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

EMBO J. 2006 Feb 22;25(4):739-51. doi: 10.1038/sj.emboj.7600981. Epub 2006 Feb 2.


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 RARalpha 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 RARalpha-target genes activation, via the control of the dynamics of the interactions of the coactivator with RARalpha. Then, phosphorylation inhibits transcription via promoting the degradation of SRC-3. In line with this, inhibition of p38MAPK markedly enhances RARalpha-mediated transcription and RA-dependent induction of cell differentiation. SRC-3 phosphorylation and degradation occur only within the context of RARalpha 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 RARalpha transcriptional activity is regulated by SRC-3 through coordinated events that are fine-tuned by RA and p38MAPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / metabolism*
  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • COS Cells
  • Chlorocebus aethiops
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • HL-60 Cells
  • Histone Acetyltransferases
  • Humans
  • Mice
  • Multiprotein Complexes / metabolism
  • Nuclear Receptor Coactivator 3
  • Oncogene Proteins / metabolism*
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein Processing, Post-Translational / physiology*
  • Receptors, Retinoic Acid / metabolism*
  • Retinoic Acid Receptor alpha
  • Trans-Activators / metabolism*
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology*
  • Tretinoin / metabolism
  • Tretinoin / pharmacology
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Antineoplastic Agents
  • Multiprotein Complexes
  • Oncogene Proteins
  • RARA protein, human
  • Rara protein, mouse
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Trans-Activators
  • Tretinoin
  • Acetyltransferases
  • Histone Acetyltransferases
  • NCOA3 protein, human
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3
  • p38 Mitogen-Activated Protein Kinases