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Coactivators enable glucocorticoid receptor recruitment to fine-tune estrogen receptor transcriptional responses

Michael J Bolt1, Fabio Stossi, Justin Y Newberg

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Nucleic Acids Research
|February 28, 2013
PubMed

Insights

Nuclear receptors (NRs) influence each other

Area of Science:

  • Endocrinology and Molecular Biology
  • Cellular and Molecular Physiology
  • Gene Regulation and Chromatin Dynamics

Background:

  • Nuclear receptors (NRs) are critical regulators of numerous pathophysiological processes.
  • The intricate mechanisms governing NR cross-talk and coordinated responses remain incompletely understood.
  • Understanding NR interactions is crucial for deciphering complex hormonal signaling pathways.

Purpose of the Study:

  • To investigate whether and how steroid nuclear receptors (NRs) can modulate each other's activity upon co-agonist stimulation.
  • To elucidate the molecular players involved in the interplay between estrogen receptor alpha (ERα) and other type I NRs.
  • To determine the functional consequences of NR cross-talk on endogenous gene expression in cancer cells.

Main Methods:

  • Development of a unique system for direct visualization and quantification of ERα DNA binding, co-regulator recruitment, and transcriptional activity.
  • Utilizing dual agonist treatment to study NR interactions in a co-regulatory context.
  • Focusing on ERα/glucocorticoid receptor interplay, involving specific steroid receptor coactivators (SRC-2, SRC-3) and mediator component MED14.
  • Validation of observed NR cross-talk on endogenous target genes within breast cancer cell models.

Main Results:

  • ERα DNA binding is a prerequisite for the co-recruitment of other type I nuclear receptors following dual agonist treatment.
  • The interplay between ERα and glucocorticoid receptor necessitates the involvement of SRC-2, SRC-3, and MED14.
  • Cooperative NR cross-talk was confirmed to influence the expression of endogenous genes in breast cancer cells.

Conclusions:

  • Estrogen receptor alpha (ERα) DNA loading is essential for the co-recruitment of other nuclear receptors (NRs) under dual agonist conditions.
  • The cross-talk between ERα and glucocorticoid receptor is mediated by steroid receptor coactivators (SRC-2, SRC-3) and MED14.
  • This study reveals an additional layer of mechanistic complexity in how NRs interact on chromatin, particularly under multiple hormonal stimuli, with implications for diseases like breast cancer.

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