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Article

  • The EMBO Journal (2006) 25, 739 - 751
  • doi:10.1038/sj.emboj.7600981

Published online: 2 February 2006

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

Maurizio Giannì1,2, Edoardo Parrella1, Ivan Raska Jr1, Emilie Gaillard2, Elisa Agnese Nigro1, Claudine Gaudon2, Enrico Garattini1 and Cécile Rochette-Egly2

  1. Laboratorio di Biologia Molecolare, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italia
  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, UMR 7104, Illkirch, France

Correspondence to:

Cécile Rochette-Egly, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGMBC), Parc d' innovation, 1 Rue Laurent Fries, BP 163, CU de Strasbourg, 67 404 Illkirch Cedex, France. Tel.: +33 3 88 65 34 59; Fax: +33 3 88 65 32 01; E-mail: cegly@igbmc.u-strasbg.fr

Received 1 July 2005; Accepted 10 January 2006

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.

  • Keywords:

    • coactivator,
    • nuclear receptor,
    • phosphorylation,
    • proteasome,
    • retinoic acid,
    • SRC-3/AIB1