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

Timothy L. Ramsey, Kelly E. Risinger, Sarah Jernigan, Kathleen A. Mattingly, Carolyn M. Klinge

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Estrogen receptor β (ERβ) has been reported to have lower estradiol (E2)-induced transcriptional activity than human (h)ERα from estrogen response element (ERE)-driven reporters in transiently transfected cells. Conflicting data for activities of full-length and short hERβ [hERβ1, 530 amino acids (aa); and hERβ1s, 477aa] have been reported. To test the hypothesis that hERβ1 has higher transcriptional activity than hERβ1s, we compared E2, 2,3-bis(4-hydroxyphenyl)propionitrile (a selective ERβ agonist), and resveratrol-induced transcription by hERβ1, hERβ1s, and rat (r) ERβ with hERα on different EREs in transiently transfected CHO-K1 and HEC-1A cells. Our results demonstrate for the first time that hERβ1 has similar E2-induced activity to hERα and greater activity than rERβ or hERβ1s 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 hERβ1 and hERβ1s than for rERβ or hERα. We found that transcriptional differences between the ERβ isoforms and ERα 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 hERβ1 correlated with increased binding affinity. Coactivators steroid receptor coactivator-1 and cAMP response element binding protein-binding protein synergistically activated hERα and ERβ transcription and showed reduced efficacy with rERβ and hERβ1s, suggesting a role for the N terminus of ERβ1 in coactivator interaction. Collectively, these data indicate that the cellular expression of ERβ isoforms may differentially impact ERE-regulated target gene expression in a ligand-dependent manner. (Endocrinology 145: 149-160, 2004).

Original languageEnglish (US)
Pages (from-to)149-160
Number of pages12
JournalEndocrinology
Volume145
Issue number1
DOIs
StatePublished - Jan 2004
Externally publishedYes

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Response Elements
Estrogen Receptors
Protein Isoforms
Estrogens
Ligands
Nuclear Receptor Coactivator 1
Cyclic AMP Response Element-Binding Protein
Endocrinology
Protein Binding
Human Activities
Estradiol
Carrier Proteins
Gene Expression
Amino Acids

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Estrogen Receptor β Isoforms Exhibit Differences in Ligand-Activated Transcriptional Activity in an Estrogen Response Element Sequence-Dependent Manner. / Ramsey, Timothy L.; Risinger, Kelly E.; Jernigan, Sarah; Mattingly, Kathleen A.; Klinge, Carolyn M.

In: Endocrinology, Vol. 145, No. 1, 01.2004, p. 149-160.

Research output: Contribution to journalArticle

Ramsey, Timothy L. ; Risinger, Kelly E. ; Jernigan, Sarah ; Mattingly, Kathleen A. ; Klinge, Carolyn M. / Estrogen Receptor β Isoforms Exhibit Differences in Ligand-Activated Transcriptional Activity in an Estrogen Response Element Sequence-Dependent Manner. In: Endocrinology. 2004 ; Vol. 145, No. 1. pp. 149-160.
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AB - Estrogen receptor β (ERβ) has been reported to have lower estradiol (E2)-induced transcriptional activity than human (h)ERα from estrogen response element (ERE)-driven reporters in transiently transfected cells. Conflicting data for activities of full-length and short hERβ [hERβ1, 530 amino acids (aa); and hERβ1s, 477aa] have been reported. To test the hypothesis that hERβ1 has higher transcriptional activity than hERβ1s, we compared E2, 2,3-bis(4-hydroxyphenyl)propionitrile (a selective ERβ agonist), and resveratrol-induced transcription by hERβ1, hERβ1s, and rat (r) ERβ with hERα on different EREs in transiently transfected CHO-K1 and HEC-1A cells. Our results demonstrate for the first time that hERβ1 has similar E2-induced activity to hERα and greater activity than rERβ or hERβ1s 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 hERβ1 and hERβ1s than for rERβ or hERα. We found that transcriptional differences between the ERβ isoforms and ERα 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 hERβ1 correlated with increased binding affinity. Coactivators steroid receptor coactivator-1 and cAMP response element binding protein-binding protein synergistically activated hERα and ERβ transcription and showed reduced efficacy with rERβ and hERβ1s, suggesting a role for the N terminus of ERβ1 in coactivator interaction. Collectively, these data indicate that the cellular expression of ERβ isoforms may differentially impact ERE-regulated target gene expression in a ligand-dependent manner. (Endocrinology 145: 149-160, 2004).

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