Endocrine Abstracts

It is well established that nuclear retinoic acid (RA) receptors (RARα, RARβ and RARγ) activate gene expression through a complex and evergrowing network of dynamic interactions with coregulatory protein complexes, which are coordinated by the ligand.

Adding more complexity to this scenario, we demonstrated that RARs are also targets for phosphorylation processes, which govern their transcriptional activity in cooperation with the ligand. Indeed, following RA addition, p38MAPK is rapidly activated, resulting in the phosphorylation of the C-terminal Ligand-Binding Domain of RARs. This phosphorylation process controls the recruitment of the cdk7/cyclin H/MAT-1 subcomplex of the general transcription factor TFIIH through the docking of cyclin H and therefore the phosphorylation of the N-terminal domain of RARs by cdk7. The RAR coregulators (SRC-3/AIB1) are also phosphorylated by the p38MAPK pathway. These RA-induced phosphorylation processes control the dynamics of the interactions between RARs and their coregulators. Their also control the recruitment of RARs at response elements within the promoters of target genes. Then phosphorylation signals the end of transcription via promoting the degradation of RARs and their coactivators.

We propose a model in which RAR activity is regulated by a phosphorylation code defined by two kinases, cdk7/TFIIH and p38MAPK. This code participates in cooperation with the ligand to switch on and off the RA response of RAR-target genes. This would be an intervention point for drug development for cancers caracterized by aberrant kinase activities.