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The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators.

Publication ,  Journal Article
Wijayaratne, AL; McDonnell, DP
Published in: J Biol Chem
September 21, 2001

The human estrogen receptor alpha-isoform (ERalpha) is a nuclear transcription factor that displays a complex pharmacology. In addition to classical agonists and antagonists, the transcriptional activity of ERalpha can be regulated by selective estrogen receptor modulators, a new class of drugs whose relative agonist/antagonist activity is determined by cell context. It has been demonstrated that the binding of different ligands to ERalpha results in the formation of unique ERalpha-ligand conformations. These conformations have been shown to influence ERalpha-cofactor binding and, therefore, have a profound impact on ERalpha pharmacology. In this study, we demonstrate that the nature of the bound ligand also influences the stability of ERalpha, revealing an additional mechanism by which the pharmacological activity of a compound is determined. Of note we found that although all ERalpha-ligand complexes can be ubiquitinated and degraded by the 26 S proteasome in vivo, the mechanisms by which they are targeted for proteolysis appear to be different. Specifically, for agonist-activated ERalpha, an inverse relationship between transcriptional activity and receptor stability was observed. This relationship does not extend to selective estrogen receptor modulators and pure antagonists. Instead, it appears that with these compounds, the determinant of receptor stability is the ligand-induced conformation of ERalpha. We conclude that the different conformational states adopted by ERalpha in the presence of different ligands influence transcriptional activity directly by regulating cofactor binding and indirectly by modulating receptor stability.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

September 21, 2001

Volume

276

Issue

38

Start / End Page

35684 / 35692

Location

United States

Related Subject Headings

  • Ubiquitins
  • Tumor Cells, Cultured
  • Receptors, Estrogen
  • Ligands
  • Humans
  • Estrogen Receptor alpha
  • Estrogen Antagonists
  • Biochemistry & Molecular Biology
  • 34 Chemical sciences
  • 32 Biomedical and clinical sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

September 21, 2001

Volume

276

Issue

38

Start / End Page

35684 / 35692

Location

United States

Related Subject Headings

  • Ubiquitins
  • Tumor Cells, Cultured
  • Receptors, Estrogen
  • Ligands
  • Humans
  • Estrogen Receptor alpha
  • Estrogen Antagonists
  • Biochemistry & Molecular Biology
  • 34 Chemical sciences
  • 32 Biomedical and clinical sciences