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The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process

Pierre Chymkowitch1, Nicolas Le May, Pierre Charneau

  • 1Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, INSERM, Université de Strasbourg, Illkirch cedex, France.

The EMBO Journal
|December 16, 2010
PubMed

Insights

TFIIH kinase cdk7 phosphorylates the androgen receptor (AR) at S515, a crucial step for gene expression. This phosphorylation regulates AR protein turnover and ensures accurate gene transactivation.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Cancer Research

Background:

  • Nuclear receptors require post-translational modifications for gene expression.
  • Hormonal stimuli trigger complex signaling cascades.
  • Androgen receptor (AR) activity is central to various biological processes.

Purpose of the Study:

  • To investigate the role of TFIIH-mediated phosphorylation of AR in gene transactivation.
  • To elucidate the mechanism by which AR phosphorylation regulates its turnover.
  • To understand the implications of impaired AR phosphorylation in disease.

Main Methods:

  • Site-directed mutagenesis to create AR/S515A mutant.
  • Silencing of cdk7 kinase.
  • Analysis of AR ubiquitination and degradation.
  • Assessment of transcription machinery and E3 ligase recruitment.

Main Results:

  • TFIIH's cdk7 kinase phosphorylates AR at S515, essential for transactivation.
  • Phosphorylation regulates cyclic recruitment of transcription machinery and MDM2 E3 ligase for AR ubiquitination and proteasomal degradation.
  • Impaired phosphorylation (AR/S515A mutant, cdk7 silencing, or xeroderma pigmentosum cells) disrupts transactivation and favors CHIP ligase recruitment.
  • AR phosphorylation controls nuclear receptor turnover at target gene promoters.

Conclusions:

  • TFIIH-mediated AR phosphorylation at S515 is a key regulatory step in androgen receptor-dependent gene expression.
  • This phosphorylation event governs AR protein stability by modulating its ubiquitination and degradation.
  • Dysregulation of AR phosphorylation impacts transactivation and offers potential therapeutic targets.

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