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Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
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Published on: September 21, 2011

Macromolecular synthesis inhibitors perturb glucocorticoid receptor trafficking

Xavier Dezitter1, Bernadette Masselot, Meryem Tardivel

  • 1Jean-Pierre Aubert Research Center, Lille, France.

The Journal of Steroid Biochemistry and Molecular Biology
|May 17, 2011
PubMed

Insights

Transcription and translation inhibitors, like actinomycin D and cycloheximide, prevent glucocorticoid-induced apoptosis by directly affecting glucocorticoid receptor (GR) trafficking and activation, not just protein synthesis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Glucocorticoids induce apoptosis, a process often thought to require new protein synthesis.
  • The role of macromolecular synthesis inhibitors in this process and their direct effects on the glucocorticoid receptor (GR) remain unclear.

Purpose of the Study:

  • To investigate the direct effects of transcription and translation inhibitors on glucocorticoid receptor (GR) function and trafficking.
  • To determine if these inhibitors prevent glucocorticoid-induced apoptosis by altering GR activation.

Main Methods:

  • Treatment of thymocytes with various inhibitors (actinomycin D, DRB, cycloheximide, puromycin, α-amanitin).
  • Assay of mitochondrial membrane integrity, glucocorticoid binding, GR turnover, and GR nuclear translocation.
  • Experiments conducted on different thymocyte subpopulations (CD4+CD8+, CD4+CD8-).

Main Results:

  • Actinomycin D (Act D) and cycloheximide (CHX) inhibited early loss of mitochondrial membrane integrity in a dose-dependent manner.
  • Act D and CHX reduced glucocorticoid binding, GR turnover, and impaired GR nuclear translocation.
  • All tested inhibitors (Act D, DRB, CHX, puromycin) prevented GR nuclear translocation and glucocorticoid-induced apoptosis in thymocyte subsets.

Conclusions:

  • Macromolecular synthesis inhibitors directly impact GR activation and trafficking.
  • Alterations in GR functional properties by these inhibitors are likely responsible for preventing glucocorticoid-induced cell death.

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