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Estrogen Receptor ß Isoforms Exhibit Differences in Ligand-Activated Transcriptional Activity in an Estrogen Response Element Sequence-Dependent Manner

Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40292

Address all correspondence and requests for reprints to: Carolyn Klinge, Department of Biochemistry, Room 603, 319 Abraham Flexner Way, Louisville, Kentucky 40202. E-mail: carolyn.klinge{at}louisville.edu.

Estrogen receptor ß (ERß) has been reported to have lower estradiol (E₂)-induced transcriptional activity than human (h)ER from estrogen response element (ERE)-driven reporters in transiently transfected cells. Conflicting data for activities of full-length and short hERß [hERß1, 530 amino acids (aa); and hERß1s, 477aa] have been reported. To test the hypothesis that hERß1 has higher transcriptional activity than hERß1s, we compared E₂, 2,3-bis(4-hydroxyphenyl)propionitrile (a selective ERß agonist), and resveratrol-induced transcription by hERß1, hERß1s, and rat (r) ERß with hER on different EREs in transiently transfected CHO-K1 and HEC-1A cells. Our results demonstrate for the first time that hERß1 has similar E₂-induced activity to hER and greater activity than rERß or hERß1s on a consensus palindromic ERE, either as a single or double copy; a minimal ERE; and the nonpalindromic pS2 ERE. 2,3-Bis(4-hydroxyphenyl)propionitrile showed greater efficacy with hERß1 and hERß1s than for rERß or hER. We found that transcriptional differences between the ERß isoforms and ER depend on the ERE sequence, confirming that the DNA sequence bound by ER is an allosteric effector of ER action. For the minimal 13-bp ERE and the pS2 ERE, the increase in transcriptional activity with hERß1 correlated with increased binding affinity. Coactivators steroid receptor coactivator-1 and cAMP response element binding protein-binding protein synergistically activated hER and ERß transcription and showed reduced efficacy with rERß and hERß1s, suggesting a role for the N terminus of ERß1 in coactivator interaction. Collectively, these data indicate that the cellular expression of ERß isoforms may differentially impact ERE-regulated target gene expression in a ligand-dependent manner.

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