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

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/S...

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Bibliographic Details
Published in:The EMBO journal 2006-02, Vol.25 (4), p.739-751
Main Authors: Giannì, Maurizio, Parrella, Edoardo, Raska Jr, Ivan, Gaillard, Emilie, Nigro, Elisa Agnese, Gaudon, Claudine, Garattini, Enrico, Rochette-Egly, Cécile
Format: Article
Language:English
Subjects:
coactivator
nuclear receptor
phosphorylation
proteasome
retinoic acid
SRC-3/AIB1
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Summary: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.
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7600981