P38MAPK-dependent phosphorylation and degradation of SRC-3/AIB1 and RARalpha-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 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.
Mesh Terms:
Acetyltransferases, Animals, Antineoplastic Agents, COS Cells, Cercopithecus aethiops, Gene Expression Regulation, HL-60 Cells, Histone Acetyltransferases, Humans, Mice, Multiprotein Complexes, Nuclear Receptor Coactivator 3, Oncogene Proteins, Phosphorylation, Protein Processing, Post-Translational, Receptors, Retinoic Acid, Trans-Activators, Transcription, Genetic, Tretinoin, p38 Mitogen-Activated Protein Kinases
EMBO J.
Date: Feb. 22, 2006
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