Giannì Maurizio, Parrella Edoardo, Raska Ivan, Gaillard Emilie, Nigro Elisa Agnese, Gaudon Claudine, Garattini Enrico, Rochette-Egly Cécile
Laboratorio di Biologia Molecolare, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italia.
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.
核视黄酸（RA）受体（RARs）通过与共调节因子的动态相互作用，协同配体和磷酸化过程来激活基因表达。在此我们表明，在RARα亚型的RA依赖性激活过程中，p160共激活因子pCIP/ACTR/AIB-1/RAC-3/TRAM-1/SRC-3被p38丝裂原活化蛋白激酶（p38MAPK）磷酸化。SRC-3的磷酸化与RARα靶基因激活的初始促进相关，这是通过控制共激活因子与RARα相互作用的动力学来实现的。然后，磷酸化通过促进SRC-3的降解来抑制转录。与此一致，抑制p38MAPK可显著增强RARα介导的转录以及RA依赖性的细胞分化诱导。SRC-3的磷酸化和降解仅在RARα复合物的背景下发生，这表明RAR亚型通过决定共激活因子对p38MAPK的可及性来定义一种磷酸化密码。我们提出了一个模型，其中RARα的转录活性由SRC-3通过由RA和p38MAPK精细调节的协同事件来调控。
