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Ligand-dependent degradation of retinoid X receptors does not require transcriptional activity or coactivator

D L Osburn1, G Shao, H M Seidel

  • 1Nuclear Receptor Discovery, Ligand Pharmaceuticals, San Diego, California 92121, USA.

Molecular and Cellular Biology
|July 5, 2001
PubMed

Insights

Retinoid X receptors (RXRs) are degraded upon ligand binding, even when partnered with other receptors. This degradation is triggered by structural changes, not transcriptional activity.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Ubiquitin-mediated proteolysis regulates key cellular processes.
  • Transcription factor activity is often linked to protein stability.
  • Targeted protein destruction is a mechanism for gene expression control.

Purpose of the Study:

  • To investigate the degradation of retinoid X receptors (RXRs).
  • To determine the role of ligand binding in RXR stability.
  • To elucidate the mechanism of RXR degradation.

Main Methods:

  • Ligand binding assays.
  • Mutagenesis of RXR activation domain.
  • Analysis of protein degradation pathways.
  • Reporter gene assays.

Main Results:

  • Agonist ligand binding induces degradation of RXRs.
  • RXR degradation occurs even when heterodimerized with RAR or TR receptors.
  • Degradation is independent of corepressor release, coactivator binding, or transcriptional activity.
  • Mutational analysis identified the ligand-dependent activation domain as critical for degradation.

Conclusions:

  • RXR degradation is a ligand-dependent process.
  • Structural or conformational changes, rather than transcriptional activity, trigger RXR destruction.
  • This provides a model for targeted transcription factor degradation.

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