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Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements.

Publication ,  Journal Article
Hall, JM; McDonnell, DP; Korach, KS
Published in: Mol Endocrinol
March 2002

Hormone-activated ERs (ERalpha and ERbeta) bind with high affinity to specific DNA sequences, estrogen response elements (EREs), located within the regulatory regions of target genes. Once considered to function solely as receptor tethers, there is an increasing amount of recent evidence to suggest that the sequence of the ERE can influence receptor activity. In this study, we have performed a systematic analysis of the role of different EREs in ER pharmacology. Specifically, by measuring ER activity on the vitellogenin A2, complement 3 gene, pS2, and lactoferrin EREs, we demonstrate that the activities of E2 and xenoestrogen ligands through ERalpha and ERbeta are significantly influenced by the nature of the response element. Using a series of ERalpha and ERbeta interacting peptides that contain the coactivator-binding motif LXXLL, we show that the type of ERE with which the receptor associates regulates the structure of the coactivator pocket on ER. Furthermore, using a novel ELISA developed to measure ER-coactivator interactions revealed that these different conformational states of ERalpha and ERbeta are functionally relevant, as they dictate receptor coactivator binding preference. Together, these results indicate that the DNA response element is a key regulator of receptor structure and biological activity and suggest the ERE sequence influences the recruitment of coactivators to the ER at target gene promoters. We propose that DNA-induced alteration of protein structure and coregulator recruitment may serve as a universal regulatory component for differential gene expression by other nuclear hormone receptors and unrelated transcription factors.

Duke Scholars

Published In

Mol Endocrinol

DOI

ISSN

0888-8809

Publication Date

March 2002

Volume

16

Issue

3

Start / End Page

469 / 486

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Transcription Factors
  • Structure-Activity Relationship
  • Response Elements
  • Receptors, Estrogen
  • Protein Conformation
  • Nuclear Receptor Coactivator 2
  • Nuclear Receptor Coactivator 1
  • Liver Neoplasms
 

Citation

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Hall, J. M., McDonnell, D. P., & Korach, K. S. (2002). Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements. Mol Endocrinol, 16(3), 469–486. https://doi.org/10.1210/mend.16.3.0814
Hall, Julie M., Donald P. McDonnell, and Kenneth S. Korach. “Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements.Mol Endocrinol 16, no. 3 (March 2002): 469–86. https://doi.org/10.1210/mend.16.3.0814.
Hall, Julie M., et al. “Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements.Mol Endocrinol, vol. 16, no. 3, Mar. 2002, pp. 469–86. Pubmed, doi:10.1210/mend.16.3.0814.

Published In

Mol Endocrinol

DOI

ISSN

0888-8809

Publication Date

March 2002

Volume

16

Issue

3

Start / End Page

469 / 486

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Transfection
  • Transcription Factors
  • Structure-Activity Relationship
  • Response Elements
  • Receptors, Estrogen
  • Protein Conformation
  • Nuclear Receptor Coactivator 2
  • Nuclear Receptor Coactivator 1
  • Liver Neoplasms