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Cullin 3 mediates SRC-3 ubiquitination and degradation to control the retinoic acid response

Christine Ferry1, Samia Gaouar, Benoit Fischer

  • 1Department of Functional Genomics and Cancer, Institut National de la Santé et de la Recherche Médicale U964, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7104, Université de Strasbourg, BP 10142, 67404 Illkirch Cedex, France.

Proceedings of the National Academy of Sciences of the United States of America
|December 8, 2011
PubMed

Insights

Retinoic acid (RA) triggers the degradation of SRC-3 coactivator via phosphorylation and ubiquitination, involving CUL-3 and RBX1. This process controls transcription dynamics and contributes to RA's antiproliferative effects.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • SRC-3 is a crucial coactivator for nuclear receptors, including retinoic acid (RA) receptor α.
  • SRC-3's function is modulated by post-translational modifications like phosphorylation and ubiquitination.
  • Previous studies showed RA induces proteasomal degradation of SRC-3.

Purpose of the Study:

  • To identify the E3 ubiquitin ligase complex responsible for RA-induced SRC-3 degradation.
  • To elucidate the role of SRC-3 phosphorylation in its ubiquitination and degradation.
  • To understand how SRC-3 post-translational modifications regulate transcription dynamics and RA's antiproliferative effects.

Main Methods:

  • RNAi screen targeting E3 ubiquitin ligases.
  • Western blotting to detect protein levels and modifications.
  • Immunoprecipitation to study protein-protein interactions.
  • Nuclear localization studies.

Main Results:

  • CUL-3 and RBX1 were identified as key components of the E3 ubiquitin ligase complex mediating RA-induced SRC-3 ubiquitination and degradation.
  • RA-induced ubiquitination of SRC-3 requires prior phosphorylation at serine 860.
  • Phosphorylation at serine 860 promotes the binding of the CUL-3-based E3 ligase to SRC-3 in the nucleus.
  • Coordinated phosphorylation, ubiquitination, and degradation of SRC-3 regulate transcriptional dynamics.

Conclusions:

  • The CUL-3/RBX1 E3 ligase complex, regulated by SRC-3 phosphorylation, is essential for RA-induced SRC-3 degradation.
  • This regulatory pathway plays a significant role in controlling transcription and mediating the antiproliferative actions of retinoic acid.

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