Abstract
AbstractThe nuclear retinoic acid (RA) receptor alpha (RAR&x03B1;) is a transcriptional transregulator that controls the expression of specific gene subsets through binding at response elements and dynamic interactions with coregulators, which are coordinated by the ligand. Here, we highlighted a novel paradigm in which the transcription of RAR&x03B1;-target genes is controlled by phosphorylation cascades initiated by the rapid RA activation of the p38MAPK/MSK1 pathway. We demonstrate that MSK1 phosphorylates RAR&x03B1; at S369 located in the Ligand Binding Domain, allowing the binding of TFIIH and thereby phosphorylation of the N-terminal domain at S77 by cdk7/cyclin H. MSK1 also phosphorylates Histone H3 at S10. Finally, the phosphorylation cascade initiated by MSK1 is required for the recruitment of RAR&x03B1;/TFIIH complexes to response elements and subsequently for RAR&x03B1; target genes activation. Cancer cells characterized by a deregulated p38MAPK/MSK1 pathway, do not respond to RA, outlining the essential contribution of the RA-triggered phosphorylation cascade in RA signaling.
Highlights
Nuclear Retinoic Acid (RA) receptors (RARs) consist of three subtypes, α (NR1B1), β (NR1B2) and γ (NR1B3) 1-3 which function as ligand-dependent transcriptional regulators heterodimerized with Retinoid X Receptors (RXRs)
In Mouse Embryo Fibroblasts (MEF), p38MAPK was activated within minutes following RA treatment
After RA treatment of MCF7 cells and MEFs, there was an increase in the activated, phosphorylated form of MSK1 which paralleled the increase in phosphorylated p38MAPK (Fig. 1d,e)
Summary
Nuclear Retinoic Acid (RA) receptors (RARs) consist of three subtypes, α (NR1B1), β (NR1B2) and γ (NR1B3) 1-3 which function as ligand-dependent transcriptional regulators heterodimerized with Retinoid X Receptors (RXRs). The basic mechanism for transcriptional regulation by RARs relies on binding to specific response elements (RAREs) located in the promoters of target genes and on ligand-induced structural rearrangements in the Ligand Binding Domain (LBD) that direct the association/dissociation of coregulator complexes with different enzymatic activities including Histone Acetyltransferases/Deacetylases, Histone Methyltransferases/Demethylases, Kinases/Phosphatases, Ubiquitin-ligases/deubiquitinases or DNA-dependent ATPases [4,5,6]. The exchanges between coregulatory complexes and RARs are dynamic and coordinated [7,8]. In fine, they cooperate to alter the chromatin structure surrounding the promoter of target genes, paving the way for the recruitment of the transcription machinery including RNA Polymerase II and the General Transcription Factors 9. Because p38MAPK is activated in response to RA 15-17, we explored whether there is a connection between this kinase signaling pathway, RARα phosphorylation and the induction of RARα-target genes
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