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Turning off estrogen receptor beta-mediated transcription requires estrogen-dependent receptor proteolysis

Yukiyo Tateishi1, Raku Sonoo, Yu-ichi Sekiya

  • 1Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki 305-8572, Japan.

Molecular and Cellular Biology
|August 31, 2006
PubMed

Insights

Estrogen receptor beta (ERbeta) degradation, regulated by the ubiquitin-proteasome pathway and CHIP, turns off transcription. Ligand withdrawal triggers ERbeta proteolysis, downregulating its activity.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Endocrinology

Background:

  • Nuclear receptors (NRs) regulate gene transcription in response to ligand binding.
  • Downregulation of NR activity is crucial, especially upon ligand withdrawal.
  • The precise mechanisms for turning off NR-mediated transcription are under investigation.

Purpose of the Study:

  • To elucidate the role of the ubiquitin-proteasome pathway in terminating estrogen receptor beta (ERbeta) transcription.
  • To identify the specific regions and factors involved in ERbeta degradation and transcriptional silencing.

Main Methods:

  • Investigated estrogen-dependent proteolysis of ERbeta.
  • Utilized interfering RNA to suppress carboxyl terminus of HSC70-interacting protein (CHIP) expression.
  • Analyzed the impact of CHIP suppression on ERbeta-mediated transcription upon ligand dose reduction.

Main Results:

  • ERbeta undergoes estrogen-dependent proteolysis, a process regulated by its N-terminal and C-terminal domains.
  • The N-terminal region recruits the ubiquitin ligase CHIP for ERbeta degradation.
  • The C-terminal F domain protects ligand-unbound ERbeta from proteolysis.
  • CHIP suppression prevented the downregulation of ERbeta transcription after ligand withdrawal.

Conclusions:

  • The ubiquitin-proteasome pathway, mediated by CHIP, is essential for turning off ERbeta-mediated transcription.
  • Ligand-dependent proteolysis selectively eliminates the active form of ERbeta upon ligand withdrawal.
  • This mechanism ensures the effective downregulation of nuclear receptor activity.

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