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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
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Effects of selective estrogen receptor modulators (SERMs) on coactivator nuclear receptor (NR) box binding to

Kelli S Bramlett1, Thomas P Burris

  • 1Gene Regulation, Bone, and Inflammation Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.

Molecular Genetics and Metabolism
|July 20, 2002
PubMed

Insights

Selective estrogen receptor modulators (SERMs) act as antagonists, decreasing coactivator binding to estrogen receptors (ERs). These compounds do not enhance, but rather inhibit, NR box recruitment to ER alpha and ER beta.

Area of Science:

  • Molecular Endocrinology
  • Nuclear Receptor Signaling
  • Pharmacology

Background:

  • Coactivators are essential for nuclear receptor-mediated gene activation.
  • p160 proteins, a class of coactivators, interact with nuclear receptors via Nuclear Receptor (NR) boxes.
  • Estrogen Receptors (ERs) mediate the effects of estrogen and are modulated by Selective Estrogen Receptor Modulators (SERMs).

Purpose of the Study:

  • To investigate the effect of SERMs on the recruitment of p160 coactivator NR boxes to ER alpha and ER beta.
  • To compare the binding affinities of various NR boxes to ER subtypes in the presence of different ligands.

Main Methods:

  • Utilized a coactivator interaction assay based on time-resolved fluorescence technology.
  • Assessed the binding of 10 NR boxes from SRC-1, -2, and -3 to ER alpha and ER beta.
  • Tested ligands included 17beta-estradiol (E2), 4-OH tamoxifen, LY 117018, and ICI 182780.

Main Results:

  • SERMs did not enhance NR box binding to ER alpha or ER beta; instead, they acted as potent antagonists, decreasing estradiol-dependent NR box binding.
  • All tested SERMs exhibited inverse agonism, dose-dependently reducing hormone-independent NR box binding to ER beta.
  • A clear receptor-specific preferential binding pattern was observed between E2-bound ER alpha/beta and various natural NR boxes.

Conclusions:

  • The SERMs examined function as antagonists of ER alpha and ER beta NR box binding, failing to increase coactivator recruitment.
  • SERMs demonstrate inverse agonism, reducing basal coactivator binding to ER beta.
  • Estrogen receptor subtypes exhibit distinct preferences for interacting with different NR boxes.

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