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Different modulation of ER-mediated transactivation by xenobiotic nuclear receptors depending on the estrogen

Gyesik Min1

  • 1Department of Microbiological Engineering, Jinju National University, Jinju, Gyeongsangnam-Do, 660-758 Korea. g-min@jinju.ac.kr

Annals of the New York Academy of Sciences
|March 8, 2007
PubMed

Insights

Constitutive androstane receptor (CAR), steroid and xenobiotic receptor (SXR), and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) differentially modulate estrogen receptor (ER) activity. Their effects vary based on the specific estrogen response element and cell type, impacting ER-mediated transactivation.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Pharmacology

Background:

  • Constitutive androstane receptor (CAR) inhibits ER-mediated transactivation in Hep G2 cells.
  • Steroid and xenobiotic receptor (SXR) represses synthetic estrogen receptor (ER) transactivation, but its effect on endogenous promoters is unclear.
  • Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) effects on ER transactivation are not fully understood, especially on endogenous promoters.

Purpose of the Study:

  • To investigate the effects of CAR, SXR, and PPAR-gamma on ER-mediated transactivation of endogenous and synthetic promoters in various cell lines.
  • To determine the influence of these xenobiotic nuclear receptors (XNRs) on ER transactivation in Hep G2, breast cancer, and ovarian cell lines.
  • To elucidate how XNRs modulate ER activity based on specific estrogen response elements (EREs) and cellular context.

Main Methods:

  • Examined ER transactivation of the endogenous vitellogenin B1 promoter and synthetic 4ERE reporter in Hep G2 cells.
  • Assessed dose-dependent and single-dose effects of CAR, SXR, and PPAR-gamma on ER-mediated transactivation in MDA-MB-231, MCF-7-K3, and CHO-S cells.
  • Utilized luciferase reporter assays to quantify ER transactivation modulated by XNRs.

Main Results:

  • CAR repressed ER transactivation of the vitellogenin B1 promoter in Hep G2 cells, consistent with previous findings on synthetic promoters.
  • PPAR-gamma potentiated ER transactivation of the vitellogenin B1 promoter, while SXR had no effect in Hep G2 cells.
  • In MDA-MB-231 cells, CAR modestly stimulated ER transactivation at low doses, with no significant effects observed for SXR and PPAR-gamma across all doses. No significant modulation was observed in CHO-S and MCF-7-K3 cells.

Conclusions:

  • Xenobiotic nuclear receptors (XNRs) exhibit cell-type and promoter-specific modulation of estrogen receptor (ER) activity.
  • The interaction between XNRs and ER is dependent on the nature of the estrogen response element (ERE) and the cellular environment.
  • Findings highlight the complex interplay of nuclear receptors in regulating estrogen signaling, with implications for understanding endocrine disruption and drug development.

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