P38MAPK-dependent phosphorylation and degradation of SRC-3/AIB1 and RARα-mediated transcription

Maurizio Giannì, Edoardo Parrella, Ivan Raska, Emilie Gaillard, Elisa Agnese Nigro, Claudine Gaudon, Enrico Garattini, Cécile Rochette-Egly

Research output: Contribution to journalArticlepeer-review

Abstract

Nuclear retinoic acid (RA) receptors (RARs) activate gene expression through dynamic interactions with coregulators in coordination with the ligand and phosphorylation processes. Here we show that during RA-dependent activation of the RARα isotype, the p160 coactivator pCIP/ACTR/AIB-1/RAC-3/TRAM-1/ SRC-3 is phosphorylated by p38MAPK. SRC-3 phosphorylation has been correlated to an initial facilitation of RARα-target genes activation, via the control of the dynamics of the interactions of the coactivator with RARα. Then, phosphorylation inhibits transcription via promoting the degradation of SRC-3. In line with this, inhibition of p38MAPK markedly enhances RARα-mediated transcription and RA-dependent induction of cell differentiation. SRC-3 phosphorylation and degradation occur only within the context of RARα complexes, suggesting that the RAR isotype defines a phosphorylation code through dictating the accessibility of the coactivator to p38MAPK. We propose a model in which RARα transcriptional activity is regulated by SRC-3 through coordinated events that are fine-tuned by RA and p38MAPK.

Original languageEnglish
Pages (from-to)739-751
Number of pages13
JournalEMBO Journal
Volume25
Issue number4
DOIs
Publication statusPublished - Feb 22 2006

Keywords

  • Coactivator
  • Nuclear receptor
  • Phosphorylation
  • Proteasome
  • Retinoic acid
  • SRC-3/AIB1

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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