dimers formed are a heterogeneous population of homo- and heterodimers. To circumvent the pivotal dimerization step in ER action and hence produce a homogeneous ER heterodimer population, we utilized a genetic fusion strategy. We joined the cDNAs of ER and/or ERß to produce single-chain ERs to simulate the ER homo- and heterodimers. The fusion ERs interacted with ERE and E2 in a manner similar to that observed with the ER dimers. The homofusion receptors mimicked the functions of the parent ER dimers in the ERE-dependent and -independent pathways in transfected mammalian cells, whereas heterofusion receptors emulated the transregulatory properties of the ER dimer. These results suggest that ER is the functionally dominant partner in the ER/ß heterodimer.

Present address: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.

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